• #### Subscription and Copyright Information

in Trends in Neurosciences on April 01, 2020 12:00 AM.

• #### Editorial Board and Contents

in Trends in Neurosciences on April 01, 2020 12:00 AM.

• #### Planning with Brain-inspired AI. (arXiv:2003.12353v1 [cs.AI])

This article surveys engineering and neuroscientific models of planning as a cognitive function, which is regarded as a typical function of fluid intelligence in the discussion of general intelligence. It aims to present existing planning models as references for realizing the planning function in brain-inspired AI or artificial general intelligence (AGI). It also proposes themes for the research and development of brain-inspired AI from the viewpoint of tasks and architecture.

in arXiv: Quantitative Biology: Neurons and Cognition on March 30, 2020 01:30 AM.

• #### Going in circles is the way forward: the role of recurrence in visual inference. (arXiv:2003.12128v1 [q-bio.NC])

Biological visual systems exhibit abundant recurrent connectivity. State-of-the-art neural network models for visual recognition, by contrast, rely heavily or exclusively on feedforward computation. Any finite-time recurrent neural network (RNN) can be unrolled along time to yield an equivalent feedforward neural network (FNN). This important insight suggests that computational neuroscientists may not need to engage recurrent computation, and that computer-vision engineers may be limiting themselves to a special case of FNN if they build recurrent models. Here we argue, to the contrary, that FNNs are a special case of RNNs and that computational neuroscientists and engineers should engage recurrence to understand how brains and machines can (1) achieve greater and more flexible computational depth, (2) compress complex computations into limited hardware, (3) integrate priors and priorities into visual inference through expectation and attention, (4) exploit sequential dependencies in their data for better inference and prediction, and (5) leverage the power of iterative computation.

in arXiv: Quantitative Biology: Neurons and Cognition on March 30, 2020 01:30 AM.

• #### Improved algorithm for neuronal ensemble inference by Monte Carlo method. (arXiv:1911.06509v1 [cond-mat.dis-nn] CROSS LISTED)

Neuronal ensemble inference is one of the significant problems in the study of biological neural networks. Various methods have been proposed for ensemble inference from their activity data taken experimentally. Here we focus on Bayesian inference approach for ensembles with generative model, which was proposed in recent work. However, this method requires large computational cost, and the result sometimes gets stuck in bad local maximum solution of Bayesian inference. In this work, we give improved Bayesian inference algorithm for these problems. We modify ensemble generation rule in Markov chain Monte Carlo method, and introduce the idea of simulated annealing for hyperparameter control. We also compare the performance of ensemble inference between our algorithm and the original one.

in arXiv: Quantitative Biology: Neurons and Cognition on March 30, 2020 01:30 AM.

• #### Component response rate variation underlies the stability of highly complex finite systems. (arXiv:1806.01029v6 [q-bio.PE] UPDATED)

The stability of a complex system generally decreases with increasing system size and interconnectivity, a counterintuitive result of widespread importance across the physical, life, and social sciences. Despite recent interest in the relationship between system properties and stability, the effect of variation in response rate across system components remains unconsidered. Here I vary the component response rates ($\boldsymbol{\gamma}$) of randomly generated complex systems. I use numerical simulations to show that when component response rates vary, the potential for system stability increases. These results are robust to common network structures, including small-world and scale-free networks, and cascade food webs. Variation in $\boldsymbol{\gamma}$ is especially important for stability in highly complex systems, in which the probability of stability would otherwise be negligible. At such extremes of simulated system complexity, the largest stable complex systems would be unstable if not for variation in $\boldsymbol{\gamma}$. My results therefore reveal a previously unconsidered aspect of system stability that is likely to be pervasive across all realistic complex systems.

in arXiv: Quantitative Biology: Neurons and Cognition on March 30, 2020 01:30 AM.

• #### Gaussian graphical models reveal inter-modal and inter-regional conditional dependencies of brain alterations in Alzheimer's disease. (arXiv:1804.00049v3 [q-bio.NC] UPDATED)

Alzheimer's disease (AD) is characterized by a sequence of pathological changes, which are commonly assessed in vivo using MRI and PET. Currently, the most approaches to analyze statistical associations between brain regions rely on Pearson correlation. However, these are prone to spurious correlations arising from uninformative shared variance. Notably, there are no appropriate multivariate statistical models available that can easily integrate dozens of variables derived from such data, being able to use the additional information provided from the combination of data sources. Gaussian graphical models (GGMs) can estimate the conditional dependency from given data, which is expected to reflect the underlying causal relationships. We applied GGMs to assess multimodal regional brain alterations in AD. We obtained data from N=972 subjects from the Alzheimer's Disease Neuroimaging Initiative. The mean amyloid load (AV45-PET), glucose metabolism (FDG-PET), and gray matter volume (MRI) were calculated. GGMs were estimated using a Bayesian framework for the combined multimodal data to obtain conditional dependency networks. Conditional dependency matrices were much sparser (10% density) than Pearson correlation matrices (50% density). Within modalities, conditional dependency networks yielded clusters connecting anatomically adjacent regions. For associations between different modalities, only few region-specific connections remained. Graph-theoretical network statistics were significantly altered between groups, with a biphasic u-shape trajectory. GGMs removed shared variance among multimodal measures of regional brain alterations in MCI and AD, and yielded sparser matrices compared to Pearson correlation networks. Therefore, GGMs may be used as alternative to thresholding-approaches typically applied to correlation networks to obtain the most informative relations between variables.

in arXiv: Quantitative Biology: Neurons and Cognition on March 30, 2020 01:30 AM.

• #### The bits of wire that can devastate lion populations

Nature, Published online: 30 March 2020; doi:10.1038/d41586-020-00928-2

Simple snares aimed at catching African game for the table take a huge toll on carnivores, too.

in Nature on March 30, 2020 12:00 AM.

• #### Brain MRI analysis using a deep learning based volutionary approach

Publication date: Available online 28 March 2020

Source: Neural Networks

in Neural Networks on March 29, 2020 06:00 PM.

• #### Automata complete computation with Hodgkin–Huxley neural networks composed of synfire rings

Publication date: Available online 28 March 2020

Source: Neural Networks

Author(s): Jérémie Cabessa, Aubin Tchaptchet

in Neural Networks on March 29, 2020 06:00 PM.

• #### Complete representation of action space and value in all striatal pathways.

The dorsal striatum plays a central role in motor and decision programs, such as the selection and execution of particular actions and the evaluation of their outcomes. A standard circuit model has emerged based on the striatal organization where projection neurons with specific molecular and long-range connectivity identities encode discrete and possibly opposing action signals. We used large-scale cell-type specific imaging of calcium signals during motor and decision behaviors to map the activity of individual striatal projection neurons (SPNs) that form the three major output pathways of the striatum: SPNs of the D1+ direct, the A2A+ indirect, and the Oprm1+ patch pathway. We found that during exploration or choice behaviors SPNs showed a pathway-independent representation of the discrete phases and action variables. The tuning of individual SPNs was action and context-dependent, together covering the entire task space, and included pathway-independent representation of decision-variables such as action value in a dynamic choice task. We propose that the three major SPN pathways broadcast in parallel the complete representation of the task space to downstream targets, including task- and phase-specific signals of action value and choice.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### A kernel-based method to calculate local field potentials from networks of spiking neurons

The local field potential (LFP) is usually calculated from current sources arising from transmembrane currents, in particular in asymmetric cellular morphologies such as pyramidal neurons. Here, we adopt a different point of view and relate the spiking of neurons to the LFP through efferent synaptic connections and provide a method to calculate LFPs. We show that the so-called unitary LFPs (uLFP) provide the key to such a calculation. We show experimental measurements and simulations of uLFPs in neocortex and hippocampus, for both excitatory and inhibitory neurons. We fit a "kernel" function to measurements of uLFPs, and we estimate its spatial and temporal spread by using simulations of morphologically detailed reconstructions of hippocampal pyramidal neurons. Assuming that LFPs are the sum of uLFPs generated by every neuron in the network, the LFP generated by excitatory and inhibitory neurons can be calculated by convolving the trains of action potentials with the kernels estimated from uLFPs. This provides a method to calculate the LFP from networks of spiking neurons, even for point neurons for which the LFP is not easily defined. We show examples of LFPs calculated from networks of point neurons.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Dynamic inhibition of sensory responses mediated by an olfactory corticofugal system

Processing of sensory information is substantially modulated by centrifugal projections from higher cortical areas, yet their behavioral relevance and underlying neural mechanisms remain unclear in most cases. The anterior olfactory nucleus (AON) is part of the olfactory cortex and its extensive connections to lower and higher brain centers put it in a prime position to modulate early sensory information in the olfactory system. Here, we show that optogenetic activation of AON neurons in awake animals was not perceived as an odorant equivalent cue. However, AON activation during odorant presentation reliably suppressed odor responses. This AON mediated effect was fast and constant across odors and concentrations. Likewise, activation of glutamatergic AON projections to the olfactory bulb (OB) transiently inhibited the excitability of mitral/tufted cells (MTCs) that relay olfactory input to cortex. Single-unit MTC recordings revealed that optogenetic activation of glutamatergic AON terminals in the OB transiently decreased sensory-evoked MTC spiking, regardless of the strength or polarity of the sensory response. These findings suggest that glutamatergic AON projections to the OB suppress early olfactory processing by inhibiting OB output neurons and that the AON can dynamically gate sensory throughput to the cortex.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Input dependent modulation of olfactory bulb activity by GABAergic basal forebrain projections

Basal forebrain modulation of central circuits is associated with active sensation, attention and learning. While cholinergic modulations have been studied extensively the effect of non-cholinergic basal forebrain subpopulations on sensory processing remains largely unclear. Here, we directly compare optogenetic manipulation effects of two major basal forebrain subpopulations on principal neuron activity in an early sensory processing area, i.e. mitral/tufted cells (MTCs) in the olfactory bulb. In contrast to cholinergic projections, which consistently increased MTC firing, activation of GABAergic fibers from basal forebrain to the olfactory bulb lead to differential modulation effects: while spontaneous MTC activity is mainly inhibited, odor evoked firing is predominantly enhanced. Moreover, sniff triggered averages revealed an enhancement of maximal sniff evoked firing amplitude and an inhibition of firing rates outside the maximal sniff phase. These findings demonstrate that GABAergic neuromodulation affects MTC firing in a bimodal, sensory-input dependent way, suggesting that GABAergic basal forebrain modulation could be an important factor in attention mediated filtering of sensory information to the brain.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Monitoring phagocytic uptake of amyloid β into glial cell lysosomes in real time

Phagocytosis by glial cells is essential to regulate brain function during development and disease. Given recent interest in using amyloid {beta} (A{beta})-targeted antibodies as a therapy for patients with Alzheimer's disease, removal of A{beta} by phagocytosis is likely protective early in Alzheimer's disease, but remains poorly understood. Impaired phagocytic function of glial cells surrounding A{beta} plaques during later stages in Alzheimer's disease likely contributes to worsened disease outcomes, but the underlying mechanisms of how this occurs remain unknown. We have developed a human A{beta}1-42 analogue (A{beta}pH) that exhibits green fluorescence upon internalization into the acidic phagosomes of cells but is non-fluorescent at physiological pH. This allowed us to image, for the first time, glial uptake of A{beta}pH in real time in live animals. Microglia phagocytose more A{beta}pH than astrocytes in culture, in brain slices and in vivo. A{beta}pH can be used to investigate the phagocytic mechanisms removing A{beta} from the extracellular space, and thus could become a useful tool to study A{beta} clearance at different stages of Alzheimer's disease.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Age dependent trans-cellular propagation of human tau aggregates in Drosophila disease models

Tauopathies is a class of neurodegenerative disorders which involves the transformation of physiological tau into pathogenic tau. One of the prime causes reported to drive this conversion is tau hyperphosphorylation and the subsequent propagation of pathogenic protein aggregates across the nervous system. Although past attempts have been made to deduce the details of tau propagation, yet not much is known about its mechanism. A better understanding of this aspect of disease pathology can prove to be beneficial for the development of diagnostic and therapeutic approaches. In our work, we utilize the plethora of advantages procured by Drosophila to introduce a novel in-vivo tauopathy propagation model. For the first time, we demonstrate that the human tau (h-tau) possesses an intrinsic property to spread trans-cellularly in the fly nervous system irrespective of the tau allele or the neuronal tissue type. Aggregate migration restricted by targeted down-regulation of a specific kinase, elucidates the role of hyper-phosphorylation in its movement. On the contrary to the previous models, the present system enables a rapid, convenient and robust in-vivo study of tau migration pathology. Henceforth, the developed model would not only be immensely helpful in uncovering the mechanistic in-depths of tau propagation pathology but also aid in modifier and/or drug screening for amelioration of tauopathies.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Estrogen and sex-dependent loss of the vocal learning system in female zebra finches

Sex hormones alter the organization of the brain during early development and coordinate various behaviors throughout life. In zebra finches, song learning is limited to males, and the associated song learning brain pathway only matures in males and atrophies in females. This atrophy can be reversed by giving females exogenous estrogen during early post-hatch development, but whether normal male song system development requires estrogen is uncertain. For the first time in songbirds, we administered exemestane, a potent third generation estrogen synthesis inhibitor, from the day of hatching until adulthood. We examined the behavior, brain, and transcriptome of individual song nuclei of these pharmacologically manipulated animals. We found that males with long-term exemestane treatment had diminished male-specific plumage, impaired song learning, but retained normal song nuclei sizes and most, but not all, of their specialized transcriptome. Consistent with prior findings, females with long-term estrogen treatment retained a functional song system, and we further observed their song nuclei had specialized gene expression profiles similar, but not identical to males. We also observed that different song nuclei responded to estrogen manipulation differently, with Area X in the striatum being the most altered by estrogen modulation. These findings support the hypothesis that song learning is an ancestral trait in both sexes, which was subsequently suppressed in females of some species, and that estrogen has come to play a critical role in modulating this suppression as well as refinement of song learning

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### In Vivo Localization of Deep Brain Implants in Mice

Electrophysiology provides a direct readout of neuronal activity at a temporal precision only limited by the sampling rate. However, interrogating deep brain structures, implanting multiple targets or aiming at unusual angles still poses significant challenges even for expert operators, and errors are only discovered by post-hoc histological reconstruction. Here, we propose a method combining the high-resolution information about bone landmarks provided by micro-CT scanning with the soft tissue contrast of the MRI, which allowed us to precisely localize electrodes and optic fibers in mice in vivo. This enables arbitrating the success of implantation directly after surgery with a precision comparable to the gold standard histological reconstruction. Adjustment of the recording depth with electrode microdrives or early termination of unsuccessful experiments saves many working hours, while fast 3-dimensional feedback helps surgeons to avoid systematic errors. Increased aiming precision will allow more precise targeting of small or deep brain nuclei and multiple targeting of specific cortical layers.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Anthrax Toxin as a Molecular Platform to Target Nociceptive Neurons and Modulate Pain

Bacterial toxins are able to act on neurons to modulate signaling and function. Here, we find that nociceptive sensory neurons that mediate pain are enriched in the receptor for anthrax toxins, ANTXR2. Anthrax Edema Toxin (ET) induced cAMP and PKA signaling in Nav1.8+ nociceptive neurons and modulated pain in vivo. Peripherally administered ET mediated mechanical allodynia in naive mice and during B. anthracis infection. Intrathecally administered ET produced analgesic effects, potently blocking pain-like behaviors in multiple mouse models of inflammatory and chronic neuropathic pain. Nociceptor-specific ablation of ANTXR2 attenuated ET-induced signaling and analgesia. Modified anthrax toxin successfully delivered exogenous protein cargo into nociceptive neurons, illustrating utility of the anthrax toxin system as a molecular platform to target pain. ET further induced signaling in human iPSC-derived sensory neurons. Our findings highlight novel interactions between a bacterial toxin and nociceptors that may be utilized for developing new pain therapeutics.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Arf1-Ablation-Induced Neuronal Damage Promotes Neurodegeneration Through an NLRP3 Inflammasome-Meningeal γδ T cell-IFNγ-Reactive Astrocyte Pathway

Neurodegenerative diseases are often initiated from neuronal injury or disease and propagated through neuroinflammation and immune response. However, the mechanisms by which injured neurons induce neuroinflammation and immune response that feedback to damage neurons are largely unknown. Here, we demonstrate that Arf1 ablation in adult mouse neurons resulted in activation of a reactive microglia-A1 astrocyte-C3 pathway in the hindbrain and midbrain but not in the forebrain, which caused demyelination, axon degeneration, synapse loss, and neurodegeneration. We further find that the Arf1-ablated neurons released peroxided lipids and ATP that activated an NLRP3 inflammasome in microglia to release IL-1b;, which together with elevated chemokines recruited and activated gamma delta T cells in meninges. The activated gamma delta T cells then secreted IFNg; that entered into parenchyma to activate the microglia-A1 astrocyte-C3 neurotoxic pathway for destroying neurons and oligodendrocytes. Finally, we show that the Arf1-reduction-induced neuroinflammation-IFNg-gliosis pathway exists in human neurodegenerative diseases, particularly in amyotrophic lateral sclerosis and multiple sclerosis. This study illustrates perhaps the first complete mechanism of neurodegeneration in a mouse model. Our findings introduce a new paradigm in neurodegenerative research and provide new opportunities to treat neurodegenerative disorders.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Custom-molded headcases have limited efficacy in reducing head motion for fMRI

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Quantifying myelin content in brain tissue using color spatial light interference microscopy (cSLIM)

Deficient myelination of the brain is associated with neurodevelopmental delays, particularly in high-risk infants, such as those born small in relation to their gestational age (SGA). New methods are needed to further study this condition. Here, we employ Color Spatial Light Interference Microscopy (cSLIM), which uses a brightfield objective and RGB camera to generate pathlength-maps with nanoscale sensitivity in conjunction with a regular brightfield image. Using tissue sections stained with Luxol Fast Blue, the myelin structures were segmented from a brightfield image. Using a binary mask, those portions were quantitatively analyzed in the corresponding phase maps. We first used the CLARITY method to remove tissue lipids and validate the sensitivity of cSLIM to lipid content. We then applied cSLIM to brain histology slices. These specimens are from a previous MRI study, which demonstrated that appropriate for gestational age (AGA) piglets have increased internal capsule myelination (ICM) compared to small for gestational age (SGA) piglets and that a hydrolyzed fat diet improved ICM in both. The identity of samples was blinded until after statistical analyses.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Differential Effects of Propofol and Ketamine on Critical Brain Dynamics

Whether the brain operates at a critical "tipping" point is a long standing scientific question, with evidence from both cellular and systems-scale studies suggesting that the brain does sit in, or near, a critical regime. Neuroimaging studies of humans in altered states of consciousness have prompted the suggestion that maintenance of critical dynamics is necessary for the emergence of consciousness and complex cognition, and that reduced or disorganized consciousness may be associated with deviations from criticality. Unfortunately, many of the cellular-level studies reporting signs of criticality were performed in non-conscious systems (in vitro neuronal cultures) or unconscious animals (e.g. anaesthetized rats). Here we attempted to address this knowledge gap by exploring critical brain dynamics in invasive ECoG recordings from multiple sessions with a single macaque as the animal transitioned from consciousness to unconsciousness under different anaesthetics (ketamine and propofol). We use a previously-validated test of criticality: avalanche dynamics to assess the differences in brain dynamics between normal consciousness and both drug-states. Propofol and ketamine were selected due to their differential effects on consciousness (ketamine, but not propofol, is known to induce an exotic state known as "dissociative anaesthesia"). Our analyses indicate that propofol dramatically restricted the size and duration of avalanches, while ketamine allowed for a more awake-like dynamic to persist. In addition, propofol, but not ketamine, triggered a large reduction in the complexity of brain dynamics. All states, however, showed some signs of persistent criticality when testing for exponent relations and universal shape-collapse. Further, maintenance of critical brain dynamics may be important for regulation and control of conscious awareness.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Prion protein lowering is a disease-modifying therapy across prion strains, disease stages, and endpoints

Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains, with no evidence for the development of drug resistance. We demonstrate that less than 25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Both neuroinflammation measured through live animal bioluminescence imaging and neuronal injury measured by plasma neurofilament light chain can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change in these biomarkers. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. Taken together, these results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### The effects of dynamic arm movements during prolonged whole-body tilt on the perception of gravitational direction

Do body movements contribute to the perception of the gravitational space? To answer this question, we investigated the influence of arm movements against gravity on the estimation of the gravitational direction or body tilt orientation. In Experiment 1, we asked the participants to perform static or dynamic arm movements during prolonged whole-body tilt and evaluated their effect on subjective visual vertical (SVV) at the tilt position (during-tilt session) and after tilting back to upright position (post-tilt session). In Experiment 2, we assessed how these arm movements at the tilt position affected subjective postural vertical (SPV). We observed that shifts of SVV induced by prolonged tilt were suppressed only by dynamic arm movements. On the other hand, SPV also shifted after prolonged tilt but was not influenced by either static or dynamic arm movements. The present results suggest that the central nervous system (CNS) utilises not only vestibular or static body somatosensory signals, but also additional cues generated by dynamic body movements for the perception of the gravitational direction.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Brain structures associated with reading and their abnormalities in dyslexia: a wholebrainanalysis

Developmental dyslexia (DD) is a highly prevalent neurodevelopmental disorder, which is devastating for individuals in modern societies in which fluent reading skill is mandatory for leading a normal life. Research on the neural origins of DD has continued for half a century, yielding, however, inconsistent results. It has also lacked a thorough characterization of the association between abnormal neuroanatomy and skills vital for reading. The current study was set out to determine abnormalities of grey and white matter volumes in adults with DD and associations between brain structures and reading and related skills. To this end, we conducted a whole-brain voxel based morphometry following current guidelines on state-of-the-art analysis approaches and rigorous neuropsychological testing. We found decreased volumes of grey matter in DD, comprising a left-hemispheric network including superior temporal and inferior frontal gyri, insula, the limbic system, and basal ganglia, and white matter, including the right middle temporal gyrus and hippocampus. These results are both consistent with the most robust previous findings on structural abnormalities in the left frontotemporal network in DD and yield novel insight to the role of subcortical structures in DD, scarcely studied so far. Moreover, areas with decreased grey matter volumes in DD were positively associated with technical reading scores (both groups included). This provides particularly strong support for the conclusion that the grey matter regions that we identified to have a low volume in DD comprise the core areas vital for reading.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Disarrangement of Endoplasmic reticulum-mitochondria communication impairs Ca2+ homeostasis in FRDA

Friedreich ataxia (FRDA) is a neurodegenerative disorder characterized by neuromuscular and neurological manifestations. It is caused by mutations in gene FXN, which results in loss of the mitochondrial protein frataxin. Endoplasmic Reticulum-mitochondria associated membranes (MAMs) are inter-organelle structures involved in the regulation of essential cellular processes, including lipid metabolism and calcium signaling. In the present study, we have analyzed in both, unicellular and multicellular models of FRDA, an analysis of calcium management and of integrity of MAMs. We observed that function of MAMs is compromised in our cellular model of FRDA, which was improved upon treatment with antioxidants. In agreement, promoting mitochondrial calcium uptake was sufficient to restore several defects caused by frataxin deficiency in Drosophila Melanogaster. Remarkably, our findings describe for the first time frataxin as a member of the protein network of MAMs, where interacts with two of the main proteins implicated in endoplasmic reticulum-mitochondria communication. These results suggest a new role of frataxin, indicate that FRDA goes beyond mitochondrial defects and highlight MAMs as novel therapeutic candidates to improve patient's conditions.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Homeostatic structural plasticity leads to the formation of memory engrams through synaptic rewiring in recurrent networks

Brain networks store new memories using functional and structural synaptic plasticity. Memory formation is generally attributed to Hebbian plasticity, while homeostatic plasticity is thought to have an ancillary role in stabilizing network dynamics. Here we report that homeostatic plasticity alone can also lead to the formation of stable memories. We analyze this phenomenon using a new theory of network remodeling, combined with numerical simulations of recurrent spiking neural networks that exhibit structural plasticity based on firing rate homeostasis. These networks are able to store repeatedly presented patterns and recall them upon the presentation of incomplete cues. Storing is fast, governed by the homeostatic drift. In contrast, forgetting is slow, driven by a diffusion process. Joint stimulation of neurons induces the growth of associative connections between them, leading to the formation of memory engrams. In conclusion, homeostatic structural plasticity induces a specific type of "silent memories", different from conventional attractor states.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### The Stochastic Resonance model of auditory perception: A unified explanation of tinnitus development, Zwicker tone illusion, and residual inhibition.

Stochastic Resonance (SR) has been proposed to play a major role in auditory perception, and to maintain optimal information transmission from the cochlea to the auditory system. By this, the auditory system could adapt to changes of the auditory input at second or even sub-second timescales. In case of reduced auditory input, somatosensory projections to the dorsal cochlear nucleus would be disinhibited in order to improve hearing thresholds by means of SR. As a side effect, the increased somatosensory input corresponding to the observed tinnitus-associated neuronal hyperactivity is then perceived as tinnitus. In addition, the model can also explain transient phantom tone perceptions occurring after ear plugging, or the Zwicker tone illusion. Vice versa, the model predicts that via stimulation with acoustic noise, SR would not be needed to optimize information transmission, and hence somatosensory noise would be tuned down, resulting in a transient vanishing of tinnitus, an effect referred to as residual inhibition.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Whole-organism behavioral profiling reveals a role for dopamine in state-dependent motor program coupling in C. elegans

Animal behaviors are commonly organized into long-lasting states that coordinately impact the generation of diverse motor outputs such as feeding, locomotion, and grooming. However, the neural mechanisms that coordinate these diverse motor programs remain poorly understood. Here, we examine how the distinct motor programs of the nematode C. elegans are coupled together across behavioral states. We describe a new imaging platform that permits automated, simultaneous quantification of each of the main C. elegans motor programs over hours or days. Analysis of these whole-organism behavioral profiles shows that the motor programs coordinately change as animals switch behavioral states. Utilizing genetics, optogenetics, and calcium imaging, we identify a new role for dopamine in coupling locomotion and egg-laying together across states. These results provide new insights into how the diverse motor programs throughout an organism are coordinated and suggest that neuromodulators like dopamine can couple motor circuits together in a state-dependent manner.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Disruption by virtual reality of the cortical oscillations related to visuotactile integration during an embodiment process

Virtual reality (VR) enables fast, free, and highly controllable experimental body image setting. Illusions pertaining to a body, like the rubber hand illusion (RHI), can be easily conducted in VR settings, and some phenomena, such as full-body illusions, are only realized in virtual environments. However, the multisensory integration process in VR is not yet fully understood, and we must clarify the limitations and whether specific phenomena can also occur in real life or only in VR settings. One useful investigative approach is measuring brain activities during a psychological experiment. Electroencephalography (EEG) oscillatory activities provide insight into the human multisensory integration process. Unfortunately, the data can be vulnerable to VR noise, which causes measurement and analytical difficulties for EEG data recorded in VR environments. Here, we took care to provide an experimental RHI setting using a head-mounted display, which provided a VR visual space and VR dummy hand along with EEG measurements. We compared EEG data taken in both real and VR environments and observed the gamma and theta band oscillatory activities. Ultimately, we saw statistically significant differences between congruent (RHI) and incongruent (not RHI) conditions in the real environment, which agrees with previous studies. No difference in the VR condition could be observed, suggesting that the VR setting itself altered the perceptual and sensory integration mechanisms. Thus, we must model this difference between real and VR settings whenever we use VR to investigate our bodily self-perception.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Visual featural topography in the human ventral visual pathway

Visual object recognition in humans and nonhuman primates is achieved by the ventral visual pathway (ventral occipital-temporal cortex: VOTC). A classical debate is whether the seemingly domain-based structure in higher-order VOTC simply reflects distributional patterns of certain visual features. Combining computational vision models, fMRI experiments using a parametric-modulation approach, and natural image statistics of common objects, we depicted the neural distribution of a comprehensive set of visual features in VOTC, identifying voxel sensitivities to specific feature sets across geometry/shape, Fourier power, and color. We found that VOTC's sensitivity pattern to these visual features fully predicts its domain-based organization (adjusted R-squared around .95), and is partly independent of object domain information. The visual feature sensitivity pattern, in turn, is significantly explained by relationships to types of response/action computation (Navigation, Fight-or-Flight, and Manipulation), more so than the "object domain" structure, as revealed by behavioral ratings and natural image statistics. These results offer the first comprehensive visual featural map in VOTC and a plausible theoretical explanation as a mapping onto different types of downstream response systems.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Changes within neural population codes can be inferred from psychophysical threshold studies

The use of population encoding models has come to dominate the study of human visual neuroscience, serving as a primary tool for making inferences about neural code changes based on indirect measurements. A popular approach in computational neuroimaging is to use such models to obtain estimates of neural population responses via inverted encoding modeling. Recent research suggests that this approach may be prone to identifiability problems, with multiple mechanisms of encoding change producing similar changes in the estimated population responses. Psychophysical data might be able to provide additional constraints to infer the encoding change mechanism underlying some behavior of interest. However, computational work aimed at determining to what extent different mechanisms can be differentiated using psychophysics is lacking. Here, we used simulation to explore exactly which of a number of changes in neural population codes could be differentiated from observed changes in psychophysical thresholds. Eight mechanisms of encoding change were under study, chosen because they have been proposed in the previous literature as mechanisms for improved task performance (e.g., due to attention or learning): specific and nonspecific gain, specific and nonspecific tuning, specific suppression, specific suppression plus gain, and inward and outward tuning shifts. We simulated psychophysical thresholds as a function of both external noise (TvN curves) or stimulus value (TvS curves) for a number of variations of each one of the models. With the exception of specific gain and specific tuning, all studied mechanisms produced qualitatively different patterns of change in the TvN and TvS curves, suggesting that psychophysical studies can be used as a complement to inverted encoding modeling, and provide strong constraints on inferences based on the latter. We use our results to provide recommendations for interested researchers and to re-interpret previous psychophysical data in terms of mechanisms of encoding change.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Shared and distinct patterns of atypical cortical morphometry in children with autism and anxiety

Autism spectrum disorder (ASD) and anxiety disorders (ANX) are common neurodevelopmental conditions with several overlapping symptoms. Notably, many children and adolescents with ASD also have an ANX diagnosis, suggesting shared pathological mechanisms. Here, we leveraged structural imaging and phenotypic data from 82 closely matched children (28 ASD, 28 ANX, 26 typically developing controls). Our neuroimaging paradigm assessed cortical thickness and studied inter-regional structural covariance networks. Both ASD and ANX presented with atypical structural network organization relative to controls. Specifically, ASD presented with increased thickness in temporal and parietal midline cortices, while ANX was associated with increased cortical thickness in the left inferior frontal and precentral gyri. Despite the overall difference in the spatial distributions of these clusters, unconstrained spin permutation testing showed that statistical maps from the ANX-vs-controls and ASD-vs-controls analyses were significantly correlated. The two diagnostic groups also presented with common decreases in structural covariance patterns, collectively pointing to decreased structural coupling between lateral frontal, lateral temporal, and temporo-parietal regions. Dimensional analysis of trait anxiety and social responsiveness partially recapitulated diagnosis-based findings. Collectively, our findings provide evidence for both shared as well as distinct effects of ASD and ANX on regional and inter-regional structural network organization.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance, and new strategies that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we found that purine metabolites strongly correlated with radiation resistance. Inhibiting purine, but not pyrimidine, synthesis radiosensitized GBM cells and patient-derived neurospheres by impairing DNA repair in a nucleoside-dependent fashion. Likewise, administration of exogenous purine nucleosides protected sensitive GBM models from radiation by promoting DNA repair. Combining an FDA-approved inhibitor of de novo purine synthesis with radiation arrested growth in GBM xenograft models and depleted intratumoral guanylates. High expression of the rate-limiting enzyme of de novo GTP synthesis was associated with shorter survival in GBM patients. Together, these findings indicate that inhibiting de novo purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Anticipatory responses along motion trajectories in awake monkey area V1

What are the neural mechanisms underlying motion integration of translating objects? Visual motion integration is generally conceived of as a feedforward, hierarchical, information processing. However, feedforward models fail to account for many contextual effects revealed using natural moving stimuli. In particular, a translating object evokes a sequence of transient feedforward responses in the primary visual cortex but also propagations of activity through horizontal and feedback pathways. We investigated how these pathways shape the representation of a translating bar in monkey V1. We show that, for long trajectories, spiking activity builds-up hundreds of milliseconds before the bar enters the neurons receptive fields. Using VSDI and LFP recordings guided by a phenomenological model of propagation dynamics, we demonstrate that this anticipatory response arises from the interplay between horizontal and feedback networks driving V1 neurons well ahead of their feedforward inputs. This mechanism could subtend several perceptual contextual effects observed with translating objects.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Differential effect of value and salience on saccadic reaction times

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### A novel setup for simultaneous two-photon functional imaging and precise spectral and spatial visual stimulation in Drosophila

Motion vision has been extensively characterized in Drosophila melanogaster, but substantially less is known about how flies process colour, or how spectral information affects other visual modalities. To accurately dissect the components of the early visual system responsible for processing colour, we developed a versatile visual stimulation setup to probe combined spatial, temporal and spectral response properties. Using flies expressing neural activity indicators, we tracked visual responses in the medulla to a projected colour stimulus (i.e. narrow bands of light). The introduction of custom Semrock bandpass optical filters enables simultaneous two-photon imaging and visual stimulation over a large range of wavelengths. A specialized screen material scatters each band of light across the spectrum equally at all locations of the screen, thus enabling presentation of spatially structured stimuli. We show layer-specific shifts of spectral response properties in the medulla correlating with projection regions of photoreceptor terminals.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### The roles of online and offline replay in planning

Animals and humans replay neural patterns encoding trajectories through their environment, both whilst they solve decision-making tasks and during rest. Both on-task and off-task replay are believed to contribute to flexible decision making, though how their relative contributions differ remains unclear. We investigated this question by using magnetoencephalography to study human subjects while they performed a decision-making task that was designed to reveal the decision algorithms employed. We characterized subjects in terms of how flexibly each adjusted their choices to changes in temporal, spatial and reward structure. The more flexible a subject, the more they replayed trajectories during task performance, and this replay was coupled with re-planning of the encoded trajectories. The less flexible a subject, the more they replayed previously and subsequently preferred trajectories during rest periods between task epochs. The data suggest that online and offline replay both participate in planning but support distinct decision strategies.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

• #### Ergothioneine, a metabolite of the gut bacterium Lactobacillus reuteri, protects against stress-induced sleep disturbances

The relationships between depression and gut microbiota, particularly those involving the immune system, have become a major focus of recent research. Here, we analyzed changes in gut microbiota and their sulfur metabolites in the feces of a depression rat model using the modified 14-day social defeat stress (SDS) paradigm. Our results showed that SDS increased fecal Lactobacillus reuteri in correlation with ergothioneine levels at around day 11, which continued for at least one month following SDS administration. In vitro study further revealed that L. reuteri is capable of producing ergothioneine. Although the known anti-inflammatory and anti-oxidative actions of ergothioneine suggested that the increased fecal ergothioneine levels may be related to intestinal anti-inflammatory defense mechanisms, no change was observed in the plasma ergothioneine levels during the same observation period, indicating that the defense mechanisms may not be sufficiently reflected in the body. As ergothioneine is a natural ingredient that is absorbed mainly from the upper gastrointestinal tract, we hypothesized that oral ergothioneine may exert antidepressant effects. As expected, oral administration of ergothioneine prior to and during the SDS paradigm had a preventative effect on SDS-induced depressive behaviors, such as social avoidance and depression-like sleep abnormalities, particularly those of rapid eye movement sleep. These findings indicate that ergothioneine, a metabolite of L. reuteri, may be a common substance in the microbiota-gut-brain axis that prevents stress-induced sleep disturbances, especially those associated with depression.

in bioRxiv: Neuroscience on March 29, 2020 12:00 AM.

## Abstract

Sleep and stress independently enhance emotional memory consolidation. In particular, theta oscillations (4–7 Hz) during rapid eye movement (REM) sleep increase coherence in an emotional memory network (i.e., hippocampus, amygdala, and prefrontal cortex) and enhance emotional memory. However, little is known about how stress during learning might interact with subsequent REM theta activity to affect emotional memory. In the current study, we examined whether the relationship between REM theta activity and emotional memory differs as a function of pre‐encoding stress exposure and reactivity. Participants underwent a psychosocial stressor (the Trier Social Stress Task; n = 32) or a comparable control task (n = 32) prior to encoding. Task‐evoked cortisol reactivity was assessed by salivary cortisol rise from pre‐ to post‐stressor, and participants in the stress condition were additionally categorized as high or low cortisol responders via a median split. During incidental encoding, participants studied 150 line drawings of negative, neutral, and positive images, followed by the complete color photo. All participants then slept overnight in the lab with polysomnographic recording. The next day, they were given a surprise recognition memory task. Results showed that memory was better for emotional relative to neutral information. Critically, these findings were observed only in the stress condition. No emotional memory benefit was observed in the control condition. In stressed participants, REM theta power significantly predicted memory for emotional information, specifically for positive items. This relationship was observed only in high cortisol responders. For low responders and controls, there was no relationship between REM theta and memory of any valence. These findings provide evidence that elevated stress at encoding, and accompanying changes in neuromodulators such as cortisol, may interact with theta activity during REM sleep to promote selective consolidation of emotional information.

in Hippocampus on March 28, 2020 02:21 PM.

• #### Cover Image, Volume 30, Issue 3

Cover legend: The cover image is based on the Research Article Modulation of local field potentials and neuronal activity in primate hippocampus during saccades by Guillaume Doucet et al, https://doi.org/10.1002/hipo.23140.

Cover image © Kelly Bullock Art Images.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

In the adult mouse hippocampus, new neurons are produced by radial glia‐like (RGL) neural stem cells in the subgranular zone, which extend their apical processes toward the molecular layer, and express the astrocyte marker glial fibrillary acidic protein, but not the astrocyte marker S100β. In rodent models of epilepsy, adult hippocampal neurogenesis was reported to be increased after acute and mild seizures, but to be decreased by chronic and severe epilepsy. In the present study, we investigated how the severity of seizures affects neurogenesis and RGL neural stem cells in acute stages of epilepsy, using an improved mouse pilocarpine model in which pilocarpine‐induced hypothermia was prevented by maintaining body temperature, resulting in a high incidence rate of epileptic seizures and low rate of mortality. In mice that experienced seizures without status epilepticus (SE), the number of proliferating progenitors and immature neurons were significantly increased, whereas no changes were observed in RGL cells. In mice that experienced seizures with SE, the number of proliferating progenitors and immature neurons were unchanged, but the number of RGL cells with an apical process was significantly reduced. Furthermore, the processes of the majority of RGL cells extended inversely toward the hilus, and about half of the aberrant RGL cells expressed S100β. These results suggest that seizures with SE lead to changes in the polarity and properties of RGL neural stem cells, which may direct them toward astrocyte differentiation, resulting in the reduction of neural stem cells producing new granule cells. This also suggests the possibility that cell polarity of RGL stem cells is important for maintaining the stemness of adult neural stem cells.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

Converging evidence suggests a relationship between aerobic exercise and hippocampal neuroplasticity that interactively impacts hippocampally dependent memory. The majority of human studies have focused on the potential for exercise to reduce brain atrophy and attenuate cognitive decline in older adults, whereas animal studies often center on exercise‐induced neurogenesis and hippocampal plasticity in the dentate gyrus (DG) of young adult animals. In the present study, initially sedentary young adults (18–35 years) participated in a moderate‐intensity randomized controlled exercise intervention trial (ClinicalTrials.gov; NCT02057354) for a duration of 12 weeks. The aims of the study were to investigate the relationship between change in cardiorespiratory fitness (CRF) as determined by estimated MAX, hippocampally dependent mnemonic discrimination, and change in hippocampal subfield volume. Results show that improving CRF after exercise training is associated with an increased volume in the left DG/CA3 subregion in young adults. Consistent with previous studies that found exercise‐induced increases in anterior hippocampus in older adults, this result was specific to the hippocampal head, or most anterior portion, of the subregion. Our results also demonstrate a positive relationship between change in CRF and change in corrected accuracy for trials requiring the highest level of discrimination on a putative behavioral pattern separation task. This relationship was observed in individuals who were initially lower‐fit, suggesting that individuals who show greater improvement in their CRF may receive greater cognitive benefit. This work extends animal models by providing evidence for exercise‐induced neuroplasticity specific to the neurogenic zone of the human hippocampus.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

The uncal apex is an anatomical landmark frequently used for segmenting the hippocampus into its anterior and posterior segments, a necessary step for computing many measurements of its long axis. It functions well, as it is both local to the hippocampus and easy to identify. However, in spite of widespread use and definition in the EADC‐ADNI Harmonized Hippocampal Protocol (HarP), how the uncal apex is influenced by gross hippocampal changes during normal aging has not been established, nor has the possible impact on measures of anterior hippocampus (aHPC) and posterior hippocampus (pHPC) volume. Here I drew upon three large data sets to describe and confirm these relationships, investigating them in one large data set and replicating my findings in the two others, evaluating a total of 4,434 hippocampi. I found the uncal apex fell in an increasingly more anterior position with increasing age. This age‐related retraction of the uncus began after age 36, with the sharpest effects arising after age 60. This phenomenon exaggerates age‐related aHPC volume decreases while simultaneously underestimating age‐related pHPC volume decreases, a pattern I confirmed by juxtaposing uncal apex and MNI space‐based landmarking. A hippocampally based reference frame was also rendered unstable by age‐related shifts in the posterior extent of the hippocampus. Both the uncal apex and hippocampal reference frame should therefore be used with caution in aging research, or in research involving other demographic or disease factors known to evoke gross changes in the hippocampus. Instead, MNI coordinate‐based heuristics may be appropriate for segmenting the hippocampus in study designs involving such factors. Apex‐based segmentation is still attractive, however, in study designs where advanced age and atrophy are not used as regressors, including investigations into long‐axis effects in healthy young adults. Progress toward localizing functional divisions within the hippocampus is needed to identify best practices for the field.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

Prohormone convertase 2 (PC2) is essential for the biosynthesis of many neuropeptides, including several of them in hippocampus. In mouse brain, lacking an enzymatically active PC2 (PC2‐null) causes accumulation of many neuropeptides in their precursor or intermediate forms. Little is known about how a PC2‐null state may affect the function of the hippocampus. In this study, adult PC2‐null mice and their wildtype (WT) littermates were subjected to three analyses to determine possible changes associated with PC2‐null at physiological, behavioral, and molecular levels, respectively, under normal and stressed conditions. Electrophysiological recordings of hippocampal slices were performed to measure evoked field‐excitatory postsynaptic potentials (EPSP), long‐term potentiation (LTP), and paired‐pulse facilitation (PPF). Morris water maze (MWM) testing was conducted to examine behavioral changes that are indicative of hippocampal integrity. Quantitative mass spectrometry analysis was used to determine changes in the hippocampal proteome in response to a focal cerebral ischemic insult. We found that there were no significant differences in the threshold of evoked EPSPs between PC2‐null and WT animals. However, an increase in LTP in both triggering rate and amplitude was observed in PC2‐null mice, suggesting that PC2 may be involved in regulating synaptic strength. The PPF, on the other hand, showed a decrease in PC2‐null mice, suggesting a presynaptic mechanism. Consistent with changes in LTP, PC2‐null mice displayed decreased latencies in finding the escape platform in the MWM test. Further, after distal focal cerebral ischemia, the hippocampal proteomes incurred changes in both WT and PC2‐null mice, with a prominent change in proteins associated with neurotransmission, exocytosis, and transport processes seen in the PC2‐null but not WT mice. Taken together, our results suggest that PC2 is involved in regulating hippocampal synaptic plasticity, learning, and memory behaviors, as well as the hippocampal response to stresses originating in other regions of the brain.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

There is evidence for a hippocampal long axis anterior–posterior (AP) differentiation in memory processing, which may have implications for the changes in episodic memory performance seen across development and aging. The hippocampus shows substantial structural changes with age, but the lifespan trajectories of hippocampal sub‐regions along the AP axis are not established. The aim of the present study was to test whether the micro‐ and macro‐structural age‐trajectories of the anterior (aHC) and posterior (pHC) hippocampus are different. In a single‐center longitudinal study, 1,790 cognitively healthy participants, 4.1–93.4 years of age, underwent a total of 3,367 MRI examinations and 3,033 memory tests sessions over 1–6 time points, spanning an interval up to 11.1 years. T1‐weighted scans were used to estimate the volume of aHC and pHC (macrostructure), and diffusion tensor imaging to measure mean diffusion (MD, microstructure) within each region. We found that the macro‐ and microstructural lifespan‐trajectories of aHC and pHC were clearly distinguishable, with partly common and partly unique variance shared with age. aHC showed a protracted period of microstructural development, while pHC microstructural development as indexed by MD was more or less completed in early childhood. In contrast, pHC showed larger unique aging‐related changes. An aHC–pHC difference was also observed for volume, with pHC changing relatively more with higher age. All regions showed age‐dependent relationships with episodic memory. aHC micro‐ and macrostructure was significantly related to verbal memory independently of age, but the relationships were still strongest among the older participants. We suggest that memory processes supported by each sub‐region improve or decline in concert with volumetric and microstructural changes in the same age‐period. Future research should disentangle the lifespan relationship between changes in these structural properties and different memory processes, encoding versus retrieval in particular, as well as other cognitive functions depending on the hippocampal long‐axis specialization.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

The cellular and synaptic architecture of the rodent hippocampus has been described in thousands of peer‐reviewed publications. However, no human‐ or machine‐readable public catalog of synaptic electrophysiology data exists for this or any other neural system. Harnessing state‐of‐the‐art information technology, we have developed a cloud‐based toolset for identifying empirical evidence from the scientific literature pertaining to synaptic electrophysiology, for extracting the experimental data of interest, and for linking each entry to relevant text or figure excerpts. Mining more than 1,200 published journal articles, we have identified eight different signal modalities quantified by 90 different methods to measure synaptic amplitude, kinetics, and plasticity in hippocampal neurons. We have designed a data structure that both reflects the differences and maintains the existing relations among experimental modalities. Moreover, we mapped every annotated experiment to identified potential connections, that is, specific pairs of presynaptic and postsynaptic neuron types. To this aim, we leveraged Hippocampome.org, an open‐access knowledge base of morphologically, electrophysiologically, and molecularly characterized neuron types in the rodent hippocampal formation. Specifically, we have implemented a computational pipeline to systematically translate neuron type properties into formal queries in order to find all compatible potential connections. With this system, we have collected nearly 40,000 synaptic data entities covering 88% of the 3,120 potential connections in Hippocampome.org. Correcting membrane potentials with respect to liquid junction potentials significantly reduced the difference between theoretical and experimental reversal potentials, thereby enabling the accurate conversion of all synaptic amplitudes to conductance. This data set allows for large‐scale hypothesis testing of the general rules governing synaptic signals. To illustrate these applications, we confirmed several expected correlations between synaptic measurements and their covariates while suggesting previously unreported ones. We release all data open‐source at Hippocampome.org in order to further research across disciplines.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

The ventral portion of the rodent hippocampus (HPC; anterior in primates) has been implicated in the detection and resolution of approach–avoidance conflict, which arises when an organism encounters a stimulus that predicts both positive and negative outcomes. Previous work has found differential regulation of approach–avoidance conflict behavior by the CA3 and CA1 subfields, with inhibition of ventral CA3 increasing approach toward conflicting stimuli and inhibition of the ventral CA1 potentiating avoidance. Here, we sought to extend these findings by investigating the role of the dentate gyrus (DG), the input region of the HPC, in learned approach–avoidance conflict processing in rats. Animals were first trained to acquire three different visuotactile cue‐outcome associations in separate arms of a Y‐maze (appetitive, aversive, and neutral). Postacquisition, they were administered a “conflict test,” in which they were presented with a choice between exploring an arm in which the appetitive and aversive cues were concurrently presented (conflict stimulus), and another arm containing the neutral stimulus. GABAR‐mediated inactivation of the ventral DG, but not dorsal DG, potentiated approach behavior toward the conflict stimulus, similar to the effects of ventral CA3 inactivation. In contrast, dorsal DG, but not ventral DG, inactivation was found to impair performance on a metric spatial discrimination task, which is commonly used as a test of pattern separation. The findings of this study demonstrate a robust double dissociation between the ventral and dorsal aspects of the DG, in line with previous reports of functional differences along the longitudinal axis of the HPC.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

Phase precessing place cells encode spatial information on fine timescales via the timing of their spikes. This phase code has been extensively studied on linear tracks and for short runs in the open field. However, less is known about the phase code on unconstrained trajectories lasting tens of minutes, typical of open field foraging. In previous work (Monsalve‐Mercado and Leibold, Physical Review Letters, 119, 38101 (2017)), an analytic expression was derived for the spike‐time cross‐correlation between phase precessing place cells during natural foraging in the open field. This expression makes two predictions on how this phase code differs from the linear track case: cross‐correlations are symmetric with respect to time, and they represent the distance between pairs of place fields in that the theta‐filtered cross‐correlations around zero time lag are positive for cells with nearby fields while they are negative for those with fields further apart. Here we analyze several available open field recordings and show that these predictions hold for pairs of CA1 place cells. We also show that the relationship remains during remapping in CA1, and it is also present in place cells in area CA3. For CA1 place cells of Fmr1‐null mice, which exhibit normal place fields but somewhat weaker temporal coordination with respect to theta compared to wild type, the cross‐correlations still remain symmetric but the relationship to place field overlap is largely lost. The relationship discussed here describes how spatial information is communicated by place cells to downstream areas in a finer theta‐timescale, relevant for learning and memory formation in behavioral tasks lasting tens of minutes in the open field.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

Prior research shows that contextual reminders can reactivate hippocampal links to previously consolidated memories, rendering them susceptible to being updated with new information which then is reconsolidated. Studies implicate sleep in the reconsolidation of reactivated memories, but it is unknown what role sleep plays in updating of a previously consolidated trace with new information. We tracked participants' sleep during an episodic reconsolidation paradigm, first with actigraphy (Experiment 1) then with polysomnography (Experiment 2). Our paradigm involved two learning sessions and a retrieval session, each separated by 48 hr. We reminded participants of the first learning experience immediately prior to the second, which led them to update the earlier memory with elements of the later experience. In Experiment 1, less sleep after Session 1 and more sleep after Session 2 are associated with increased updating. In Experiment 2, N2 sleep spindles (SSs) after the reminder and new learning are associated with more updating, but primarily when spindle activity after Session 1 is low. Thus, total sleep time and N2 SSs contribute to sleep‐dependent updating of episodic memory. This outcome is consistent with other work connecting SS activity to the integration of novel information into existing knowledge structures, extended here with the study of how variations in sleep over successive nights contribute to this process. We discuss some possible roles of spindles in the decontextualization of hippocampal memory over time. Although much work addresses the role of sleep in the consolidation of new memories, this work uniquely addresses the contribution of sleep to the updating of a previously consolidated trace with new information.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

The present study asked whether the specific method of reactivation modulates the impact of new learning on reactivated episodic memories. The study consisted of three sessions that were spaced 48 hr apart. It used an ABAC paradigm that allowed for the simultaneous assessment of retroactive interference (RI: reduced A–B recall after A–C learning) and intrusions from C into A–B recall. In Session 1, participants learned a list of paired‐associates A–B. In Session 2, memory for A–B was reactivated or not and then participants either learned a second list of paired‐associates A–C or completed a control task. Three different reminder conditions were compared to a no‐reminder condition: a test condition, in which participants were asked to recall B in response to A, a restudy condition, in which A–B pairs were presented again for study, and a cue‐word only reminder condition, in which A cues were presented in an unrelated rating task. In Session 3, recall of A–B was tested. Moderate or indirect reactivation of A–B (presentation of cue‐words only) resulted in high RI effects and intrusion rates, whereas strong and direct reactivation (test and restudy) drastically reduced these effects. We suggest that direct reactivation of A–B before A–C learning strengthens memory and draws attention to list differences, thereby enhancing list segregation, and reducing memory updating.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

Hippocampal subfield segmentation on in vivo MRI is of great interest for cognition, aging, and disease research. Extant subfield segmentation protocols have been based on neuroanatomical references, but these references often give limited information on anatomical variability. Moreover, there is generally a mismatch between the orientation of the histological sections and the often anisotropic coronal sections on in vivo MRI. To address these issues, we provide a detailed description of hippocampal anatomy using a postmortem dataset containing nine specimens of subjects with and without dementia, which underwent a 9.4 T MRI and histological processing. Postmortem MRI matched the typical orientation of in vivo images and segmentations were generated in MRI space, based on the registered annotated histological sections. We focus on the following topics: the order of appearance of subfields, the location of subfields relative to macroanatomical features, the location of subfields in the uncus and tail and the composition of the dark band, a hypointense layer visible in T2‐weighted MRI. Our main findings are that: (a) there is a consistent order of appearance of subfields in the hippocampal head, (b) the composition of subfields is not consistent in the anterior uncus, but more consistent in the posterior uncus, (c) the dark band consists only of the CA‐stratum lacunosum moleculare, not the strata moleculare of the dentate gyrus, (d) the subiculum/CA1 border is located at the middle of the width of the hippocampus in the body in coronal plane, but moves in a medial direction from anterior to posterior, and (e) the variable location and composition of subfields in the hippocampal tail can be brought back to a body‐like appearance when reslicing the MRI scan following the curvature of the tail. Our findings and this publicly available dataset will hopefully improve anatomical accuracy of future hippocampal subfield segmentation protocols.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

It is well known that distributed learning (DL) leads to improved memory performance compared with massed learning (ML) (i.e., spacing effect). However, the extent to which the hippocampus is involved in the spacing effect at shorter and longer retention intervals remains unclear. To address this issue, two groups of participants were asked to encode face–scene pairs at 20‐min, 1‐day, and 1‐month intervals before they were scanned using fMRI during an associative recognition task. The pairs were repeated six times in either a massed (i.e., six times in 1 day) or a distributed (i.e., six times over 3 days, twice per day) manner. The results showed that compared with that in the ML group, the activation of the left hippocampus was stronger in the DL group when the participants retrieved old pairs correctly and rejected new pairs correctly at different retention intervals. In addition, the posterior hippocampus was more strongly activated when the new associations were rejected correctly after DL than ML, especially at the 1‐month interval. Hence, our results provide evidence that the hippocampus is involved in better memory performance after DL compared to ML at both shorter and longer retention intervals.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

When new information is relevant to prior knowledge or schema, it can be learned and remembered better. Rodent studies have suggested that the hippocampus and ventromedial prefrontal cortex (vmPFC) are important for processing schema‐related information. However, there are inconsistent findings from human studies on the involvement of the hippocampus and its interaction with the vmPFC in schema‐related memory retrieval. To address these issues, we used a human analog of the rodent spatial schema task to compare brain activity during immediate retrieval of paired associations (PAs) in schema‐consistent and schema‐inconsistent conditions. The results showed that the anterior hippocampus was more involved in retrieving PAs in the schema‐consistent condition than in the schema‐inconsistent condition. Connectivity analyses showed that the anterior hippocampus had stronger coupling with the vmPFC when the participants retrieved newly learned PAs successfully in the schema‐consistent (vs. schema‐inconsistent) condition, whereas the coupling of the posterior hippocampus with the vmPFC showed the opposite. Taken together, the results shed light on how the long axis of the hippocampus and vmPFC interact to serve memory retrieval via different networks that differ by schema condition.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

M‐type (KCNQ2/3) K+ channels play dominant roles in regulation of active and passive neuronal discharge properties such as resting membrane potential, spike‐frequency adaptation, and hyper‐excitatory states. However, plasticity of M‐channel expression and function in nongenetic forms of epileptogenesis are still not well understood. Using transgenic mice with an EGFP reporter to detect expression maps of KCNQ2 mRNA, we assayed hyperexcitability‐induced alterations in KCNQ2 transcription across subregions of the hippocampus. Pilocarpine and pentylenetetrazol chemoconvulsant models of seizure induction were used, and brain tissue examined 48 hr later. We observed increases in KCNQ2 mRNA in CA1 and CA3 pyramidal neurons after chemoconvulsant‐induced hyperexcitability at 48 hr, but no significant change was observed in dentate gyrus (DG) granule cells. Using chromogenic in situ hybridization assays, changes to KCNQ3 transcription were not detected after hyper‐excitation challenge, but the results for KCNQ2 paralleled those using the KCNQ2‐mRNA reporter mice. In mice 7 days after pilocarpine challenge, levels of KCNQ2 mRNA were similar in all regions to those from control mice. In brain‐slice electrophysiology recordings, CA1 pyramidal neurons demonstrated increased M‐current amplitudes 48 hr after hyperexcitability; however, there were no significant changes to DG granule cell M‐current amplitude. Traumatic brain injury induced significantly greater KCNQ2 expression in the hippocampal hemisphere that was ipsilateral to the trauma. In vivo, after a secondary challenge with subconvulsant dose of pentylenetetrazole, control mice were susceptible to tonic–clonic seizures, whereas mice administered the M‐channel opener retigabine were protected from such seizures. This study demonstrates that increased excitatory activity promotes KCNQ2 upregulation in the hippocampus in a cell‐type specific manner. Such novel ion channel expressional plasticity may serve as a compensatory mechanism after a hyperexcitable event, at least in the short term. The upregulation described could be potentially leveraged in anticonvulsant enhancement of KCNQ2 channels as therapeutic target for preventing onset of epileptogenic seizures.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

The hippocampal system contains neural populations that encode an animal's position and velocity as it navigates through space. Here, we show that such populations can embed two codes within their spike trains: a firing rate code ( R ) conveyed by within‐cell spike intervals, and a co‐firing rate code () conveyed by between‐cell spike intervals. These two codes behave as conjugates of one another, obeying an analog of the uncertainty principle from physics: information conveyed in R comes at the expense of information in , and vice versa. An exception to this trade‐off occurs when spike trains encode a pair of conjugate variables, such as position and velocity, which do not compete for capacity across R and . To illustrate this, we describe two biologically inspired methods for decoding R and , referred to as sigma and sigma‐chi decoding, respectively. Simulations of head direction and grid cells show that if firing rates are tuned for position (but not velocity), then position is recovered by sigma decoding, whereas velocity is recovered by sigma‐chi decoding. Conversely, simulations of oscillatory interference among theta‐modulated “speed cells” show that if co‐firing rates are tuned for position (but not velocity), then position is recovered by sigma‐chi decoding, whereas velocity is recovered by sigma decoding. Between these two extremes, information about both variables can be distributed across both channels, and partially recovered by both decoders. These results suggest that populations with different spatial and temporal tuning properties—such as speed versus grid cells—might not encode different information, but rather, distribute similar information about position and velocity in different ways across R and . Such conjugate coding of position and velocity may influence how hippocampal populations are interconnected to form functional circuits, and how biological neurons integrate their inputs to decode information from firing rates and spike correlations.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

Though it has been known for over half a century that interference with the normal activity of septohippocampal neurons can abolish hippocampal theta rhythmicity, a definitive answer to the question of its function has remained elusive. To clarify the role of septal circuits and theta in location‐specific activity of place cells and spatial behavior, three drugs were delivered to the medial septum of rats: Tetracaine, a local anesthetic; muscimol, a GABA‐A agonist; and gabazine, a GABA‐A antagonist. All three drugs disrupted normal oscillatory activity in the hippocampus. However, tetracaine and muscimol both reduced spatial firing and interfered with the rat's ability to navigate to a hidden goal. After gabazine, location‐specific firing was preserved in the absence of theta, but rats were unable to accurately locate the hidden goal. These results indicate that theta is unnecessary for location‐specific firing of hippocampal cells, and that place cell activity cannot support accurate navigation when septal circuits are disrupted.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

Grid cells in medial entorhinal cortex are notoriously variable in their responses, despite the striking hexagonal arrangement of their spatial firing fields. Indeed, when the animal moves through a firing field, grid cells often fire much more vigorously than predicted or do not fire at all. The source of this trial‐to‐trial variability is not completely understood. By analyzing grid‐cell spike trains from mice running in open arenas and on linear tracks, we characterize the phenomenon of “missed” firing fields using the statistical theory of zero inflation. We find that one major cause of grid‐cell variability lies in the spatial representation itself: firing fields are not as strongly anchored to spatial location as the averaged grid suggests. In addition, grid fields from different cells drift together from trial to trial, regardless of whether the environment is real or virtual, or whether the animal moves in light or darkness. Spatial realignment across trials sharpens the grid representation, yielding firing fields that are more pronounced and significantly narrower. These findings indicate that ensembles of grid cells encode relative position more reliably than absolute position.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

The left and right rodent hippocampi exhibit striking lateralization in some of the very neural substrates considered to be critical for hippocampal cognitive function. Despite this, there is an overwhelming lack of consideration for hemispheric differences in studies of the rodent hippocampus. Asymmetries identified so far suggest that a bilateral model of the hippocampus will be essential for an understanding of this brain region, and perhaps of the brain more widely. Although hypotheses have been proposed to explain how the left and right hippocampi contribute to behavior and cognition, these hypotheses have either been refuted by more recent studies or have been limited in the scope of data they explain. Here, I will first review data on human and rodent hippocampal lateralization. The implications of these data suggest that considering the hippocampus as a bilateral structure with functional lateralization will be critical moving forward in understanding the function and mechanisms of this brain region. In exploring these implications, I will then propose a hypothesis of the hippocampus as a bilateral structure. This discrete‐continuous hypothesis proposes that the left and right hippocampi contribute to spatial memory and navigation in a complementary manner. Specifically, the left hemisphere stores spatial information as discrete, salient locations, and the right hemisphere represents space continuously, contributing to route computation and flexible spatial navigation. Consideration of hippocampal lateralization in designing future studies may provide insight into the function of the hippocampus and resolve debates concerning its function.

in Hippocampus on March 28, 2020 02:21 PM.

• #### Nadel special issue introduction

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

There is considerable evidence from non‐human animal studies that the anterior and posterior regions of the hippocampus have different anatomical connections and support different behavioural functions. Although there are some recent human studies using functional magnetic resonance imaging (fMRI) that have addressed this idea directly in the memory and spatial processing domains and provided support for it, there has been no broader meta‐analysis of the fMRI literature to determine if there is consistent evidence for functional dissociations in anterior and posterior hippocampus across all of the different cognitive domains in which the hippocampus participates. The purpose of this review is to address this gap in our knowledge using three approaches. One approach involved PubMed searches to identify relevant fMRI papers reporting hippocampal activation during episodic encoding and retrieval, semantic retrieval, working memory, spatial navigation, simulation/scene construction, transitive inference, and social cognition tasks. The second was to use a large meta‐analytic database (neurosynth) to find text terms and coactivation maps associated with the anterior and posterior hippocampal regions identified in the literature search. The third approach was to contrast the resting‐state functional connectivity of the anterior and posterior hippocampal regions using a publicly available database that includes a large sample of adults. These three approaches provided converging evidence that not only are cognitive processes differently distributed along the hippocampal axis, but there also are distinct areas coactivated and functionally connected with the anterior and posterior segments. This anterior/posterior distinction involving multiple cognitive domains is consistent with the animal literature and provides strong support from fMRI for the idea of functional dissociations across the long axis of the hippocampus.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

α‐Thalassemia X‐linked intellectual disability (ATR‐X) syndrome is a neurodevelopmental disorder caused by mutations in the ATRX gene that encodes a SNF2‐type chromatin‐remodeling protein. The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of Atrx loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of Atrx in postnatal forebrain excitatory neurons (ATRX‐cKO) causes deficits in long‐term hippocampus‐dependent spatial memory. Thus, we hypothesized that ATRX‐cKO mice will display impaired hippocampal synaptic transmission and plasticity. In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane‐anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including paired‐pulse facilitation (PPF) at 50‐ms interpulse interval, and by their long‐term potentiation (LTP) induced by theta‐frequency burst stimulation. Baseline single‐pulse excitatory response at each synapse did not differ between ATRX‐cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX‐cKO mice. While basal dendritic LTP of the first‐pulse excitatory response was not affected in ATRX‐cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long‐term spatial memory deficits in ATRX‐cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR‐X syndrome patients.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

Multiple trace theory (Nadel & Moscovitch, Current Opinion in Neurobiology, 1997, 7, 217–227) has proven to be one of the most novel and influential recent memory theories, and played an essential role in shifting perspective on systems‐level memory consolidation. Here, we briefly review its impact and testable predictions and focus our discussion primarily on nonhuman animal experiments. Perhaps, the most often supported claim is that episodic memory tasks should exhibit comparable severity of retrograde amnesia (RA) for recent and remote memories after extensive damage to the hippocampus (HPC). By contrast, there appears to be little or no experimental support for other core predictions, such as temporally limited RA after extensive HPC damage in semantic memory tasks, temporally limited RA for episodic memories after partial HPC damage, or the existence of storage of multiple HPC traces with repeated reactivations. Despite these shortcomings, it continues to be a highly cited HPC memory theory.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

The encoding of information in spike phase relative to local field potential (LFP) oscillations offers several theoretical advantages over equivalent firing rate codes. One notable example is provided by place and grid cells in the rodent hippocampal formation, which exhibit phase precession—firing at progressively earlier phases of the 6–12 Hz movement‐related theta rhythm as their spatial firing fields are traversed. It is often assumed that such phase coding relies on a high amplitude baseline oscillation with relatively constant frequency. However, sustained oscillations with fixed frequency are generally absent in LFP and spike train recordings from the human brain. Hence, we examine phase coding relative to LFP signals with broadband low‐frequency (2–20 Hz) power but without regular rhythmicity. We simulate a population of grid cells that exhibit phase precession against a baseline oscillation recorded from depth electrodes in human hippocampus. We show that this allows grid cell firing patterns to multiplex information about location, running speed and movement direction, alongside an arbitrary fourth variable encoded in LFP frequency. This is of particular importance given recent demonstrations that movement direction, which is essential for path integration, cannot be recovered from head direction cell firing rates. In addition, we investigate how firing phase might reduce errors in decoded location, including those arising from differences in firing rate across grid fields. Finally, we describe analytical methods that can identify phase coding in the absence of high amplitude LFP oscillations with approximately constant frequency, as in single unit recordings from the human brain and consistent with recent data from the flying bat. We note that these methods could also be used to detect phase coding outside of the spatial domain, and that multi‐unit activity can substitute for the LFP signal. In summary, we demonstrate that the computational advantages offered by phase coding are not contingent on, and can be detected without, regular rhythmicity in neural activity.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

Lynn Nadel has been a trailblazer in memory research for decades. In just one example, Nadel and Zola‐Morgan [Infantile amnesia, In Infant memory, Springer, Boston, MA, 1984, pp. 145–172] were the first to present the provocative notion that the extended development of the hippocampus may underlie the period of infantile amnesia. In this special issue of Hippocampus to honor Lynn Nadel, we review some of his major contributions to the field of memory development, with an emphasis on his observations that behavioral memory assessments follow an uneven, yet protracted developmental course. We present data emphasizing this point from memory‐related eye movements [Hannula & Ranganath, Neuron, 2009, 63(5), 592–599]. Eye tracking is a sensitive behavioral measure, allowing for an indication of memory function even without overt responses, which is seemingly ideal for the investigation of memory in early childhood or in other nonverbal populations. However, the behavioral manifestation of these eye movements follows a U‐shaped trajectory—and one that must be understood before these indictors could be broadly used as a marker of memory. We examine the change in preferential looking time to target stimuli in school‐aged children and adults, and compare these eye movement responses to explicit recall measures. Our findings indicate change in the nature and timing of these eye movements in older children, causing us to question how 6‐month‐old infants may produce eye movements that initially appear to have the same properties as those measured in adulthood. We discuss these findings in the context of our current understanding of memory development, particularly the period of infantile amnesia.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

In rodents, pyramidal cell firing patterns from waking may be replayed in nonrapid eye movement sleep (NREM) sleep during hippocampal sharp wave ripples (HC‐SWR). In humans, HC‐SWR have only been recorded with electrodes implanted to localize epileptogenicity. Here, we characterize human HC‐SWR with rigorous rejection of epileptiform activity, requiring multiple oscillations and coordinated sharp waves. We demonstrated typical SWR in those rare HC recordings which lack interictal epileptiform spikes (IIS) and with no or minimal seizure involvement. These HC‐SWR have a similar rate (~12 min−1 on average, variable across NREM stages and anterior/posterior HC) and apparent intra‐HC topography (ripple maximum in putative stratum pyramidale, slow wave in radiatum) as rodents, though with lower frequency (~85 Hz compared to ~140 Hz in rodents). Similar SWR are found in HC with IIS, but no significant seizure involvement. These SWR were modulated by behavior, being largely absent (<2 min−1) except during NREM sleep in both Stage 2 (~9 min−1) and Stage 3 (~15 min−1), distinguishing them from IIS. This study quantifies the basic characteristics of a strictly selected sample of SWR recorded in relatively healthy human hippocampi.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

Behavioral data shows that humans and animals have the capacity to learn rules of associations applied to specific examples, and generalize these rules to a broad variety of contexts. This article focuses on neural circuit mechanisms to perform a context‐dependent association task that requires linking sensory stimuli to behavioral responses and generalizing to multiple other symmetrical contexts. The model uses neural gating units that regulate the pattern of physiological connectivity within the circuit. These neural gating units can be used in a learning framework that performs low‐rank matrix factorization analogous to recommender systems, allowing generalization with high accuracy to a wide range of additional symmetrical contexts. The neural gating units are trained with a biologically inspired framework involving traces of Hebbian modification that are updated based on the correct behavioral output of the network. This modeling demonstrates potential neural mechanisms for learning context‐dependent association rules and for the change in selectivity of neurophysiological responses in the hippocampus. The proposed computational model is evaluated using simulations of the learning process and the application of the model to new stimuli. Further, human subject behavioral experiments were performed and the results validate the key observation of a low‐rank synaptic matrix structure linking stimuli to responses.

in Hippocampus on March 28, 2020 02:21 PM.

## Abstract

A number of theories of hippocampal function have placed spatial context at the center of richly recollected memories, but the subjective and objective ways that spatial context underlies the recollection of single words has been largely overlooked and underexplained. In this study, we conducted three experiments to investigate the involvement of spatial context in the recollection of single words. In all three experiments, participants encoded single words with varying features such as location and color. The subjective experience of recollection was measured using remember/know judgments and participant self‐report of the types of information they recollected about the words. Objectively, recollection was measured using source memory judgments for both spatial and non‐spatial features associated with the words. Our results provide evidence that spatial context frequently accompanies the recollection of single, isolated words, reviving discussions on the role of the hippocampus in spatial and detailed recollection.

in Hippocampus on March 28, 2020 02:21 PM.

• #### Issue Information ‐ TOC

in Hippocampus on March 28, 2020 02:21 PM.

• #### Synchronization of complex networks with time-varying delay of unknown bound via delayed impulsive control

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Zhilu Xu, Xiaodi Li, Peiyong Duan

in Neural Networks on March 28, 2020 01:40 PM.

• #### Learning in the machine: To share or not to share?

Publication date: Available online 25 March 2020

Source: Neural Networks

Author(s): Jordan Ott, Erik Linstead, Nicholas LaHaye, Pierre Baldi

in Neural Networks on March 28, 2020 01:40 PM.

• #### Weighted discriminative collaborative competitive representation for robust image classification

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Jianping Gou, Lei Wang, Zhang Yi, Yunhao Yuan, Weihua Ou, Qirong Mao

in Neural Networks on March 28, 2020 01:40 PM.

• #### Preserving differential privacy in deep neural networks with relevance-based adaptive noise imposition

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Maoguo Gong, Ke Pan, Yu Xie, A.K. Qin, Zedong Tang

in Neural Networks on March 28, 2020 01:40 PM.

• #### On the localness modeling for the self-attention based end-to-end speech synthesis

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Shan Yang, Heng Lu, Shiyin Kang, Liumeng Xue, Jinba Xiao, Dan Su, Lei Xie, Dong Yu

in Neural Networks on March 28, 2020 01:40 PM.

• #### Supervised learning in spiking neural networks: A review of algorithms and evaluations

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Xiangwen Wang, Xianghong Lin, Xiaochao Dang

in Neural Networks on March 28, 2020 01:40 PM.

• #### Training high-performance and large-scale deep neural networks with full 8-bit integers

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Yukuan Yang, Lei Deng, Shuang Wu, Tianyi Yan, Yuan Xie, Guoqi Li

in Neural Networks on March 28, 2020 01:40 PM.

• #### Prediction of admission in pediatric emergency department with deep neural networks and triage textual data

Publication date: Available online 18 March 2020

Source: Neural Networks

Author(s): Bruno P. Roquette, Hitoshi Nagano, Ernesto C. Marujo, Alexandre C. Maiorano

in Neural Networks on March 28, 2020 01:40 PM.

• #### NeuroBayesSLAM: Neurobiologically inspired Bayesian integration of multisensory information for robot navigation

Publication date: June 2020

Source: Neural Networks, Volume 126

Author(s): Taiping Zeng, Fengzhen Tang, Daxiong Ji, Bailu Si

in Neural Networks on March 28, 2020 01:40 PM.

• #### Constructing large-scale cortical brain networks from scalp EEG with Bayesian nonnegative matrix factorization

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Chanlin Yi, Chunli Chen, Yajing Si, Fali Li, Tao Zhang, Yuanyuan Liao, Yuanling Jiang, Dezhong Yao, Peng Xu

in Neural Networks on March 28, 2020 01:40 PM.

• #### CNN–MHSA: A Convolutional Neural Network and multi-head self-attention combined approach for detecting phishing websites

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Xi Xiao, Dianyan Zhang, Guangwu Hu, Yong Jiang, Shutao Xia

in Neural Networks on March 28, 2020 01:40 PM.

• #### Causal importance of low-level feature selectivity for generalization in image recognition

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Jumpei Ukita

in Neural Networks on March 28, 2020 01:40 PM.

• #### Reachable set bounding for neural networks with mixed delays: Reciprocally convex approach

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Ruihan Chen, Song Zhu, Yongqiang Qi, Yuxin Hou

in Neural Networks on March 28, 2020 01:40 PM.

• #### Deep neural networks with a set of node-wise varying activation functions

Publication date: June 2020

Source: Neural Networks, Volume 126

Author(s): Jinhyeok Jang, Hyunjoong Cho, Jaehong Kim, Jaeyeon Lee, Seungjoon Yang

in Neural Networks on March 28, 2020 01:40 PM.

• #### Exponential synchronization of memristive neural networks with time-varying delays via quantized sliding-mode control

Publication date: June 2020

Source: Neural Networks, Volume 126

Author(s): Bo Sun, Shengbo Wang, Yuting Cao, Zhenyuan Guo, Tingwen Huang, Shiping Wen

in Neural Networks on March 28, 2020 01:40 PM.

• #### Mu-net: Multi-scale U-net for two-photon microscopy image denoising and restoration

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Sehyung Lee, Makiko Negishi, Hidetoshi Urakubo, Haruo Kasai, Shin Ishii

in Neural Networks on March 28, 2020 01:40 PM.

• #### Robust min–max optimal control design for systems with uncertain models: A neural dynamic programming approach

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Mariana Ballesteros, Isaac Chairez, Alexander Poznyak

in Neural Networks on March 28, 2020 01:40 PM.

• #### SOMprocessor: A high throughput FPGA-based architecture for implementing Self-Organizing Maps and its application to video processing

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Miguel Angelo de Abreu de Sousa, Ricardo Pires, Emilio Del-Moral-Hernandez

in Neural Networks on March 28, 2020 01:40 PM.

• #### Event-triggered synchronization of discrete-time neural networks: A switching approach

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Sanbo Ding, Zhanshan Wang

in Neural Networks on March 28, 2020 01:40 PM.

• #### Recommendation via Collaborative Autoregressive Flows

Publication date: June 2020

Source: Neural Networks, Volume 126

Author(s): Fan Zhou, Yuhua Mo, Goce Trajcevski, Kunpeng Zhang, Jin Wu, Ting Zhong

in Neural Networks on March 28, 2020 01:40 PM.

• #### New optimization algorithms for neural network training using operator splitting techniques

Publication date: Available online 26 March 2020

Source: Neural Networks

Author(s): Cristian Daniel Alecsa, Titus Pinţa, Imre Boros

in Neural Networks on March 28, 2020 01:40 PM.

• #### Low-rank discriminative regression learning for image classification

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Yuwu Lu, Zhihui Lai, Wai Keung Wong, Xuelong Li

in Neural Networks on March 28, 2020 01:40 PM.

• #### Global exponential stabilization and lag synchronization control of inertial neural networks with time delays

Publication date: June 2020

Source: Neural Networks, Volume 126

Author(s): Jichen Shi, Zhigang Zeng

in Neural Networks on March 28, 2020 01:40 PM.

• #### Chimera states in hybrid coupled neuron populations

Publication date: June 2020

Source: Neural Networks, Volume 126

Author(s): Ali Calim, Joaquin J. Torres, Mahmut Ozer, Muhammet Uzuntarla

in Neural Networks on March 28, 2020 01:40 PM.

• #### Skeleton-based Chinese sign language recognition and generation for bidirectional communication between deaf and hearing people

Publication date: May 2020

Source: Neural Networks, Volume 125

Author(s): Qinkun Xiao, Minying Qin, Yuting Yin

in Neural Networks on March 28, 2020 01:40 PM.

• #### Cross-modal dual subspace learning with adversarial network

Publication date: June 2020

Source: Neural Networks, Volume 126

Author(s): Fei Shang, Huaxiang Zhang, Jiande Sun, Liqiang Nie, Li Liu

in Neural Networks on March 28, 2020 01:40 PM.

• #### Finite-time synchronization of fractional-order gene regulatory networks with time delay

Publication date: June 2020

Source: Neural Networks, Volume 126

Author(s): Yuanhua Qiao, Hongyun Yan, Lijuan Duan, Jun Miao

in Neural Networks on March 28, 2020 01:40 PM.

• #### Corrigendum to “A model of operant learning based on chaotically varying synaptic strength” [Neural Netw. 108 (2018) 114–127]

Publication date: Available online 8 March 2019

Source: Neural Networks

Author(s): Tianqi Wei, Barbara Webb

in Neural Networks on March 28, 2020 01:40 PM.

• #### Reduced social investigation and increased injurious behavior in transgenic 5xFAD mice

In 5xFAD mice, transgenic (TG) males cannot be reliably housed together due to home‐cage aggression between 2 and 5 months of age, unlike wild‐type (WT)‐only and mixed‐genotype cages. Six‐month‐old TG males and females also exhibit reduced investigation of free‐roaming, but not restrained, conspecifics relative to WT controls.

## Abstract

Social withdrawal and agitation/aggression are common behavioral and psychological symptoms of dementia presented by Alzheimer's disease (AD) patients, with males exhibiting more aggressive behaviors than females. Some transgenic mouse models of AD also exhibit social withdrawal and aggression, but many of these models only recapitulate the early stages of the disease. By comparison, the 5xFAD mouse model of AD exhibits rapid, progressive neurodegeneration, and is suitable for modeling cognitive and behavioral deficits at early, mid‐, and late‐stage disease progression. Anecdotal reports suggest that transgenic 5xFAD males exhibit high levels of aggression compared to wild‐type controls, but to date, indirect genetic effects in this strain have not been studied. We measured home‐cage behaviors in 5xFAD males housed in three different group‐housing conditions (transgenic‐only, wild‐type only, and mixed‐genotype) and social approach behaviors when exposed to a novel free‐roaming or restrained, wild‐type or transgenic conspecific. Transgenic‐only home cages required earlier separation due to injuries arising from aggression compared to wild‐type‐only or mixed‐genotype cages, despite no obvious increase in the frequency of aggressive behaviors. Transgenic 5xFAD males and females also spent less time investigating free‐roaming conspecifics compared to wild‐type controls, but they showed normal investigation of restrained conspecifics; the genotype of the conspecific did not affect approach behavior, and there was no aggression observed in transgenic males. These findings provide evidence in an animal model that amyloid pathology ultimately leads to avoidance of novel social stimuli, and that frequent interactions between individuals exhibiting an AD phenotype further exacerbates aggressive behaviors.

• #### Murine maternal dietary restriction affects neural Humanin expression and cellular profile

Neuroprotective, anti‐apoptotic peptide Humanin is expressed in fetal brain with specific localization pattern and ontogeny. Maternal dietary restriction associated intra‐uterine growth restriction alters fetal brain Humanin expression in a sex and location specific manner while diminishing fetal neural progenitors, neurons, and glia.

## Abstract

To understand the cellular basis for the neurodevelopmental effects of intrauterine growth restriction (IUGR), we examined the global and regional expression of various cell types within murine (Mus musculus) fetal brain. Our model employed maternal calorie restriction to 50% daily food intake from gestation day 10–19, producing IUGR offspring. Offspring had smaller head sizes with larger head:body ratios indicating a head sparing IUGR effect. IUGR fetuses at embryonic day 19 (E19) had reduced nestin (progenitors), β‐III tubulin (immature neurons), Glial fibrillary acidic protein (astrocytes), and O4 (oligodendrocytes) cell lineages via immunofluorescence quantification and a 30% reduction in cortical thickness. No difference was found in Bcl‐2 or Bax (apoptosis) between controls and IUGR, though qualitatively, immunoreactivity of doublecortin (migration) and Ki67 (proliferation) was decreased. In the interest of examining a potential therapeutic peptide, we next investigated a novel pro‐survival peptide, mouse Humanin (mHN). Ontogeny examination revealed highest mHN expression at E19, diminishing by postnatal day 15 (P15), and nearly absent in adult (3 months). Subanalysis by sex at E19 yielded higher mHN expression among males during fetal life, without significant difference between sexes postnatally. Furthermore, female IUGR mice at E19 had a greater increase in cortical mHN versus the male fetus over their respective controls. We conclude that maternal dietary restriction‐associated IUGR interferes with neural progenitors differentiating into the various cellular components populating the cerebral cortex, and reduces cerebral cortical size. mHN expression is developmental stage and sex specific, with IUGR, particularly in the females, adaptively increasing its expression toward mediating a pro‐survival approach against nutritional adversity.

• #### Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats

Maternal deprivation, a model of child neglect, increases VTA dopamine (DA) neuronal excitability through impaired interaction between AKAP150 and PKA resulting in GABAergic dysfunction. This neuroadaptation may be affected through HDAC2 and is reversible by in vivo HDAC inhibition suggesting the potential therapeutic efficacy of HDAC inhibitors in reversal of VTA DA dysfunction.

## Abstract

Traumatic early life stress (ELS) is linked to dopamine (DA) dysregulation which increases the probability of developing psychiatric disorders in adolescence and adulthood. Our prior studies demonstrated that a severe early life stressor, a 24‐hr maternal deprivation (MD) in juvenile male rats, could lead to altered DA signaling from the ventral tegmental area (VTA) due to impairment of GABAergic synaptic plasticity (promoting GABAergic long‐term depression, LTD) with concomitant changes in the abundance of synaptic regulators including A‐kinase anchoring protein (AKAP150). Importantly, these MD‐induced synaptic changes in the VTA were accompanied by upregulation of histone deacetylase 2, histone hypoacetylation, and were reversible by HDAC inhibition. Using cell‐attached and whole‐cell patch clamp recordings, we found that MD stress also increased spontaneous VTA DA neuronal activity and excitability in juvenile male rats without affecting intrinsic excitability. Postsynaptic chemical disruption of AKAP150 and protein kinase A interaction increased VTA DA neuronal excitability in control non‐MD rats mimicking the effects of MD on DA cell excitability with similar changes in membrane properties. Interestingly, this disruption decreased MD‐induced VTA DA hyperexcitability. This MD‐induced DA neuronal hyperexcitability could also be normalized at 24 hr after injection of the class 1 HDAC inhibitor, CI‐994. Altogether, our data suggest that AKAP150 plays a critical role in the regulation of VTA DA neuronal excitability and that HDAC‐mediated targeting of AKAP150 signaling could normalize VTA DA dysfunction following ELS thereby providing novel therapeutic targets for prevention of later life psychopathology.

## Abstract

Presbycusis, or age‐related hearing loss (ARHL), occurs in most mammals with variations in the age of onset, rate of decline, and magnitude of degeneration in the central nervous system and inner ear. The affected cochlear structures include the stria vascularis and its vasculature, spiral ligament, sensory hair cells and auditory neurons. Dysfunction of the stria vascularis results in a reduced endocochlear potential. Without this potential, the cochlear amplification provided by the electro‐motility of the outer hair cells is insufficient, and a high‐frequency hearing‐loss results. Degeneration of the sensory cells, especially the outer hair cells also leads to hearing loss due to lack of amplification. Neuronal degeneration, another hallmark of ARHL, most likely underlies difficulties with speech discrimination, especially in noisy environments. Noise exposure is a major cause of ARHL. It is well‐known to cause sensory cell degeneration, especially the outer hair cells at the high frequency end of the cochlea. Even loud, but not uncomfortable, sound levels can lead to synaptopathy and ultimately neuronal degeneration. Even in the absence of a noisy environment, aged cells degenerate. This pathology most likely results from damage to mitochondria and contributes to degenerative changes in the stria vascularis, hair cells, and neurons. The genetic underpinnings of ARHL are still unknown and most likely involve various combinations of genes. At present, the only effective strategy for reducing ARHL is prevention of noise exposure. If future strategies can improve mitochondrial activity and reduce oxidative damage in old age, these should also bring relief.

• #### Ontogeny of inter‐alpha inhibitor protein (IAIP) expression in human brain

Inter‐alpha inhibitor proteins (IAIPS) are expressed in the nucleus and cytoplasm of neurons and astrocytes in the developing and adult human brain. Cytoplasmic IAIP expression is more abundant in the adult brain than in the brain of the younger age groups. IAIPs probably play a potential role in neonatal brain development and endogenous neuroprotection.

## Abstract

Inter‐alpha inhibitor proteins (IAIPs) are naturally occurring immunomodulatory molecules found in most tissues. We have reported ontogenic changes in the expression of IAIPs in brain during development in sheep and abundant expression of IAIPs in fetal and neonatal rodent brain in a variety of cellular types and brain regions. Although a few studies identified bikunin, light chain of IAIPs, in adult human brain, the presence of the complete endogenous IAIP protein complex has not been reported in human brain. In this study, we examined the immunohistochemical expression of endogenous IAIPs in human cerebral cortex from early in development through the neonatal period and in adults using well‐preserved postmortem brains. We examined total, nuclear, and cytoplasmic staining of endogenous IAIPs and their expression in neurofilament light polypeptide–positive neurons and glial fibrillary acidic protein (GFAP)–positive astrocytes. IAIPs were ubiquitously detected for the first time in cerebral cortical cells at 24–26, 27–28, 29–36, and 37–40 weeks of gestation and in adults. Quantitative analyses revealed that IAIPs were predominately localized in the nucleus in all age groups, but cytoplasmic IAIP expression was more abundant in adult than in the younger ages. Immunoreactivity of IAIPs was expressed in neurons and astrocytes in all age groups. In addition, IAIP co‐localization with GFAP‐positive astrocytes was more abundant in adults than in the developing brain. We conclude that IAIPs exhibit ubiquitous expression, and co‐localize with neurons and astrocytes in the developing and adult human brain suggesting a potential role for IAIPs in development and endogenous neuroprotection.

• #### Ultrastructural defects in stereocilia and tectorial membrane in aging mouse and human cochleae

We have described and investigated the pathologies of aging cochlea in both mice and humans to identify where aging pathologies are similar and different between the two. We have identified common pathological changes that are likely to have significant effects on hearing, improving the understanding of age‐related hearing loss.

## Abstract

The aging cochlea is subjected to a number of pathological changes to play a role in the onset of age‐related hearing loss (ARHL). Although ARHL has often been thought of as the result of the loss of hair cells, it is in fact a disorder with a complex etiology, arising from the changes to both the organ of Corti and its supporting structures. In this study, we examine two aging pathologies that have not been studied in detail despite their apparent prevalence; the fusion, elongation, and engulfment of cochlear inner hair cell stereocilia, and the changes that occur to the tectorial membrane (TM), a structure overlying the organ of Corti that modulates its physical properties in response to sound. Our work demonstrates that similar pathological changes occur in these two structures in the aging cochleae of both mice and humans, examines the ultrastructural changes that underlie stereocilial fusion, and identifies the lost TM components that lead to changes in membrane structure. We place these changes into the context of the wider pathology of the aging cochlea, and identify how they may be important in particular for understanding the more subtle hearing pathologies that precede auditory threshold loss in ARHL.

• #### Olfactory ensheathing cells from the nasal mucosa and olfactory bulb have distinct membrane properties

Olfactory ensheathing cells (OECs) are specialized glia, which wrap the axons of olfactory neurons that mediate the sense of smell. Their physiological roles during olfaction are largely unknown. Our electrophysiological characterization suggests that peripheral and central OECs are functionally distinct. Peripheral OECs have large weak inward rectifier currents, whereas central OECs have smaller strong inward rectifier currents and strong outward rectifier currents. These distinct sets of membrane properties may point to regional specializations in vivo.

## Abstract

Transplantation of olfactory ensheathing cells (OECs) is a potential therapy for the regeneration of damaged neurons. While they maintain tissue homeostasis in the olfactory mucosa (OM) and olfactory bulb (OB), their regenerative properties also support the normal sense of smell by enabling continual turnover and axonal regrowth of olfactory sensory neurons (OSNs). However, the molecular physiology of OECs is not fully understood, especially that of OECs from the mucosa. Here, we carried out whole‐cell patch‐clamp recordings from individual OECs cultured from the OM and OB of the adult rat, and from the human OM. A subset of OECs from the rat OM cultured 1–3 days in vitro had large weakly rectifying K+ currents, which were sensitive to Ba2+ and desipramine, blockers of Kir4‐family channels. Kir4.1 immunofluorescence was detectable in cultured OM cells colabeled for the OEC marker S100, and in S100‐labeled cells found adjacent to OSN axons in mucosal sections. OECs cultured from rat OB had distinct properties though, displaying strongly rectifying inward currents at hyperpolarized membrane potentials and strongly rectifying outward currents at depolarized potentials. Kir4.1 immunofluorescence was not evident in OECs adjacent to axons of OSNs in the OB. A subset of human OECs cultured from the OM of adults had membrane properties comparable to those of the rat OM that is dominated by Ba2+‐sensitive weak inwardly rectifying currents. The membrane properties of peripheral OECs are different to those of central OECs, suggesting they may play distinct roles during olfaction.

• #### A common genetic variant rs2821557 in KCNA3 is linked to the severity of multiple sclerosis

Case‐series study involving 101 multiple sclerosis patients revealed a link between KCNA3 polymorphism rs2821557 and the rate of disease progression. Minor C allele carriers exhibited significantly higher incidence of the rapid disease course and higher counts of CXCR3+ TEM cells compared to TT genotype carriers.

## Abstract

The rate of symptom accumulation distinguishes between slowly and rapidly progressing forms of multiple sclerosis (MS). Given that a patient's genetics can affect the rate of disease progression, identification of genetic variants associated with rapid disease progression should provide valuable information for timely prognosis and development of optimal treatment plans. We hypothesized that the polymorphism rs2821557 in the human KCNA3 gene encoding a voltage‐gated potassium channel Kv1.3 might be one of these genetic variants, given the role of Kv1.3 in neuroinflammation, as well as the location and gain‐of‐function effect of this polymorphism. To test this hypothesis we performed an analytic study exploring the relationships between rs2821557 polymorphism and disease progression in a cohort of MS patients. The rs2821557 genotype and the rate of disease progression based on Multiple Sclerosis Severity Score (MSSS) were determined for 101 patients (68 females and 33 males). Peripheral blood CD4+ lymphocyte subpopulations (Tnaive, TCM, TEM) and the expression of chemokine receptors (CXCR5, CXCR3, CCR6, CCR4) were estimated by flow cytometry. The comparisons between groups by genotype (TT, TC, CC) and allelic approach analysis (T vs. C) revealed a significantly higher incidence of the rapid disease course (MSSS ≥ 7.5) among minor C allele carriers (CC and TC) compared to patients with the TT genotype. Furthermore, C allele carriers had higher counts of CXCR3+ TEM cells than homozygous T allele carriers. In conclusion, accelerated MS progression in C allele carriers is likely linked to enhanced Kv1.3‐mediated accumulation of pathogenic CXCR3+ TEM cells and exacerbated neuroinflammation.

• #### The impact of aging on the subregions of the fusiform gyrus in healthy older adults

We investigated associations between age and regional gray matter in subregions of the fusiform gyrus. This was achieved by integrating imaging‐based signal intensities with cytoarchitectonically defined tissue probabilities. Our analyses revealed significant negative correlations in all subregions but with differing trajectories.

## Abstract

The fusiform gyrus is known to decrease in size with increasing age. However, reported findings are inconsistent and existing studies differ in terms of the cohorts examined and/or the methods applied. Here, we analyzed age‐related links in four distinct subregions of the fusiform gyrus through integrating imaging‐based intensity information with microscopically defined cytoarchitectonic probabilities. In addition to age effects we investigated sex effects as well as age‐by‐sex interactions in a relatively large sample of 468 healthy subjects (272 females/196 males) covering a broad age range (42–97 years). We observed significant negative correlations between age and all four subregions of the fusiform gyrus indicating volume decreases over time, albeit with subregion‐specific trajectories. Additionally, we observed significant negative quadratic associations with age for some subregions, suggesting an accelerating volume loss over time. These findings may serve as a frame of reference for future cross‐sectional as well as longitudinal studies, not only for normative samples but also potentially for clinical conditions that present with abnormal atrophy of the fusiform gyrus. We did not detect any significant sex differences or sex‐by‐age interactions, suggesting that the size of the fusiform gyrus is similar in male and female brains and that age‐related atrophy follows a similar trajectory in both men and women.

• #### Neuropeptide Y modulates membrane excitability in neonatal rat mesencephalic V neurons

Neuropeptide Y (NPY) facilitates spontaneous bursting discharge produced by a constant depolarizing current stimulus accompanying with increase of intra‐burst frequency in mesencephalic V neuron (a). Facilitation of persistent sodium current activation and modulation of channel gating by NPY are potentially involved in those effects (b,c).

## Abstract

Neuropeptide Y (NPY) is one of a number of neuropeptides with powerful orexigenic effects. Intracerebroventricular administration of NPY induces increases in food intake and alters feeding rate. Besides it role in feeding behavior, NPY also has significant effects on neuronal systems related to other spontaneous behaviors such as rearing and grooming. In the present study, we examined the direct effects of NPY on mesencephalic V neurons (Mes V), which are important sensory neurons involved in oral motor reflexes and rhythmical jaw movements, as well as masticatory proprioception. Coronal brain slices were prepared from neonatal Sprague‐Dawley rats (P3‐17) and whole‐cell patch clamp recordings were obtained from Mes V neurons. Bath application of NPY depolarized the membrane potential and induced inward current in most neurons. Application of NPY shortened the duration of the afterhyperpolarization following an action potential, and increased the mean spike frequency during repetitive discharge. In those neurons which exhibited rhythmical burst discharge in response to maintained current injection, the bursting frequency was also increased. These effects were mediated predominately by both Y1 and Y5 receptors.

## Abstract

Perinatal hypoxic‐ischemic (HI)‐related brain injury is an important cause of morbidity and long‐standing disability in newborns. The only currently approved therapeutic strategy available to reduce brain injury in the newborn is hypothermia. Therapeutic hypothermia can only be used to treat HI encephalopathy in full‐term infants and survivors remain at high risk for a wide spectrum of neurodevelopmental abnormalities as a result of residual brain injury. Therefore, there is an urgent need for adjunctive therapeutic strategies. Inflammation and neurovascular damage are important factors that contribute to the pathophysiology of HI‐related brain injury and represent exciting potential targets for therapeutic intervention. In this review, we address the role of each component of the neurovascular unit (NVU) in the pathophysiology of HI‐related injury in the neonatal brain. Disruption of the blood–brain barrier (BBB) observed in the early hours after an HI‐related event is associated with a response at the basal lamina level, which comprises astrocytes, pericytes, and immune cells, all of which could affect BBB function to further exacerbate parenchymal injury. Future research is required to determine potential drugs that could prevent or attenuate neurovascular damage and/or augment repair. However, some studies have reported beneficial effects of hypothermia, erythropoietin, stem cell therapy, anti‐cytokine therapy and metformin in ameliorating several different facets of damage to the NVU after HI‐related brain injury in the perinatal period.

## Abstract

Sleep is an evolutionarily conserved and powerful drive, although its complete functions are still unknown. One possible function of sleep is that it promotes brain development. The amount of sleep is greatest during ages when the brain is rapidly developing, and sleep has been shown to influence critical period plasticity. This supports a role for sleep in brain development and suggests that abnormal sleep in early life may lead to abnormal development. Autism spectrum disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States. It is estimated that insomnia affects 44%–86% of the ASD population, predicting the severity of ASD core symptoms and associated behavioral problems. Sleep problems impact the quality of life of both ASD individuals and their caregivers, thus it is important to understand why they are so prevalent. In this review, we explore the role of sleep in early life as a causal factor in ASD. First, we review fundamental steps in mammalian sleep ontogeny and regulation and how sleep influences brain development. Next, we summarize current knowledge gained from studying sleep in animal models of ASD. Ultimately, our goal is to highlight the importance of understanding the role of sleep in brain development and the use of animal models to provide mechanistic insight into the origin of sleep problems in ASD.

## Abstract

This article provides an overview of recent advances in understanding the effects of alcohol use disorders (AUD) on the brain from the perspective of magnetic resonance imaging (MRI) research in preclinical models and clinical studies. As a noninvasive investigational tool permitting assessment of morphological, metabolic, and hemodynamic changes over time, MRI offers insight into the dynamic course of alcoholism beginning with initial exposure through periods of binge drinking and escalation, sobriety, and relapse and has been useful in differential diagnosis of neurological diseases associated with AUD. Structural MRI has revealed acute and chronic effects of alcohol on both white and gray matter volumes. MR Spectroscopy, able to quantify brain metabolites in vivo, has shed light on biochemical alterations associated with alcoholism. Diffusion tensor imaging permits microstructural characterization of white matter fiber tracts. Functional MRI has allowed for elucidation of hemodynamic responses at rest and during task engagement. Positron emission tomography, a non‐MRI imaging tool, has led to a deeper understanding of alcohol‐induced receptor and neurotransmitter changes during various stages of drinking and abstinence. Together, such in vivo imaging tools have expanded our understanding of the dynamic course of alcoholism including evidence for regional specificity of the effects of AUD, hints at mechanisms underlying the shift from casual to compulsive use of alcohol, and profound recovery with sustained abstinence.

## Abstract

Habits are an important mechanism by which organisms can automate the control of behavior to alleviate cognitive demand. However, transitions to habitual control are risky because they lead to inflexible responding in the face of change. The question of how the brain controls transitions into habit is thus an intriguing one. How do we regulate when our repeated actions become automated? When is it advantageous or disadvantageous to release actions from cognitive control? Decades of research have identified a variety of methods for eliciting habitual responding in animal models. Progress has also been made to understand which brain areas and neural circuits control transitions into habit. Here, I discuss existing research on behavioral and neural circuit models for habit formation (with an emphasis on striatal circuits), and discuss strategies for combining information from different paradigms and levels of analysis to prompt further progress in the field.

## Abstract

Preterm birth and associated brain injury are the primary cause of cerebral palsy and developmental disabilities and are among the most serious global health issues that modern society faces. Current therapy for infants suffering from premature brain injury is still mainly supportive, and there are no effective treatments. Thus there is a pressing need for comparative and translational studies on how to reduce brain injury and to increase regeneration and brain repair in preterm infants. There is strong supporting evidence for the use of umbilical cord blood (UCB)‐derived stem cell therapy for treating preterm brain injury and neurological sequelae. UCB‐derived stem cell therapy is effective in many animal models and has been shown to be feasible in clinical trials. Most of these therapies are still experimental, however. In this review, we focus on recent advances on the efficacy of UCB‐derived stem cell therapy in preterm infants with brain injury, and discuss the potential mechanisms behind their therapeutic effects as well as application strategies for future preclinical and clinical trials.

## Abstract

Neurodevelopmental disorders (NDDs) such as intellectual disability and autism spectrum disorder consistently show a male bias in prevalence, but it remains unclear why males and females are affected with different frequency. While many behavioral studies of transgenic NDD models have focused only on males, the requirement by the National Institutes of Health to consider sex as a biological variable has promoted the comparison of male and female performance in wild‐type and mutant animals. Here, we review examples of rodent models of NDDs in which sex‐specific deficits were identified in molecular, physiological, and/or behavioral responses, showing sex differences in susceptibility to disruption of genes mutated in NDDs. Haploinsufficiency in genes involved in mechanisms such as synaptic function (GABRB3 and NRXN1), chromatin remodeling (CHD8, EMHT1, and ADNP), and intracellular signaling (CC2D1A and ERK1) lead to more severe behavioral outcomes in males. However, in the absence of behavioral deficits, females can still present with cellular and electrophysiological changes that could be due to compensatory mechanisms or differential allocation of molecular and cellular functions in the two sexes. By contrasting these findings with mouse models where females are more severely affected (MTHFR and AMBRA1), we propose a framework to approach the study of sex‐specific deficits possibly leading to sex bias in NDDs.

## Abstract

Calcium (Ca2+) is a ubiquitous mediator of a multitude of cellular functions in the central nervous system (CNS). Intracellular Ca2+ is tightly regulated by cells, including entry via plasma membrane Ca2+ permeable channels. Of specific interest for this review are L‐type voltage‐dependent Ca2+ channels (L‐VDCCs), due to their pleiotropic role in several CNS disorders. Currently, there are numerous approved drugs that target L‐VDCCs, including dihydropyridines. These drugs are safe and effective for the treatment of humans with cardiovascular disease and may also confer neuroprotection. Here, we review the potential of L‐VDCCs as a target for the treatment of CNS disorders with a focus on microglia L‐VDCCs. Microglia, the resident immune cells of the brain, have attracted recent attention for their emerging inflammatory role in several CNS diseases. Intracellular Ca2+ regulates microglia transition from a resting quiescent state to an “activated” immune‐effector state and is thus a valuable target for manipulation of microglia phenotype. We will review the literature on L‐VDCC expression and function in the CNS and on microglia in vitro and in vivo and explore the therapeutic landscape of L‐VDCC‐targeting agents at present and future challenges in the context of Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropsychiatric diseases, and other CNS disorders.

## Abstract

The extracellular matrix (ECM) provides protection, rigidity, and structure toward cells. It consists, among others, of a wide variety of glycoproteins and proteoglycans, which act together to produce a complex and dynamic environment, most relevant in transmembrane events. In the brain, the ECM occupies a notable proportion of its volume and maintains the homeostasis of central nervous system (CNS). In addition, remodeling of the ECM, that is transient changes in ECM proteins regulated by matrix metalloproteinases (MMPs), is an important process that modulates cell behavior upon injury, thereby facilitating recovery. Failure of ECM remodeling plays an important role in the pathogenesis of multiple sclerosis (MS), a neurodegenerative demyelinating disease of the CNS with an inflammatory response against protective myelin sheaths that surround axons. Remyelination of denuded axons improves the neuropathological conditions of MS, but this regeneration process fails over time, leading to chronic disease progression. In this review, we uncover abnormal ECM remodeling in MS lesions by discussing ECM remodeling in experimental demyelination models, that is when remyelination is successful, and compare alterations in ECM components to the ECM composition and MMP expression in the parenchyma of demyelinated MS lesions, that is when remyelination fails. Inter‐ and intralesional differences in ECM remodeling in the distinct white matter MS lesions are discussed in terms of consequences for oligodendrocyte behavior and remyelination (failure). Hence, the review will aid to understand how abnormal ECM remodeling contributes to remyelination failure in MS lesions and assists in developing therapeutic strategies to promote remyelination.

## Abstract

Brain‐derived neurotrophic factor (BDNF) is an extensively studied protein that is evolutionarily conserved and widely distributed in the brain of vertebrates. It acts via its cognate receptors TrkB and p75NTR and plays a central role in the developmental neurogenesis, neuronal survival, proliferation, differentiation, synaptic plasticity, learning and memory, adult hippocampal neurogenesis, and brain regeneration. BDNF has also been implicated in a plethora of neurological disorders. Hence, understanding the processes that are controlled by BDNF and their regulating mechanisms is important. Although, BDNF has been thoroughly studied in the mammalian models, contradictory effects of its functions have been reported on several occasions. These contradictory effects may be attributed to the sheer complexity of the mammalian brain. The study of BDNF and its associated functions in a simpler vertebrate model may provide some clarity about the effects of BDNF on the neurophysiology of the brain. Keeping that in mind, this review aims at summarizing the current knowledge about the distribution of BDNF and its associated functions in the zebrafish brain. The main focus of the review is to give a comparative overview of BDNF distribution and function in zebrafish and mammals with respect to distinct life stages. We have also reviewed the regulation of bdnf gene in zebrafish and discussed its role in developmental and adult neurogenesis.

## Abstract

Over the past decade, many studies have focused on clarifying the roles of different N‐methyl‐d‐aspartate (NMDA) receptor subunits in cerebral ischemia, hoping to develop subunit‐selective drugs. Recently, more attention was given to studying the role of GluN2C in ischemia damage, which may lead to the development of new NMDA receptor antagonists for cerebral ischemia. Results showed that GluN2C inhibition or knockout can effectively alleviate the ischemic injury caused by middle cerebral artery occlusion and, contrarily, can aggravate the damage to hippocampal CA1 circuit caused by transient global cerebral ischemia. These results indicate the complicated roles of GluN2C in cerebral ischemia. In this minireview, we focus on these findings, describe the roles of GluN2C from different cell origins in ischemic damage, and explain the above inconsistent experimental results.

• #### Blockade of dopamine D1 receptors in male rats disrupts morphine reward in pain naïve but not in chronic pain states

We tested the hypothesis that the neural mechanism of opiate reward are dissociable in pain‐naïve and chronic pain states. Using the chronic constriction injury (CCI) model of neuropathic pain, both CCI and sham rats displayed a CPP to morphine. The effect was blocked by dopamine D1 receptor antagonism but only in pain‐naïve rats, adding to evidence that chronic pain modifies brain reward circuits.

## Abstract

The rewarding effect of opiates is mediated through dissociable neural systems in drug naïve and drug‐dependent states. Neuroadaptations associated with chronic drug use are similar to those produced by chronic pain, suggesting that opiate reward could also involve distinct mechanisms in chronic pain and pain‐naïve states. We tested this hypothesis by examining the effect of dopamine (DA) antagonism on morphine reward in a rat model of neuropathic pain.Neuropathic pain was induced in male Sprague‐Dawley rats through chronic constriction (CCI) of the sciatic nerve; reward was assessed in the conditioned place preference (CPP) paradigm in separate groups at early (4‐8 days post‐surgery) and late (11‐15 days post‐surgery) phases of neuropathic pain. Minimal effective doses of morphine that produced a CPP in early and late phases of neuropathic pain were 6 mg/kg and 2 mg/kg respectively. The DA D1 receptor antagonist, SCH23390, blocked a morphine CPP in sham, but not CCI, rats at a higher dose (0.5 mg/kg), but had no effect at a lower dose (0.1 mg/kg). The DA D2 receptor antagonist, eticlopride (0.1 and 0.5 mg/kg), had no effect on a morphine CPP in sham or CCI rats, either in early or late phases of neuropathic pain. In the CPP paradigm, morphine reward involves DA D1 mechanisms in pain‐naïve but not chronic pain states. This could reflect increased sensitivity to drug effects in pain versus no pain conditions and/or differential mediation of opiate reward in these two states.

## Abstract

The finding of mirror neurons (MNs) has provided a biological substrate to a new concept of cognition, relating data on actions and perceptions not only to integrate perception in action planning and execution but also as a neural mechanism supporting a wide range of cognitive functions. Here we first summarize data on MN localization and role in primates, then we report findings in normal human subjects: functional magnetic resonance imaging and neurophysiological studies sustain that MNs have a role in motor learning and recognizing actions and intentions of others, and they also support an embodied view of language, empathy, and memory. Then, we detail the results of literature searching on MNs and embodied cognition in Parkinson's disease (PD), frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS), and in mild cognitive impairment (MCI)/Alzheimer's disease (AD). In PD the network of MN could be altered, but its hyperactivation might support motor and cognitive performances at least in early stages. In the ALS/FTD continuum, preliminary evidence points out to an involvement of the MN network, which could explain language and inter‐subjectivity deficits shown in patients affected by these clinical entities. In the MCI/AD spectrum, a few recent studies suggest a possible progressive involvement from posterior to anterior areas of the MN network, with the brain putting in place compensatory mechanisms in early stages. Reinterpreting neurodegenerative diseases at the light of the new views about brain organization stemming from the discovery of MN could help to better comprehend clinical manifestations and open new pathways to rehabilitation.

• #### Single‐cell RNA sequencing study of retinal immune regulators identified CD47 and CD59a expression in photoreceptors—Implications in subretinal immune regulation

In the inner retina (from GCL to IPL), ganglion cells express high levels of CD200, CD47, and CX3CL1, followed by amacrine cells. Vascular endothelial cells express CD200 and CD47. They also express complement factor H and CD59a. In the outer retina (from INL to ONL), horizontal cells, on the one hand, express high levels of CD200 and CD47, whereas bipolar cells express only low levels of TGFβ2 and CD47. Photoreceptors, on the other hand, express CD59a and CD47 and the expression is increased in disease conditions such as retinal detachment and uveoretinitis. Immune activation (including microglial and complement activation) in the inner retina may be regulated predominately by ganglion cells and vascular endothelial cells with the support from amacrine cells, whereas immune activation in the outer retina may be regulated by horizontal cell and photoreceptors. Müller cells, which span throughout the neuroretina, express TGFβ2 and CD47 and may participate in the regulation of all types of retinal immune activation. BM, Bruch's membrane; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; ONL, outer nuclear layer; OPL, outer plexiform layer; RPE, retinal pigment epithelium.

## Abstract

The neuroretina is protected by its own defense system, that is microglia and the complement system. Under normal physiological conditions, microglial activation is tightly regulated by the neurons although the underlying mechanism remains elusive. Using published single‐cell RNA sequencing data sets, we found that immune regulatory molecules including CD200, CD47, CX3CL1, TGFβ, and complement inhibitor CD59a are expressed by various retinal neurons. Importantly, we found that photoreceptors express higher levels of CD47 and CD59a, which was further confirmed in cultured 661W cells, WERI‐Rb1 cells, and microdissected photoreceptors from human eyes. The expression of CD59a mRNA in 661W cells was upregulated by TNFα and hypoxia, whereas LPS, hypoxia, and IL‐4 upregulated CD47 mRNA expression in 661W cells. Immunofluorescence staining detected strong CD59a immunoreactivity in the outer nuclear layer, inner/outer segments, and discrete staining in ganglion cell layer (GCL), inner plexiform layer (IPL), and outer plexiform layer. The expression of CD59a in photoreceptors was increased in the detached retina, but decreased in retinas from experimental autoimmune uveoretinitis (EAU) mice. In EAU retina, CD59a was highly expressed by active immune cells. CD47 was detected in GCL, IPL, and inner nuclear layer and some photoreceptors. The expression of CD47 in photoreceptors was also increased in the detached retina but decreased in EAU retina. In a coculture system, 661W enhanced arginase‐1 and reduced IL‐6 mRNA expression in BV2 microglial cells. Our results suggest that photoreceptors express immune regulatory molecules and may have the potential to regulate immune activation in the outer retina/subretinal space under pathophysiological conditions.

## Abstract

The striatal dopamine system has long been studied in the context of reward learning, motivation, and movement. Given the prominent role dopamine plays in a variety of adaptive behavioral states, as well as diseases like addiction, it is essential to understand the full complexity of dopamine neurons and the striatal systems they target. A growing number of studies are uncovering details of the heterogeneity in dopamine neuron subpopulations. Here, we review that work to synthesize current understanding of dopamine system heterogeneity across three levels, anatomical organization, functions in behavior, and modes of action, wherein we focus on signaling profiles and local mechanisms for modulation of dopamine release. Together, these studies reveal new and emerging dimensions of the striatal dopamine system, informing its contribution to dynamic motivational and decision‐making processes.

## Abstract

Neurodegeneration refers to the complex process of progressive degeneration or neuronal apoptosis leading to a set of incurable and debilitating conditions. Physiologically, apoptosis is important in proper growth and development. However, aberrant and unrestricted apoptosis can lead to a variety of degenerative conditions including neurodegenerative diseases. Although dysregulated apoptosis has been implicated in various neurodegenerative disorders, the triggers and molecular mechanisms underlying such untimely and faulty apoptosis are still unknown. Hippo signaling pathway is one such apoptosis‐regulating mechanism that has remained evolutionarily conserved from Drosophila to mammals. This pathway has gained a lot of attention for its tumor‐suppressing task, but recent studies have emphasized the soaring role of this pathway in inflaming neurodegeneration. In addition, strategies promoting inactivation of this pathway have aided in the rescue of neurons from anomalous apoptosis. So, a thorough understanding of the relationship between the Hippo pathway and neurodegeneration may serve as a guide for the development of therapy for various degenerative diseases. The current review focuses on the mechanism of the Hippo signaling pathway, its upstream and downstream regulatory molecules, and its role in the genesis of numerous neurodegenerative diseases. The recent efforts employing the Hippo pathway components as targets for checking neurodegeneration have also been highlighted.

• #### Neurocognitive and psychiatric disorders‐related axonal degeneration in Parkinson's disease

This study demonstrates that axonal loss, indicated by a reduction in the intracellular volume fraction, is a major factor underlying white matter pathology related to neurocognitive and psychiatric disorders in Parkinson's disease. Furthermore, patients with neurocognitive and psychiatric disorders had broader axonal pathology (posterior predominant) compared with those without such disorders.

## Abstract

Neurocognitive and psychiatric disorders have significant consequences for quality of life in patients with Parkinson's disease (PD). In the current study, we evaluated microstructural white matter (WM) alterations associated with neurocognitive and psychiatric disorders in PD using neurite orientation dispersion and density imaging (NODDI) and linked independent component analysis (LICA). The indices of NODDI were compared between 20 and 19 patients with PD with and without neurocognitive and psychiatric disorders, respectively, and 25 healthy controls using tract‐based spatial statistics and tract‐of‐interest analyses. LICA was applied to model inter‐subject variability across measures. A widespread reduction in axonal density (indexed by intracellular volume fraction [ICVF]) was demonstrated in PD patients with and without neurocognitive and psychiatric disorders, as compared with healthy controls. Compared with patients without neurocognitive and psychiatric disorders, patients with neurocognitive and psychiatric disorders exhibited more extensive (posterior predominant) decreases in axonal density. Using LICA, ICVF demonstrated the highest contribution (59% weight) to the main effects of diagnosis that reflected widespread decreases in axonal density. These findings suggest that axonal loss is a major factor underlying WM pathology related to neurocognitive and psychiatric disorders in PD, whereas patients with neurocognitive and psychiatric disorders had broader axonal pathology, as compared with those without. LICA suggested that the ICVF can be used as a useful biomarker of microstructural changes in the WM related to neurocognitive and psychiatric disorders in PD.

• #### Characterization of Drosophila octopamine receptor neuronal expression using MiMIC‐converted Gal4 lines

New octopamine receptor MiMIC‐Gal4 lines, in conjunction with B3RT‐Tdc2‐LexA intersectional genetics, reveal potential neuronal octopamine autoreceptor locations in Drosophila melanogaster. This intersectional genetic tool can be further utilized to identify the subset of Tdc2‐expressing neurons within any Gal4 driver of interest.

## Abstract

Octopamine, the invertebrate analog of norepinephrine, is known to modulate a large variety of behaviors in Drosophila including feeding initiation, locomotion, aggression, and courtship, among many others. Significantly less is known about the identity of the neurons that receive octopamine input and how they mediate octopamine‐regulated behaviors. Here, we characterize adult neuronal expression of MiMIC‐converted Trojan‐Gal4 lines for each of the five Drosophila octopamine receptors. Broad neuronal expression was observed for all five octopamine receptors, yet distinct differences among them were also apparent. Use of immunostaining for the octopamine neurotransmitter synthesis enzyme Tdc2, along with a novel genome‐edited conditional Tdc2‐LexA driver, revealed all five octopamine receptors express in Tdc2/octopamine neurons to varying degrees. This suggests autoreception may be an important circuit mechanism by which octopamine modulates behavior.

• #### Structural plasticity of GABAergic and glutamatergic networks in the motor thalamus of parkinsonian monkeys

Reduced prevalence and increased size of glutamatergic cortical terminals in contact with thalamocortical neurons in the basal ganglia‐receiving region of the ventral motor thalamus in MPTP‐treated parkinsonian monkeys. The electron micrographs show vGluT1‐immunoreactive corticothalamic terminals in normal and parkinsonian monkeys.

## Abstract

In the primate thalamus, the parvocellular ventral anterior nucleus (VApc) and the centromedian nucleus (CM) receive GABAergic projections from the internal globus pallidus (GPi) and glutamatergic inputs from motor cortices. In this study, we used electron microscopy to assess potential structural changes in GABAergic and glutamatergic microcircuits in the VApc and CM of MPTP‐treated parkinsonian monkeys. The intensity of immunostaining for GABAergic markers in VApc and CM did not differ between control and parkinsonian monkeys. In the electron microscope, three major types of terminals were identified in both nuclei: (a) vesicular glutamate transporter 1 (vGluT1)‐positive terminals forming asymmetric synapses (type As), which originate from the cerebral cortex, (b) GABAergic terminals forming single symmetric synapses (type S1), which likely arise from the reticular nucleus and GABAergic interneurons, and (c) GABAergic terminals forming multiple symmetric synapses (type S2), which originate from GPi. The density of As terminals outnumbered that of S1 and S2 terminals in VApc and CM of control and parkinsonian animals. No significant change was found in the abundance and synaptic connectivity of S1 and S2 terminals in VApc or CM of MPTP‐treated monkeys, while the prevalence of “As” terminals in VApc of parkinsonian monkeys was 51.4% lower than in controls. The cross‐sectional area of vGluT1‐positive boutons in both VApc and CM of parkinsonian monkeys was significantly larger than in controls, but their pattern of innervation of thalamic cells was not altered. Our findings suggest that the corticothalamic system undergoes significant synaptic remodeling in the parkinsonian state.

• #### Distribution, number, and certain neurochemical identities of infracortical white matter neurons in the brains of three megachiropteran bat species

Immunohistochemical staining for parvalbumin reveals the presence of large, multipolar, white matter interstitial cells (white matter neurons) in the subcortical white matter of the telencephalon of the Egyptian fruit bat.

## Abstract

A large population of infracortical white matter neurons, or white matter interstitial cells (WMICs), are found within the subcortical white matter of the mammalian telencephalon. We examined WMICs in three species of megachiropterans, Megaloglossus woermanni, Casinycteris argynnis, and Rousettus aegyptiacus, using immunohistochemical and stereological techniques. Immunostaining for neuronal nuclear marker (NeuN) revealed substantial numbers of WMICs in each species—M. woermanni 124,496 WMICs, C. argynnis 138,458 WMICs, and the larger brained R. aegyptiacus having an estimated WMIC population of 360,503. To examine the range of inhibitory neurochemical types we used antibodies against parvalbumin, calbindin, calretinin, and neural nitric oxide synthase (nNOS). The calbindin and nNOS immunostained neurons were the most commonly observed, while those immunoreactive for calretinin and parvalbumin were sparse. The proportion of WMICs exhibiting inhibitory neurochemical profiles was ~26%, similar to that observed in previously studied primates. While for the most part the WMIC population in the megachiropterans studied was similar to that observed in other mammals, the one feature that differed was the high proportion of WMICs immunoreactive to calbindin, whereas in primates (macaque monkey, lar gibbon and human) the highest proportion of inhibitory WMICs contain calretinin. Interestingly, there appears to be an allometric scaling of WMIC numbers with brain mass. Further quantitative comparative work across more mammalian species will reveal the developmental and evolutionary trends associated with this infrequently studied neuronal population.

• #### ZEBrA: Zebra finch Expression Brain Atlas—A resource for comparative molecular neuroanatomy and brain evolution studies

The Zebra finch Expression Brain Atlas (ZEBrA; www.zebrafinchatlas.org) is a web‐based resource that maps the expression of genes linked to a broad range of functions onto the brain of zebra finches. ZEBrA is a first of its kind gene expression brain atlas for a bird species and a first for any sauropsid. ZEBrA's > 3,200 high‐resolution digital images of in situ hybridized sections for ~650 genes (as of June 2019) are presented in alignment with an annotated histological atlas and can be browsed down to cellular resolution.

## Abstract

An in‐depth understanding of the genetics and evolution of brain function and behavior requires a detailed mapping of gene expression in functional brain circuits across major vertebrate clades. Here we present the Zebra finch Expression Brain Atlas (ZEBrA; www.zebrafinchatlas.org, RRID: SCR_012988), a web‐based resource that maps the expression of genes linked to a broad range of functions onto the brain of zebra finches. ZEBrA is a first of its kind gene expression brain atlas for a bird species and a first for any sauropsid. ZEBrA's >3,200 high‐resolution digital images of in situ hybridized sections for ~650 genes (as of June 2019) are presented in alignment with an annotated histological atlas and can be browsed down to cellular resolution. An extensive relational database connects expression patterns to information about gene function, mouse expression patterns and phenotypes, and gene involvement in human diseases and communication disorders. By enabling brain‐wide gene expression assessments in a bird, ZEBrA provides important substrates for comparative neuroanatomy and molecular brain evolution studies. ZEBrA also provides unique opportunities for linking genetic pathways to vocal learning and motor control circuits, as well as for novel insights into the molecular basis of sex steroids actions, brain dimorphisms, reproductive and social behaviors, sleep function, and adult neurogenesis, among many fundamental themes.

• #### Distribution of Aromatase in the Brain of the African Cichlid Fish Astatotilapia burtoni: Aromatase Expression, But Not Estrogen Receptors, Varies with Female Reproductive‐State

Aromatase b, the gene encoding the aromatase enzyme that synthesizes estrogens, is found primarily in GFAP‐expressing radial glial cells along the ventricles throughout the brain of female African cichlid fish Astatotilapia burtoni. Transcript levels of aromb in microdissected brain regions are greater in gravid compared to mouth brooding and recovering females, but levels of estrogen receptors do not change. Brain‐derived estradiol in females may serve important and conserved roles in reproductive‐state plasticity.

## Abstract

Estrogen synthesis and signaling in the brains of vertebrates has pleotropic effects ranging from neurogenesis to modulation of behaviors. The majority of studies on brain‐derived estrogens focus on males, but estrogenic signaling in females likely plays important roles in regulation of reproductive cycling and social behaviors. We used females of the mouth brooding African cichlid fish, Astatotilapia burtoni, to test for reproductive state‐dependent changes in estrogenic signaling capacity within microdissected brain nuclei that are important for social behaviors. Expression levels of the rate‐limiting enzyme aromatase, but not estrogen receptors, measured by qPCR changes across the reproductive cycle. Gravid females that are close to spawning had higher aromatase levels in all brain regions compared to females with lower reproductive potential. This brain aromatase expression was positively correlated with circulating estradiol levels and ovarian readiness. Using chromogenic in situ hybridization (ISH) we localized aromatase‐expressing cells to ependymal regions bordering the ventricles from the forebrain to the hindbrain, and observed more abundant staining in gravid compared to mouth brooding females in most regions. Staining was most prominent in subpallial telencephalic regions, and diencephalic regions of the preoptic area, thalamus, and hypothalamus, but was also observed in sensory and sensorimotor areas of the midbrain and hindbrain. Aromatase expression was observed in radial glial cells, revealed by co‐localization with the glial marker GFAP and absence of co‐localization with the neuronal marker HuC/D. Collectively these results support the idea that brain‐derived estradiol in females may serve important functions in reproductive state‐dependent physiological and behavioral processes across vertebrates.

• #### Blockade of astrocytic activation delays the occurrence of severe hypoxia‐induced seizure and respiratory arrest in mice

Representative recordings in hypoxia loading experiments in two groups of mice, one pretreated with vehicle alone and the other with arundic acid, an inhibitor of astrocytic activation. From top to bottom: oxygen concentration in a chamber (Fo2), respiratory flow (whole body plethysmogram, inspiration upward), EEG spectrogram in the mouse with vehicle alone, respiratory flow, and EEG spectrogram in the mouse with arundic acid. The percentage of mice with respiratory arrest was significantly smaller in the arundic acid group as compared to the vehicle group. Time from the start of hypoxia to the occurrence of seizures was significantly longer in the mice with arundic acid than that in the vehicle group. Arundic acid delayed the occurrence of severe hypoxia‐induced seizures and prevented subsequent respiratory arrest.

## Abstract

Seizures are induced when subjects are exposed to severe hypoxia. It is followed by ventilatory fall‐off and eventual respiratory arrest, which may underlie the pathophysiology of death in patients with epilepsy and severe respiratory disorders. However, the mechanisms of hypoxia‐induced seizures have not been fully understood. Because astrocytes are involved in various neurological disorders, we aimed to investigate whether astrocytes are operational in seizure generation and respiratory arrest in a severe hypoxic condition. We examined the effects of astrocytic activation blockade on responses of EEG and ventilation to severe hypoxia. Adult mice were divided into two groups; in one group (n = 24) only vehicle was injected, and in the other group (n = 24) arundic acid, an inhibitory modulator of astrocytic activation, was administered before initiation of recording. After recording EEG and ventilation by whole body plethysmography in room air, the gas in the recording chamber was switched to 5% oxygen (nitrogen balanced) until a seizure and ventilatory depression occurred, followed by prompt switch back to room air. Severe hypoxia initially increased ventilation, followed by a seizure and ventilatory suppression in all mice examined. Fourteen mice without arundic acid showed respiratory arrest during loading of hypoxia. However, 22 mice pretreated with arundic acid did not suffer from respiratory arrest. Time from the onset of hypoxia to the occurrence of seizures was significantly longer in the group with arundic acid than that in the group without arundic acid. We suggest that blockade of astrocytic activation delays the occurrence of seizures and prevents respiratory arrest.

• #### P2X7 and A2A receptor endogenous activation protects against neuronal death caused by CoCl2‐induced photoreceptor toxicity in the zebrafish retina

ATP‐activated P2X7 (P2RX7) and adenosine receptors are involved in the progression of the majority of retinopathies leading to blindness. Purinergic signaling regulates progenitor proliferative activity in regeneration, growth, and development as well as proliferative retinopathies. We found that BzATP—a potent agonist of P2RX7—in vivo treatment provoked photoreceptor death and regeneration via multipotent progenitor mitotic activation. Furthermore, extracellular ATP via P2RX7 and adenosine via A2AR are key signals regulating retina regeneration with neuroprotective activity following photoreceptor injury.

## Abstract

Injured retinas in mammals do not regenerate and heal with loss of function. The adult retina of zebrafish self‐repairs after damage by activating cell‐intrinsic mechanisms, which are regulated by extrinsic signal interactions. Among relevant regulatory extrinsic systems, purinergic signaling regulates progenitor proliferation during retinogenesis and regeneration and glia proliferation in proliferative retinopathies. ATP‐activated P2X7 (P2RX7) and adenosine (P1R) receptors are involved in the progression of almost all retinopathies leading to blindness. Here, we examined P2RX7 and P1R participation in the retina regenerative response induced by photoreceptor damage caused by a specific dose of CoCl2. First, we found that treatment of uninjured retinas with a potent agonist of P2RX7 (BzATP) provoked photoreceptor damage and mitotic activation of multipotent progenitors. In CoCl2‐injured retinas, blockade of endogenous extracellular ATP activity on P2RX7 caused further neurodegeneration, Müller cell gliosis, progenitor proliferation, and microglia reactivity. P2RX7 inhibition in injured retinas also increased the expression of lin28a and tnfα genes, which are related to multipotent progenitor proliferation. Levels of hif1α, vegf3r, and vegfaa mRNA were enhanced by blockade of P2RX7 immediately after injury, indicating hypoxic like damage and endothelial cell growth and proliferation. Complete depletion of extracellular nucleotides with an apyrase treatment strongly potentiated cell death and progenitor proliferation induced with CoCl2. Blockade of adenosine P1 and A2A receptors (A2AR) had deleterious effects and deregulated normal timing for progenitor and precursor cell proliferation following photoreceptor damage. ATP via P2RX7 and adenosine via A2AR are survival extracellular signals key for retina regeneration in zebrafish.

• #### Distributions of hypothalamic neuron populations coexpressing tyrosine hydroxylase and the vesicular GABA transporter in the mouse

Nissl‐based maps of the distribution of tyrosine hydroxylase immunoreactivity in hypothalamic neurons that coexpress the vesicular GABA transporter revealed striking colocalization within the zona incerta. These neurons also express dopamine immunoreactivity but not dopamine beta‐hydroxylase; thus, dopamine is the likely terminal catecholamine produced by these cells.

## Abstract

The hypothalamus contains catecholaminergic neurons marked by the expression of tyrosine hydroxylase (TH). As multiple chemical messengers coexist in each neuron, we determined if hypothalamic TH‐immunoreactive (ir) neurons express vesicular glutamate or GABA transporters. We used Cre/loxP recombination to express enhanced GFP (EGFP) in neurons expressing the vesicular glutamate (vGLUT2) or GABA transporter (vGAT), then determined whether TH‐ir neurons colocalized with native EGFP Vglut2 ‐ or EGFP Vgat ‐fluorescence, respectively. EGFP Vglut2 neurons were not TH‐ir. However, discrete TH‐ir signals colocalized with EGFP Vgat neurons, which we validated by in situ hybridization for Vgat mRNA. To contextualize the observed pattern of colocalization between TH‐ir and EGFP Vgat , we first performed Nissl‐based parcellation and plane‐of‐section analysis, and then mapped the distribution of TH‐ir EGFP Vgat neurons onto atlas templates from the Allen Reference Atlas (ARA) for the mouse brain. TH‐ir EGFP Vgat neurons were distributed throughout the rostrocaudal extent of the hypothalamus. Within the ARA ontology of gray matter regions, TH‐ir neurons localized primarily to the periventricular hypothalamic zone, periventricular hypothalamic region, and lateral hypothalamic zone. There was a strong presence of EGFP Vgat fluorescence in TH‐ir neurons across all brain regions, but the most striking colocalization was found in a circumscribed portion of the zona incerta (ZI)—a region assigned to the hypothalamus in the ARA—where every TH‐ir neuron expressed EGFP Vgat . Neurochemical characterization of these ZI neurons revealed that they display immunoreactivity for dopamine but not dopamine β‐hydroxylase. Collectively, these findings indicate the existence of a novel mouse hypothalamic population that may signal through the release of GABA and/or dopamine.

• #### Developmental characterization of Zswim5 expression in the progenitor domains and tangential migration pathways of cortical interneurons in the mouse forebrain

We investigated the expression pattern of Zswim5, an MGE‐enriched gene in the mouse forebrain. Zswim5 was expressed in differentiating progenitors of cortical GABAergic interneurons that were undergoing tangential migration, suggesting potential regulation of the development of cortical interneurons by Zswim5.

## Abstract

GABAergic interneurons play an essential role in modulating cortical networks. The progenitor domains of cortical interneurons are localized in developing ventral forebrain, including the medial ganglionic eminence (MGE), caudal ganglionic eminence (CGE), preoptic area (POA), and preoptic hypothalamic border domain (POH). Here, we characterized the expression pattern of Zswim5, an MGE‐enriched gene in the mouse forebrain. At E11.5–E13.5, prominent Zswim5 expression was detected in the subventricular zone (SVZ) of MGE, POA, and POH, but not CGE of ventral telencephalon where progenitors of cortical interneurons resided. At E15.5 and E17.5, Zswim5 expression remained in the MGE/pallidum primordium and ventral germinal zone. Zswim5 mRNA was markedly decreased after birth and was absent in the adult forebrain. Interestingly, the Zswim5 expression pattern resembled the tangential migration pathways of cortical interneurons. Zswim5‐positive cells in the MGE appeared to migrate from the MGE through the SVZ of LGE to overlying neocortex. Indeed, Zswim5 was co‐localized with Nkx2.1 and Lhx6, markers of progenitors and migratory cortical interneurons. Double labeling showed that Ascl1/Mash1‐positive cells co‐expressed Zswim5. Zswim5 expressing cells contained none or at most low levels of Ki67 but co‐expressed Tuj1 in the SVZ of MGE. These results suggest that Zswim5 is immediately upregulated as progenitors exiting cell cycle become postmitotic. Given that recent studies have elucidated that the cell fate of cortical interneurons is determined shortly after becoming postmitotic, the timing of Zswim5 expression in early postmitotic interneurons suggests a potential role of Zswim5 in regulation of neurogenesis and tangential migration of cortical interneurons.

• #### Mild carotid stenosis creates gradual, progressive, lifelong brain, and eye damage: An experimental laboratory rat model

Mild occlusion affects behavior, brain, and eyes morphology. Diffusion‐tensor imaging revealed brain abnormalities in both groups, but only bilateral rats show effects in the optic nerve. Histology revealed for those areas changes in astrocytes, microglia, and number of apoptotic cells. Bilateral occlusion produced a severe damage to both eyes while in unilateral the damage was only in the occluded side.

## Abstract

In humans, carotid stenosis of 70% and above might be the cause of clinical symptoms such as transient ischemic attack and stroke. No clinical or animal studies have evaluated mild carotid occlusion, and few examined unilateral occlusion. Here, Westar rats underwent bilateral or unilateral carotid occlusion of 28–45%. Long‐term effects were evaluated 9–11 months later. We conducted cognitive evaluation using spatial learning in a water maze and exploration behavior in an open field. Morphology of the brain was examined by MRI using diffusion‐tensor imaging (DTI) and immunohistochemistry staining of the brain and eyes. Cognitive deficit was found in spatial memory and exploration behavior in both occluded groups. Brain and eyes histology presented severe damage in the bilateral group, compared to the unilateral one. DTI revealed an increase in mean diffusivity (MD) in the ventral thalamus and a decrease in fractional anisotropy in optic nerve and optic tract in bilateral rats, while unilateral rats showed only an increase in MD in the ventral pons. In those areas, a significant change in astrocytes, microglia, and number of apoptotic cells were found. Bilateral occlusion produced severe damage to both retinas, while unilateral occlusion produced damage mainly in the occluded side. We found that mild carotid stenosis, even in a unilateral occlusion, creates behavioral abnormalities presented by brain and eye histopathology. The results support our hypothesis that gradual formation of mild carotid stenosis along the life course leads to progressive damage that may create different degenerative diseases at a later age.

• #### Majority of cerebrospinal fluid‐contacting neurons in the spinal cord of C57Bl/6 N mice is present in ectopic position unlike in other studied experimental mice strains and mammalian species

In contrast with other vertebrate species, vast majority of CSF‐cNs in the spinal cord of C57Bl/6 N mice is located in ectopic distal ventral position. Our data indicate that missense mutations in Crb1 and Cyfip2 are responsible for aberrant morphology and ectopic position of CSF‐cNs in C57Bl/6 N mice.

## Abstract

Cerebrospinal fluid contacting neurons (CSF‐cNs) represent a specific class of neurons located in close vicinity of brain ventricles and central canal. In contrast with knowledge gained from other vertebrate species, we found that vast majority of CSF‐cNs in the spinal cord of C57Bl/6 N mice is located in ectopic distal ventral position. However, we found that small number of ectopic CSF‐cNs is present also in spinal cord of other investigated experimental mice strains (C57Bl/6J, Balb/C) and mammalian species (Wistar rats, New Zealand White rabbits). Similarly as the proximal populations, ectopic CSF‐cNs retain PKD2L1‐immunoreactivity and synaptic contacts with other neurons. On the other side, they show rather multipolar morphology lacking thick dendrite contacting central canal lumen. Ectopic CSF‐cNs in the spinal cord of C57Bl/6 N mice emerge during whole period devoted to production of CSF‐cNs and reach their ventral destinations during first postnatal weeks. In order to identify major gene, whose impairment could trigger translocation of CSF‐cNs outside the central canal area, we took advantage of close consanguinity of C57Bl/6J substrain with normal CSF‐cN distribution and C57Bl/6 N substrain with majority of CSF‐cNs in ectopic position. Employing in silico analyses, we ranked polymorphisms in C57Bl/6 N substrain and selected genes Crb1, Cyfip2, Adamts12, Plk1 and Herpud2 as the most probable candidates, whose product dysfunction might be responsible for the ectopic distribution of CSF‐cNs. Furthermore, segregation analysis of F2 progeny of parental C57Bl/6 N and Balb/C mice revealed that polymorphic loci of Crb1and Cyfip2 underlie the ectopic position of CSF‐cNs in the spinal cord of C57Bl/6 N mice.

• #### The role of PDLIM1, a PDZ‐LIM domain protein, at the ribbon synapses in the chicken retina

We report that a protein belonged to the PDLIM family is associated to the retinal periactive zone in cones of the chicken retina. PDLIM1, is a cytoskeletal protein that acts as an adapter that allows the trafficking of other proteins, like kinases, to the cytoskeleton and plays a role in controlling neurite outgrowth. The data in this work demonstrated that PDLIM1 delineates the cone's terminals and intermingles between the ribbons of the synapses. The localization of PDLIM1 could be of importance not only for understanding the molecular anatomy of the terminal ending in cones, but also to knowledge the fine mechanisms of the process of neurotransmission.

## Abstract

PDLIM's protein family is involved in the rearrangement of the actin cytoskeleton. In the present study, we describe the localization of PDLIM1 in chicken photoreceptors. This study provides evidence that this protein is present at the cone pedicles, as well as in other synapses of the chicken retina. Here, we demonstrate the expression pattern of PDLIM1 through immunofluorescence staining, immunoblots, subcellular fractionation, and immunoprecipitation experiments. Also, we consider the possibility that PDLIM1 may be involved in the synaptic vesicle endocytosis and/or the presynaptic trafficking of synaptic vesicles back to the nonready releasable pool. This endocytotic/exocytotic coupling requires a tight link between exocytic vesicle fusion at defined release sites and endocytic retrieval of synaptic vesicle membranes. In turn, photoreceptor ribbon synaptic structure depends on the cytoskeleton arrangement, both at the active zone‐related with exocytosis—as well as at the endocytic zone—periactive zone. To our knowledge, the PDLIM1 protein has not been observed in the pre synapses of the retina. Thus, the present study describes the expression and subcellular localization of PDLIM1 for the first time, as well as its modulation by visual environment in the chicken retina.

• #### Spatial models of cell distribution in human lumbar dorsal root ganglia

Dorsal root ganglia (DRG) are novel targets for neural interface technologies that treat neurological disorders, such as chronic pain and spinal cord injury. The three‐dimensional cellular anatomy of DRG are not well‐mapped, particularly in humans, limiting the effectiveness of neurotechnology. We developed a semi‐automated algorithm to quantify the three‐dimensional distribution of neural elements in histologically‐processed tissue. We applied this algorithm to sequential NF200‐stained histology slices obtained from human lumbar DRG and demonstrated that cell bodies typically congregate around the dorsal edge of the ganglia. These results are crucial to the development of safe and effective clinical neural interface technologies.

## Abstract

Dorsal root ganglia (DRG), which contain the somata of primary sensory neurons, have increasingly been considered as novel targets for clinical neural interfaces, both for neuroprosthetic and pain applications. Effective use of either neural recording or stimulation technologies requires an appropriate spatial position relative to the target neural element, whether axon or cell body. However, the internal three‐dimensional spatial organization of human DRG neural fibers and somata has not been quantitatively described. In this study, we analyzed 202 cross‐sectional images across the length of 31 human L4 and L5 DRG from 10 donors. We used a custom semi‐automated graphical user interface to identify the locations of neural elements in the images and normalize the output to a consistent spatial reference for direct comparison by spinal level. By applying a recursive partitioning algorithm, we found that the highest density of cell bodies at both spinal levels could be found in the inner 85% of DRG length, the outer‐most 25–30% radially, and the dorsal‐most 69–76%. While axonal density was fairly homogeneous across the DRG length, there was a distinct low density region in the outer 7–11% radially. These findings are consistent with previous qualitative reports of neural distribution in DRG. The quantitative measurements we provide will enable improved targeting of future neural interface technologies and DRG‐focused pharmaceutical therapies, and provide a rigorous anatomical description of the bridge between the central and peripheral nervous systems.

• #### Neural coding of action in three dimensions: Task‐ and time‐invariant reference frames for visuospatial and motor‐related activity in parietal area V6A

Visually guided action requires integrating information from multiple sources and encoding flexible action representations. We look at objects that we might reach, but also use them as a cue to act in another spatial location. This research article examines the sensorimotor transformations in parietal cortex occurring when we perform various actions in three‐dimensional space.

## Abstract

Goal‐directed movements involve a series of neural computations that compare the sensory representations of goal location and effector position, and transform these into motor commands. Neurons in posterior parietal cortex (PPC) control several effectors (e.g., eye, hand, foot) and encode goal location in a variety of spatial coordinate systems, including those anchored to gaze direction, and to the positions of the head, shoulder, or hand. However, there is little evidence on whether reference frames depend also on the effector and/or type of motor response. We addressed this issue in macaque PPC area V6A, where previous reports using a fixate‐to‐reach in depth task, from different starting arm positions, indicated that most units use mixed body/hand‐centered coordinates. Here, we applied singular value decomposition and gradient analyses to characterize the reference frames in V6A while the animals, instead of arm reaching, performed a nonspatial motor response (hand lift). We found that most neurons used mixed body/hand coordinates, instead of “pure” body‐, or hand‐centered coordinates. During the task progress the effect of hand position on activity became stronger compared to target location. Activity consistent with body‐centered coding was present only in a subset of neurons active early in the task. Applying the same analyses to a population of V6A neurons recorded during the fixate‐to‐reach task yielded similar results. These findings suggest that V6A neurons use consistent reference frames between spatial and nonspatial motor responses, a functional property that may allow the integration of spatial awareness and movement control.

• #### Do all mammals dream?

Photograph of the ventral surface of the brain of the pygmy sperm whale (Kogia breviceps). Of all mammals, the combination of unusual sleep physiology and associated neuroanatomy, cetaceans are the least likely mammals to experience vivid dream mentation while sleeping. Scale bar = 1 cm.

## Abstract

The presence of dreams in human sleep, especially in REM sleep, and the detection of physiologically similar states in mammals has led many to ponder whether animals experience similar sleep mentation. Recent advances in our understanding of the anatomical and physiological correlates of sleep stages, and thus dreaming, allow a better understanding of the possibility of dream mentation in nonhuman mammals. Here, we explore the potential for dream mentation, in both non‐REM and REM sleep across mammals. If we take a hard‐stance, that dream mentation only occurs during REM sleep, we conclude that it is unlikely that monotremes, cetaceans, and otariid seals while at sea, have the potential to experience dream mentation. Atypical REM sleep in other species, such as African elephants and Arabian oryx, may alter their potential to experience REM dream mentation. Alternatively, evidence that dream mentation occurs during both non‐REM and REM sleep, indicates that all mammals have the potential to experience dream mentation. This non‐REM dream mentation may be different in the species where non‐REM is atypical, such as during unihemispheric sleep in aquatic mammals (cetaceans, sirens, and Otariid seals). In both scenarios, the cetaceans are the least likely mammalian group to experience vivid dream mentation due to the morphophysiological independence of their cerebral hemispheres. The application of techniques revealing dream mentation in humans to other mammals, specifically those that exhibit unusual sleep states, may lead to advances in our understanding of the neural underpinnings of dreams and conscious experiences.

• #### Multi‐glomerular projection of single olfactory receptor neurons is conserved among amphibians

The formation of an odor map in the olfactory bulb of vertebrates is based on the general assumption that axons of individual olfactory receptor neurons do not branch and connect to single glomeruli. Here, we show that this general principle does not apply to the olfactory system of amphibians, which exhibits a multi‐glomerular wiring scheme and a putatively different odor coding strategy. Our data underline the need to acknowledge biological diversity to fully understand odor coding in vertebrates.

## Abstract

Individual receptor neurons in the peripheral olfactory organ extend long axons into the olfactory bulb forming synapses with projection neurons in spherical neuropil regions, called glomeruli. Generally, odor map formation and odor processing in all vertebrates is based on the assumption that receptor neuron axons exclusively connect to a single glomerulus without any axonal branching. We comparatively tested this hypothesis in multiple fish and amphibian species (both sexes) by applying sparse cell electroporation to trace single olfactory receptor neuron axons. Sea lamprey (jawless fish) and zebrafish (bony fish) support the unbranched axon concept, with 94% of axons terminating in single glomeruli. Contrastingly, axonal projections of the axolotl (salamander) branch extensively before entering up to six distinct glomeruli. Receptor neuron axons labeled in frog species (Pipidae, Bufonidae, Hylidae, and Dendrobatidae) predominantly bifurcate before entering a glomerulus and 59 and 50% connect to multiple glomeruli in larval and postmetamorphotic animals, respectively. Independent of developmental stage, lifestyle, and adaptations to specific habitats, it seems to be a common feature of amphibian olfactory receptor neuron axons to frequently bifurcate and connect to multiple glomeruli. Our study challenges the unbranched axon concept as a universal vertebrate feature and it is conceivable that also later diverging vertebrates deviate from it. We propose that this unusual wiring logic evolved around the divergence of the terrestrial tetrapod lineage from its aquatic ancestors and could be the basis of an alternative way of odor processing.

• #### Evolution of neural processing for visual perception in vertebrates

Visual perception requires both visual information and attention. This review compares, across classes of vertebrates, the functional and anatomical characteristics of (a) the neural pathways that process visual information about objects, and (b) stimulus selection pathways that determine the objects to which an animal attends.

## Abstract

Visual perception requires both visual information and attention. This review compares, across classes of vertebrates, the functional and anatomical characteristics of (a) the neural pathways that process visual information about objects, and (b) stimulus selection pathways that determine the objects to which an animal attends. Early in the evolution of vertebrate species, visual perception was dominated by information transmitted via the midbrain (retinotectal) visual pathway, and attention was probably controlled primarily by a selection network in the midbrain. In contrast, in primates, visual perception is dominated by information transmitted via the forebrain (retinogeniculate) visual pathway, and attention is mediated largely by networks in the forebrain. In birds and nonprimate mammals, both the retinotectal and retinogeniculate pathways contribute critically to visual information processing, and both midbrain and forebrain networks play important roles in controlling attention. The computations and processing strategies in birds and mammals share some strikingly similar characteristics despite over 300 million years of independent evolution and being implemented by distinct brain architectures. The similarity of these functional characteristics suggests that they provide valuable advantages to visual perception in advanced visual systems. A schema is proposed that describes the evolution of the pathways and computations that enable visual perception in vertebrate species.

• #### Retinal morphology in Astyanax mexicanus during eye degeneration

Here we use immunohistochemistry to show that the degenerating retina of the cavefish Astyanax mexicanus is marked by two important features. First, the neuroretina contains all cell types commonly see in the circuit. Presumably these components will later degenerate as the lens dies. Second, the outer segments of the photoreceptors are already malformed from early stages of development. It is interesting to note how evolution has severed a cell in half.

## Abstract

The teleost Astyanax mexicanus is one species extant in two readily available forms. One that lives in Mexican rivers and various convergent forms that live in nearby caves. These fish are born with eyes but in the cavefish, they degenerate during development. It is known that the lens of cavefish undergoes apoptosis and that some cells in the neuroretina also die. It has not been described, however, if glia and various components of the neuroretina form before complete eye degeneration. Here we examined the development of the retina of the closest living ancestor that lives in the rivers and two independently adapted of cavefish. We report that although the neuroretina is smaller and more compact, it has all cell types and layers including amacrine cells and Müller glia. While various makers for photoreceptors are present in the cavefish inner segments, the outer segments of the photoreceptors in cavefish are missing from the earliest stages examined. This shows that the machinery for visual transducing discs might still be present but not organized in one part of the cell. It is interesting to note that the deficiencies in Astyanax cavefish resemble retinal diseases, such as retinitis pigmentosa.

• #### Perineural application of resiniferatoxin on uninjured L3 and L4 nerves completely alleviates thermal and mechanical hypersensitivity following L5 nerve injury in rats

Confocal images of triple immunofluorescent labeling for TRPV1 (green), IB4 (red) and CGRP (blue), in a section of the left fourth lumbar (L4) DRG showing the effects of the perinerual application of resiniferatoxin (RTX) onto left L4 nerve. This treatment causes a remarkable reduction in the number of TRPV1, IB4 and CGRP immnuoreactive neurons in the corresponding treated L4 DRG compared to the right control (cont) L4 DRG.

## Abstract

Fifth lumbar (L5) nerve injury in rats causes neuropathic pain manifested with thermal and mechanical hypersensitivity in the ipsilateral hind paw. This study aimed to determine whether the elimination of unmyelinated primary afferents of the adjacent uninjured nerves (L3 and L4) would alleviate peripheral neuropathic pain. Different concentrations of capsaicin or its analog, resiniferatoxin (RTX), were applied perineurally on either the left L4 or L3 and L4 nerves in Wistar rats whose left L5 nerves were ligated and cut. The application of both capsaicin and RTX on the L4 nerve significantly reduced both thermal and mechanical hypersensitivity. However, only the application of RTX on both L3 and L4 nerves completely alleviated all neuropathic manifestations. Interestingly, responses to thermal and mechanical stimuli were preserved, despite RTX application on uninjured L3, L4, and L5 nerves, which supply the plantar skin in rats. Perineural application of RTX caused downregulation of TRPV1, CGRP, and IB4 binding and upregulation of VIP in the corresponding dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. In comparison, VGLUT1 and NPY immunoreactivities were not altered. RTX application did not cause degenerative or ultrastructural changes in the treated nerves and corresponding DRGs. The results demonstrate that RTX induces neuroplasticity, rather than structural changes in primary afferents, that are responsible for alleviating hypersensitivity and chronic pain. Furthermore, this study suggests that treating uninjured adjacent spinal nerves may be used to manage chronic neuropathic pain following peripheral nerve injury.

• #### Cover Image, Volume 528, Issue 8

The cover image is based on the Original Article Somatosensory corticospinal tract axons sprout within the cervical cord following a dorsal root/dorsal column spinal injury in the rat. by Corinna Darian‐Smith, Jamie Ahloy‐Dallaire, Karen Fisher et al., https://doi.org/10.1002/cne.24826.

• #### Sensory systems in birds: What we have learned from studying sensory specialists

Jack Pettigrew was a pioneer in his approach to understanding sensory systems in birds. Here, we review his seminal research on owls as well as more recent studies aimed at understanding the evolution of sensory specializations in hummingbirds and tactile‐feeding species. We also review Pettigrew's work on two unusual, and rarely studied, Australian bird species that exhibit unique auditory and visual specializations in order to occupy their unique niches. Overall, we conclude that a comparative approach can yield unique insights into sensory system function in birds, as well as other vertebrates.

## Abstract

“Diversity” is an apt descriptor of the research career of Jack Pettigrew as it ranged from the study of trees, to clinical conditions, to sensory neuroscience. Within sensory neuroscience, he was fascinated by the evolution of sensory systems across species. Here, we review some of his work on avian sensory specialists and research that he inspired in others. We begin with an overview of the importance of the Wulst in stereopsis and the need for further study of the Wulst in relation to binocularity across avian species. Next, we summarize recent anatomical, behavioral, and physiological studies on optic flow specializations in hummingbirds. Beyond vision, we discuss the first evidence of a tactile “fovea” in birds and how this led to detailed studies of tactile specializations in waterfowl and sensorimotor systems in parrots. We then describe preliminary studies by Pettigrew of two endemic Australian species, the plains‐wanderer (Pedionomus torquatus) and letter‐winged kite (Elanus scriptus), that suggest the evolution of some unique auditory and visual specializations in relation to their unique behavior and ecology. Finally, we conclude by emphasizing the importance of a comparative and integrative approach to understanding avian sensory systems and provide an example of one system that has yet to be properly examined: tactile facial bristles in birds. Through reviewing this research and offering future avenues for discovery, we hope that others also embrace the comparative approach to understanding sensory system evolution in birds and other vertebrates.

• #### Identification of spinal afferent nerve endings in the colonic mucosa and submucosa that communicate directly with the spinal cord: The gut–brain axis

Spinal afferent nerve endings in the submucosa of mouse distal colon that arise from a single nonpeptidergic spinal afferent neuron whose cell body originated in lumbosacral dorsal root ganglia (DRG). The nerve endings identified from this single sensory neuron were labeled after injection of neuronal tracer into DRG.

## Abstract

The major sensory nerve pathway between the colon and central nervous system (spinal cord and brain) that underlies the gut–brain axis, is via spinal afferent neurons, with cell bodies in dorsal root ganglia (DRG). Our aim was to identify the sensory nerve endings in the colon that arise from single colorectal‐projecting DRG neurons. C57BL/6 mice were anesthetized and lumbosacral L6‐S1 DRG injected with dextran biotin. Mice recovered for 7 days. The whole colon was then removed and stained to visualize single axons and nerve endings immunoreactive to calcitonin gene‐related peptide (CGRP). Single axons arising from DRG were identified in the distal colon and their morphological features and CGRP immunoreactivity characterized. After entering the colon, single axons ramified rostrally or caudally along many rows of myenteric ganglia with little circumferential displacement, giving off varicose endings in multiple ganglia. Nerve endings arising from two classes of colorectal‐projecting DRG neuron were identified. One class was peptidergic neurons that had nerve endings in circular muscle, myenteric ganglia, and submucosa. Another class of nonpeptidergic neurons innervated mucosal crypts, myenteric ganglia, and submucosa. Different morphological types of nerve endings which innervate different anatomical layers of colon can arise from the same axon and sensory neuron in DRG. These findings suggest single peptidergic and nonpeptidergic sensory neurons in DRG are potentially capable of detecting sensory stimuli from different anatomical layers of the colon, via different types of nerve endings.

• #### Centrifugal projections to the main olfactory bulb revealed by transsynaptic retrograde tracing in mice

Retrograde transsynaptic virus (a) allowed to trace (two to three synapses) projections onto the main olfactory bulb (b). Monosynaptic cholera toxin b (a) was a control to differentiate direct and indirect projections. The MOB mainly receives indirect projections from hypothalamic nuclei (c) and reward‐related regions (c1), underlining the role of olfaction in feeding (d).

## Abstract

A wide range of evidence indicates that olfactory perception is strongly involved in food intake. However, the polysynaptic circuitry linking the brain areas involved in feeding behavior to the olfactory regions is not well known. The aim of this article was to examine such circuits. Thus, we described, using hodological tools such as transsynaptic viruses (PRV152) transported in a retrograde manner, the long‐distance indirect projections (two to three synapses) onto the main olfactory bulb (MOB). The ß‐subunit of the cholera toxin which is a monosynaptic retrograde tracer was used as a control to be able to differentiate between direct and indirect projections. Our tracing experiments showed that the arcuate nucleus of the hypothalamus, as a major site for regulation of food intake, sends only very indirect projections onto the MOB. Indirect projections to MOB also originate from the solitary nucleus which is involved in energy homeostasis. Other indirect projections have been evidenced in areas of the reward circuit such as VTA and accumbens nucleus. In contrast, direct projections to the MOB arise from melanin‐concentrating hormone and orexin neurons in the lateral hypothalamus. Functional significances of these projections are discussed in relation to the role of food odors in feeding and reward‐related behavior.

• #### A cell type‐specific expression map of NCoR1 and SMRT transcriptional co‐repressors in the mouse brain

Schematic representation of NCoR1 and SMRT distribution in neuronal and non‐neuronal cell types. Five major types of brain cells (glutamatergic and GABAergic neurons, astrocytes, oligodendrocytes, and microglia) are depicted within a representative coronal slice of the mouse brain. Both NCor1 and SMRT broadly localize within the nuclei of most neuronal cells. However, a diverse pattern of expression is detected in non‐neuronal cells. While NCoR1 is expressed in a small fraction of astrocytes, SMRT is not expressed in GFAP+ astrocytes or in Iba1+ microglia.

## Abstract

The ability to rapidly change gene expression patterns is essential for differentiation, development, and functioning of the brain. Throughout development, or in response to environmental stimuli, gene expression patterns are tightly regulated by the dynamic interplay between transcription activators and repressors. Nuclear receptor corepressor 1 (NCoR1) and silencing mediator for retinoid or thyroid‐hormone receptors (SMRT) are the best characterized transcriptional co‐repressors from a molecular point of view. They mediate epigenetic silencing of gene expression in a wide range of developmental and homeostatic processes in many tissues, including the brain. For instance, NCoR1 and SMRT regulate neuronal stem cell proliferation and differentiation during brain development and they have been implicated in learning and memory. However, we still have a limited understanding of their regional and cell type‐specific expression in the brain. In this study, we used fluorescent immunohistochemistry to map their expression patterns throughout the adult mouse brain. Our findings reveal that NCoR1 and SMRT share an overall neuroanatomical distribution, and are detected in both excitatory and inhibitory neurons. However, we observed striking differences in their cell type‐specific expression in glial cells. Specifically, all oligodendrocytes express NCoR1, but only a subset express SMRT. In addition, NCoR1, but not SMRT, was detected in a subset of astrocytes and in the microglia. These novel observations are corroborated by single cell transcriptomics and emphasize how NCoR1 and SMRT may contribute to distinct biological functions, suggesting an exclusive role of NCoR1 in innate immune responses in the brain.

• #### Cytoarchitecture and myeloarchitecture of the entorhinal cortex of the common marmoset monkey (Callithrix jacchus)

We provide a detailed analysis of the cytoarchitecture, myeloarchitecture and neurochemical considerations about the organization of the entorhinal cortex in the common marmoset (Callithrix jacchus). Variations of the basic lamination patterns permit the delineation of six different areas in the Entorhinal cortex.

## Abstract

The entorhinal cortex (EC) is associated with impaired cognitive function such as in the case of Alzheimer's disease, Parkinson's disease and Huntington's disease. The present study provides a detailed analysis of the cytoarchitectural and myeloarchitectural organization of the EC in the common marmoset Callithrix jacchus. Data were collected using Nissl and fiber stained preparations, supplemented with acetylcholinesterase and parvalbumin immunohistochemistry. The EC layers and subfields in the marmoset seem to be architectonically similar to those that have been proposed in nonhuman primates and humans to date; however, slight differences could be revealed using the present techniques. Throughout its rostrocaudal length, the entorhinal cortex presents a clear six‐layered pattern. The entorhinal cortex is divided into six fields, named mainly in accordance to their rostrocaudal and mediolateral positions. At rostral levels, the neurons tend to be organized in patches that are surrounded by large, thick, radially oriented bundles of fibers, and the deep layers are poorly developed. At caudal levels, the divisions are more laminated in appearance. AChE staining at the borders of adjacent fields are consistent with the changes in layering revealed in Nissl‐stained sections, of which the lateral regions of the EC display denser AChE staining than that of the medial banks. PV immunoreactivity was found in the labeled somata, dendrites, and axons in all layers and subdivisions. Additionally, we distinguished three subtypes of PV‐immunoreactive neurons: multipolar, bipolar and spherical‐shaped neurons, based on the shape of the somata and the disposition of the dendrites.

• #### Reorganization of longitudinal compartments in the laterally protruding paraflocculus of the postnatal mouse cerebellum

The paraflocculus (PFl), neighbored by the flocculus (Fl) and copula pyramidis (Cop), forms remarkable protrusion between postnatal Days 1 and 7 (P1, P7) in the mouse cerebellum. The paravermal compartment of pcdh10+ Purkinje cells (arrowheads) migrate laterally to become accommodated within the laterally oriented striped compartmentalization in the bulb‐shaped paraflocculus.

## Abstract

The paraflocculus and the neighboring smaller flocculus form a remarkable protrusion in the ventrolateral aspect of the mouse cerebellum, in which the longitudinal compartments are conspicuously oriented perpendicularly to the sagittal plane. The developmental process of such anatomical arrangements in these lobules has not been fully clarified. Here, we used the genetic tractability of pcdh10‐lacZ knock‐in (OL‐KO), IP 3 R1‐nls‐lacZ transgenic (1NM13) and Gpr26cre‐Ai9‐AldocV mice to track the development of compartments and examined local longitudinal orientation of Purkinje cells within the paraflocculus and flocculus. We observed a distinct pcdh10‐positive (pcdh10+) compartment in the flocculus, whereas the paraflocculus and other lobules had a continuous paravermal pcdh10+ compartment, in the embryonic OL‐KO cerebellum. During the first postnatal week, the parafloccular pcdh10+ compartment shifted laterally to the most lateral edge in the caudal part of the protruding paraflocculus. Although the most medial edge of the parafloccular pcdh10+ compartment remained in the nonprotruding part of the paraflocculus, it was disrupted from the originally continuous pcdh10+ compartment in the copula pyramidis. The local longitudinal orientation changed gradually along with the mediolateral extent of the copula pyramidis, almost becoming perpendicular to the sagittal plane in the laterally connected paraflocculus in the adult cerebellum. This rotational change in orientation was derived from the short U‐shaped embryonic cerebellum, in which the surfaces of the flocculus and paraflocculus were oriented laterally. These results indicated that the peculiar compartmental organization of the paraflocculus originates from the embryonic common hemispheric compartmental organization and shaped by the significant reorganization process in the first postnatal week.

• #### Hippocampal oscillatory dynamics and sleep atonia are altered in an animal model of fibromyalgia: Implications in the search for biomarkers

Monoamine depletion by reserpine has evidenced to induce pain and depression in rats, two comorbid symptoms in fibromyalgia patients. In this study, we have tested if also sleep disorders appear following monoamine depletion, mimicking also this key symptom of the disease. We found a disruption of the normal sleep patterns, together with increased motor activity during sleep, as well as a loss of the hierarchical oscillatory coupling. These alterations can explain muscular pain and cognitive disturbances also present in fibromyalgia patients. Our results support that reserpine injection could provide a useful model also to mimic sleep alterations as well as to search for new oscillatory biomarkers in fibromyalgia.

## Abstract

The pathogenesis of fibromyalgia is still unknown. Core symptoms include pain, depression, and sleep disturbances with high comorbidity, suggesting alterations in the monoaminergic system as a common origin of this disease. The reserpine‐induced myalgia (RIM) model lowers pain thresholds and produces depressive‐like symptoms. The present work aims to evaluate temporal dynamics in the oscillatory profiles and motor activity during sleep in this model and to evaluate if the model mimics the sleep disorders that occur in fibromyalgia patients. Hippocampal and electromyogram activity were recorded in chronically implanted rats. Following 3 days of basal recordings, reserpine was administered on three consecutive days to achieve the RIM. Postreserpine recordings were taken on alternate days for 21 days. Reserpine induced changes in the sleep architecture with more transitions between states, and a different pattern between the administration period and postreserpine weeks. Administration days were characterized by a larger amount of rapid eyes movement sleep with dominant theta waves without atonia. Following the reserpinization, theta oscillations were always more fragmented and with lower frequency. On the postreserpine days, sleep was dominated by slow‐wave sleep with fast intrusions and reduced hierarchical coupling with spindles and ripples. Simultaneous electromyography recordings also showed muscle twitches during sleep and the dissociation of theta activity and muscle atonia. Abnormally high slow waves, alpha/delta intrusions, frequent transitions, and muscle twitches are common traits in fibromyalgia. Therefore, our analyses support the validity of the RIM model to study sleep disorders in fibromyalgia, and provide new insights into the research of oscillographic biomarkers.

• #### Heterogeneous vestibulocerebellar mossy fiber projections revealed by single axon reconstruction in the mouse

Here, we report the morphology of single vestibulocerebellar axons originating from the medial vestibular nucleus (MVN) in mice. Three identified groups (red, blue, and green) of axons which projected differently to the vestibular nuclei and to the nodulus (X) and flocculus (Fl) indicated functionally distinct heterogeneous populations of vestibulocerebellar neurons.

## Abstract

A significant population of neurons in the vestibular nuclei projects to the cerebellum as mossy fibers (MFs) which are involved in the control and adaptation of posture, eye‐head movements, and autonomic function. However, little is known about their axonal projection patterns. We studied the morphology of single axons of medial vestibular nucleus (MVN) neurons as well as those originating from primary afferents, by labeling with biotinylated dextran amine (BDA). MVN axons (n = 35) were classified into three types based on their major predominant termination patterns. The Cbm‐type terminated only in the cerebellum (15 axons), whereas others terminated in the cerebellum and contralateral vestibular nuclei (cVN/Cbm‐type, 13 axons), or in the cerebellum and ipsilateral vestibular nuclei (iVN/Cbm‐type, 7 axons). Cbm‐ and cVN/Cbm‐types mostly projected to the nodulus and uvula without any clear relationship with longitudinal stripes in these lobules. They were often bilateral, and sometimes sent branches to the flocculus and to other vermal lobules. Also, the iVN/Cbm‐type projected mainly to the ipsilateral nodulus. Neurons of these types of axons showed different distribution within the MVN. The number of MF terminals of some vestibulocerebellar axons, iVN/Cbm‐type axons in particular, and primary afferent axons were much smaller than observed in previously studied MF axons originating from major precerebellar nuclei and the spinal cord. The results demonstrated that a heterogeneous population of MVN neurons provided divergent MF inputs to the cerebellum. The cVN/Cbm‐ and iVN/Cbm‐types indicate that some excitatory neuronal circuits within the vestibular nuclei supply their collaterals to the vestibulocerebellum as MFs.

• #### Expression and distribution of trophoblast glycoprotein in the mouse retina

Trophoblast glycoprotein (TPBG) is a leucine‐rich repeat glycoprotein with an intracellular PDZ‐binding motif that is localized to the dendrites and axon terminals of retinal rod bipolar cells and in the cell body and dendrites of an uncharacterized amacrine cell. Immunofluorescent labeling of TPBG in rod bipolar cells is significantly reduced in the TRPM1 knockout retina, yet total retinal TPBG is constant. This suggests that antibody access may be blocked in certain activity states, possibly by TPBG binding to a PDZ protein in a light‐ or phosphorylation‐dependent manner.

## Abstract

We recently identified the leucine‐rich repeat (LRR) adhesion protein, trophoblast glycoprotein (TPBG), as a novel PKCα‐dependent phosphoprotein in retinal rod bipolar cells (RBCs). Since TPBG has not been thoroughly examined in the retina, this study characterizes the localization and expression patterns of TPBG in the developing and adult mouse retina using two antibodies, one against the N‐terminal LRR domain and the other against the C‐terminal PDZ‐interacting motif. Both antibodies labeled RBC dendrites in the outer plexiform layer and axon terminals in the IPL, as well as a putative amacrine cell with their cell bodies in the inner nuclear layer (INL) and a dense layer in the middle of the inner plexiform layer (IPL). In live transfected HEK293 cells, TPBG was localized to the plasma membrane with the N‐terminal LRR domain facing the extracellular space. TPBG immunofluorescence in RBCs was strongly altered by the loss of TRPM1 in the adult retina, with significantly less dendritic and axon terminal labeling in TRPM1 knockout compared to wild type, despite no change in total TPBG detected by immunoblotting. During retinal development, TPBG expression increases dramatically just prior to eye opening with a time course closely correlated with that of TRPM1 expression. In the retina, LRR proteins have been implicated in the development and maintenance of functional bipolar cell synapses, and TPBG may play a similar role in RBCs.

## Objective

There is much controversy about the neurobiological mechanisms underlying the effects of sleep‐disordered breathing on the brain. The aim of this study was to investigate the association between markers of sleep‐related hypoxemia and brain anatomy.

## Methods

We used data from a large‐scale cohort from the general population (n = 775, 50.6% males, age range = 45–86 years, mean age = 60.3 ± 9.9) that underwent full polysomnography and brain MRI to correlate respiratory variables with regional brain volume estimates.

## Results

After adjusting for age, gender, and cardiovascular risk factors, only mean oxygen saturation during sleep was associated with bilateral volume of hippocampus (right: p = 0.001; left: p < 0.001), thalamus (right: p < 0.001; left: p < 0.001), putamen (right: p = 0.001; left: p = 0.001) and angular gyrus (right: p = 0.011; left: p = 0.001). We observed the same relationship in left hemispheric amygdala (p = 0.010), caudate (p = 0.008), inferior frontal gyrus (p = 0.004) and supramarginal gyrus (p = 0.003). The other respiratory variables ‐ lowest oxygen saturation, % of sleep time with oxygen saturation < 90%, apnea‐hypopnea index and oxygen desaturation index ‐ did not show any significant association with brain volumes.

## Interpretation

Lower mean oxygen saturation during sleep was associated with atrophy of cortical and subcortical brain areas known for high sensitivity to oxygen supply. Their vulnerability to hypoxemia may contribute to behavioral phenotype and cognitive decline in patients with sleep‐disordered breathing.

in Annals of Neurology on March 28, 2020 01:40 PM.

## Objective

Dominant optic atrophy (DOA) is the most common inherited optic neuropathy with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed.

## Methods

We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted NGS or whole‐exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient‐derived fibroblasts.

## Results

Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance while the others were sporadic, including de novo mutations. Biallelic mutations were found in three probands with severe syndromic optic neuropathy, acting as recessive or phenotype‐modifier variants. All the DOA‐associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28‐associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA‐associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28‐associated AFG3L2 mutations. Patients' fibroblasts showed an abnormal OPA1 processing, with accumulation of the fission‐inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells.

## Interpretation

This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscore the pivotal role of OPA1 and its processing in the pathogenesis of DOA.

in Annals of Neurology on March 28, 2020 01:40 PM.

• #### A model of tuberculosis clustering in low incidence countries reveals more transmission in the United Kingdom than the Netherlands between 2010 and 2015

by Ellen Brooks-Pollock, Leon Danon, Hester Korthals Altes, Jennifer A. Davidson, Andrew M. T. Pollock, Dick van Soolingen, Colin Campbell, Maeve K. Lalor

Tuberculosis (TB) remains a public health threat in low TB incidence countries, through a combination of reactivated disease and onward transmission. Using surveillance data from the United Kingdom (UK) and the Netherlands (NL), we demonstrate a simple and predictable relationship between the probability of observing a cluster and its size (the number of cases with a single genotype). We demonstrate that the full range of observed cluster sizes can be described using a modified branching process model with the individual reproduction number following a Poisson lognormal distribution. We estimate that, on average, between 2010 and 2015, a TB case generated 0.41 (95% CrI 0.30,0.60) secondary cases in the UK, and 0.24 (0.14,0.48) secondary cases in the NL. A majority of cases did not generate any secondary cases. Recent transmission accounted for 39% (26%,60%) of UK cases and 23%(13%,37%) of NL cases. We predict that reducing UK transmission rates to those observed in the NL would result in 538(266,818) fewer cases annually in the UK. In conclusion, while TB in low incidence countries is strongly associated with reactivated infections, we demonstrate that recent transmission remains sufficient to warrant policies aimed at limiting local TB spread.

in PLoS Computational Biology on March 27, 2020 09:00 PM.

• #### Comparative study of population genomic approaches for mapping colony-level traits

by Shani Inbar, Pnina Cohen, Tal Yahav, Eyal Privman

Social insect colonies exhibit colony-level phenotypes such as social immunity and task coordination, which are produced by the individual phenotypes. Mapping the genetic basis of such phenotypes requires associating the colony-level phenotype with the genotypes in the colony. In this paper, we examine alternative approaches to DNA extraction, library construction, and sequencing for genome wide association studies (GWAS) of colony-level traits using a population sample of Cataglyphis niger ants. We evaluate the accuracy of allele frequency estimation from sequencing a pool of individuals (pool-seq) from each colony using either whole-genome sequencing or reduced representation genomic sequencing. Based on empirical measurement of the experimental noise in sequenced DNA pools, we show that reduced representation pool-seq is drastically less accurate than whole-genome pool-seq. Surprisingly, normalized pooling of samples did not result in greater accuracy than un-normalized pooling. Subsequently, we evaluate the power of the alternative approaches for detecting quantitative trait loci (QTL) of colony-level traits by using simulations that account for an environmental effect on the phenotype. Our results can inform experimental designs and enable optimizing the power of GWAS depending on budget, availability of samples and research goals. We conclude that for a given budget, sequencing un-normalized pools of individuals from each colony provides optimal QTL detection power.

in PLoS Computational Biology on March 27, 2020 09:00 PM.

• #### What is replication?

by Brian A. Nosek, Timothy M. Errington

Credibility of scientific claims is established with evidence for their replicability using new data. According to common understanding, replication is repeating a study’s procedure and observing whether the prior finding recurs. This definition is intuitive, easy to apply, and incorrect. We propose that replication is a study for which any outcome would be considered diagnostic evidence about a claim from prior research. This definition reduces emphasis on operational characteristics of the study and increases emphasis on the interpretation of possible outcomes. The purpose of replication is to advance theory by confronting existing understanding with new evidence. Ironically, the value of replication may be strongest when existing understanding is weakest. Successful replication provides evidence of generalizability across the conditions that inevitably differ from the original study; Unsuccessful replication indicates that the reliability of the finding may be more constrained than recognized previously. Defining replication as a confrontation of current theoretical expectations clarifies its important, exciting, and generative role in scientific progress.

in PLoS Biology on March 27, 2020 09:00 PM.

• #### Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice

by Bo Xia, Xiao Chen Shi, Bao Cai Xie, Meng Qing Zhu, Yan Chen, Xin Yi Chu, Guo He Cai, Min Liu, Shi Zhen Yang, Grant A. Mitchell, Wei Jun Pang, Jiang Wei Wu

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora–derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.

in PLoS Biology on March 27, 2020 09:00 PM.

• #### Combating antiscience: Are we preparing for the 2020s?

by Peter J. Hotez

In the last half of the 2010s, we saw an upswing in antiscience movements and unprecedented attacks on scientists in the United States and elsewhere. All indications suggest that this trend will not slow or reverse anytime soon, and it is now increasingly apparent that it will fall to the scientists themselves to respond, engage a skeptical public, and lead the defense of science. Accordingly, we must recognize opportunities to both reorganize science doctoral and postdoctoral training and incentivize senior scientists as a means to establish a new ecosystem for science public engagement. Such activities may become essential if the assaults on our profession continue or expand. Today, the commitment of young scientists to public service is at an all-time high. However, we must work quickly to capture that enthusiasm and channel it into a social good, lest we lose this opportunity. Potentially, open-access publishers could play a central role.

in PLoS Biology on March 27, 2020 09:00 PM.

• #### This is real

in Science Express TOC RSS Feed on March 27, 2020 05:52 PM.

• #### Targeted gene silencing in vivo by platelet membrane-coated metal-organic framework nanoparticles

Small interfering RNA (siRNA) is a powerful tool for gene silencing that has been used for a wide range of biomedical applications, but there are many challenges facing its therapeutic use in vivo. Here, we report on a platelet cell membrane–coated metal-organic framework (MOF) nanodelivery platform for the targeted delivery of siRNA in vivo. The MOF core is capable of high loading yields, and its pH sensitivity enables endosomal disruption upon cellular uptake. The cell membrane coating provides a natural means of biointerfacing with disease substrates. It is shown that high silencing efficiency can be achieved in vitro against multiple target genes. Using a murine xenograft model, significant antitumor targeting and therapeutic efficacy are observed. Overall, the biomimetic nanodelivery system presented here provides an effective means of achieving gene silencing in vivo and could be used to expand the applicability of siRNA across a range of disease-relevant applications.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Four-wave mixing of topological edge plasmons in graphene metasurfaces

We study topologically protected four-wave mixing (FWM) interactions in a plasmonic metasurface consisting of a periodic array of nanoholes in a graphene sheet, which exhibits a wide topological bandgap at terahertz frequencies upon the breaking of time reversal symmetry by a static magnetic field. We demonstrate that due to the significant nonlinearity enhancement and large life time of graphene plasmons in specific configurations, a net gain of FWM interaction of plasmonic edge states located in the topological bandgap can be achieved with a pump power of less than 10 nW. In particular, we find that the effective nonlinear edge-waveguide coefficient is about ~= 1.1 x 1013 W–1 m–1, i.e., more than 10 orders of magnitude larger than that of commonly used, highly nonlinear silicon photonic nanowires. These findings could pave a new way for developing ultralow-power-consumption, highly integrated, and robust active photonic systems at deep-subwavelength scale for applications in quantum communications and information processing.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Light-triggered topological programmability in a dynamic covalent polymer network

Dynamic covalent polymer networks exhibit unusual adaptability while maintaining the robustness of conventional covalent networks. Typically, their network topology is statistically nonchangeable, and their material properties are therefore nonprogrammable. By introducing topological heterogeneity, we demonstrate a concept of topology isomerizable network (TIN) that can be programmed into many topological states. Using a photo-latent catalyst that controls the isomerization reaction, spatiotemporal manipulation of the topology is realized. The overall result is that the network polymer can be programmed into numerous polymers with distinctive and spatially definable (thermo-) mechanical properties. Among many opportunities for practical applications, the unique attributes of TIN can be explored for use as shape-shifting structures, adaptive robotic arms, and fracture-resistant stretchable devices, showing a high degree of design versatility. The TIN concept enriches the design of polymers, with potential expansion into other materials with variations in dynamic covalent chemistries, isomerizable topologies, and programmable macroscopic properties.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### A novel physical mechanism of liquid flow slippage on a solid surface

Viscous liquids often exhibit flow slippage on solid walls. The occurrence of flow slippage has a large impact on the liquid transport and the resulting energy dissipation, which are crucial for many applications. It is natural to expect that slippage takes place to reduce the dissipation. However, (i) how the density fluctuation is affected by the presence of the wall and (ii) how slippage takes place through forming a gas layer remained elusive. Here, we report possible answers to these fundamental questions: (i) Density fluctuation is intrinsically enhanced near the wall even in a quiescent state irrespective of the property of wall, and (ii) it is the density dependence of the viscosity that destabilizes the system toward gas-layer formation under shear flow. Our scenario of shear-induced gas-phase formation provides a natural physical explanation for wall slippage of liquid flow, covering the slip length ranging from a microscopic (nanometers) to macroscopic (micrometers) scale.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Extreme cavity expansion in soft solids: Damage without fracture

Cavitation is a common damage mechanism in soft solids. Here, we study this using a phase separation technique in stretched, elastic solids to controllably nucleate and grow small cavities by several orders of magnitude. The ability to make stable cavities of different sizes, as well as the huge range of accessible strains, allows us to systematically study the early stages of cavity expansion. Cavities grow in a scale-free manner, accompanied by irreversible bond breakage that is distributed around the growing cavity rather than being localized to a crack tip. Furthermore, cavities appear to grow at constant driving pressure. This has strong analogies with the plasticity that occurs surrounding a growing void in ductile metals. In particular, we find that, although elastomers are normally considered as brittle materials, small-scale cavity expansion is more like a ductile process. Our results have broad implications for understanding and controlling failure in soft solids.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Nonreciprocal transport in gate-induced polar superconductor SrTiO3

Polar conductors/superconductors with Rashba-type spin-orbit interaction are potential material platforms for quantum transport and spintronic functionalities. One of their inherent properties is the nonreciprocal transport, where the rightward and leftward currents become inequivalent, reflecting spatial inversion/time-reversal symmetry breaking. Such a rectification effect originating from the polar symmetry has been recently observed at interfaces or bulk Rashba semiconductors, while its mechanism in a polar superconductor remains elusive. Here, we report the nonreciprocal transport in gate-induced two-dimensional superconductor SrTiO3, which is a Rashba superconductor candidate. In addition to the gigantic enhancement of nonreciprocal signals in the superconducting fluctuation region, we found kink and sharp peak structures around critical temperatures, which reflect the crossover behavior from the paraconductivity origin to the vortex origin, based on a microscopic theory. The present result proves that the nonreciprocal transport is a powerful tool for investigating the interfacial/polar superconductors without inversion symmetry, where rich exotic features are theoretically prognosticated.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Soft crystal martensites: An in situ resonant soft x-ray scattering study of a liquid crystal martensitic transformation

Liquid crystal blue phases (BPs) are three-dimensional soft crystals with unit cell sizes orders of magnitude larger than those of classic, atomic crystals. The directed self-assembly of BPs on chemically patterned surfaces uniquely enables detailed in situ resonant soft x-ray scattering measurements of martensitic phase transformations in these systems. The formation of twin lamellae is explicitly identified during the BPII-to-BPI transformation, further corroborating the martensitic nature of this transformation and broadening the analogy between soft and atomic crystal diffusionless phase transformations to include their strain-release mechanisms.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Ultra-large electric field-induced strain in potassium sodium niobate crystals

Electromechanical coupling in piezoelectric materials allows direct conversion of electrical energy into mechanical energy and vice versa. Here, we demonstrate lead-free (KxNa1–x)NbO3 single crystals with an ultrahigh large-signal piezoelectric coefficient d33* of 9000 pm V–1, which is superior to the highest value reported in state-of-the-art lead-based single crystals (~2500 pm V–1). The enhanced electromechanical properties in our crystals are realized by an engineered compositional gradient in the as-grown crystal, allowing notable reversible non-180° domain wall motion. Moreover, our crystals exhibit temperature-insensitive strain performance within the temperature range of 25°C to 125°C. The enhanced temperature stability of the response also allows the materials to be used in a wider range of applications that exceed the temperature limits of current lead-based piezoelectric crystals.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Twist again: Dynamically and reversibly controllable chirality in liquid crystalline elastomer microposts

Photoresponsive liquid crystalline elastomers (LCEs) constitute ideal actuators for soft robots because their light-induced macroscopic shape changes can be harnessed to perform specific articulated motions. Conventional LCEs, however, do not typically exhibit complex modes of bending and twisting necessary to perform sophisticated maneuvers. Here, we model LCE microposts encompassing side-chain mesogens oriented along a magnetically programmed nematic director, and azobenzene cross-linkers, which determine the deformations of illuminated posts. On altering the nematic director orientation from vertical to horizontal, the post’s bending respectively changes from light-seeking to light-avoiding. Moreover, both modeling and subsequent experiments show that with the director tilted at 45°, the initially achiral post reversibly twists into a right- or left-handed chiral structure, controlled by the angle of incident light. We exploit this photoinduced chirality to design "chimera" posts (encompassing two regions with distinct director orientations) that exhibit simultaneous bending and twisting, mimicking motions exhibited by the human musculoskeletal system.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Two-photon quantum interference and entanglement at 2.1 {mu}m

Quantum-enhanced optical systems operating within the 2- to 2.5-μm spectral region have the potential to revolutionize emerging applications in communications, sensing, and metrology. However, to date, sources of entangled photons have been realized mainly in the near-infrared 700- to 1550-nm spectral window. Here, using custom-designed lithium niobate crystals for spontaneous parametric down-conversion and tailored superconducting nanowire single-photon detectors, we demonstrate two-photon interference and polarization-entangled photon pairs at 2090 nm. These results open the 2- to 2.5-μm mid-infrared window for the development of optical quantum technologies such as quantum key distribution in next-generation mid-infrared fiber communication systems and future Earth-to-satellite communications.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Demonstration of a third-order hierarchy of topological states in a three-dimensional acoustic metamaterial

Classical wave systems have constituted an excellent platform for emulating complex quantum phenomena, such as demonstrating topological phenomena in photonics and acoustics. Recently, a new class of topological states localized in more than one dimension of a D-dimensional system, referred to as higher-order topological (HOT) states, has been reported, offering an even more versatile platform to confine and control classical radiation and mechanical motion. Here, we design and experimentally study a 3D topological acoustic metamaterial supporting third-order (0D) topological corner states along with second-order (1D) edge states and first-order (2D) surface states within the same topological bandgap, thus establishing a full hierarchy of nontrivial bulk polarization–induced states in three dimensions. The assembled 3D topological metamaterial represents the acoustic analog of a pyrochlore lattice made of interconnected molecules, and is shown to exhibit topological bulk polarization, leading to the emergence of boundary states.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Three dimensions, two microscopes, one code: Automatic differentiation for x-ray nanotomography beyond the depth of focus limit

Conventional tomographic reconstruction algorithms assume that one has obtained pure projection images, involving no within-specimen diffraction effects nor multiple scattering. Advances in x-ray nanotomography are leading toward the violation of these assumptions, by combining the high penetration power of x-rays, which enables thick specimens to be imaged, with improved spatial resolution that decreases the depth of focus of the imaging system. We describe a reconstruction method where multiple scattering and diffraction effects in thick samples are modeled by multislice propagation and the 3D object function is retrieved through iterative optimization. We show that the same proposed method works for both full-field microscopy and for coherent scanning techniques like ptychography. Our implementation uses the optimization toolbox and the automatic differentiation capability of the open-source deep learning package TensorFlow, demonstrating a straightforward way to solve optimization problems in computational imaging with flexibility and portability.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### High-frequency rectification via chiral Bloch electrons

Rectification is a process that converts electromagnetic fields into a direct current. Such a process underlies a wide range of technologies such as wireless communication, wireless charging, energy harvesting, and infrared detection. Existing rectifiers are mostly based on semiconductor diodes, with limited applicability to small-voltage or high-frequency inputs. Here, we present an alternative approach to current rectification that uses the intrinsic electronic properties of quantum crystals without using semiconductor junctions. We identify a previously unknown mechanism for rectification from skew scattering due to the inherent chirality of itinerant electrons in time-reversal invariant but inversion-breaking materials. Our calculations reveal large, tunable rectification effects in graphene multilayers and transition metal dichalcogenides. Our work demonstrates the possibility of realizing high-frequency rectifiers by rational material design and quantum wave function engineering.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Chemical boundary engineering: A new route toward lean, ultrastrong yet ductile steels

For decades, grain boundary engineering has proven to be one of the most effective approaches for tailoring the mechanical properties of metallic materials, although there are limits to the fineness and types of microstructures achievable, due to the rapid increase in grain size once being exposed to thermal loads (low thermal stability of crystallographic boundaries). Here, we deploy a unique chemical boundary engineering (CBE) approach, augmenting the variety in available alloy design strategies, which enables us to create a material with an ultrafine hierarchically heterogeneous microstructure even after heating to high temperatures. When applied to plain steels with carbon content of only up to 0.2 weight %, this approach yields ultimate strength levels beyond 2.0 GPa in combination with good ductility (>20%). Although demonstrated here for plain carbon steels, the CBE design approach is, in principle, applicable also to other alloys.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Atomic-scale insights into the interfacial instability of superlubricity in hydrogenated amorphous carbon films

The origin of instability or even disappearance of the superlubricity state in hydrogenated amorphous carbon (a-C:H) film in the presence of oxygen or water molecules is still controversial. Here, we address this puzzle regarding the tribochemical activities of sliding interfaces at the nanoscale. The results reveal that gaseous oxygen molecules disable the antifriction capacity of a-C:H by surface dehydrogenation of tribo-affected hydrocarbon bonds. In comparison, oxygen incorporation into the hydrocarbon matrix induces the formation of a low-density surface shear band, owing to which the friction state depends on the oxygen content. High friction of a-C:H film in humid environment originates from the "tumor-like" heterogeneous structures as formed in the highly oxidized tribolayer. Notably, an appropriate doping of silicon can completely shield the moisture effect by forming a silica-like tribolayer. These outcomes shed substantial lights upon the roadmap for achieving robust superlubricity of carbon films in a wide range of environments.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Chiral superconductivity in the alternate stacking compound 4Hb-TaS2

Van der Waals materials offer unprecedented control of electronic properties via stacking of different types of two-dimensional materials. A fascinating frontier, largely unexplored, is the stacking of strongly correlated phases of matter. We study 4Hb-TaS2, which naturally realizes an alternating stacking of 1T-TaS2 and 1H-TaS2 structures. The former is a well-known Mott insulator, which has recently been proposed to host a gapless spin-liquid ground state. The latter is a superconductor known to also host a competing charge density wave state. This raises the question of how these two components affect each other when stacked together. We find a superconductor with a Tc of 2.7 Kelvin and anomalous properties, of which the most notable one is a signature of time-reversal symmetry breaking, abruptly appearing at the superconducting transition. This observation is consistent with a chiral superconducting state.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Mitigating cavitation erosion using biomimetic gas-entrapping microtextured surfaces (GEMS)

Cavitation refers to the formation and collapse of vapor bubbles near solid boundaries in high-speed flows, such as ship propellers and pumps. During this process, cavitation bubbles focus fluid energy on the solid surface by forming high-speed jets, leading to damage and downtime of machinery. In response, numerous surface treatments to counteract this effect have been explored, including perfluorinated coatings and surface hardening, but they all succumb to cavitation erosion eventually. Here, we report on biomimetic gas-entrapping microtextured surfaces (GEMS) that robustly entrap air when immersed in water regardless of the wetting nature of the substrate. Crucially, the entrapment of air inside the cavities repels cavitation bubbles away from the surface, thereby preventing cavitation damage. We provide mechanistic insights by treating the system as a potential flow problem of a multi-bubble system. Our findings present a possible avenue for mitigating cavitation erosion through the application of inexpensive and environmentally friendly materials.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Generation of multiple ultrastable optical frequency combs from an all-fiber photonic platform

Frequency-stabilized optical frequency combs have created many high-precision applications. Accurate timing, ultralow phase noise, and narrow linewidth are prerequisites for achieving the ultimate performance of comb-based systems. Ultrastable cavity-based comb-noise stabilization methods have enabled sub–10–15-level frequency instability. However, these methods are complex and alignment sensitive, and their use has been mostly confined to advanced metrology laboratories. Here, we have established a simple, compact, alignment-free, and potentially low-cost all-fiber photonics-based stabilization method for generating multiple ultrastable combs. The achieved performance includes 1-femtosecond timing jitter, few times 10–15-level frequency instability, and <5-hertz linewidth, rivalling those of cavity-stabilized combs. This method features flexibility in configuration: As a representative example, two combs were stabilized with 180-hertz repetition rate difference and ~1-hertz relative linewidth and could be used as an ultrastable, octave-spanning dual-comb spectroscopy source. The demonstrated method constitutes a mechanically robust and reconfigurable tool for generating multiple ultrastable combs suitable for field applications.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Cooperative deformation in high-entropy alloys at ultralow temperatures

High-entropy alloys exhibit exceptional mechanical properties at cryogenic temperatures, due to the activation of twinning in addition to dislocation slip. The coexistence of multiple deformation pathways raises an important question regarding how individual deformation mechanisms compete or synergize during plastic deformation. Using in situ neutron diffraction, we demonstrate the interaction of a rich variety of deformation mechanisms in high-entropy alloys at 15 K, which began with dislocation slip, followed by stacking faults and twinning, before transitioning to inhomogeneous deformation by serrations. Quantitative analysis showed that the cooperation of these different deformation mechanisms led to extreme work hardening. The low stacking fault energy plus the stable face-centered cubic structure at ultralow temperatures, enabled by the high-entropy alloying, played a pivotal role bridging dislocation slip and serration. Insights from the in situ experiments point to the role of entropy in the design of structural materials with superior properties.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Scaling, rotation, and channeling behavior of helical and skyrmion spin textures in thin films of Te-doped Cu2OSeO3

Topologically nontrivial spin textures such as vortices, skyrmions, and monopoles are promising candidates as information carriers for future quantum information science. Their controlled manipulation including creation and annihilation remains an important challenge toward practical applications and further exploration of their emergent phenomena. Here, we report controlled evolution of the helical and skyrmion phases in thin films of multiferroic Te-doped Cu2OSeO3 as a function of material thickness, dopant, temperature, and magnetic field using in situ Lorentz phase microscopy. We report two previously unknown phenomena in chiral spin textures in multiferroic Cu2OSeO3: anisotropic scaling and channeling with a fixed-Q state. The skyrmion channeling effectively suppresses the recently reported second skyrmion phase formation at low temperature. Our study provides a viable way toward controlled manipulation of skyrmion lattices, envisaging chirality-controlled skyrmion flow circuits and enabling precise measurement of emergent electromagnetic induction and topological Hall effects in skyrmion lattices.

in Science Advances current issue on March 27, 2020 05:50 PM.

• #### Chronic Activation of Gp1 mGluRs Leads to Distinct Refinement of Neural Network Activity through Non-Canonical p53 and Akt Signaling

Abstract

Group 1 metabotropic glutamate receptors (Gp1 mGluRs), including mGluR1 and mGluR5, are critical regulators for neuronal and synaptic plasticity. Dysregulated Gp1 mGluR signaling is observed with various neurologic disorders, including Alzheimer’s disease, Parkinson’s disease, epilepsy, and autism spectrum disorders (ASDs). It is well established that acute activation of Gp1 mGluRs leads to elevation of neuronal intrinsic excitability and long-term synaptic depression. However, it remains unknown how chronic activation of Gp1 mGluRs can affect neural activity and what molecular mechanisms might be involved. In the current study, we employed a multielectrode array (MEA) recording system to evaluate neural network activity of primary mouse cortical neuron cultures. We demonstrated that chronic activation of Gp1 mGluRs leads to elevation of spontaneous spike frequency while burst activity and cross-electrode synchronization are maintained at the baseline. We further showed that these neural network properties are achieved through proteasomal degradation of Akt that is dependent on the tumor suppressor p53. Genetically knocking down p53 disrupts the elevation of spontaneous spike frequency and alters the burst activity and cross-electrode synchronization following chronic activation of Gp1 mGluRs. Importantly, these deficits can be restored by pharmacologically inhibiting Akt to mimic inactivation of Akt mediated by p53. Together, our findings reveal the effects of chronic activation of Gp1 mGluRs on neural network activity and identify a unique signaling pathway involving p53 and Akt for these effects. Our data can provide insights into constitutively active Gp1 mGluR signaling observed in many neurologic and psychiatric disorders.

in eNeuro current issue on March 27, 2020 04:30 PM.

• #### Cellular basis of bitter-driven aversive behaviors in Drosophila larva

ABSTRACT

Feeding, a critical behavior for survival, consists of a complex series of behavioral steps. In Drosophila larvae, the initial steps of feeding are food choice, during which the quality of a potential food source is judged, and ingestion, during which the selected food source is ingested into the digestive tract. It remains unclear whether these steps employ different mechanisms of neural perception. Here, we provide insight into the two initial steps of feeding in Drosophila larva. We find that substrate choice and ingestion are determined by independent circuits at the cellular level. First, we took 22 candidate bitter compounds and examined their influence on choice preference and ingestion behavior. Interestingly, certain bitter tastants caused different responses in choice and ingestion, suggesting distinct mechanisms of perception. We further provide evidence that certain gustatory receptor neurons (GRNs) in the external terminal organ are involved in determining choice preference, and a pair of larval pharyngeal GRNs is involved in mediating both avoidance and suppression of ingestion. Our results show that feeding behavior is coordinated by a multi-step regulatory process employing relatively independent neural elements. These findings are consistent with a model in which distinct sensory pathways act as modulatory circuits controlling distinct subprograms during feeding.

Significance Statement Here we provide molecular and cellular evidence that feeding can indeed be dissected into two distinct steps, namely the determination of preference and initiation of ingestion. We find that bitter tastants have individual characteristics when negatively affecting feeding, with most chemicals negatively affecting both preference and ingestion, and certain chemicals negatively affecting only preference. These characteristics are due to different sensory neurons being responsible for detecting different bitter compounds. The different sensory neurons appear to act in relatively independent neural circuits to differentially affect the multiple steps that comprise feeding.

in RSS PAP on March 27, 2020 04:30 PM.

• #### Differential effects of nasal inflammation and odor deprivation on layer-specific degeneration of the mouse olfactory bulb

Abstract

Harmful environmental agents cause nasal inflammation, and chronic nasal inflammation induces a loss of olfactory sensory neurons and reversible atrophy of the olfactory bulb (OB). Here, we investigated the mechanisms underlying this inflammation-induced OB atrophy by histologically and biochemically comparing the OB changes in mouse models of nasal inflammation and odor deprivation. In addition, we examined whether odor stimulation is necessary for OB recovery from atrophy. One group of adult male C57BL/6 mice was administered lipopolysaccharide unilaterally for 10 weeks to induce nasal inflammation (control animals received saline), and a second group received unilateral naris closures for 10 weeks of odor deprivation. The OBs atrophied in both models, but odor deprivation shrank the glomerular, external plexiform, mitral, and granule cell layers, whereas the olfactory nerve, glomerular, and external plexiform layers atrophied as a result of nasal inflammation. Additionally, nasal inflammation, but not odor deprivation, caused neuroinflammation in the OB, inducing glial activation and elevated expression of IL–1β and TNFα. After 10 weeks of nasal inflammation, mice were housed for another 10 weeks with no additional treatment or with unilateral naris closure. Nasal inflammation and glial activation subsided in both groups, but glomerular and external plexiform layers recovered only in those with no additional treatment. Our findings demonstrate that nasal inflammation and odor deprivation differentially induce layer-specific degeneration in the OB, that loss of olfactory sensory neuron activity rather than neuroinflammation is a major cause of inflammation-induced OB atrophy, and that odor stimulation is required for OB recovery from atrophy.

Significance Chronic nasal inflammation causes a loss of olfactory sensory neurons and atrophy of the olfactory bulb, which recovers when inflammation subsides. To reveal the mechanisms underlying inflammation-induced olfactory bulb atrophy, we compared the histological and biochemical changes in olfactory bulbs in mouse models of nasal inflammation and odor deprivation. In addition, we examined whether odor stimulation was required for the recovery of the olfactory bulb from atrophy. Our findings revealed that nasal inflammation and odor deprivation differentially induce layer-specific degeneration in the olfactory bulb, that loss of olfactory sensory neuron activity rather than neuroinflammation is a major cause of inflammation-induced olfactory bulb atrophy, and that odor stimulation is required for the olfactory bulb to recover from atrophy.

in RSS PAP on March 27, 2020 04:30 PM.

• #### Accelerated Analog Neuromorphic Computing. (arXiv:2003.11996v1 [cs.NE])

This paper presents the concepts behind the BrainScales (BSS) accelerated analog neuromorphic computing architecture. It describes the second-generation BrainScales-2 (BSS-2) version and its most recent in-silico realization, the HICANN-X Application Specific Integrated Circuit (ASIC), as it has been developed as part of the neuromorphic computing activities within the European Human Brain Project (HBP). While the first generation is implemented in an 180nm process, the second generation uses 65nm technology. This allows the integration of a digital plasticity processing unit, a highly-parallel micro processor specially built for the computational needs of learning in an accelerated analog neuromorphic systems. The presented architecture is based upon a continuous-time, analog, physical model implementation of neurons and synapses, resembling an analog neuromorphic accelerator attached to build-in digital compute cores. While the analog part emulates the spike-based dynamics of the neural network in continuous-time, the latter simulates biological processes happening on a slower time-scale, like structural and parameter changes. Compared to biological time-scales, the emulation is highly accelerated, i.e. all time-constants are several orders of magnitude smaller than in biology. Programmable ion channel emulation and inter-compartmental conductances allow the modeling of nonlinear dendrites, back-propagating action-potentials as well as NMDA and Calcium plateau potentials. To extend the usability of the analog accelerator, it also supports vector-matrix multiplication. Thereby, BSS-2 supports inference of deep convolutional networks as well as local-learning with complex ensembles of spiking neurons within the same substrate.

in q-bio.NC updates on arXiv.org on March 27, 2020 01:30 AM.

• #### Thalamo-cortical spiking model of incremental learning combining perception, context and NREM-sleep-mediated noise-resilience. (arXiv:2003.11859v1 [q-bio.NC])

The brain exhibits capabilities of fast incremental learning from few noisy examples, as well as the ability to associate similar memories in autonomously-created categories and to combine contextual hints with sensory perceptions. Together with sleep, these mechanisms are thought to be key components of many high-level cognitive functions. Yet, little is known about the underlying processes and the specific roles of different brain states. In this work, we exploited the combination of context and perception in a thalamo-cortical model based on a soft winner-take-all circuit of excitatory and inhibitory spiking neurons. After calibrating this model to express awake and deep-sleep states with features comparable with biological measures, we demonstrate the model capability of fast incremental learning from few examples, its resilience when proposed with noisy perceptions and contextual signals, and an improvement in visual classification after sleep due to induced synaptic homeostasis and association of similar memories.

in q-bio.NC updates on arXiv.org on March 27, 2020 01:30 AM.

• #### Neural encoding and interpretation for high-level visual cortices based on fMRI using image caption features. (arXiv:2003.11797v1 [cs.CV])

On basis of functional magnetic resonance imaging (fMRI), researchers are devoted to designing visual encoding models to predict the neuron activity of human in response to presented image stimuli and analyze inner mechanism of human visual cortices. Deep network structure composed of hierarchical processing layers forms deep network models by learning features of data on specific task through big dataset. Deep network models have powerful and hierarchical representation of data, and have brought about breakthroughs for visual encoding, while revealing hierarchical structural similarity with the manner of information processing in human visual cortices. However, previous studies almost used image features of those deep network models pre-trained on classification task to construct visual encoding models. Except for deep network structure, the task or corresponding big dataset is also important for deep network models, but neglected by previous studies. Because image classification is a relatively fundamental task, it is difficult to guide deep network models to master high-level semantic representations of data, which causes into that encoding performance for high-level visual cortices is limited. In this study, we introduced one higher-level vision task: image caption (IC) task and proposed the visual encoding model based on IC features (ICFVEM) to encode voxels of high-level visual cortices. Experiment demonstrated that ICFVEM obtained better encoding performance than previous deep network models pre-trained on classification task. In addition, the interpretation of voxels was realized to explore the detailed characteristics of voxels based on the visualization of semantic words, and comparative analysis implied that high-level visual cortices behaved the correlative representation of image content.

in q-bio.NC updates on arXiv.org on March 27, 2020 01:30 AM.

• #### Cognitive computation using neural representations of time and space in the Laplace domain. (arXiv:2003.11668v1 [q-bio.NC])

Memory for the past makes use of a record of what happened when---a function over past time. Time cells in the hippocampus and temporal context cells in the entorhinal cortex both code for events as a function of past time, but with very different receptive fields. Time cells in the hippocampus can be understood as a compressed estimate of events as a function of the past. Temporal context cells in the entorhinal cortex can be understood as the Laplace transform of that function, respectively. Other functional cell types in the hippocampus and related regions, including border cells, place cells, trajectory coding, splitter cells, can be understood as coding for functions over space or past movements or their Laplace transforms. More abstract quantities, like distance in an abstract conceptual space or numerosity could also be mapped onto populations of neurons coding for the Laplace transform of functions over those variables. Quantitative cognitive models of memory and evidence accumulation can also be specified in this framework allowing constraints from both behavior and neurophysiology. More generally, the computational power of the Laplace domain could be important for efficiently implementing data-independent operators, which could serve as a basis for neural models of a very broad range of cognitive computations.

in q-bio.NC updates on arXiv.org on March 27, 2020 01:30 AM.

• #### R-FORCE: Robust Learning for Random Recurrent Neural Networks. (arXiv:2003.11660v1 [q-bio.NC])

Random Recurrent Neural Networks (RRNN) are the simplest recurrent networks to model and extract features from sequential data. The simplicity however comes with a price; RRNN are known to be susceptible to diminishing/exploding gradient problem when trained with gradient-descent based optimization. To enhance robustness of RRNN, alternative training approaches have been proposed. Specifically, FORCE learning approach proposed a recursive least squares alternative to train RRNN and was shown to be applicable even for the challenging task of target-learning, where the network is tasked with generating dynamic patterns with no guiding input. While FORCE training indicates that solving target-learning is possible, it appears to be effective only in a specific regime of network dynamics (edge-of-chaos). We thereby investigate whether initialization of RRNN connectivity according to a tailored distribution can guarantee robust FORCE learning. We are able to generate such distribution by inference of four generating principles constraining the spectrum of the network Jacobian to remain in stability region. This initialization along with FORCE learning provides a robust training method, i.e., Robust-FORCE (R-FORCE). We validate R-FORCE performance on various target functions for a wide range of network configurations and compare with alternative methods. Our experiments indicate that R-FORCE facilitates significantly more stable and accurate target-learning for a wide class of RRNN. Such stability becomes critical in modeling multi-dimensional sequences as we demonstrate on modeling time-series of human body joints during physical movements.

in q-bio.NC updates on arXiv.org on March 27, 2020 01:30 AM.

• #### Transfer between long-term and short-term memory using Conceptors. (arXiv:2003.11640v1 [cs.NE])

We introduce a recurrent neural network model of working memory combining short-term and long-term components. e short-term component is modelled using a gated reservoir model that is trained to hold a value from an input stream when a gate signal is on. e long-term component is modelled using conceptors in order to store inner temporal patterns (that corresponds to values). We combine these two components to obtain a model where information can go from long-term memory to short-term memory and vice-versa and we show how standard operations on conceptors allow to combine long-term memories and describe their effect on short-term memory.

in q-bio.NC updates on arXiv.org on March 27, 2020 01:30 AM.

• #### Human information processing in complex networks. (arXiv:1906.00926v2 [physics.soc-ph] UPDATED)

Humans communicate using systems of interconnected stimuli or concepts -- from language and music to literature and science -- yet it remains unclear how, if at all, the structure of these networks supports the communication of information. Although information theory provides tools to quantify the information produced by a system, traditional metrics do not account for the inefficient ways that humans process this information. Here we develop an analytical framework to study the information generated by a system as perceived by a human observer. We demonstrate experimentally that this perceived information depends critically on a system's network topology. Applying our framework to several real networks, we find that they communicate a large amount of information (having high entropy) and do so efficiently (maintaining low divergence from human expectations). Moreover, we show that such efficient communication arises in networks that are simultaneously heterogeneous, with high-degree hubs, and clustered, with tightly-connected modules -- the two defining features of hierarchical organization. Together, these results suggest that many communication networks are constrained by the pressures of information transmission, and that these pressures select for specific structural features.

in q-bio.NC updates on arXiv.org on March 27, 2020 01:30 AM.

• #### Publisher Correction: Forms of prediction in the nervous system

Nature Reviews Neuroscience, Published online: 27 March 2020; doi:10.1038/s41583-020-0296-0

Publisher Correction: Forms of prediction in the nervous system

in Nature Reviews Neuroscience - Issue - nature.com science feeds on March 27, 2020 12:00 AM.

• #### An egg timing circuit

Nature Reviews Neuroscience, Published online: 27 March 2020; doi:10.1038/s41583-020-0294-2

The neural circuitry that coordinates mating and egg laying in female flies is identified.

in Nature Reviews Neuroscience - Issue - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Improved squeezing of noise

Nature Photonics, Published online: 27 March 2020; doi:10.1038/s41566-020-0616-y

Two articles in Nature Photonics demonstrate how Einstein–Podolsky–Rosen entanglement can reduce quantum noise in gravitational-wave interferometers.

in Nature Photonics - Issue - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Towards low-loss photonics

Nature Photonics, Published online: 27 March 2020; doi:10.1038/s41566-020-0615-z

Low-loss composite systems based on integrating transition metal dichalcogenide monolayers on silicon nitride waveguides exhibit an unexpectedly strong electro-refractive response at near-infrared wavelengths, which is crucial for optical communications.

in Nature Photonics - Issue - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Superfast photon counting

Nature Photonics, Published online: 27 March 2020; doi:10.1038/s41566-020-0614-0

The news that superconducting nanowire detectors can detect single photons with a timing precision of just a few picoseconds will benefit applications ranging from sensing to quantum communications.

in Nature Photonics - Issue - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Ultrashort electron probe opportunities

Nature Photonics, Published online: 27 March 2020; doi:10.1038/s41566-020-0613-1

Technology borrowed from electron accelerator and beam physics looks set to push the performance of ultrafast-electron-diffraction-based pump–probe studies of matter.

in Nature Photonics - Issue - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Shrimp eye scattering

Nature Photonics, Published online: 27 March 2020; doi:10.1038/s41566-020-0611-3

Shrimp eye scattering

in Nature Photonics - Issue - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Adar RNA editing-dependent and -independent effects are required for brain and innate immune functions in Drosophila

Nature Communications, Published online: 27 March 2020; doi:10.1038/s41467-020-15435-1

Human RNA editing enzymes ADAR1 and ADAR2 are required for innate immune functions and neurological functions, respectively. Here, the authors show that Drosophila Adar has both innate immune and brain functions, despite being the homolog of mammalian ADAR2.

in Nature Communications - current - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Ultrafast 27 GHz cutoff frequency in vertical WSe2 Schottky diodes with extremely low contact resistance

Nature Communications, Published online: 27 March 2020; doi:10.1038/s41467-020-15419-1

Two-dimensional materials show promise for 5G wireless communication applications. Here, the authors report vertical Schottky diodes based on thick mechanically exfoliated WSe2 flakes having low ohmic contact resistance of 50 Ω and ultrafast cutoff frequency of 27 GHz.

in Nature Communications - current - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Atomically dispersed cobalt catalyst anchored on nitrogen-doped carbon nanosheets for lithium-oxygen batteries

Nature Communications, Published online: 27 March 2020; doi:10.1038/s41467-020-15416-4

The performance of Li-O2 batteries is largely determined by the oxygen electrocatalytic reactions at the cathode. Here, the authors report cobalt single-atom catalysts anchored on carbon nanosheets. The design improves oxygen redox kinetics and enables good electrochemical performance.

in Nature Communications - current - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain

Nature Communications, Published online: 27 March 2020; doi:10.1038/s41467-020-15411-9

Human microglia present unique features; therefore, chimeric mouse models can enhance modelling of human microglia response in health and disease. Here, the authors show that hiPSC-derived mature microglia developed in the mouse brain, retain their identity and respond to demyelination.

in Nature Communications - current - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Structural basis for the increased processivity of D-family DNA polymerases in complex with PCNA

Nature Communications, Published online: 27 March 2020; doi:10.1038/s41467-020-15392-9

Replicative DNA polymerases (DNAPs) have evolved the ability to copy the genome with high processivity and fidelity. Here, the authors present a cryo-EM structure of the DNA-bound PolD–PCNA complex from Pyrococcus abyssi to reveal the molecular basis for the interaction and cooperativity between a replicative DNAP and PCNA.

in Nature Communications - current - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Atomic-level handedness determination of chiral crystals using aberration-corrected scanning transmission electron microscopy

Nature Communications, Published online: 27 March 2020; doi:10.1038/s41467-020-15388-5

Handedness or chirality determination of crystals has always been challenging for chemists, biologists and materials scientists. Here, the authors report a method for handedness determination by atomic-resolution imaging using Cs-corrected scanning transmission electron microscopy.

in Nature Communications - current - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Integrative differential expression and gene set enrichment analysis using summary statistics for scRNA-seq studies

Nature Communications, Published online: 27 March 2020; doi:10.1038/s41467-020-15298-6

Differential expression (DE) and gene set enrichment (GSE) analysis tend to be carried out separately. Here, the authors present iDEA (integrative Differential expression and gene set Enrichment Analysis) for the analysis of scRNAseq data which uses a Baysian approach to jointly model DE and GSE for improved power in both tasks.

in Nature Communications - current - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Heat health risk assessment in Philippine cities using remotely sensed data and social-ecological indicators

Nature Communications, Published online: 27 March 2020; doi:10.1038/s41467-020-15218-8

Evaluating the heat risk among city dwellers is important. Here, the authors assessed the heat risk in Philippine cities using remote sensing data and social-ecological indicators and found that the cities at high or very high risk are found in Metro Manila, where levels of heat hazard and exposure are high.

in Nature Communications - current - nature.com science feeds on March 27, 2020 12:00 AM.

• #### Daily briefing: A radical proposal to infect healthy people with the coronavirus to test vaccines

Nature, Published online: 27 March 2020; doi:10.1038/d41586-020-00953-1

A ‘human challenge’ study would involve exposing perhaps 100 healthy young people to the coronavirus and seeing whether those who get the vaccine escape infection. Plus: UK prime minister Boris Johnson has tested positive for coronavirus, and Neanderthals enjoyed a nice bit of fish.

in Nature on March 27, 2020 12:00 AM.

• #### Coronapod: Old treatments and new hopes

Nature, Published online: 27 March 2020; doi:10.1038/d41586-020-00940-6

Could blood plasma from coronavirus survivors be an effective short-term treatment for patients?

in Nature on March 27, 2020 12:00 AM.

• #### University pays millions to researchers who sued over sexual-harassment allegations

Nature, Published online: 27 March 2020; doi:10.1038/d41586-020-00937-1

The US$9.4-million settlement ends a lawsuit brought over the way the University of Rochester in New York handled allegations against cognitive scientist Florian Jaeger. in Nature on March 27, 2020 12:00 AM. • #### Why a landmark treaty to stop ocean biopiracy could stymie research Nature, Published online: 27 March 2020; doi:10.1038/d41586-020-00912-w Several cancer and HIV drugs have come from marine organisms, but scientists worry that a new agreement to save species could hinder some research. in Nature on March 27, 2020 12:00 AM. • #### Tens of thousands of scientists are redeploying to fight coronavirus Nature, Published online: 27 March 2020; doi:10.1038/d41586-020-00905-9 As labs shut down around the world, researchers are finding creative ways to donate their time, supplies and expertise. in Nature on March 27, 2020 12:00 AM. • #### Rare ozone hole opens over Arctic — and it’s big Nature, Published online: 27 March 2020; doi:10.1038/d41586-020-00904-w Cold temperatures and a strong polar vortex allowed chemicals to gnaw away at the protective ozone layer in the north. in Nature on March 27, 2020 12:00 AM. • #### Coronavirus papers: Viral proteins point to potential treatments Nature, Published online: 27 March 2020; doi:10.1038/d41586-020-00502-w A selection of the latest research on COVID-19. in Nature on March 27, 2020 12:00 AM. • #### Coronavirus latest: pandemic could have killed 40 million without any action Nature, Published online: 27 March 2020; doi:10.1038/d41586-020-00154-w Updates on the respiratory illness that has infected hundreds of thousands of people and killed several thousand. in Nature on March 27, 2020 12:00 AM. • #### A Practical Guide to Using CV Analysis for Determining the Locus of Synaptic Plasticity Long-term synaptic plasticity is widely believed to underlie learning and memory in the brain. Whether plasticity is primarily expressed pre- or postsynaptically has been the subject of considerable debate for many decades. More recently, it is generally agreed that the locus of plasticity depends on a number of factors, such as developmental stage, induction protocol, and synapse type. Since presynaptic expression alters not just the gain but also the short-term dynamics of a synapse, whereas postsynaptic expression only modifies the gain, the locus has fundamental implications for circuits dynamics and computations in the brain. It therefore remains crucial for our understanding of neuronal circuits to know the locus of expression of long-term plasticity. One classical method for elucidating whether plasticity is pre- or postsynaptically expressed is based on analysis of the coefficient of variation (CV), which serves as a measure of noise levels of synaptic neurotransmission. Here, we provide a practical guide to using CV analysis for the purposes of exploring the locus of expression of long-term plasticity, primarily aimed at beginners in the field. We provide relatively simple intuitive background to an otherwise theoretically complex approach as well as simple mathematical derivations for key parametric relationships. We list important pitfalls of the method, accompanied by accessible computer simulations to better illustrate the problems (downloadable from GitHub), and we provide straightforward solutions for these issues. in Frontiers in Synaptic Neuroscience on March 27, 2020 12:00 AM. • #### Phosphorylation-Dependent Regulation of Ca2+-Permeable AMPA Receptors During Hippocampal Synaptic Plasticity Experience-dependent learning and memory require multiple forms of plasticity at hippocampal and cortical synapses that are regulated by N-methyl-D-aspartate receptors (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (NMDAR, AMPAR). These plasticity mechanisms include long-term potentiation (LTP) and depression (LTD), which are Hebbian input-specific mechanisms that rapidly increase or decrease AMPAR synaptic strength at specific inputs, and homeostatic plasticity that globally scales-up or -down AMPAR synaptic strength across many or even all inputs. Frequently, these changes in synaptic strength are also accompanied by a change in the subunit composition of AMPARs at the synapse due to the trafficking to and from the synapse of receptors lacking GluA2 subunits. These GluA2-lacking receptors are most often GluA1 homomeric receptors that exhibit higher single-channel conductance and are Ca2+-permeable (CP-AMPAR). This review article will focus on the role of protein phosphorylation in regulation of GluA1 CP-AMPAR recruitment and removal from hippocampal synapses during synaptic plasticity with an emphasis on the crucial role of local signaling by the cAMP-dependent protein kinase (PKA) and the Ca2+calmodulin-dependent protein phosphatase 2B/calcineurin (CaN) that is coordinated by the postsynaptic scaffold protein A-kinase anchoring protein 79/150 (AKAP79/150). in Frontiers in Synaptic Neuroscience on March 27, 2020 12:00 AM. • #### The Requirement of Sox2 for the Spinal Cord Motor Neuron Development of Zebrafish Sex-determining region Y box 2 (Sox2), expressed in neural tissues, plays an important role as a transcription factor not only in the pluripotency and proliferation of neuronal cells but also in the opposite function of cell differentiation. Nevertheless, how Sox2 is linked to motor neuron development remains unknown. Here, we showed that Sox2 was localized in the motor neurons of spinal cord by in situ hybridization and cell separation, which acted as a positive regulator of motor neuron development. The deficiency of Sox2 in zebrafish larvae resulted in abnormal PMN development, including truncated but excessively branched CaP axons, loss of MiP, and increase of undifferentiated neuron cells. Importantly, transcriptome analysis showed that Sox2-depleted embryos caused many neurogenesis, axonogenesis, axon guidance, and differentiation-related gene expression changes, which further support the vital function of Sox2 in motor neuron development. Taken together, these data indicate that Sox2 plays a crucial role in the motor neuron development by regulating neuron differentiation and morphology of neuron axons. in Frontiers in Molecular Neuroscience on March 27, 2020 12:00 AM. • #### Predicting Long-Term After-Effects of Theta-Burst Stimulation on Supplementary Motor Network Through One-Session Response To understand the neural mechanism of repetitive transcranial magnetic stimulation (rTMS), the after-effects following one session or multiple days of stimulation have been widely investigated. However, the relation between the short-term effect (STE) and long-term effect (LTE) of rTMS is largely unknown. This study aims to explore whether the after-effects of 5-day rTMS on supplementary motor area (SMA) network could be predicted by one-session response. A primary cohort of 38 healthy participants underwent five daily sessions of real or sham continuous theta-burst stimulation (cTBS) on the left SMA. Resting-state functional magnetic resonance imaging (fMRI) data were acquired at the first (before and after the first stimulation) and sixth experimental day. The SMA connectivity changes after the first cTBS and after 5 days of stimulation were defined as STE and LTE, respectively. Compared to the baseline, significant STE and LTE were found in the bilateral paracentral gyrus (ParaCG) after real stimulation, suggesting shared neural correlates of short- and long-term stimulations. Region-of-interest analysis indicated that the resting-state functional connectivity between SMA and ParaCG increased after real stimulation, while no significant change was found after sham stimulation. Leave-one-out cross-validation indicated that the LTE in ParaCG could be predicted by the STE after real but not sham stimulations. In an independent cohort, the after-effects of rTMS on ParaCG and short- to long-term prediction were reproduced at the region-of-interest level. These imaging evidences indicate that one-session rTMS can aid to predict the regions responsive to long-term stimulation and the individualized response degree. in Frontiers in Neuroscience: Neural Technology on March 27, 2020 12:00 AM. • #### Deep Temporal Organization of fMRI Phase Synchrony Modes Promotes Large-Scale Disconnection in Schizophrenia Itinerant dynamics of the brain generates transient and recurrent spatiotemporal patterns in neuroimaging data. Characterizing metastable functional connectivity (FC) – particularly at rest and using functional magnetic resonance imaging (fMRI) – has shaped the field of dynamic functional connectivity (DFC). Mainstream DFC research relies on (sliding window) correlations to identify recurrent FC patterns. Recently, functional relevance of the instantaneous phase synchrony (IPS) of fMRI signals has been revealed using imaging studies and computational models. In the present paper, we identify the repertoire of whole-brain inter-network IPS states at rest. Moreover, we uncover a hierarchy in the temporal organization of IPS modes. We hypothesize that connectivity disorder in schizophrenia (SZ) is related to the (deep) temporal arrangement of large-scale IPS modes. Hence, we analyze resting-state fMRI data from 68 healthy controls (HC) and 51 SZ patients. Seven resting-state networks (and their sub-components) are identified using spatial independent component analysis. IPS is computed between subject-specific network time courses, using analytic signals. The resultant phase coupling patterns, across time and subjects, are clustered into eight IPS states. Statistical tests show that the relative expression and mean lifetime of certain IPS states have been altered in SZ. Namely, patients spend (45%) less time in a globally coherent state and a subcortical-centered state, and (40%) more time in states reflecting anticoupling within the cognitive control network, compared to the HC. Moreover, the transition profile (between states) reveals a deep temporal structure, shaping two metastates with distinct phase synchrony profiles. A metastate is a collection of states such that within-metastate transitions are more probable than across. Remarkably, metastate occupation balance is altered in SZ, in favor of the less synchronous metastate that promotes disconnection across networks. Furthermore, the trajectory of IPS patterns is less efficient, less smooth, and more restricted in SZ subjects, compared to the HC. Finally, a regression analysis confirms the diagnostic value of the defined IPS measures for SZ identification, highlighting the distinctive role of metastate proportion. Our results suggest that the proposed IPS features may be used for classification studies and for characterizing phase synchrony modes in other (clinical) populations. in Frontiers in Neuroscience: Brain Imaging Methods on March 27, 2020 12:00 AM. • #### Quantitative Identification of Major Depression Based on Resting-State Dynamic Functional Connectivity: A Machine Learning Approach Introduction Developing a machine learning-based approach which could provide quantitative identification of major depressive disorder (MDD) is essential for the diagnosis and intervention of this disorder. However, the performances of traditional algorithms using static functional connectivity (SFC) measures were unsatisfactory. In the present work, we exploit the hidden information embedded in dynamic functional connectivity (DFC) and developed an accurate and objective image-based diagnosis system for MDD. Methods MRI images were collected from 99 participants including 56 healthy controls and 43 MDD patients. DFC was calculated using a sliding-window algorithm. A non-linear support vector machine (SVM) approach was then used with the DFC matrices as features to distinguish MDD patients from healthy controls. The spatiotemporal characteristics of the most discriminative features were then investigated. Results The area under the curve (AUC) of the SVM classifier with DFC measures reached 0.9913, while this value is only 0.8685 for the algorithm using SFC measures. Spatially, the most discriminative 28 connections distributed in the visual network (VN), somatomotor network (SMN), dorsal attention network (DAN), ventral attention network (VAN), limbic network (LN), frontoparietal network (FPN), and default mode network (DMN), etc. Notably, a large portion of these connections were associated with the FPN, DMN, and VN. Temporally, the most discriminative connections transited from the cortex to deeper regions. Conclusion The results clearly suggested that DFC is superior to SFC and provide a reliable quantitative identification method for MDD. Our findings may furnish a better understanding of the neural mechanisms of MDD as well as improve accurate diagnosis and early intervention of this disorder. in Frontiers in Neuroscience: Brain Imaging Methods on March 27, 2020 12:00 AM. • #### Associations Between Individual Differences in Mathematical Competencies and Surface Anatomy of the Adult Brain Previously conducted structural magnetic resonance imaging (MRI) studies on the neuroanatomical correlates of mathematical abilities and competencies have several methodological limitations. Besides small sample sizes, the majority of these studies have employed voxel-based morphometry (VBM)—a method that, although it is easy to implement, has some major drawbacks. Taking this into account, the current study is the first to investigate in a large sample of typically developed adults the associations between mathematical abilities and variations in brain surface structure by using surface-based morphometry (SBM). SBM is a method that also allows the investigation of brain morphometry by avoiding the pitfalls of VBM. Eighty-nine young adults were tested with a large battery of psychometric tests to measure mathematical competencies in four different areas: (1) simple arithmetic; (2) complex arithmetic; (3) higher-order mathematics; and (4) numerical intelligence. Also, we asked participants for their mathematics grades for their final school exams. Inside the MRI scanner, we collected high-resolution T1-weighted anatomical images from each subject. SBM analyses were performed with the computational anatomy toolbox (CAT12) and indices for cortical thickness, for cortical surface complexity, for gyrification, and sulcal depth were calculated. Further analyses revealed associations between: (1) the cortical surface complexity of the right superior temporal gyrus and numerical intelligence; (2) the depth of the right central sulcus and adults’ ability to solve complex arithmetic problems; and (3) the depth of the left parieto-occipital sulcus and adults’ higher-order mathematics competence. Interestingly, no relationships with previously reported brain regions were observed, thus, suggesting the importance of similar research to confirm the role of the brain regions found in this study. in Frontiers in Human Neuroscience on March 27, 2020 12:00 AM. • #### Event-Related Potentials to Changes in Sound Intensity Demonstrate Alterations in Brain Function Related to Depression and Aging Measures of the brain’s automatic electrophysiological responses to sounds represent a potential tool for identifying age- and depression-related neural markers. However, these markers have rarely been studied related to aging and depression within one study. Here, we investigated auditory event-related potentials (ERPs) in the brain that may show different alterations related to aging and depression. We used an oddball condition employing changes in sound intensity to investigate: (i) sound intensity dependence; (ii) sensory gating; and (iii) change detection, all within a single paradigm. The ERPs of younger (18–40 years) and older (62–80 years) depressed female participants and age-matched non-depressed participants were measured. Intensity dependence was examined as the difference between N1 responses to repeated high- and low-intensity sounds, sensory gating as N1 responses to rare and repeated sounds, and change detection as indexed by the mismatch negativity (MMN). We found that intensity dependence was greater in older participants than younger ones, indicating effects related to aging but not to depression. For sensory gating, we found depression- and age-related alterations as increased N1 responses. No group differences were found for MMN. Although a sensory gating deficit was expected in older adults, this study is the first to demonstrate age-related overexcitability in sound intensity dependency. The results indicate that automatic brain responses to sound intensity changes are suitable for studying age- and depression-related neural markers but may not be sensitive enough to differentiate the effects of aging and depression. in Frontiers in Human Neuroscience on March 27, 2020 12:00 AM. • #### Man’s Pursuit of Meaning: Unexpected Termination Bolsters One’s Autonomous Motivation in an Irrelevant Ensuing Activity Meaningfulness has been suggested as one of the fundamental psychological needs, as one would actively pursue meaning in both his/her work life and personal life. Previous studies consistently showed that a lack of meaning in work would reduce one’s autonomous motivation in the current job, which is the motivation to engage in self-determined activities driven by one’s own interests or personal beliefs. However, researchers overlooked the fact that in work settings, it is not uncommon that people work on multiple tasks in a row. As a result, the cross-task effect of work meaningfulness remains understudied. Based on the meaning maintenance model (MMM) and the suggested fluid compensation strategy, we predicted that the disappearance of the meaning of work may induce a compensatory response and thus enhance one’s autonomous motivation in an irrelevant ensuing activity. To test this hypothesis, we invited participants to work on an encyclopedic knowledge quiz in Session 1 and a StopWatch (SW) task in Session 2. A between-subject design was adopted. While participants in the control group successfully completed their tasks in Session 1, those in the experimental group encountered unexpected program quits by the end of the quiz, and their previous efforts suddenly became futile and meaningless. Electroencephalography was recorded during the experiment to measure reward positivity (RewP). In Session 2, a more pronounced RewP in the win–lose difference wave was observed in the experimental group in contrast to the control group, suggesting that the disappearance of the meaning of work enhanced one’s autonomous motivation in an irrelevant activity that follows. Therefore, results of this study provided preliminary electrophysiological evidence for one’s pursuit of meaning and the compensation effect induced by the disappearance of the meaning of work. in Frontiers in Human Neuroscience on March 27, 2020 12:00 AM. • #### Proceedings of the Seventh Annual Deep Brain Stimulation Think Tank: Advances in Neurophysiology, Adaptive DBS, Virtual Reality, Neuroethics and Technology The Seventh Annual Deep Brain Stimulation (DBS) Think Tank held on September 8th of 2019 addressed the most current: (1) use and utility of complex neurophysiological signals for development of adaptive neurostimulation to improve clinical outcomes; (2) Advancements in recent neuromodulation techniques to treat neuropsychiatric disorders; (3) New developments in optogenetics and DBS; (4) The use of augmented Virtual reality (VR) and neuromodulation; (5) commercially available technologies; and (6) ethical issues arising in and from research and use of DBS. These advances serve as both “markers of progress” and challenges and opportunities for ongoing address, engagement, and deliberation as we move to improve the functional capabilities and translational value of DBS. It is in this light that these proceedings are presented to inform the field and initiate ongoing discourse. As consistent with the intent, and spirit of this, and prior DBS Think Tanks, the overarching goal is to continue to develop multidisciplinary collaborations to rapidly advance the field and ultimately improve patient outcomes. in Frontiers in Human Neuroscience on March 27, 2020 12:00 AM. • #### Resveratrol Preincubation Enhances the Therapeutic Efficacy of hUC-MSCs by Improving Cell Migration and Modulating Neuroinflammation Mediated by MAPK Signaling in a Mouse Model of Alzheimer’s Disease Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are promising for the treatment of Alzheimer’s disease (AD). However, their low rate of migration and survival in the brain limit their clinical applicability. This study is designed to improve the therapeutic potential of hUC-MSCs by preincubating them with resveratrol, a natural polyphenol capable of regulating cell destiny. Herein, we demonstrate that resveratrol preincubation enhances the migration of hUC-MSCs in vitro, as well as their survival and homing into the hippocampus of AD mice in vivo. Moreover, resveratrol-primed MSCs were better able to inhibit amyloid-β peptide (Aβ) deposition, Tau hyperphosphorylation, and oxidative stress, all while improving learning and memory. Notably, we found that hUC-MSCs inhibited neuroinflammation by reacting with astrocytes and microglial cells and suppressing mitogen-activated protein kinases (MAPKs), extracellular signal kinases (ERK), p38 kinases (p38), and c-Jun N-terminal kinases (JNK) signaling pathways in the hippocampus of AD mice. Furthermore, resveratrol pretreatment enhanced these effects. Conclusively, the current study revealed that resveratrol preconditioning protected hUC-MSCs against the hostile microenvironment characteristic of AD and enhanced their viability and homing into the brain of AD mice. The use of resveratrol-pretreated hUC-MSCs is thereby proposed to be a promising therapy for AD. in Frontiers in Cellular Neuroscience on March 27, 2020 12:00 AM. • #### Deficits in Motor Performance, Neurotransmitters and Synaptic Plasticity in Elderly and Experimental Parkinsonian Mice Lacking GPR37 Parkinson’s disease (PD) etiology is attributed to aging and the progressive neurodegeneration of dopamine (DA) neurons of substantia nigra pars compacta (SNc). GPR37 is an orphan G-protein Coupled Receptor (GPCR) that is linked to the juvenile form of PD. In addition, misfolded GPR37 has been found in Lewy bodies. However, properly folded GPR37 found at the cell membrane appears to exert neuroprotection. In the present study we investigated the role of GPR37 in motor deficits due to aging or toxin-induced experimental parkinsonism. Elderly GPR37 knock out (KO) mice displayed hypolocomotion and worse fine movement performance compared to their WT counterparts. Striatal slice electrophysiology reveiled that GPR37 KO mice show profound decrease in long term potentiation (LTP) formation which is accompanied by an alteration in glutamate receptor subunit content. GPR37 KO animals exposed to intrastriatal 6-hydroxydopamine (6-OHDA) show poorer score in the behavioral cylinder test and more loss of the DA transporter (DAT) in striatum. The GPR37 KO striata exhibit a significant increase in GABA which is aggravated after DA depletion. Our data indicate that GPR37 KO mice have DA neuron deficit, enhanced striatal GABA levels and deficient corticostriatal LTP. They also respond stronger to 6-OHDA-induced neurotoxicity. Taken together, the data indicate that properly functional GPR37 may counteract aging processes and parkinsonism. in Frontiers in Ageing Neuroscience on March 27, 2020 12:00 AM. • #### Mitigating the impact of conference and travel cancellations on researchers’ futures The need to protect public health during the current COVID-19 pandemic has necessitated conference cancellations on an unprecedented scale. As the scientific community adapts to new working conditions, it is important to recognize that some of our actions may disproportionately affect early-career researchers and scientists from countries with limited research funding. We encourage all conference organizers, funders and institutions who are able to do so to consider how they can mitigate the unintended consequences of conference and travel cancellations and we provide seven recommendations for how this could be achieved. The proposed solutions may also offer long-term benefits for those who normally cannot attend conferences, and thus lead to a more equitable future for generations of researchers. in eLife on March 27, 2020 12:00 AM. • #### Unc-4 acts to promote neuronal identity and development of the take-off circuit in the Drosophila CNS The Drosophila ventral nerve cord (VNC) is composed of thousands of neurons born from a set of individually identifiable stem cells. The VNC harbors neuronal circuits required to execute key behaviors, such as flying and walking. Leveraging the lineage-based functional organization of the VNC, we investigated the developmental and molecular basis of behavior by focusing on lineage-specific functions of the homeodomain transcription factor, Unc-4. We found that Unc-4 functions in lineage 11A to promote cholinergic neurotransmitter identity and suppress the GABA fate. In lineage 7B, Unc-4 promotes proper neuronal projections to the leg neuropil and a specific flight-related take-off behavior. We also uncovered that Unc-4 acts peripherally to promote proprioceptive sensory organ development and the execution of specific leg-related behaviors. Through time-dependent conditional knock-out of Unc-4, we found that its function is required during development, but not in the adult, to regulate the above events. in eLife on March 27, 2020 12:00 AM. • #### A calibrated optogenetic toolbox of stable zebrafish opsin lines Optogenetic actuators with diverse spectral tuning, ion selectivity and kinetics are constantly being engineered providing powerful tools for controlling neural activity with subcellular resolution and millisecond precision. Achieving reliable and interpretable in vivo optogenetic manipulations requires reproducible actuator expression and calibration of photocurrents in target neurons. Here, we developed nine transgenic zebrafish lines for stable opsin expression and calibrated their efficacy in vivo. We first used high-throughput behavioural assays to compare opsin ability to elicit or silence neural activity. Next, we performed in vivo whole-cell electrophysiological recordings to quantify the amplitude and kinetics of photocurrents and test opsin ability to precisely control spiking. We observed substantial variation in efficacy, associated with differences in both opsin expression level and photocurrent characteristics, and identified conditions for optimal use of the most efficient opsins. Overall, our calibrated optogenetic toolkit will facilitate the design of controlled optogenetic circuit manipulations. in eLife on March 27, 2020 12:00 AM. • #### Stimulus salience determines defensive behaviors elicited by aversively conditioned serial compound auditory stimuli Assessing the imminence of threatening events using environmental cues enables proactive engagement of appropriate avoidance responses. The neural processes employed to anticipate event occurrence depend upon which cue properties are used to formulate predictions. In serial compound stimulus (SCS) conditioning in mice, repeated presentations of sequential tone (CS1) and white noise (CS2) auditory stimuli immediately prior to an aversive event (US) produces freezing and flight responses to CS1 and CS2, respectively (Fadok et al., 2017). Recent work reported that these responses reflect learned temporal relationships of CS1 and CS2 to the US (Dong et al., 2019). However, we find that frequency and sound pressure levels, not temporal proximity to the US, are the key factors underlying SCS-driven conditioned responses. Moreover, white noise elicits greater physiological and behavioral responses than tones even prior to conditioning. Thus, stimulus salience is the primary determinant of behavior in the SCS paradigm, and represents a potential confound in experiments utilizing multiple sensory stimuli. in eLife on March 27, 2020 12:00 AM. • #### Optimization of energy state transition trajectory supports the development of executive function during youth Executive function develops during adolescence, yet it remains unknown how structural brain networks mature to facilitate activation of the fronto-parietal system, which is critical for executive function. In a sample of 946 human youths (ages 8-23y) who completed diffusion imaging, we capitalized upon recent advances in linear dynamical network control theory to calculate the energetic cost necessary to activate the fronto-parietal system through the control of multiple brain regions given existing structural network topology. We found that the energy required to activate the fronto-parietal system declined with development, and the pattern of regional energetic cost predicts unseen individuals' brain maturity. Finally, energetic requirements of the cingulate cortex were negatively correlated with executive performance, and partially mediated the development of executive performance with age. Our results reveal a mechanism by which structural networks develop during adolescence to reduce the theoretical energetic costs of transitions to activation states necessary for executive function. in eLife on March 27, 2020 12:00 AM. • #### Reducing RSV hospitalisation in a lower-income country by vaccinating mothers-to-be and their households Respiratory syncytial virus is the leading cause of lower respiratory tract infection among infants. RSV is a priority for vaccine development. In this study, we investigate the potential effectiveness of a two-vaccine strategy aimed at mothers-to-be, thereby boosting maternally acquired antibodies of infants, and their household cohabitants, further cocooning infants against infection. We use a dynamic RSV transmission model which captures transmission both within households and communities, adapted to the changing demographics and RSV seasonality of a low-income country. Model parameters were inferred from past RSV hospitalisations, and forecasts made over a 10-year horizon. We find that a 50% reduction in RSV hospitalisations is possible if the maternal vaccine effectiveness can achieve 75 days of additional protection for newborns combined with a 75% coverage of their birth household co-inhabitants (∼7.5% population coverage). in eLife on March 27, 2020 12:00 AM. • #### Ten Simple Rules for organizing a non–real-time web conference by Ana Arnal, Irene Epifanio, Pablo Gregori, Vicente Martínez in PLoS Computational Biology on March 26, 2020 09:00 PM. • #### Ten simple rules for providing effective bioinformatics research support by Judit Kumuthini, Michael Chimenti, Sven Nahnsen, Alexander Peltzer, Rebone Meraba, Ross McFadyen, Gordon Wells, Deanne Taylor, Mark Maienschein-Cline, Jian-Liang Li, Jyothi Thimmapuram, Radha Murthy-Karuturi, Lyndon Zass Life scientists are increasingly turning to high-throughput sequencing technologies in their research programs, owing to the enormous potential of these methods. In a parallel manner, the number of core facilities that provide bioinformatics support are also increasing. Notably, the generation of complex large datasets has necessitated the development of bioinformatics support core facilities that aid laboratory scientists with cost-effective and efficient data management, analysis, and interpretation. In this article, we address the challenges—related to communication, good laboratory practice, and data handling—that may be encountered in core support facilities when providing bioinformatics support, drawing on our own experiences working as support bioinformaticians on multidisciplinary research projects. Most importantly, the article proposes a list of guidelines that outline how these challenges can be preemptively avoided and effectively managed to increase the value of outputs to the end user, covering the entire research project lifecycle, including experimental design, data analysis, and management (i.e., sharing and storage). In addition, we highlight the importance of clear and transparent communication, comprehensive preparation, appropriate handling of samples and data using monitoring systems, and the employment of appropriate tools and standard operating procedures to provide effective bioinformatics support. in PLoS Computational Biology on March 26, 2020 09:00 PM. • #### Seven quick tips for analysis scripts in neuroimaging by Marijn van Vliet in PLoS Computational Biology on March 26, 2020 09:00 PM. • #### Preregistration of exploratory research: Learning from the golden age of discovery by Ulrich Dirnagl Preregistration of study protocols and, in particular, Registered Reports are novel publishing formats that are currently gaining substantial traction. Besides rating the research question and soundness of methodology over outstanding significance of the results, they can help with antagonizing inadequate statistical power, selective reporting of results, undisclosed analytic flexibility, as well as publication bias. Preregistration works well when a clear hypothesis, primary outcome, and mode of analysis can be formulated. But is it also applicable and useful in discovery research, which develops theories and hypotheses, measurement techniques, and generates evidence that justifies further research? I will argue that only slight modifications are needed to harness the potential of preregistration and make exploratory research more trustworthy and useful. in PLoS Biology on March 26, 2020 09:00 PM. • #### Efficient, stable silicon tandem cells enabled by anion-engineered wide-bandgap perovskites Maximizing the power conversion efficiency (PCE) of perovskite-silicon tandem solar cells that can exceed the Shockley-Queisser single-cell limit requires a high performing, stable perovskite top cell with a wide band gap. We developed a stable perovskite solar cell with a band gap of ~1.7 electron volt that retained over 80% of its initial PCE of 20.7% after 1000 hours of continuous illumination. Anion engineering of phenethylammonium (PEA)-based two-dimensional (2D) additives was critical for controlling the structural and electrical properties of 2D passivation layers based on a PbI2-framework. The high PCE of 26.7% of a monolithic two-terminal wide gap perovskite/Si tandem solar cell was made possible by the ideal combination of spectral responses of the top and bottom cells. in Science Express TOC RSS Feed on March 26, 2020 05:48 PM. • #### Topological funneling of light Dissipation is a general feature of non-Hermitian systems. But rather than being an unavoidable nuisance, non-Hermiticity can be precisely controlled and, hence, used for sophisticated applications such as optical sensors with enhanced sensitivity. In our work, we implement a non-Hermitian photonic mesh lattice by tailoring the anisotropy of the inter-site coupling. The appearance of an interface results in a complete collapse of the entire eigenmode spectrum, leading to an exponential localization of all modes at the interface. As a consequence, any light field within the lattice travels toward this interface, irrespective of its shape and input position. Based on this topological phenomenon, dubbed "non-Hermitian skin effect," we demonstrate a highly efficient funnel for light. in Science Express TOC RSS Feed on March 26, 2020 05:48 PM. • #### Unconstrained genome targeting with near-PAMless engineered CRISPR-Cas9 variants Manipulation of DNA by CRISPR-Cas enzymes requires the recognition of a protospacer adjacent motif (PAM), limiting target site recognition to a subset of sequences. To remove this constraint, we engineered variants of Streptococcus pyogenes Cas9 (SpCas9) to eliminate the NGG PAM requirement. We developed a variant named SpG capable of targeting an expanded set of NGN PAMs, and further optimized this enzyme to develop a near-PAMless SpCas9 variant named SpRY (NRN>NYN PAMs). SpRY nuclease and base-editor variants can target almost all PAMs, exhibiting robust activities on a wide range of sites with NRN PAMs in human cells and lower but substantial activity on those with NYN PAMs. Using SpG and SpRY, we generated previously inaccessible disease-relevant genetic variants, supporting the utility of high-resolution targeting across genome editing applications. in Science Express TOC RSS Feed on March 26, 2020 05:48 PM. • #### Transcription polymerase-catalyzed emergence of novel RNA replicons Transcription polymerases can exhibit an unusual mode of regenerating certain RNA templates from RNA, yielding systems that can replicate and evolve with RNA as information carrier. Two classes of pathogenic RNAs (Hepatitis delta virus in animals and viroids in plants) are copied by host transcription polymerases. Using in vitro RNA replication by the transcription polymerase of T7 bacteriophage as an experimental model, we identify hundreds of new replicating RNAs, define three mechanistic hallmarks of replication (subterminal de novo initiation, RNA shape-shifting and interrupted rolling circle synthesis) and describe emergence from DNA seeds as a mechanism for the origin of novel RNA replicons. These results inform models for the origins and replication of naturally occurring RNA genetic elements and suggest a means by which diverse RNA populations could be propagated as hereditary material in cellular contexts. in Science Express TOC RSS Feed on March 26, 2020 05:47 PM. • #### Structure of a trapped radical transfer pathway within a ribonucleotide reductase holocomplex Ribonucleotide reductases (RNRs) are a diverse family of enzymes that are alone capable of generating 2'-deoxynucleotides de novo and are thus critical in DNA biosynthesis and repair. The nucleotide reduction reaction in all RNRs requires the generation of a transient active site thiyl radical, and in class I RNRs this process involves a long-range radical transfer between two subunits, α and β. Due to the transient subunit association, an atomic resolution structure of an active α2β2 RNR complex has been elusive. Here we use a doubly-substituted β2, E52Q/(2,3,5)-trifluorotyrosine122-β2 to trap wildtype-α2 in long-lived α2β2 complex. We report the structure of this complex by cryo-electron microscopy to 3.6-Å resolution, allowing for structural visualization of a 32-Å-long radical transfer pathway that affords RNR activity. in Science Express TOC RSS Feed on March 26, 2020 05:47 PM. • #### The historical roots of economic development This article reviews an emerging area of research within economics that seeks to better understand contemporary economic outcomes by taking a historical perspective. The field has established that many of the contemporary differences in comparative economic development have their roots in the distant past. The insights gained from this literature are not only of academic importance but also useful for thinking about policies that help to address global development moving forward. I provide examples of recent studies that have begun to take on this important next step in the literature by using insights gleaned from historical analyses to better understand policy and its optimal design. in Science current issue on March 26, 2020 05:40 PM. • #### Last Interglacial Iberian Neandertals as fisher-hunter-gatherers Marine food–reliant subsistence systems such as those in the African Middle Stone Age (MSA) were not thought to exist in Europe until the much later Mesolithic. Whether this apparent lag reflects taphonomic biases or behavioral distinctions between archaic and modern humans remains much debated. Figueira Brava cave, in the Arrábida range (Portugal), provides an exceptionally well preserved record of Neandertal coastal resource exploitation on a comparable scale to the MSA and dated to ~86 to 106 thousand years ago. The breadth of the subsistence base—pine nuts, marine invertebrates, fish, marine birds and mammals, tortoises, waterfowl, and hoofed game—exceeds that of regional early Holocene sites. Fisher-hunter-gatherer economies are not the preserve of anatomically modern people; by the Last Interglacial, they were in place across the Old World in the appropriate settings. in Science current issue on March 26, 2020 05:40 PM. • #### Flux-induced topological superconductivity in full-shell nanowires Hybrid semiconductor-superconductor nanowires have emerged as a promising platform for realizing topological superconductivity (TSC). Here, we present a route to TSC using magnetic flux applied to a full superconducting shell surrounding a semiconducting nanowire core. Tunneling into the core reveals a hard induced gap near zero applied flux, corresponding to zero phase winding, and a gapped region with a discrete zero-energy state around one applied flux quantum, corresponding to 2 phase winding. Theoretical analysis indicates that the winding of the superconducting phase can induce a transition to a topological phase supporting Majorana zero modes. Measured Coulomb blockade peak spacing around one flux quantum shows a length dependence that is consistent with the existence of Majorana modes at the ends of the nanowire. in Science current issue on March 26, 2020 05:40 PM. • #### Stepping up to leadership in Science current issue on March 26, 2020 05:40 PM. • #### Interglacial instability of North Atlantic Deep Water ventilation Disrupting North Atlantic Deep Water (NADW) ventilation is a key concern in climate projections. We use (sub)centennially resolved bottom water 13C records that span the interglacials of the last 0.5 million years to assess the frequency of and the climatic backgrounds capable of triggering large NADW reductions. Episodes of reduced NADW in the deep Atlantic, similar in magnitude to glacial events, have been relatively common and occasionally long-lasting features of interglacials. NADW reductions were triggered across the range of recent interglacial climate backgrounds, which demonstrates that catastrophic freshwater outburst floods were not a prerequisite for large perturbations. Our results argue that large NADW disruptions are more easily achieved than previously appreciated and that they occurred in past climate conditions similar to those we may soon face. in Science current issue on March 26, 2020 05:40 PM. • #### Peptide signaling for drought-induced tomato flower drop The premature abscission of flowers and fruits limits crop yield under environmental stress. Drought-induced flower drop in tomato plants was found to be regulated by phytosulfokine (PSK), a peptide hormone previously known for its growth-promoting and immune-modulating activities. PSK formation in response to drought stress depends on phytaspase 2, a subtilisin-like protease of the phytaspase subtype that generates the peptide hormone by aspartate-specific processing of the PSK precursor in the tomato flower pedicel. The mature peptide acts in the abscission zone where it induces expression of cell wall hydrolases that execute the abscission process. Our results provide insight into the molecular control of abscission as regulated by proteolytic processing to generate a small plant peptide hormone. in Science current issue on March 26, 2020 05:40 PM. • #### No consistent ENSO response to volcanic forcing over the last millennium The El Niño–Southern Oscillation (ENSO) shapes global climate patterns yet its sensitivity to external climate forcing remains uncertain. Modeling studies suggest that ENSO is sensitive to sulfate aerosol forcing associated with explosive volcanism but observational support for this effect remains ambiguous. Here, we used absolutely dated fossil corals from the central tropical Pacific to gauge ENSO’s response to large volcanic eruptions of the last millennium. Superposed epoch analysis reveals a weak tendency for an El Niño–like response in the year after an eruption, but this response is not statistically significant, nor does it appear after the outsized 1257 Samalas eruption. Our results suggest that those models showing a strong ENSO response to volcanic forcing may overestimate the size of the forced response relative to natural ENSO variability. in Science current issue on March 26, 2020 05:40 PM. • #### Ultrahigh-field 67Zn NMR reveals short-range disorder in zeolitic imidazolate framework glasses The structure of melt-quenched zeolitic imidazole framework (ZIF) glasses can provide insights into their glass-formation mechanism. We directly detected short-range disorder in ZIF glasses using ultrahigh-field zinc-67 solid-state nuclear magnetic resonance spectroscopy. Two distinct Zn sites characteristic of the parent crystals transformed upon melting into a single tetrahedral site with a broad distribution of structural parameters. Moreover, the ligand chemistry in ZIFs appeared to have no controlling effect on the short-range disorder, although the former affected their phase-transition behavior. These findings reveal structure-property relations and could help design metal-organic framework glasses. in Science current issue on March 26, 2020 05:40 PM. • #### Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors, but only a small subset of these cells generates metastases. We conducted an in vivo genome-wide CRISPR activation screen in CTCs from breast cancer patients to identify genes that promote distant metastasis in mice. Genes coding for ribosomal proteins and regulators of translation were enriched in this screen. Overexpression of RPL15, which encodes a component of the large ribosomal subunit, increased metastatic growth in multiple organs and selectively enhanced translation of other ribosomal proteins and cell cycle regulators. RNA sequencing of freshly isolated CTCs from breast cancer patients revealed a subset with strong ribosome and protein synthesis signatures; these CTCs expressed proliferation and epithelial markers and correlated with poor clinical outcome. Therapies targeting this aggressive subset of CTCs may merit exploration as potential suppressors of metastatic progression. in Science current issue on March 26, 2020 05:40 PM. • #### The dark matter interpretation of the 3.5-keV line is inconsistent with blank-sky observations Observations of nearby galaxies and galaxy clusters have reported an unexpected x-ray emission line around 3.5 kilo–electron volts (keV). Proposals to explain this line include decaying dark matter—in particular, that the decay of sterile neutrinos with a mass around 7 keV could match the available data. If this interpretation is correct, the 3.5-keV line should also be emitted by dark matter in the halo of the Milky Way. We used more than 30 megaseconds of XMM-Newton (X-ray Multi-Mirror Mission) blank-sky observations to test this hypothesis, finding no evidence of the 3.5-keV line emission from the Milky Way halo. We set an upper limit on the decay rate of dark matter in this mass range, which is inconsistent with the possibility that the 3.5-keV line originates from dark matter decay. in Science current issue on March 26, 2020 05:40 PM. • #### Observation of dynamical fermionization The wave function of a Tonks-Girardeau (T-G) gas of strongly interacting bosons in one dimension maps onto the absolute value of the wave function of a noninteracting Fermi gas. Although this fermionization makes many aspects of the two gases identical, their equilibrium momentum distributions are quite different. We observed dynamical fermionization, where the momentum distribution of a T-G gas evolves from bosonic to fermionic after its axial confinement is removed. The asymptotic momentum distribution after expansion in one dimension is the distribution of rapidities, which are the conserved quantities associated with many-body integrable systems. Our measurements agree well with T-G gas theory. We also studied momentum evolution after the trap depth is suddenly changed to a new nonzero value, and we observed the theoretically predicted bosonic-fermionic oscillations. in Science current issue on March 26, 2020 05:40 PM. • #### Frequency-comb spectroscopy on pure quantum states of a single molecular ion Spectroscopy is a powerful tool for studying molecules and is commonly performed on large thermal molecular ensembles that are perturbed by motional shifts and interactions with the environment and one another, resulting in convoluted spectra and limited resolution. Here, we use quantum-logic techniques to prepare a trapped molecular ion in a single quantum state, drive terahertz rotational transitions with an optical frequency comb, and read out the final state nondestructively, leaving the molecule ready for further manipulation. We can resolve rotational transitions to 11 significant digits and derive the rotational constant of 40CaH+ to be BR = 142 501 777.9(1.7) kilohertz. Our approach is suited for a wide range of molecular ions, including polyatomics and species relevant for tests of fundamental physics, chemistry, and astrophysics. in Science current issue on March 26, 2020 05:40 PM. • #### Type-II Ising pairing in few-layer stanene Spin-orbit coupling has proven indispensable in the realization of topological materials and, more recently, Ising pairing in two-dimensional superconductors. This pairing mechanism relies on inversion symmetry–breaking and sustains anomalously large in-plane polarizing magnetic fields whose upper limit is predicted to diverge at low temperatures. Here, we show that the recently discovered superconductor few-layer stanene, epitaxially strained gray tin (α-Sn), exhibits a distinct type of Ising pairing between carriers residing in bands with different orbital indices near the -point. The bands are split as a result of spin-orbit locking without the participation of inversion symmetry–breaking. The in-plane upper critical field is strongly enhanced at ultralow temperature and reveals the predicted upturn. in Science current issue on March 26, 2020 05:40 PM. • #### The evolutionary dynamics and fitness landscape of clonal hematopoiesis Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance remains largely unknown. Blood sequencing data from ~50,000 individuals reveal how mutation, genetic drift, and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem cells, and quantify the fitness advantages of key pathogenic variants, at single-nucleotide resolution, as well as the distribution of fitness effects (fitness landscape) within commonly mutated driver genes. These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age. in Science current issue on March 26, 2020 05:40 PM. • #### Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome–coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo–electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection. in Science current issue on March 26, 2020 05:40 PM. • #### A strange strange metal in Science current issue on March 26, 2020 05:40 PM. • #### It's in the air in Science current issue on March 26, 2020 05:40 PM. • #### Determining odd from even in Science current issue on March 26, 2020 05:40 PM. • #### Feed the dog in Science current issue on March 26, 2020 05:40 PM. • #### A silver lining for hurricanes in Science current issue on March 26, 2020 05:40 PM. • #### In search of a male contraceptive in Science current issue on March 26, 2020 05:40 PM. • #### A mitotic error code in Science current issue on March 26, 2020 05:40 PM. • #### Inflamed by TLR4 internalization in Science current issue on March 26, 2020 05:40 PM. • #### Salting neutrophils' game in Science current issue on March 26, 2020 05:40 PM. • #### Single-Pulse TMS over the Parietal Cortex Does Not Impair Sensorimotor Perturbation-Induced Changes in Motor Commands Abstract Intermittent exposure to a sensorimotor perturbation, such as a visuomotor rotation, is known to cause a directional bias on the subsequent movement that opposes the previously experienced perturbation. To date, it is unclear whether the parietal cortex is causally involved in this postperturbation movement bias. In a recent electroencephalogram study, Savoie et al. (2018) observed increased parietal activity in response to an intermittent visuomotor perturbation, raising the possibility that the parietal cortex could subserve this change in motor behavior. The goal of the present study was to causally test this hypothesis. Human participants (N = 28) reached toward one of two visual targets located on either side of a fixation point, while being pseudorandomly submitted to a visuomotor rotation. On half of all rotation trials, single-pulse transcranial magnetic stimulation (TMS) was applied over the right (N = 14) or left (N = 14) parietal cortex 150 ms after visual feedback provision. To determine whether TMS influenced the postperturbation bias, reach direction was compared on trials that followed rotation with (RS + 1) and without (R + 1) TMS. It was hypothesized that interfering with parietal activity would reduce the movement bias following rotated trials. Results revealed a significant and robust postrotation directional bias compared with both rotation and null rotation trials. Contrary to our hypothesis, however, neither left nor right parietal stimulation significantly impacted the postrotation bias. These data suggest that the parietal areas targeted here may not be critical for perturbation-induced motor output changes to emerge. in eNeuro current issue on March 26, 2020 04:30 PM. • #### Muscarinic-Dependent miR-182 and QR2 Expression Regulation in the Anterior Insula Enables Novel Taste Learning Abstract In a similar manner to other learning paradigms, intact muscarinic acetylcholine receptor (mAChR) neurotransmission or protein synthesis regulation in the anterior insular cortex (aIC) is necessary for appetitive taste learning. Here we describe a parallel, local molecular pathway, where -aminobutyric acid type a receptor (GABAAR) control of mAChR activation causes upregulation of microRNA-182 (miR-182) and quinone reductase 2 (QR2) mRNA destabilization in the rodent aIC. Damage to long-term memory by prevention of this process, with the use of mAChR antagonist scopolamine prior to novel taste learning, can be rescued by local QR2 inhibition, demonstrating that QR2 acts downstream of local muscarinic activation. Furthermore, we prove for the first time the presence of endogenous QR2 co-factors in the brain, establishing QR2 as a functional reductase there. In turn, we show that QR2 activity causes the generation of reactive oxygen species, leading to modulation in Kv2.1 redox state. QR2 expression reduction therefore is a previously unaccounted mode of mAChR mediated inflammation reduction, and thus adds QR2 to the cadre of redox modulators in the brain. The concomitant reduction in QR2 activity during memory consolidation suggests a complementary mechanism to the well-established molecular processes of this phase, by which the cortex gleans important information from general sensory stimuli. This places QR2 as a promising new target to tackle neurodegenerative inflammation and the associated impediment of novel memory formation in diseases such as Alzheimer’s disease. Significance Statement Most studies on molecular mechanisms underlying memory consolidation have thus far focused on the transformation of electrical and synaptic activity to post-translation modifications, mRNA translation, and gene transcription regulation. Here, we explore a less studied mechanism, of the removal of an innate constraint to allow the formation of long-term memory. Our findings point to a pathway of GABAA receptor control of mAChR activation, which causes upregulation of miR-182, which can in turn lead to destabilization of QR2 mRNA in the rodent anterior insular cortex. The results propose a novel molecular cascade, complementary to the mRNA translation/transcription regulation underlying memory consolidation, by which the cortex gleans important information from general sensory stimuli. in RSS PAP on March 26, 2020 04:30 PM. • #### A prospective study of acute blood‐based biomarkers for sport‐related concussion ## Objective Prospectively characterize changes in serum proteins following sport‐related concussion and determine if candidate biomarkers discriminate concussed athletes from controls and are associated with duration of symptoms following concussion. ## Methods High school and collegiate athletes were enrolled between 2015 and 2018. Blood was collected at pre‐injury baseline and within 6 hours (early‐acute) and at 24‐48 hours (late‐acute) following concussion in football players (n = 106), matched uninjured football players (n = 84) and non‐contact sport athletes (n = 50). Glial fibrillary acidic protein, ubiquitin c‐terminal hydrolase‐L1, S100 calcium binding protein B, alpha‐II‐spectrin breakdown product 150, interleukin‐6, interleukin‐1 receptor antagonist and c‐reactive protein were measured in serum. Linear models assessed changes in protein concentrations over time. Receiver operating curves quantified the discrimination of concussed athletes from controls. A Cox proportional hazard model determined if proteins were associated with symptom recovery. ## Results All proteins except glial fibrillary acidic protein and c‐reactive protein were significantly elevated at the early‐acute phase post‐injury relative to baseline and both control groups and discriminated concussed athletes from controls with areas under the curve of 0.68‐0.84. The candidate biomarkers also significantly improved the discrimination of concussed athletes from non‐contact controls compared to symptom severity alone. Glial fibrillary acidic protein was elevated post‐injury relative to baseline in concussed athletes with a loss of consciousness or amnesia. Finally, early‐acute levels of interleukin‐1 receptor antagonist were associated with the number of days to symptom recovery. ## Interpretation Brain injury and inflammatory proteins show promise as objective diagnostic biomarkers for sport‐related concussion, while inflammatory markers may provide prognostic value. This article is protected by copyright. All rights reserved. in Annals of Neurology on March 26, 2020 10:16 AM. • #### Antiepileptic drug teratogenicity and de novo genetic variation load ## Objective The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED‐induced BDs may result from a genome‐wide increase of de novo variants in the embryo, a mechanism which we investigated. ## Methods Whole‐exome sequencing data from child‐parent trios were interrogated for de novo single‐nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED‐exposed children) vs children without BDs not exposed prenatally to AEDs (AED‐unexposed unaffected children), and AED‐exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data. ## Results 67 child‐parent trios were included: 10 with AED‐exposed children with BDs; 46 with AED‐exposed unaffected children; 11 with AED‐unexposed unaffected children. The dnSNV/indel burden did not differ between AED‐exposed children and AED‐unexposed unaffected children [median dnSNV/indel number/child (range): 3 (0‐7) vs 3 (1‐5), p = 0.50]. Among AED‐exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring likely deleterious dnSNVs/indels did not differ significantly between AED‐unexposed and AED‐exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. ## Interpretation Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED‐induced BDs. These results can be incorporated in routine patient counselling. This article is protected by copyright. All rights reserved. in Annals of Neurology on March 26, 2020 10:16 AM. • #### Predicting Recovery and Outcome After Pediatric Stroke: Results from the International Pediatric Stroke Study ## Abstract ## Objective To characterize predictors of recovery and outcome following pediatric arterial ischemic stroke, hypothesizing that age influences recovery after stroke. ## Methods We studied children enrolled in the International Pediatric Stroke Study between January 1, 2003 and July 31, 2014 with two‐year follow‐up after arterial ischemic stroke. Outcomes were defined at discharge by clinician grading and at two years by Pediatric Stroke Outcome Measure (PSOM). Demographic, clinical, and radiologic outcome predictors were examined. We defined changes in outcome from discharge to two years as recovery (improved outcome), emerging deficit (worse outcome), or no change. ## Results Our population consisted of 587 patients, including 174 with neonatal stroke and 413 with childhood stroke, with recurrent stroke in 8.2% of childhood patients. Moderate to severe neurological impairment was present in 9.4% of neonates vs 48.8% of children at discharge compared to 8.0% vs 24.7% after two years. Predictors of poor outcome included age between 28 days and one year (compared to neonates, OR 3.58, p<0.05), underlying chronic disorder (OR 2.23, p<0.05), and involvement of both small and large vascular territories (OR 2.84, p<0.05). Recovery patterns differed, with emerging deficits more common in children under one year of age (p<0.05). ## Interpretation Outcomes after pediatric stroke are generally favorable, but moderate to severe neurological impairments are still common. Age between 28 days and one year appears to be a particularly vulnerable period. Understanding the timing and predictors of recovery will allow us to better counsel families and target therapies to improve outcomes after pediatric stroke. This article is protected by copyright. All rights reserved. in Annals of Neurology on March 26, 2020 10:16 AM. • #### A hybrid P3HT-Graphene interface for efficient photostimulation of neurons. (arXiv:2003.11388v1 [q-bio.NC]) Graphene conductive properties have been long exploited in the field of organic photovoltaics and optoelectronics by the scientific community worldwide. We engineered and characterized a hybrid biointerface in which graphene is coupled with photosensitive polymers, and tested its ability to elicit lighttriggered neural activity modulation in primary neurons and blind retina explants. We designed such a graphene-based device by modifying a photoactive P3HT-based retinal interface, previously reported to rescue light sensitivity in blind rodents, with a CVD graphene layer replacing the conductive PEDOT:PSS layer to enhance charge separation. The new graphene-based device was characterized for its electrochemical features and for the ability to photostimulate primary neurons and blind retina explants, while preserving biocompatibility. Light-triggered responses, recorded by patch-clamp in vitro or MEA ex vivo, show a stronger light-transduction efficiency when the neurons are interfaced with the graphene-based device with respect to the PEDOT:PSS-based one. The possibility to ameliorate flexible photo-stimulating devices via the insertion of graphene, paves the way for potential biomedical applications of graphenebased neuronal interfaces in the context of retinal implants. in q-bio.NC updates on arXiv.org on March 26, 2020 01:30 AM. • #### Predictive coding underlies adaptation in the subcortical sensory pathway. (arXiv:2003.11328v1 [q-bio.NC]) The subcortical sensory pathways are the fundamental channels for mapping the outside world to our minds. Sensory pathways efficiently transmit information by adapting neural responses to the local statistics of the sensory input. The longstanding mechanistic explanation for this adaptive behaviour is that neuronal habituation scales activity to the local statistics of the stimuli. An alternative account is that neural coding is directly driven by expectations of the sensory input. Here we used abstract rules to manipulate expectations independently of local stimulus statistics. The ultra-high-field functional-MRI data show that expectations, and not habituation, are the main driver of the response amplitude to tones in the human auditory pathway. These results provide first unambiguous evidence of predictive coding and abstract processing in a subcortical sensory pathway, indicating that the brain only holds subjective representations of the outside world even at initial points of the processing hierarchy. in q-bio.NC updates on arXiv.org on March 26, 2020 01:30 AM. • #### Effect of Diverse Recoding of Granule Cells on Optokinetic Response in A Cerebellar Ring Network with Synaptic Plasticity. (arXiv:2003.11325v2 [q-bio.NC] UPDATED) We consider a cerebellar ring network for the optokinetic response (OKR), and investigate the effect of diverse recoding of granule (GR) cells on OKR by varying the connection probability$p_c$from Golgi to GR cells. For an optimal value of$p_c^*~(=0.06)$, individual GR cells exhibit diverse spiking patterns which are in-phase, anti-phase, or complex out-of-phase with respect to their population-averaged firing activity. Then, these diversely-recoded signals via parallel fibers (PFs) from GR cells are effectively depressed by the error-teaching signals via climbing fibers from the inferior olive which are also in-phase ones. Synaptic weights at in-phase PF-Purkinje cell (PC) synapses of active GR cells are strongly depressed via strong long-term depression (LTD), while those at anti- and complex out-of-phase PF-PC synapses are weakly depressed through weak LTD. This kind of "effective" depression (i.e., strong/weak LTD) at PF-PC synapses causes a big modulation in firing of PCs, which then exert effective inhibitory coordination on vestibular nucleus (VN) neuron (which evokes OKR). For the firing of VN neuron, the learning gain degree${\cal{L}}_g$, corresponding to the modulation gain ratio, increases with increasing learning cycle, and it saturates at about the 300th cycle. By varying$p_c$from$p_c^*$, we find that a plot of saturated learning gain degree${\cal L}_g^*$versus$p_c$forms a bell-shaped curve with a peak at$p_c^*\$ (where the diversity degree in firing of GR cells is also maximum). Consequently, the more diverse in recoding of GR cells, the more effective in motor learning for the OKR adaptation.

in q-bio.NC updates on arXiv.org on March 26, 2020 01:30 AM.

• #### Voltage distribution in a non-locally but globally electroneutral confined electrolyte medium: applications for nanophysiology. (arXiv:2003.11147v1 [cond-mat.soft])

The distribution of voltage in sub-micron cellular domains remains poorly understood. In neurons, the voltage results from the difference in ionic concentrations which are continuously maintained by pumps and exchangers. However, it not clear how electro-neutrality could be maintained by an excess of fast moving positive ions that should be counter balanced by slow diffusing negatively charged proteins. Using the theory of electro-diffusion, we study here the voltage distribution in a generic domain, which consists of two concentric disks (resp. ball) in two (resp. three) dimensions, where a negative charge is fixed in the inner domain. When global but not local electro-neutrality is maintained, we solve the Poisson-Nernst-Planck equation both analytically and numerically in dimension 1 (flat) and 2 (cylindrical) and found that the voltage changes considerably on a spatial scale which is much larger than the Debye screening length, which assumes electro-neutrality. The present result suggests that long-range voltage drop changes are expected in neuronal microcompartments, probably relevant to explain the activation of far away voltage-gated channels located on the surface.

in q-bio.NC updates on arXiv.org on March 26, 2020 01:30 AM.

• #### AHA! an 'Artificial Hippocampal Algorithm' for Episodic Machine Learning. (arXiv:1909.10340v5 [cs.NE] UPDATED)

The majority of ML research concerns slow, statistical learning of i.i.d. samples from large, labelled datasets. Animals do not learn this way. An enviable characteristic of animal learning is episodic' learning - the ability to memorise a specific experience as a composition of existing concepts, after just one experience, without provided labels. The new knowledge can then be used to distinguish between similar experiences, to generalise between classes, and to selectively consolidate to long-term memory. The Hippocampus is known to be vital to these abilities. AHA is a biologically-plausible computational model of the Hippocampus. Unlike most machine learning models, AHA is trained without external labels and uses only local credit assignment. We demonstrate AHA in a superset of the Omniglot one-shot classification benchmark. The extended benchmark covers a wider range of known hippocampal functions by testing pattern separation, completion, and recall of original input. These functions are all performed within a single configuration of the computational model. Despite these constraints, image classification results are comparable to conventional deep convolutional ANNs.

in q-bio.NC updates on arXiv.org on March 26, 2020 01:30 AM.

• #### How humans learn and represent networks. (arXiv:1909.07186v2 [physics.soc-ph] UPDATED)

Humans communicate, receive, and store information using sequences of items -- from words in a sentence or notes in music to abstract concepts in lectures and books. The networks formed by these items (nodes) and the sequential transitions between them (edges) encode important structural features of human communication and knowledge. But how do humans learn the networks of probabilistic transitions that underlie sequences of items? Moreover, what do people's internal maps of these networks look like? Here, we introduce graph learning, a growing and interdisciplinary field focused on studying how humans learn and represent networks in the world around them. We begin by describing established results from statistical learning showing that humans are adept at detecting differences in the transition probabilities between items in a sequence. We next present recent experiments that directly control for differences in transition probabilities, demonstrating that human behavior also depends critically on the abstract network structure of transitions. Finally, we present computational models that researchers have proposed to explain the effects of network structure on human behavior and cognition. Throughout, we highlight a number of exciting open questions in the study of graph learning that will require creative insights from cognitive scientists and network scientists alike.

in q-bio.NC updates on arXiv.org on March 26, 2020 01:30 AM.

• #### Abstract representations of events arise from mental errors in learning and memory. (arXiv:1805.12491v3 [q-bio.NC] UPDATED)

Humans are adept at uncovering abstract associations in the world around them, yet the underlying mechanisms remain poorly understood. Intuitively, learning the higher-order structure of statistical relationships should involve complex mental processes. Here we propose an alternative perspective: that higher-order associations instead arise from natural errors in learning and memory. Combining ideas from information theory and reinforcement learning, we derive a maximum entropy (or minimum complexity) model of people's internal representations of the transitions between stimuli. Importantly, our model (i) affords a concise analytic form, (ii) qualitatively explains the effects of transition network structure on human expectations, and (iii) quantitatively predicts human reaction times in probabilistic sequential motor tasks. Together, these results suggest that mental errors influence our abstract representations of the world in significant and predictable ways, with direct implications for the study and design of optimally learnable information sources.

in q-bio.NC updates on arXiv.org on March 26, 2020 01:30 AM.

• #### Identifying SARS-CoV-2 related coronaviruses in Malayan pangolins

Nature, Published online: 26 March 2020; doi:10.1038/s41586-020-2169-0

Identifying SARS-CoV-2 related coronaviruses in Malayan pangolins

in Nature on March 26, 2020 12:00 AM.

• #### Science-ing from home

Nature, Published online: 26 March 2020; doi:10.1038/d41586-020-00935-3

In the first of two articles about laboratory closures triggered by COVID-19, scientists affected by the shutdowns outline the tools they are using to run their research groups remotely.

in Nature on March 26, 2020 12:00 AM.

• #### Seven tips to manage your mental health and well-being during the COVID-19 outbreak

Nature, Published online: 26 March 2020; doi:10.1038/d41586-020-00933-5

Feeling overwhelmed by a lockdown and the need to suddenly adopt e-learning? Keep connected and compassionate, says clinical psychologist Desiree Dickerson.

in Nature on March 26, 2020 12:00 AM.

• #### Daily briefing: Cruise ship coronavirus outbreak gave scientists ‘an ideal experiment’

Nature, Published online: 26 March 2020; doi:10.1038/d41586-020-00932-6

The COVID-19 outbreak on the Diamond Princess has given researchers the rare opportunity to study the virus in a highly controlled population, in which almost everyone was tested. Plus: families face heartbreak as non-coronavirus clinical trials are put on hold, and the healing ozone layer is getting the jet stream back on track in the Southern Hemisphere.

in Nature on March 26, 2020 12:00 AM.

• #### Should scientists infect healthy people with the coronavirus to test vaccines?

Nature, Published online: 26 March 2020; doi:10.1038/d41586-020-00927-3

Radical proposal to conduct ‘human challenge’ studies could dramatically speed up vaccine research.

in Nature on March 26, 2020 12:00 AM.

• #### All-purpose enzymes boost CRISPR’s powers

Nature, Published online: 26 March 2020; doi:10.1038/d41586-020-00903-x

The gene-editing system could target a broad swathe of the genome with the help of versatile enzymes.

in Nature on March 26, 2020 12:00 AM.

• #### What the cruise-ship outbreaks reveal about COVID-19

Nature, Published online: 26 March 2020; doi:10.1038/d41586-020-00885-w

Close confines help the virus to spread, but closed environments are also an ideal place to study how the new coronavirus behaves.

in Nature on March 26, 2020 12:00 AM.

• #### How a starfish egg is like a quantum system

Nature, Published online: 26 March 2020; doi:10.1038/d41586-020-00881-0

Waves that travel through an egg’s outer membrane echo those seen in physical systems at much smaller — and much larger — scales.

in Nature on March 26, 2020 12:00 AM.

• #### Origins of Parkinson’s Disease in Brain Development: Insights From Early and Persistent Effects of LRRK2-G2019S on Striatal Circuits

Late-onset Parkinson’s disease (PD) is dominated clinically and experimentally by a focus on dopamine neuron degeneration and ensuing motor system abnormalities. There are, additionally, a number of non-motor symptoms – including cognitive and psychiatric – that can appear much earlier in the course of the disease and also significantly impair quality of life. The neurobiology of such cognitive and psychiatric non-motor symptoms is poorly understood. The recognition of genetic forms of late-onset PD, which are clinically similar to idiopathic forms in both motor and non-motor symptoms, raises the perspective that brain cells and circuits – and the behaviors they support – differ in significant ways from normal by virtue of the fact that these mutations are carried throughout life, including especially early developmental critical periods where circuit structure and function is particularly susceptible to the influence of experience-dependent activity. In this focused review, we support this central thesis by highlighting studies of LRRK2-G2019S mouse models. We describe work that shows that in G2019S mutants, corticostriatal activity and plasticity are abnormal by P21, the end of a period of excitatory synaptogenesis in striatum. Moreover, by young adulthood, impaired striatal synaptic and non-synaptic forms of plasticity likely underlie altered and variable performance by mutant mice in validated tasks that test for depression-like and anhedonia-like behaviors. Mechanistically, deficits in cellular, synaptic and behavioral plasticity may be unified by mutation-linked defects in trafficking of AMPAR subunits and other membrane channels, which in turn may reflect impairment in the function of the Rab family of GTPases, a major target of LRRK2 phosphorylation. These findings underscore the need to better understand how PD-related mutant proteins influence brain structure and function during an extended period of brain development, and offer new clues for future therapeutic strategies to target non-motor cognitive or psychiatric symptoms of PD.

in Frontiers in Neuroscience: Neurodegeneration on March 26, 2020 12:00 AM.

• #### Mechanotactile Sensory Feedback Improves Embodiment of a Prosthetic Hand During Active Use

There have been several advancements in the field of myoelectric prostheses to improve dexterity and restore hand grasp patterns for persons with upper limb loss, including robust control strategies, novel sensory feedback, and multifunction prosthetic terminal devices. Although these advancements have shown to improve prosthesis performance, a key element that may further improve acceptance is often overlooked. Embodiment, which encompasses the feeling of owning, controlling and locating the device without the need to constantly look at it, has been shown to be affected by sensory feedback. However, the specific aspects of embodiment that are influenced are not clearly understood, particularly when a prosthesis is actively controlled. In this work, we used a sensorized simulated prosthesis in able-bodied participants to investigate the contribution of sensory feedback, active motor control, and the combination of both to the components of embodiment; using a common methodology in the literature, namely the rubber hand illusion (RHI). Our results indicate that (1) the sensorized simulated prosthesis may be embodied by able-bodied users in a similar fashion as prosthetic devices embodied by persons with upper limb amputation, and (2) mechanotactile sensory feedback might not only be useful for improving certain aspects of embodiment, i.e., ownership and location, but also may have a modulating effect on other aspects, namely sense of agency, when provided asynchronously during active motor control tasks. This work may allow us to further investigate and manipulate factors contributing to the complex phenomenon of embodiment in relation to active motor control of a device, enabling future study of more precise quantitative measures of embodiment that do not rely as much on subjective perception.

in Frontiers in Neuroscience: Neural Technology on March 26, 2020 12:00 AM.

• #### Stimulation Strategies for Improving the Resolution of Retinal Prostheses

Electrical stimulation using implantable devices with arrays of stimulating electrodes is an emerging therapy for neurological diseases. The performance of these devices depends greatly on their ability to activate populations of neurons with high spatiotemporal resolution. To study electrical stimulation of populations of neurons, retina serves as a useful model because the neural network is arranged in a planar array that is easy to access. Moreover, retinal prostheses are under development to restore vision by replacing the function of damaged light sensitive photoreceptors, which makes retinal research directly relevant for curing blindness. Here we provide a progress review on stimulation strategies developed in recent years to improve the resolution of electrical stimulation in retinal prostheses. We focus on studies performed with explanted retinas, in which electrophysiological techniques are the most advanced. We summarize achievements in improving the spatial and temporal resolution of electrical stimulation of the retina and methods to selectively stimulate neurons with different visual functions. Future directions for retinal prostheses development are also discussed, which could provide insights for other types of neuromodulatory devices in which high-resolution electrical stimulation is required.

in Frontiers in Neuroscience: Neural Technology on March 26, 2020 12:00 AM.

• #### Using Deep Convolutional Neural Networks for Neonatal Brain Image Segmentation

Introduction

Deep learning neural networks are especially potent at dealing with structured data, such as images and volumes. Both modified LiviaNET and HyperDense-Net performed well at a prior competition segmenting 6-month-old infant magnetic resonance images, but neonatal cerebral tissue type identification is challenging given its uniquely inverted tissue contrasts. The current study aims to evaluate the two architectures to segment neonatal brain tissue types at term equivalent age.

Methods

Both networks were retrained over 24 pairs of neonatal T1 and T2 data from the Developing Human Connectome Project public data set and validated on another eight pairs against ground truth. We then reported the best-performing model from training and its performance by computing the Dice similarity coefficient (DSC) for each tissue type against eight test subjects.

Results

During the testing phase, among the segmentation approaches tested, the dual-modality HyperDense-Net achieved the best statistically significantly test mean DSC values, obtaining 0.94/0.95/0.92 for the tissue types and took 80 h to train and 10 min to segment, including preprocessing. The single-modality LiviaNET was better at processing T2-weighted images than processing T1-weighted images across all tissue types, achieving mean DSC values of 0.90/0.90/0.88 for gray matter, white matter, and cerebrospinal fluid, respectively, while requiring 30 h to train and 8 min to segment each brain, including preprocessing.

Discussion

Our evaluation demonstrates that both neural networks can segment neonatal brains, achieving previously reported performance. Both networks will be continuously retrained over an increasingly larger repertoire of neonatal brain data and be made available through the Canadian Neonatal Brain Platform to better serve the neonatal brain imaging research community.

in Frontiers in Neuroscience: Brain Imaging Methods on March 26, 2020 12:00 AM.

• #### Relationship Between Exercise and Alzheimer’s Disease: A Narrative Literature Review

This narrative review aimed to summarize evidence regarding the responses to exercise among patients with preclinical Alzheimer’s disease (AD) and the effectiveness of long-term exercise interventions in improving cognitive function and neuropsychiatric symptoms. We performed a narrative review of existing literature on the effectiveness of long-term exercise interventions in improving cognitive function and neuropsychiatric symptoms in patients with AD. Patients with AD who presented with long-term exercise interventions appeared to have improved blood flow, increased hippocampal volume, and improved neurogenesis. Most prospective studies have proven that physical inactivity is one of the most common preventable risk factors for developing AD and that higher physical activity levels are associated with a reduced risk of AD development. Physical exercise seems to be effective in improving several neuropsychiatric symptoms of AD, notably cognitive function. Compared with medications, exercise has been shown to have fewer side effects and better adherence.

in Frontiers in Neuroscience: Neurodegeneration on March 26, 2020 12:00 AM.

• #### Brain and Behavioral Asymmetry: A Lesson From Fish

It is widely acknowledged that the left and right hemispheres of human brains display both anatomical and functional asymmetries. For more than a century, brain and behavioral lateralization have been considered a uniquely human feature linked to language and handedness. However, over the past decades this idea has been challenged by an increasing number of studies describing structural asymmetries and lateralized behaviors in non-human species extending from primates to fish. Evidence suggesting that a similar pattern of brain lateralization occurs in all vertebrates, humans included, has allowed the emergence of different model systems to investigate the development of brain asymmetries and their impact on behavior. Among animal models, fish have contributed much to the research on lateralization as several fish species exhibit lateralized behaviors. For instance, behavioral studies have shown that the advantages of having an asymmetric brain, such as the ability of simultaneously processing different information and perform parallel tasks compensate the potential costs associated with poor integration of information between the two hemispheres thus helping to better understand the possible evolutionary significance of lateralization. However, these studies inferred how the two sides of the brains are differentially specialized by measuring the differences in the behavioral responses but did not allow to directly investigate the relation between anatomical and functional asymmetries. With respect to this issue, in recent years zebrafish has become a powerful model to address lateralization at different level of complexity, from genes to neural circuitry and behavior. The possibility of combining genetic manipulation of brain asymmetries with cutting-edge in vivo imaging technique and behavioral tests makes the zebrafish a valuable model to investigate the phylogeny and ontogeny of brain lateralization and its relevance for normal brain function and behavior.

in Frontiers in Neuroanatomy on March 26, 2020 12:00 AM.

• #### Cell-specific exon methylation and CTCF binding in neurons regulates calcium ion channel splicing and function

Cell-specific alternative splicing modulates myriad cell functions and is disrupted in disease. The mechanisms governing alternative splicing are known for relatively few genes and typically focus on RNA splicing factors. In sensory neurons, cell-specific alternative splicing of the presynaptic CaV channel Cacna1b gene modulates opioid sensitivity. How this splicing is regulated is unknown. We find that cell and exon -specific DNA hypomethylation permits CTCF binding, the master regulator of mammalian chromatin structure, which, in turn, controls splicing in a DRG-derived cell line. In vivo, hypomethylation of an alternative exon specifically in nociceptors, likely permits CTCF binding and expression of CaV2.2 channel isoforms with increased opioid sensitivity in mice. Following nerve injury, exon methylation is increased, and splicing is disrupted. Our studies define the molecular mechanisms of cell-specific alternative splicing of a functionally validated exon in normal and disease states – and reveal a potential target for the treatment of chronic pain.

in eLife on March 26, 2020 12:00 AM.

• #### An atypical DYRK kinase connects quorum-sensing with posttranscriptional gene regulation in Trypanosoma brucei

The sleeping sickness parasite, Trypanosoma brucei, uses quorum sensing (QS) to balance proliferation and transmission potential in the mammal bloodstream. A signal transduction cascade regulates this process, a component of which is a divergent member of the DYRK family of protein kinases, TbDYRK. Phylogenetic and mutational analysis in combination with activity and phenotypic assays revealed that TbDYRK exhibits a pre-activated confirmation and an atypical HxY activation loop motif, unlike DYRK kinases in other eukaryotes. Phosphoproteomic comparison of TbDYRK null mutants with wild type parasites identified molecules that operate on both the inhibitory 'slender retainer' and activatory 'stumpy inducer' arms of the QS control pathway. One of these molecules, the RNA-regulator TbZC3H20, regulates parasite QS, this being dependent on the integrity of its TbDYRK phosphorylation site. This analysis reveals fundamental differences to conventional DYRK family regulation and links trypanosome environmental sensing, signal transduction and developmental gene expression in a coherent pathway.

in eLife on March 26, 2020 12:00 AM.

• #### Endogenous siRNAs promote proteostasis and longevity in germline less C. elegans

How lifespan and the rate of aging are set is a key problem in biology. Small RNAs are conserved molecules that impact diverse biological processes through the control of gene expression. However, in contrast to miRNAs, the role of endo-siRNAs in aging remains unexplored. Here, by combining deep sequencing and genomic and genetic approaches in C. elegans, we reveal an unprecedented role for endo-siRNA molecules in the maintenance of proteostasis and lifespan extension in germline-less animals. Furthermore, we identify an endo-siRNA-regulated tyrosine phosphatase, which limits the longevity of germline-less animals by restricting the activity of the heat shock transcription factor HSF-1. Altogether, our findings point to endo-siRNAs as a link between germline removal and the HSF-1 proteostasis and longevity-promoting somatic pathway. This establishes a role for endo siRNAs in the aging process and identifies downstream genes and physiological processes that are regulated by the endo siRNAs to affect longevity.

in eLife on March 26, 2020 12:00 AM.

• #### Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks

Medium spiny neurons (MSNs) comprise the main body (95% in mouse) of the dorsal striatum neurons and represent dopaminoceptive GABAergic neurons. The cAMP (cyclic Adenosine MonoPhosphate)—mediated cascade of e...

in Most Recent Articles: BMC Neuroscience on March 26, 2020 12:00 AM.

• #### An <i>in</i>-<i>silico</i> human cell model reveals the influence of spatial organization on RNA splicing

by Zhaleh Ghaemi, Joseph R. Peterson, Martin Gruebele, Zaida Luthey-Schulten

Spatial organization is a characteristic of all cells, achieved in eukaryotic cells by utilizing both membrane-bound and membrane-less organelles. One of the key processes in eukaryotes is RNA splicing, which readies mRNA for translation. This complex and highly dynamical chemical process involves assembly and disassembly of many molecules in multiple cellular compartments and their transport among compartments. Our goal is to model the effect of spatial organization of membrane-less organelles (specifically nuclear speckles) and of organelle heterogeneity on splicing particle biogenesis in mammalian cells. Based on multiple sources of complementary experimental data, we constructed a spatial model of a HeLa cell to capture intracellular crowding effects. We then developed chemical reaction networks to describe the formation of RNA splicing machinery complexes and splicing processes within nuclear speckles (specific type of non-membrane-bound organelles). We incorporated these networks into our spatially-resolved human cell model and performed stochastic simulations for up to 15 minutes of biological time, the longest thus far for a eukaryotic cell. We find that an increase (decrease) in the number of nuclear pore complexes increases (decreases) the number of assembled splicing particles; and that compartmentalization is critical for the yield of correctly-assembled particles. We also show that a slight increase of splicing particle localization into nuclear speckles leads to a disproportionate enhancement of mRNA splicing and a reduction in the noise of generated mRNA. Our model also predicts that the distance between genes and speckles has a considerable effect on the mRNA production rate, with genes located closer to speckles producing mRNA at higher levels, emphasizing the importance of genome organization around speckles. The HeLa cell model, including organelles and sub-compartments, provides a flexible foundation to study other cellular processes that are strongly modulated by spatiotemporal heterogeneity.

in PLoS Computational Biology on March 25, 2020 09:00 PM.

• #### Quantifying the roles of vomiting, diarrhea, and residents vs. staff in norovirus transmission in U.S. nursing home outbreaks

by Carly Adams, David Young, Paul A. Gastañaduy, Prabasaj Paul, Zach Marsh, Aron J. Hall, Benjamin A. Lopman

The role of individual case characteristics, such as symptoms or demographics, in norovirus transmissibility is poorly understood. Six nursing home norovirus outbreaks occurring in South Carolina, U.S. from 2014 to 2016 were examined. We aimed to quantify the contribution of symptoms and other case characteristics in norovirus transmission using the reproduction number (REi) as an estimate of individual case infectivity and to examine how transmission changes over the course of an outbreak. Individual estimates of REi were calculated using a maximum likelihood procedure to infer the average number of secondary cases generated by each case. The associations between case characteristics and REi were estimated using a weighted multivariate mixed linear model. Outbreaks began with one to three index case(s) with large estimated REi’s (range: 1.48 to 8.70) relative to subsequent cases. Of the 209 cases, 155 (75%) vomited, 164 (79%) had diarrhea, and 158 (76%) were nursing home residents (vs. staff). Cases who vomited infected 2.12 (95% CI: 1.68, 2.68) times the number of individuals as non-vomiters, cases with diarrhea infected 1.39 (95% CI: 1.03, 1.87) times the number of individuals as cases without diarrhea, and resident-cases infected 1.53 (95% CI: 1.15, 2.02) times the number of individuals as staff-cases. Index cases tended to be residents (vs. staff) who vomited and infected considerably more secondary cases compared to non-index cases. Results suggest that individuals, particularly residents, who vomit are more infectious and tend to drive norovirus transmission in U.S. nursing home norovirus outbreaks. While diarrhea also plays a role in norovirus transmission, it is to a lesser degree than vomiting in these settings. Results lend support for prevention and control measures that focus on cases who vomit, particularly if those cases are residents.

in PLoS Computational Biology on March 25, 2020 09:00 PM.

by Christopher D. Chambers

Prestigious scientific journals traditionally decide which articles to accept at least partially based on the results of research. This backloaded selectivity enforces publication bias and encourages authors to selectively report their most persuasive findings, even when they are misleading, biased, and unreliable. One answer to backloaded selectivity is to curtail editorial selectivity altogether, deciding publication on the basis of technical merit alone. However, this strategy is unlikely to win appeal among highly selective journals. A third way is to frontload selectivity—reaching editorial decisions based on rigorous evaluation of the research question and methodology but before the research is conducted and thus regardless of the eventual results. This model, now offered at PLOS Biology in the form of “Preregistered Research Articles” (or Registered Reports), allows a scientific journal to maintain high selectivity for the importance and rigor of research while simultaneously eliminating outcome bias by editors, reviewers, and authors. I believe the rise of Registered Reports among selective journals will change how research is evaluated and may trigger the realization that frontloaded selectivity is the most secure way of advancing knowledge.

in PLoS Biology on March 25, 2020 09:00 PM.

• #### Early visual motion experience shapes the gap junction connections among direction selective ganglion cells

by Li Zhang, Qiwen Wu, Yifeng Zhang

Gap junction connections between neurons play critical roles in the development of the nervous system. However, studies on the sensory experience–driven plasticity during the critical period rarely examine the involvement of gap junction connections. ON-OFF direction selective ganglion cells (ooDSGCs) in the mouse retina that prefer upward motion are connected by gap junctions throughout development. Here, we show that after exposing the mice to a visual environment dominated by upward motion from eye-opening to puberty, ooDSGCs that respond preferentially to upward motion show enhanced spike synchronization, while downward motion training has the opposite effect. The effect is long-term, persisting at least three months after the training. Correlated activity during training is tightly linked to this effect: Cells trained by stimuli that promote higher levels of activity correlation show stronger gap junction connection after the training, while stimuli that produce very low activity correlation leave the cells with much weaker gap junction connections afterwards. Direct investigation of the gap junction connections among upward motion–preferring ooDSGCs show that both the percentage of electrically coupled ooDSGCs and the strength of the coupling are affected by visual motion training. Our results demonstrate that in the retina, one of the peripheral sensory systems, gap junction connections, can be shaped by experience during development.

in PLoS Biology on March 25, 2020 09:00 PM.

• #### Role of mechanical cues and hypoxia on the growth of tumor cells in strong and weak confinement: A dual in vitro-in silico approach

Characterization of tumor growth dynamics is of major importance for cancer understanding. By contrast with phenomenological approaches, mechanistic modeling can facilitate disclosing underlying tumor mechanisms and lead to identification of physical factors affecting proliferation and invasive behavior. Current mathematical models are often formulated at the tissue or organ scale with the scope of a direct clinical usefulness. Consequently, these approaches remain empirical and do not allow gaining insight into the tumor properties at the scale of small cell aggregates. Here, experimental and numerical studies of the dynamics of tumor aggregates are performed to propose a physics-based mathematical model as a general framework to investigate tumor microenvironment. The quantitative data extracted from the cellular capsule technology microfluidic experiments allow a thorough quantitative comparison with in silico experiments. This dual approach demonstrates the relative impact of oxygen and external mechanical forces during the time course of tumor model progression.

in Science Advances current issue on March 25, 2020 05:51 PM.

• #### Isolation of an elusive phosphatetrahedrane

This exploratory synthesis investigation was undertaken to determine the viability of replacing a single carbon vertex with another p-block element in a highly strained tetrahedrane molecule. Phosphorus was selected for this purpose because the stable molecular form of elemental phosphorus is tetrahedral. Our synthetic strategy was to generate an unsaturated phosphorus center bonded to a substituted cyclopropenyl group, a situation that could lead to closure to provide the desired phosphatetrahedrane framework. This was accomplished by dehydrofluorination of the in situ generated fluorophosphine H(F)P(CtBu)3. Tri-tert-butyl phosphatetrahedrane, P(CtBu)3, was then isolated in 19% yield as a low-melting, volatile, colorless solid and characterized spectroscopically and by a single-crystal x-ray diffraction study, confirming the tetrahedral nature of the molecule’s PC3 core. The molecule exhibits unexpected thermal stability.

in Science Advances current issue on March 25, 2020 05:51 PM.

• #### The insulator functions of the Drosophila polydactyl C2H2 zinc finger protein CTCF: Necessity versus sufficiency

In mammals, a C2H2 zinc finger (C2H2) protein, CTCF, acts as the master regulator of chromosomal architecture and of the expression of Hox gene clusters. Like mammalian CTCF, the Drosophila homolog, dCTCF, localizes to boundaries in the bithorax complex (BX-C). Here, we have determined the minimal requirements for the assembly of a functional boundary by dCTCF and two other C2H2 zinc finger proteins, Pita and Su(Hw). Although binding sites for these proteins are essential for the insulator activity of BX-C boundaries, these binding sites alone are insufficient to create a functional boundary. dCTCF cannot effectively bind to a single recognition sequence in chromatin or generate a functional insulator without the help of additional proteins. In addition, for boundary elements in BX-C at least four binding sites for dCTCF or the presence of additional DNA binding factors is required to generate a functional insulator.

in Science Advances current issue on March 25, 2020 05:51 PM.

• #### Biomimetic human small muscular pulmonary arteries

Changes in structure and function of small muscular arteries play a major role in the pathophysiology of pulmonary hypertension, a burgeoning public health challenge. Improved anatomically mimetic in vitro models of these microvessels are urgently needed because nonhuman vessels and previous models do not accurately recapitulate the microenvironment and architecture of the human microvascular wall. Here, we describe parallel biofabrication of photopatterned self-rolled biomimetic pulmonary arterial microvessels of tunable size and infrastructure. These microvessels feature anatomically accurate layering and patterning of aligned human smooth muscle cells, extracellular matrix, and endothelial cells and exhibit notable increases in endothelial longevity and nitric oxide production. Computational image processing yielded high-resolution 3D perspectives of cells and proteins. Our studies provide a new paradigm for engineering multicellular tissues with precise 3D spatial positioning of multiple constituents in planar moieties, providing a biomimetic platform for investigation of microvascular pathobiology in human disease.

in Science Advances current issue on March 25, 2020 05:51 PM.

• #### SKP1 drives the prophase I to metaphase I transition during male meiosis

The meiotic prophase I to metaphase I (PI/MI) transition requires chromosome desynapsis and metaphase competence acquisition. However, control of these major meiotic events is poorly understood. Here, we identify an essential role for SKP1, a core subunit of the SKP1–Cullin–F-box (SCF) ubiquitin E3 ligase, in the PI/MI transition. SKP1 localizes to synapsed chromosome axes and evicts HORMAD proteins from these regions in meiotic spermatocytes. SKP1-deficient spermatocytes display premature desynapsis, precocious pachytene exit, loss of PLK1 and BUB1 at centromeres, but persistence of HORMAD, H2AX, RPA2, and MLH1 in diplonema. Strikingly, SKP1-deficient spermatocytes show sharply reduced MPF activity and fail to enter MI despite treatment with okadaic acid. SKP1-deficient oocytes exhibit desynapsis, chromosome misalignment, and progressive postnatal loss. Therefore, SKP1 maintains synapsis in meiosis of both sexes. Furthermore, our results support a model where SKP1 functions as the long-sought intrinsic metaphase competence factor to orchestrate MI entry during male meiosis.

in Science Advances current issue on March 25, 2020 05:51 PM.

• #### Coordinated regulation of infection-related morphogenesis by the KMT2-Cre1-Hyd4 regulatory pathway to facilitate fungal infection

Entomopathogenic fungi can overcome insecticide resistance and represent promising tools for the control of mosquitoes. Better understanding of fungus-mosquito interactions is critical for improvement of fungal efficacy. Upon insect cuticle induction, pathogenic fungi undergo marked infection-related morphological differentiation. However, regulatory mechanisms of fungal infection–related morphogenesis are poorly understood. Here, we show that a histone lysine methyltransferase KMT2 in Metarhizium robertsii (MrKMT2) is up-regulated upon cuticle induction. MrKMT2 plays crucial roles in regulating infection-related morphogenesis and pathogenicity by up-regulating the transcription factor gene Mrcre1 via H3K4 trimethylation during mosquito cuticle infection. MrCre1 further regulates the cuticle-induced gene Mrhyd4 to modulate infection structure (appressorium) formation and virulence. Overall, the MrKMT2-MrCre1-MrHyd4 regulatory pathway regulates infection-related morphogenesis and pathogenicity in M. robertsii. These findings reveal that the epigenetic regulatory mechanism plays a pivotal role in regulating fungal pathogenesis in insects, and provide new insights into molecular interactions between pathogenic fungi and insect hosts.

in Science Advances current issue on March 25, 2020 05:51 PM.

• #### Breath figure-derived porous semiconducting films for organic electronics

Porous semiconductor film morphologies facilitate fluid diffusion and mass transport into the charge-carrying layers of diverse electronic devices. Here, we report the nature-inspired fabrication of several porous organic semiconductor-insulator blend films [semiconductor: P3HT (p-type polymer), C8BTBT (p-type small-molecule), and N2200 (n-type polymer); insulator: PS] by a breath figure patterning method and their broad and general applicability in organic thin-film transistors (OTFTs), gas sensors, organic electrochemical transistors (OECTs), and chemically doped conducting films. Detailed morphological analysis of these films demonstrates formation of textured layers with uniform nanopores reaching the bottom substrate with an unchanged solid-state packing structure. Device data gathered with both porous and dense control semiconductor films demonstrate that the former films are efficient TFT semiconductors but with added advantage of enhanced sensitivity to gases (e.g., 48.2%/ppm for NO2 using P3HT/PS), faster switching speeds (4.7 s for P3HT/PS OECTs), and more efficient molecular doping (conductivity, 0.13 S/m for N2200/PS).

in Science Advances current issue on March 25, 2020 05:51 PM.

• #### DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation

Imbalanced mitochondrial fission/fusion, a major cause of apoptotic cell death, often results from dysregulation of Drp1 phosphorylation of two serines, S616 and S637. Whereas kinases for Drp1-S616 phosphorylation are well-described, phosphatase(s) for its dephosphorylation remains unclear. Here, we show that dual-specificity phosphatase 6 (DUSP6) dephosphorylates Drp1-S616 independently of its known substrates ERK1/2. DUSP6 keeps Drp1-S616 phosphorylation levels low under normal conditions. The stability and catalytic function of DUSP6 are maintained through conjugation of small ubiquitin-like modifier-1 (SUMO1) and SUMO2/3 at lysine-234 (K234), which is disrupted during oxidation through transcriptional up-regulation of SUMO-deconjugating enzyme, SENP1, causing DUSP6 degradation by ubiquitin-proteasome. deSUMOylation underlies DUSP6 degradation, Drp1-S616 hyperphosphorylation, mitochondrial fragmentation, and apoptosis induced by H2O2 in cultured cells or brain ischemia/reperfusion in mice. Overexpression of DUSP6, but not the SUMOylation-deficient DUSP6K234R mutant, protected cells from apoptosis. Thus, DUSP6 exerts a cytoprotective role by directly dephosphorylating Drp1-S616, which is disrupted by deSUMOylation under oxidation.

in Science Advances current issue on March 25, 2020 05:51 PM.

• #### Irradiated tumor cell-derived microparticles mediate tumor eradication via cell killing and immune reprogramming

Radiotherapy (RT) is routinely used in cancer treatment, but expansion of its clinical indications remains challenging. The mechanism underlying the radiation-induced bystander effect (RIBE) is not understood and not therapeutically exploited. We suggest that the RIBE is predominantly mediated by irradiated tumor cell–released microparticles (RT-MPs), which induce broad antitumor effects and cause immunogenic death mainly through ferroptosis. Using a mouse model of malignant pleural effusion (MPE), we demonstrated that RT-MPs polarized microenvironmental M2 tumor-associated macrophages (M2-TAMs) to M1-TAMs and modulated antitumor interactions between TAMs and tumor cells. Following internalization of RT-MPs, TAMs displayed increased programmed cell death ligand 1 (PD-L1) expression, enhancing follow-up combined anti–PD-1 therapy that confers an ablative effect against MPE and cisplatin-resistant MPE mouse models. Immunological memory effects were induced.

in Science Advances current issue on March 25, 2020 05:51 PM.

• #### Bioenergetic-active materials enhance tissue regeneration by modulating cellular metabolic state

Cellular bioenergetics (CBE) plays a critical role in tissue regeneration. Physiologically, an enhanced metabolic state facilitates anabolic biosynthesis and mitosis to accelerate regeneration. However, the development of approaches to reprogram CBE, toward the treatment of substantial tissue injuries, has been limited thus far. Here, we show that induced repair in a rabbit model of weight-bearing bone defects is greatly enhanced using a bioenergetic-active material (BAM) scaffold compared to commercialized poly(lactic acid) and calcium phosphate ceramic scaffolds. This material was composed of energy-active units that can be released in a sustained degradation-mediated fashion once implanted. By establishing an intramitochondrial metabolic bypass, the internalized energy-active units significantly elevate mitochondrial membrane potential (m) to supply increased bioenergetic levels and accelerate bone formation. The ready-to-use material developed here represents a highly efficient and easy-to-implement therapeutic approach toward tissue regeneration, with promise for bench-to-bedside translation.

in Science Advances current issue on March 25, 2020 05:51 PM.

• #### Genetically Engineering the Nervous System with CRISPR-Cas

The multitude of neuronal subtypes and extensive interconnectivity of the mammalian brain presents a substantial challenge to those seeking to decipher its functions. While the molecular mechanisms of several neuronal functions remain poorly characterized, advances in next-generation sequencing (NGS) and gene-editing technology have begun to close this gap. The clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein (CRISPR-Cas) system has emerged as a powerful genetic tool capable of manipulating the genome of essentially any organism and cell type. This technology has advanced our understanding of complex neurologic diseases by enabling the rapid generation of novel, disease-relevant in vitro and transgenic animal models. In this review, we discuss recent developments in the rapidly accelerating field of CRISPR-mediated genome engineering. We begin with an overview of the canonical function of the CRISPR platform, followed by a functional review of its many adaptations, with an emphasis on its applications for genetic interrogation of the normal and diseased nervous system. Additionally, we discuss limitations of the CRISPR editing system and suggest how future modifications to existing platforms may advance our understanding of the brain.

in eNeuro current issue on March 25, 2020 04:30 PM.

• #### Propagating Activity in Neocortex, Mediated by Gap Junctions and Modulated by Extracellular Potassium

Abstract

Parvalbumin-expressing interneurons in cortical networks are coupled by gap junctions, forming a syncytium that supports propagating epileptiform discharges, induced by 4-aminopyridine. It remains unclear, however, whether these propagating events occur under more natural states, without pharmacological blockade. In particular, we investigated whether propagation also happens when extracellular K+ rises, as is known to occur following intense network activity, such as during seizures. We examined how increasing [K+]o affects the likelihood of propagating activity away from a site of focal (200–400 μm) optogenetic activation of parvalbumin-expressing interneurons. Activity was recorded using a linear 16-electrode array placed along layer V of primary visual cortex. At baseline levels of [K+]o (3.5 mm), induced activity was recorded only within the illuminated area. However, when [K+]o was increased above a threshold level (50th percentile = 8.0 mm; interquartile range = 7.5–9.5 mm), time-locked, fast-spiking unit activity, indicative of parvalbumin-expressing interneuron firing, was also recorded outside the illuminated area, propagating at 59.1 mm/s. The propagating unit activity was unaffected by blockade of GABAergic synaptic transmission, but it was modulated by glutamatergic blockers, and was reduced, and in most cases prevented altogether, by pharmacological blockade of gap junctions, achieved by any of the following three different drugs: quinine, mefloquine, or carbenoxolone. Washout of quinine rapidly re-established the pattern of propagating activity. Computer simulations show qualitative differences between propagating discharges in high [K+]o and 4-aminopyridine, arising from differences in the electrotonic effects of these two manipulations. These interneuronal syncytial interactions are likely to affect the complex electrographic dynamics of seizures, once [K+]o is raised above this threshold level.

in eNeuro current issue on March 25, 2020 04:30 PM.

• #### ROCK/PKA Inhibition Rescues Hippocampal Hyperexcitability and GABAergic Neuron Alterations in a Oligophrenin-1 Knock-Out Mouse Model of X-Linked Intellectual Disability

Oligophrenin-1 (Ophn1) encodes a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID) in humans. Loss of function of Ophn1 leads to impairments in the maturation and function of excitatory and inhibitory synapses, causing deficits in synaptic structure, function and plasticity. Epilepsy is a frequent comorbidity in patients with Ophn1-dependent XLID, but the cellular bases of hyperexcitability are poorly understood. Here we report that male mice knock-out (KO) for Ophn1 display hippocampal epileptiform alterations, which are associated with changes in parvalbumin-, somatostatin- and neuropeptide Y-positive interneurons. Because loss of function of Ophn1 is related to enhanced activity of Rho-associated protein kinase (ROCK) and protein kinase A (PKA), we attempted to rescue Ophn1-dependent pathological phenotypes by treatment with the ROCK/PKA inhibitor fasudil. While acute administration of fasudil had no impact on seizure activity, seven weeks of treatment in adulthood were able to correct electrographic, neuroanatomical and synaptic alterations of Ophn1 deficient mice. These data demonstrate that hyperexcitability and the associated changes in GABAergic markers can be rescued at the adult stage in Ophn1-dependent XLID through ROCK/PKA inhibition.

SIGNIFICANCE STATEMENT In this study we demonstrate enhanced seizure propensity and impairments in hippocampal GABAergic circuitry in Ophn1 mouse model of X-linked intellectual disability (XLID). Importantly, the enhanced susceptibility to seizures, accompanied by an alteration of GABAergic markers were rescued by Rho-associated protein kinase (ROCK)/protein kinase A (PKA) inhibitor fasudil, a drug already tested on humans. Because seizures can significantly impact the quality of life of XLID patients, the present data suggest a potential therapeutic pathway to correct alterations in GABAergic networks and dampen pathological hyperexcitability in adults with XLID.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Interneuron Desynchronization Precedes Seizures in a Mouse Model of Dravet Syndrome

Recurrent seizures, which define epilepsy, are transient abnormalities in the electrical activity of the brain. The mechanistic basis of seizure initiation, and the contribution of defined neuronal subtypes to seizure pathophysiology, remains poorly understood. We performed in vivo two-photon calcium imaging in neocortex during temperature-induced seizures in male and female Dravet syndrome (Scn1a+/–) mice, a neurodevelopmental disorder with prominent temperature-sensitive epilepsy. Mean activity of both putative principal cells and parvalbumin-positive interneurons (PV-INs) was higher in Scn1a+/– relative to wild-type controls during quiet wakefulness at baseline and at elevated core body temperature. However, wild-type PV-INs showed a progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/– mice. Hence, PV-IN activity remains intact interictally in Scn1a+/– mice, yet exhibits decreased synchrony immediately before seizure onset. We suggest that impaired PV-IN synchronization may contribute to the transition to the ictal state during temperature-induced seizures in Dravet syndrome.

SIGNIFICANCE STATEMENT Epilepsy is a common neurological disorder defined by recurrent, unprovoked seizures. However, basic mechanisms of seizure initiation and propagation remain poorly understood. We performed in vivo two-photon calcium imaging in an experimental model of Dravet syndrome (Scn1a+/– mice)—a severe neurodevelopmental disorder defined by temperature-sensitive, treatment-resistant epilepsy—and record activity of putative excitatory neurons and parvalbumin-positive GABAergic neocortical interneurons (PV-INs) during naturalistic seizures induced by increased core body temperature. PV-IN activity was higher in Scn1a+/– relative to wild-type controls during quiet wakefulness. However, wild-type PV-INs showed progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/– mice before seizure onset. Hence, impaired PV-IN synchronization may contribute to transition to seizure in Dravet syndrome.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Contrast Normalization Accounts for Binocular Interactions in Human Striate and Extra-striate Visual Cortex

During binocular viewing, visual inputs from the two eyes interact at the level of visual cortex. Here we studied binocular interactions in human visual cortex, including both sexes, using source-imaged steady-state visual evoked potentials over a wide range of relative contrast between two eyes. The ROIs included areas V1, V3a, hV4, hMT+, and lateral occipital cortex. Dichoptic parallel grating stimuli in each eye modulated at distinct temporal frequencies allowed us to quantify spectral components associated with the individual stimuli from monocular inputs (self-terms) and responses due to interaction between the inputs from the two eyes (intermodulation [IM] terms). Data with self-terms revealed an interocular suppression effect, in which the responses to the stimulus in one eye were reduced when a stimulus was presented simultaneously to the other eye. The suppression magnitude varied depending on visual area, and the relative contrast between the two eyes. Suppression was strongest in V1 and V3a (50% reduction) and was least in lateral occipital cortex (20% reduction). Data with IM terms revealed another form of binocular interaction, compared with self-terms. IM response was strongest at V1 and was least in hV4. Fits of a family of divisive gain control models to both self- and IM-term responses within each cortical area indicated that both forms of binocular interaction shared a common gain control nonlinearity. However, our model fits revealed different patterns of binocular interaction along the cortical hierarchy, particularly in terms of excitatory and suppressive contributions.

SIGNIFICANCE STATEMENT Using source-imaged steady-state visual evoked potentials and frequency-domain analysis of dichoptic stimuli, we measured two forms of binocular interactions: one is associated with the individual stimuli that represent interocular suppression from each eye, and the other is a direct measure of interocular interaction between inputs from the two eyes. We demonstrated that both forms of binocular interactions share a common gain control mechanism in striate and extra-striate cortex. Furthermore, our model fits revealed different patterns of binocular interaction along the visual cortical hierarchy, particularly in terms of excitatory and suppressive contributions.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Desire or Dread from Nucleus Accumbens Inhibitions: Reversed by Same-Site Optogenetic Excitations

Microinjections of a glutamate AMPA antagonist (DNQX) in medial shell of nucleus accumbens (NAc) can cause either intense appetitive motivation (i.e., 'desire') or intense defensive motivation (i.e., 'dread'), depending on site along a flexible rostrocaudal gradient and on environmental ambience. DNQX, by blocking excitatory AMPA glutamate inputs, is hypothesized to produce relative inhibitions of NAc neurons. However, given potential alternative explanations, it is not known whether neuronal inhibition is in fact necessary for NAc DNQX microinjections to generate motivations. Here we provide a direct test of whether local neuronal inhibition in NAc is necessary for DNQX microinjections to produce either desire or dread. We used optogenetic channelrhodopsin (ChR2) excitations at the same local sites in NAc as DNQX microinjections to oppose relative neuronal inhibitions induced by DNQX in female and male rats. We found that same-site ChR2 excitation effectively reversed the ability of NAc DNQX microinjections to generate appetitive motivation, and similarly reversed ability of DNQX microinjections to generate defensive motivation. Same-site NAc optogenetic excitations also attenuated recruitment of Fos expression in other limbic structures throughout the brain, which was otherwise elevated by NAc DNQX microinjections that generated motivation. However, to successfully reverse motivation generation, an optic fiber tip for ChR2 illumination needed to be located within <1 mm of the corresponding DNQX microinjector tip; that is, both truly at the same NAc site. Thus, we confirm that localized NAc neuronal inhibition is required for AMPA-blocking microinjections in medial shell to induce either positively-valenced 'desire' or negatively-valenced 'dread'.

SIGNIFICANCE STATEMENT A major hypothesis posits neuronal inhibitions in nucleus accumbens generate intense motivation. Microinjections in nucleus accumbens of glutamate antagonist, DNQX, which might suppress local neuronal firing, generate either appetitive or defensive motivation, depending on site and environmental factors. Is neuronal inhibition in nucleus accumbens required for such pharmacologically-induced motivations? Here we demonstrate that neuronal inhibition is necessary to generate appetitive or defensive motivations, using local optogenetic excitations to oppose putative DNQX-induced inhibitions. We show that excitation at the same site prevents DNQX microinjections from recruiting downstream limbic structures into neurobiological activation, and simultaneously prevents generation of either appetitive or defensive motivated behaviors. These results may be relevant to roles of nucleus accumbens mechanisms in pathological motivations, including addiction and paranoia.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Distance and Direction Codes Underlie Navigation of a Novel Semantic Space in the Human Brain

A recent proposal posits that humans might use the same neuronal machinery to support the representation of both spatial and nonspatial information, organizing concepts and memories using spatial codes. This view predicts that the same neuronal coding schemes characterizing navigation in the physical space (tuned to distance and direction) should underlie navigation of abstract semantic spaces, even if they are categorical and labeled by symbols. We constructed an artificial semantic environment by parsing a bidimensional audiovisual object space into four labeled categories. Before and after a nonspatial symbolic categorization training, 25 adults (15 females) were presented with pseudorandom sequences of objects and words during a functional MRI session. We reasoned that subsequent presentations of stimuli (either objects or words) referring to different categories implied implicit movements in the novel semantic space, and that such movements subtended specific distances and directions. Using whole-brain fMRI adaptation and searchlight model-based representational similarity analysis, we found evidence of both distance-based and direction-based responses in brain regions typically involved in spatial navigation: the medial prefrontal cortex and the right entorhinal cortex (EHC). After training, both regions encoded the distances between concepts, making it possible to recover a faithful bidimensional representation of the semantic space directly from their multivariate activity patterns, whereas the right EHC also exhibited a periodic modulation as a function of traveled direction. Our results indicate that the brain regions and coding schemes supporting relations and movements between spatial locations in mammals are "recycled" in humans to represent a bidimensional multisensory conceptual space during a symbolic categorization task.

SIGNIFICANCE STATEMENT The hippocampal formation and the medial prefrontal cortex of mammals represent the surrounding physical space by encoding distances and directions between locations. Recent works suggested that humans use the same neural machinery to organize their memories as points of an internal map of experiences. We asked whether the same brain regions and neural codes supporting spatial navigation are recruited when humans use language to organize their knowledge of the world in categorical semantic representations. Using fMRI, we show that the medial prefrontal cortex and the entorhinal portion of the hippocampal formation represent the distances and the movement directions between concepts of a novel audiovisual semantic space, and that it was possible to reconstruct, from neural data, their relationships in memory.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Covert Spatial Attention Speeds Target Individuation

Covert spatial attention has long been thought to speed visual processing. Psychophysics studies have shown that target information accrues faster at attended locations than at unattended locations. However, with behavioral evidence alone, it is difficult to determine whether attention speeds visual processing of the target or subsequent postperceptual stages of processing (e.g., converting sensory responses into decision signals). Moreover, although many studies have shown that attention can boost the amplitude of visually evoked neural responses, no robust effect has been observed on the latency of those neural responses. Here, we offer new evidence that may reconcile the neural and behavioral findings. We examined whether covert attention influenced the latency of the N2pc component, an electrophysiological marker of visual selection that has been linked with object individuation—the formation of an object representation that is distinct from the background and from other objects in the scene. To this end, we manipulated whether or not human observers (male and female) covertly attended the location of an impending search target. We found that the target evoked N2pc onset ~20 ms earlier when the target location was cued than when it was not cued. In a second experiment, we provided a direct replication of this effect, confirming that the effect of attention on N2pc latency is robust. Thus, although attention may not speed the earliest stages of sensory processing, attention does speed the critical transition between raw sensory encoding and the formation of individuated object representations.

SIGNIFICANCE STATEMENT Covert spatial attention improves processing at attended locations. Past behavioral studies have shown that information about visual targets accrues faster at attended than at unattended locations. However, it has remained unclear whether attention speeds perceptual analysis or subsequent postperceptual stages of processing. Here, we present robust evidence that attention speeds the N2pc, an electrophysiological signal that indexes the formation of individuated object representations. Our findings show that attention speeds a relatively early stage of perceptual processing while also elucidating the specific perceptual process that is speeded.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Representational Neural Mapping of Dexterous Grasping Before Lifting in Humans

The ability of humans to reach and grasp objects in their environment has been the mainstay paradigm for characterizing the neural circuitry driving object-centric actions. Although much is known about hand shaping, a persistent question is how the brain orchestrates and integrates the grasp with lift forces of the fingers in a coordinated manner. The objective of the current study was to investigate how the brain represents grasp configuration and lift force during a dexterous object-centric action in a large sample of male and female human subjects. BOLD activity was measured as subjects used a precision-grasp to lift an object with a center of mass (CoM) on the left or right with the goal of minimizing tilting the object. The extent to which grasp configuration and lift force varied between left and right CoM conditions was manipulated by grasping the object collinearly (requiring a non-collinear force distribution) or non-collinearly (requiring more symmetrical forces). Bayesian variational representational similarity analyses on fMRI data assessed the evidence that a set of cortical and cerebellar regions were sensitive to grasp configuration or lift force differences between CoM conditions at differing time points during a grasp to lift action. In doing so, we reveal strong evidence that grasping and lift force are not represented by spatially separate functionally specialized regions, but by the same regions at differing time points. The coordinated grasp to lift effort is shown to be under dorsolateral (PMv and AIP) more than dorsomedial control, and under SPL7, somatosensory PSC, ventral LOC and cerebellar control.

SIGNIFICANCE STATEMENT Clumsy disasters such as spilling, dropping, and crushing during our daily interactions with objects are a rarity rather than the norm. These disasters are avoided in part as a result of our orchestrated anticipatory efforts to integrate and coordinate grasping and lifting of object interactions, all before the lift of an object even commences. How the brain orchestrates this integration process has been largely neglected by historical approaches independently and solely focusing on reaching and grasping and the neural principles that guide them. Here, we test the extent to which grasping and lifting are represented in a spatially or temporally distinct manner and identified strong evidence for the consecutive emergence of sensitivity to grasping, then lifting within the same region.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Methamphetamine Learning Induces Persistent and Selective Nonmuscle Myosin II-Dependent Spine Motility in the Basolateral Amygdala

Nonmuscle myosin II inhibition (NMIIi) in the basolateral amygdala (BLA), but not dorsal hippocampus (CA1), selectively disrupts memories associated with methamphetamine (METH) days after learning, without retrieval. However, the molecular mechanisms underlying this selective vulnerability remain poorly understood. A known function of NMII is to transiently activate synaptic actin dynamics with learning. Therefore, we hypothesized that METH-associated learning perpetuates NMII-driven actin dynamics in synapses, leading to an extended window of vulnerability for memory disruption. We used time-lapse two-photon imaging of dendritic spine motility in acutely prepared brain slices from female and male mice following METH-associated learning as a readout of actin–myosin dynamics. Spine motility was persistently increased in the BLA, but not in CA1. Consistent with the memory disrupting effect of intra-BLA NMII inhibition, METH-induced changes to BLA spine dynamics were reversed by a single systemic injection of an NMII inhibitor. Intra-CA1 NMII inhibition, on the other hand, did not disrupt METH-associated memory. Thus, we report identification of a previously unknown ability for spine actin dynamics to persist days after stimulation and that this is under the control of NMII. Further, these perpetual NMII-driven spine actin dynamics in BLA neurons may contribute to the unique susceptibility of METH-associated memories.

SIGNIFICANCE STATEMENT There are no Food and Drug Administration-approved pharmacotherapies to prevent relapse to the use of stimulants, such as methamphetamine (METH). Environmental cues become associated with drug use, such that the memories can elicit strong motivation to seek the drug during abstinence. We previously reported that the storage of METH-associated memories is uniquely vulnerable to immediate, retrieval-independent, and lasting disruption by direct actin depolymerization or by inhibiting the actin driver nonmuscle myosin II (NMII) in the BLA or systemically. Here we report a potential structural mechanism responsible for the unique vulnerability of METH-associated memories and METH-seeking behavior to NMII inhibition within the BLA.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Neurotransmitters and Motoneuron Contacts of Multifunctional and Behaviorally Specialized Turtle Spinal Cord Interneurons

The spinal cord can appropriately generate diverse movements, even without brain input and movement-related sensory feedback, using a combination of multifunctional and behaviorally specialized interneurons. The adult turtle spinal cord can generate motor patterns underlying forward swimming, three forms of scratching, and limb withdrawal (flexion reflex). We previously described turtle spinal interneurons activated during both scratching and swimming (multifunctional interneurons), interneurons activated during scratching but not swimming (scratch-specialized interneurons), and interneurons activated during flexion reflex but not scratching or swimming (flexion reflex-selective interneurons). How multifunctional and behaviorally specialized turtle spinal interneurons affect downstream neurons was unknown. Here, we recorded intracellularly from spinal interneurons activated during these motor patterns in turtles of both sexes in vivo and filled each with dyes. We labeled motoneurons using choline acetyltransferase antibodies or earlier intraperitoneal FluoroGold injection and used immunocytochemistry of interneuron axon terminals to identify their neurotransmitter(s) and putative synaptic contacts with motoneurons. We found that multifunctional interneurons are heterogeneous with respect to neurotransmitter, with some glutamatergic and others GABAergic or glycinergic, and can directly contact motoneurons. Also, scratch-specialized interneurons are heterogeneous with respect to neurotransmitter and some directly contact motoneurons. Thus, scratch-specialized interneurons might directly excite motoneurons that are more strongly activated during scratching than forward swimming, such as hip-flexor motoneurons. Finally, and surprisingly, we found that some motoneurons are behaviorally specialized, for scratching or flexion reflex. Thus, either some limb muscles are only used for a subset of limb behaviors or some limb motoneurons are only recruited during certain limb behaviors.

SIGNIFICANCE STATEMENT Both multifunctional and behaviorally specialized spinal cord interneurons have been described in turtles, but their outputs are unknown. We studied responses of multifunctional interneurons (activated during swimming and scratching) and scratch-specialized interneurons, filled each with dyes, and used immunocytochemistry to determine their neurotransmitters and contacts with motoneurons. We found that both multifunctional and scratch-specialized interneurons are heterogeneous with respect to neurotransmitter, with some excitatory and others inhibitory. We found that some multifunctional and some scratch-specialized interneurons directly contact motoneurons. Scratch-specialized interneurons may excite motoneurons that are more strongly activated during scratching than swimming, such as hip-flexor motoneurons, or inhibit their antagonists, hip-extensor motoneurons. Surprisingly, we also found that some motoneurons are behaviorally specialized, for scratching or for flexion reflex.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Area-Specific Synapse Structure in Branched Posterior Nucleus Axons Reveals a New Level of Complexity in Thalamocortical Networks

Thalamocortical posterior nucleus (Po) axons innervating the vibrissal somatosensory (S1) and motor (MC) cortices are key links in the brain neuronal network that allows rodents to explore the environment whisking with their motile snout vibrissae. Here, using fine-scale high-end 3D electron microscopy, we demonstrate in adult male C57BL/6 wild-type mice marked differences between MC versus S1 Po synapses in (1) bouton and active zone size, (2) neurotransmitter vesicle pool size, (3) distribution of mitochondria around synapses, and (4) proportion of synapses established on dendritic spines and dendritic shafts. These differences are as large, or even more pronounced, than those between Po and ventro-posterior thalamic nucleus synapses in S1. Moreover, using single-axon transfection labeling, we demonstrate that the above differences actually occur on the MC versus the S1 branches of individual Po cell axons that innervate both areas. Along with recently-discovered divergences in efficacy and plasticity, the synaptic structure differences reported here thus reveal a new subcellular level of complexity. This is a finding that upends current models of thalamocortical circuitry, and that might as well illuminate the functional logic of other branched projection axon systems.

SIGNIFICANCE STATEMENT Many long-distance brain connections depend on neurons whose branched axons target separate regions. Using 3D electron microscopy and single-cell transfection, we investigated the mouse Posterior thalamic nucleus (Po) cell axons that simultaneously innervate motor and sensory areas of the cerebral cortex involved in whisker movement control. We demonstrate significant differences in the size of the boutons made in each area by individual Po axons, as well as in functionally-relevant parameters in the composition of their synapses. In addition, we found similarly large differences between the synapses of Po versus ventral posteromedial thalamic nucleus axons in the whisker sensory cortex. Area-specific synapse structure in individual axons implies a new, unsuspected level of complexity in long-distance brain connections.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Astrocytic YAP Promotes the Formation of Glia Scars and Neural Regeneration after Spinal Cord Injury

Yes-associated protein (YAP) transcriptional coactivator is negatively regulated by the Hippo pathway and functions in controlling the size of multiple organs, such as liver during development. However, it is not clear whether YAP signaling participates in the process of the formation of glia scars after spinal cord injury (SCI). In this study, we found that YAP was upregulated and activated in astrocytes of C57BL/6 male mice after SCI in a Hippo pathway-dependent manner. Conditional knockout (KO) of yap in astrocytes significantly inhibited astrocytic proliferation, impaired the formation of glial scars, inhibited the axonal regeneration, and impaired the behavioral recovery of C57BL/6 male mice after SCI. Mechanistically, the bFGF was upregulated after SCI and induced the activation of YAP through RhoA pathways, thereby promoting the formation of glial scars. Additionally, YAP promoted bFGF-induced proliferation by negatively controlling nuclear distribution of p27Kip1 mediated by CRM1. Finally, bFGF or XMU-MP-1 (an inhibitor of Hippo kinase MST1/2 to activate YAP) injection indeed activated YAP signaling and promoted the formation of glial scars and the functional recovery of mice after SCI. These findings suggest that YAP promotes the formation of glial scars and neural regeneration of mice after SCI, and that the bFGF-RhoA-YAP-p27Kip1 pathway positively regulates astrocytic proliferation after SCI.

SIGNIFICANCE STATEMENT Glial scars play critical roles in neuronal regeneration of CNS injury diseases, such as spinal cord injury (SCI). Here, we provide evidence for the function of Yes-associated protein (YAP) in the formation of glial scars after SCI through regulation of astrocyte proliferation. As a downstream of bFGF (which is upregulated after SCI), YAP promotes the proliferation of astrocytes through negatively controlling nuclear distribution of p27Kip1 mediated by CRM1. Activation of YAP by bFGF or XMU-MP-1 injection promotes the formation of glial scar and the functional recovery of mice after SCI. These results suggest that the bFGF-RhoA-YAP-p27Kip1 axis for the formation of glial scars may be a potential therapeutic strategy for SCI patients.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Cortical and Subcortical Effects of Transcutaneous Spinal Cord Stimulation in Humans with Tetraplegia

An increasing number of studies supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes functional recovery in humans with spinal cord injury (SCI). However, the neural mechanisms contributing to these effects remain poorly understood. Here we examined motor-evoked potentials in arm muscles elicited by cortical and subcortical stimulation of corticospinal axons before and after 20 min of TESS (30 Hz pulses with a 5 kHz carrier frequency) and sham-TESS applied between C5 and C6 spinous processes in males and females with and without chronic incomplete cervical SCI. The amplitude of subcortical, but not cortical, motor-evoked potentials increased in proximal and distal arm muscles for 75 min after TESS, but not sham-TESS, in control subjects and SCI participants, suggesting a subcortical origin for these effects. Intracortical inhibition, elicited by paired stimuli, increased after TESS in both groups. When TESS was applied without the 5 kHz carrier frequency both subcortical and cortical motor-evoked potentials were facilitated without changing intracortical inhibition, suggesting that the 5 kHz carrier frequency contributed to the cortical inhibitory effects. Hand and arm function improved largely when TESS was used with, compared with without, the 5 kHz carrier frequency. These novel observations demonstrate that TESS influences cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. We hypothesized that these parallel effects contribute to further the recovery of limb function following SCI.

SIGNIFICANCE STATEMENT Accumulating evidence supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes recovery of function in humans with spinal cord injury (SCI). Here, we show that a single session of TESS over the cervical spinal cord in individuals with incomplete chronic cervical SCI influenced in parallel the excitability cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. Importantly, these parallel physiological effects had an impact on the magnitude of improvements in voluntary motor output.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### EGF and a GSK3 Inhibitor Deplete Junctional E-cadherin and Stimulate Proliferation in the Mature Mammalian Ear

Sensory hair cell losses underlie the vast majority of permanent hearing and balance deficits in humans, but many nonmammalian vertebrates can fully recover from hearing impairments and balance dysfunctions because supporting cells (SCs) in their ears retain lifelong regenerative capacities that depend on proliferation and differentiation as replacement hair cells. Most SCs in vertebrate ears stop dividing during embryogenesis; and soon after birth, vestibular SCs in mammals transition to lasting quiescence as they develop massively thickened circumferential F-actin bands at their E-cadherin-rich adherens junctions. Here, we report that treatment with EGF and a GSK3 inhibitor thinned the circumferential F-actin bands throughout the sensory epithelium of cultured utricles that were isolated from adult mice of either sex. That treatment also caused decreases in E-cadherin, β-catenin, and YAP in the striola, and stimulated robust proliferation of mature, normally quiescent striolar SCs. The findings suggest that E-cadherin-rich junctions, which are not present in the SCs of the fish, amphibians, and birds which readily regenerate hair cells, are responsible in part for the mammalian ear's vulnerability to permanent balance and hearing deficits.

SIGNIFICANCE STATEMENT Millions of people are affected by hearing and balance deficits that arise when loud sounds, ototoxic drugs, infections, and aging cause hair cell losses. Such deficits are permanent for humans and other mammals, but nonmammals can recover hearing and balance after supporting cells regenerate replacement hair cells. Mammalian supporting cells lose the capacity to proliferate around the time they develop unique, exceptionally reinforced, E-cadherin-rich intercellular junctions. Here, we report the discovery of a pharmacological treatment that thins F-actin bands, depletes E-cadherin, and stimulates proliferation in long-quiescent supporting cells within a balance epithelium from adult mice. The findings suggest that high E-cadherin in those supporting cell junctions may be responsible, in part, for the permanence of hair cell loss in mammals.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Doc2 Proteins Are Not Required for the Increased Spontaneous Release Rate in Synaptotagmin-1-Deficient Neurons

Regulated secretion is controlled by Ca2+ sensors with different affinities and subcellular distributions. Inactivation of Syt1 (synaptotagmin-1), the main Ca2+ sensor for synchronous neurotransmission in many neurons, enhances asynchronous and spontaneous release rates, suggesting that Syt1 inhibits other sensors with higher Ca2+ affinities and/or lower cooperativities. Such sensors could include Doc2a and Doc2b, which have been implicated in spontaneous and asynchronous neurotransmitter release and compete with Syt1 for binding SNARE complexes. Here, we tested this hypothesis using triple-knock-out mice. Inactivation of Doc2a and Doc2b in Syt1-deficient neurons did not reduce the high spontaneous release rate. Overexpression of Doc2b variants in triple-knock-out neurons reduced spontaneous release but did not rescue synchronous release. A chimeric construct in which the C2AB domain of Syt1 was substituted by that of Doc2b did not support synchronous release either. Conversely, the soluble C2AB domain of Syt1 did not affect spontaneous release. We conclude that the high spontaneous release rate in synaptotagmin-deficient neurons does not involve the binding of Doc2 proteins to Syt1 binding sites in the SNARE complex. Instead, our results suggest that the C2AB domains of Syt1 and Doc2b specifically support synchronous and spontaneous release by separate mechanisms. (Both male and female neurons were studied without sex determination.)

SIGNIFICANCE STATEMENT Neurotransmission in the brain is regulated by presynaptic Ca2+ concentrations. Multiple Ca2+ sensor proteins contribute to synchronous (Syt1, Syt2), asynchronous (Syt7), and spontaneous (Doc2a/Doc2b) phases of neurotransmitter release. Genetic ablation of synchronous release was previously shown to affect other release phases, suggesting that multiple sensors may compete for similar release sites, together encoding stimulus–secretion coupling over a large range of synaptic Ca2+ concentrations. Here, we investigated the extent of functional overlap between Syt1, Doc2a, and Doc2b by reintroducing wild-type and mutant proteins in triple-knock-out neurons, and conclude that the sensors are highly specialized for different phases of release.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Synaptic Plasticity Depends on the Fine-Scale Input Pattern in Thin Dendrites of CA1 Pyramidal Neurons

Coordinated long-term plasticity of nearby excitatory synaptic inputs has been proposed to shape experience-related neuronal information processing. To elucidate the induction rules leading to spatially structured forms of synaptic potentiation in dendrites, we explored plasticity of glutamate uncaging-evoked excitatory input patterns with various spatial distributions in perisomatic dendrites of CA1 pyramidal neurons in slices from adult male rats. We show that (1) the cooperativity rules governing the induction of synaptic LTP depend on dendritic location; (2) LTP of input patterns that are subthreshold or suprathreshold to evoke local dendritic spikes (d-spikes) requires different spatial organization; and (3) input patterns evoking d-spikes can strengthen nearby, nonsynchronous synapses by local heterosynaptic plasticity crosstalk mediated by NMDAR-dependent MEK/ERK signaling. These results suggest that multiple mechanisms can trigger spatially organized synaptic plasticity on various spatial and temporal scales, enriching the ability of neurons to use synaptic clustering for information processing.

SIGNIFICANCE STATEMENT A fundamental question in neuroscience is how neuronal feature selectivity is established via the combination of dendritic processing of synaptic input patterns with long-term synaptic plasticity. As these processes have been mostly studied separately, the relationship between the rules of integration and rules of plasticity remained elusive. Here we explore how the fine-grained spatial pattern and the form of voltage integration determine plasticity of different excitatory synaptic input patterns in perisomatic dendrites of CA1 pyramidal cells. We demonstrate that the plasticity rules depend highly on three factors: (1) the location of the input within the dendritic branch (proximal vs distal), (2) the strength of the input pattern (subthreshold or suprathreshold for dendritic spikes), and (3) the stimulation of neighboring synapses.

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Local Cortical Circuit Features Arise in Networks Optimized for Associative Memory Storage

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### This Week in The Journal

in Journal of Neuroscience current issue on March 25, 2020 04:30 PM.

• #### Time-to-target simplifies optimal control of visuomotor feedback responses

Abstract

Visuomotor feedback responses vary in intensity throughout a reach, commonly explained by optimal control. Here we show that the optimal control for a range of movements with the same goal can be simplified to a time-to-target dependent control scheme. We measure our human participants’ visuomotor responses in five reaching conditions, each with different hand or cursor kinematics. Participants only produced different feedback responses when these kinematic changes resulted in different times-to-target. We complement our experimental data with a range of finite and non-finite horizon optimal feedback control models, finding that the model with time-to-target as one of the input parameters best replicates the experimental data. Overall, this suggests that time-to-target is a critical control parameter in online feedback control. Moreover, we propose that for a specific task and known dynamics, humans can instantly produce a control signal without any additional online computation allowing rapid response onset and close to optimal control.

Significance statement Human behaviour has widely been explained using stochastic optimal feedback control (OFC), formulating movement control as a set of time-dependent feedback and control gains. However, OFC is computationally expensive leading to questions about whether such a theory could be implemented in real time. Here we show that optimal feedback control could be approximated by a simple relationship between feedback gains and the time-to-target over a variety of movement kinematics, matching the evolution of visuomotor feedback gains of our human participants during reaching. As this relationship to time-to-target is similar across a wide range of kinematics, this suggests that early stages of the OFC controlled movement could be approximated by a time-to-target control, saving computational costs and allowing for rapid execution.

in RSS PAP on March 25, 2020 04:30 PM.

• #### Tractogram filtering of anatomically non-plausible fibers with geometric deep learning. (arXiv:2003.11013v1 [q-bio.NC])

Tractograms are virtual representations of the white matter fibers of the brain. They are of primary interest for tasks like presurgical planning, and investigation of neuroplasticity or brain disorders. Each tractogram is composed of millions of fibers encoded as 3D polylines. Unfortunately, a large portion of those fibers are not anatomically plausible and can be considered artifacts of the tracking algorithms. Common methods for tractogram filtering are based on signal reconstruction, a principled approach, but unable to consider the knowledge of brain anatomy. In this work, we address the problem of tractogram filtering as a supervised learning problem by exploiting the ground truth annotations obtained with a recent heuristic method, which labels fibers as either anatomically plausible or non-plausible according to well-established anatomical properties. The intuitive idea is to model a fiber as a point cloud and the goal is to investigate whether and how a geometric deep learning model might capture its anatomical properties. Our contribution is an extension of the Dynamic Edge Convolution model that exploits the sequential relations of points in a fiber and discriminates with high accuracy plausible/non-plausible fibers.

in q-bio.NC updates on arXiv.org on March 25, 2020 01:30 AM.

• #### Independent components of human brain morphology. (arXiv:2003.10514v1 [q-bio.NC])

Quantification of brain morphology has become an important cornerstone in understanding brain structure. Measures of cortical morphology such as thickness and surface area are frequently used to compare groups of subjects or characterise longitudinal changes. However, such measures are often treated as independent from each other.

A recently described scaling law, derived from a statistical physics model of cortical folding, demonstrates that there is a tight covariance between three commonly used cortical morphology measures: cortical thickness, total surface area, and exposed surface area.

We show that assuming the independence of cortical morphology measures can hide features and potentially lead to misinterpretations. Using the scaling law, we account for the covariance between cortical morphology measures and derive novel independent measures of cortical morphology. By applying these new measures, we show that new information can be gained; in our example we show that distinct morphological alterations underlie healthy ageing compared to temporal lobe epilepsy, even on the coarse level of a whole hemisphere.

We thus provide a conceptual framework for characterising cortical morphology in a statistically valid and interpretable manner, based on theoretical reasoning about the shape of the cortex.

in q-bio.NC updates on arXiv.org on March 25, 2020 01:30 AM.

• #### 50 years since the Marr, Ito, and Albus models of the cerebellum. (arXiv:2003.05647v3 [q-bio.NC] UPDATED)

Fifty years have passed since David Marr, Masao Ito, and James Albus proposed seminal models of cerebellar functions. These models share the essential concept that parallel-fiber-Purkinje-cell synapses undergo plastic changes, guided by climbing-fiber activities during sensorimotor learning. However, they differ in several important respects, including holistic versus complementary roles of the cerebellum, pattern recognition versus control as computational objectives, potentiation versus depression of synaptic plasticity, teaching signals versus error signals transmitted by climbing-fibers, sparse expansion coding by granule cells, and cerebellar internal models. In this review, we evaluate the different features of the three models based on recent computational and experimental studies. While acknowledging that the three models have greatly advanced our understanding of cerebellar control mechanisms in eye movements and classical conditioning, we propose a new direction for computational frameworks of the cerebellum. That is, hierarchical reinforcement learning with multiple internal models.

in q-bio.NC updates on arXiv.org on March 25, 2020 01:30 AM.

• #### Models Currently Implemented in MIIND. (arXiv:2003.01385v2 [q-bio.NC] UPDATED)

This is a living document that will be updated when appropriate. MIIND [1, 2] is a population-level neural simulator. It is based on population density techniques, just like DIPDE [3]. Contrary to DIPDE, MIIND is agnostic to the underlying neuron model used in its populations so any 1, 2 or 3 dimensional model can be set up with minimal effort. The resulting populations can then be grouped into large networks, e.g. the Potjans-Diesmann model [4]. The MIIND website this http URL contains training materials, and helps to set up MIIND, either by using virtual machines, a DOCKER image, or directly from source code.

in q-bio.NC updates on arXiv.org on March 25, 2020 01:30 AM.

• #### Construction of a human cell landscape at single-cell level

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2157-4

Construction of a human cell landscape at single-cell level

in Nature on March 25, 2020 12:00 AM.

• #### Author Correction: Estimating and tracking the remaining carbon budget for stringent climate targets

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2147-6

Author Correction: Estimating and tracking the remaining carbon budget for stringent climate targets

in Nature on March 25, 2020 12:00 AM.

• #### Video-based AI for beat-to-beat assessment of cardiac function

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2145-8

A video-based deep learning algorithm—EchoNet-Dynamic—accurately identifies subtle changes in ejection fraction and classifies heart failure with reduced ejection fraction using information from multiple cardiac cycles.

in Nature on March 25, 2020 12:00 AM.

• #### Integrating genomic features for non-invasive early lung cancer detection

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2140-0

Circulating tumour DNA in blood is analysed to identify genomic features that distinguish early-stage lung cancer patients from risk-matched controls, and these are integrated into a machine-learning method for blood-based lung cancer screening.

in Nature on March 25, 2020 12:00 AM.

• #### Centrosome anchoring regulates progenitor properties and cortical formation

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2139-6

CEP83-mediated anchoring of the centrosome to the apical membrane in radial glial progenitor cells regulates their mechanical properties and thereby influences the size and configuration of the mammalian cortex.

in Nature on March 25, 2020 12:00 AM.

• #### Global conservation of species’ niches

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2138-7

Protected areas would need to expand to 33.8% of the total land surface to adequately represent environmental conditions across the habitats of amphibians, birds and terrestrial mammals, far exceeding the current 17% target.

in Nature on March 25, 2020 12:00 AM.

• #### The ABC exporter IrtAB imports and reduces mycobacterial siderophores

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2136-9

The mycobacterial ABC transporter IrtAB functions as a siderophore importer despite exhibiting an exporter fold in its structure, and contains a siderophore interaction domain capable of siderophore reduction and iron release inside the cell.

in Nature on March 25, 2020 12:00 AM.

• #### A genomic and epigenomic atlas of prostate cancer in Asian populations

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2135-x

Genomic, transcriptomic and DNA methylation data from tissue samples from 208 Chinese patients with prostate cancer define the landscape of alterations in this population, and comparison with data from Western cohorts suggests that the disease may stratify into different molecular subtypes.

in Nature on March 25, 2020 12:00 AM.

• #### A conserved dendritic-cell regulatory program limits antitumour immunity

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2134-y

After taking up tumour-associated antigens, dendritic cells in mouse and human tumours upregulate a regulatory gene program that limits dendritic cell immunostimulatory function, and modulating this program can rescue antitumor immunity in mice.

in Nature on March 25, 2020 12:00 AM.

• #### Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2129-8

Analyses of mouse models of inflammation suggest some chronic inflammatory conditions may result from Z-DNA-binding protein 1 sensing endogenous Z-form nucleic acids—such as those of endogenous retroelements—through its Zα domains.

in Nature on March 25, 2020 12:00 AM.

• #### Gut stem cell necroptosis by genome instability triggers bowel inflammation

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2127-x

In mouse models of bowel inflammation, depletion of the SETDB1 histone methyltransferase leads to genome instability, which releases repression of endogenous retroviruses that triggers ZBP1-dependent necroptosis and inflammation in gut.

in Nature on March 25, 2020 12:00 AM.

• #### Parental-to-embryo switch of chromosome organization in early embryogenesis

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2125-z

Single-cell allelic HiC analysis, combined with allelic gene expression and chromatin states, reveals parent-of-origin-specific dynamics of chromosome organization and gene expression during mouse preimplantation development.

in Nature on March 25, 2020 12:00 AM.

• #### Dietary modifications for enhanced cancer therapy

Nature, Published online: 25 March 2020; doi:10.1038/s41586-020-2124-0

Dietary modifications for enhanced cancer therapy

in Nature on March 25, 2020 12:00 AM.

• #### Held in the balance

Nature Reviews Neuroscience, Published online: 25 March 2020; doi:10.1038/s41583-020-0295-1

Chandelier cells, a type of cortical interneuron targeting the axon initial segment of pyramidal cells are shown to monitor network activity and adjust their output in a homeostatic manner.

in Nature Reviews Neuroscience - Issue - nature.com science feeds on March 25, 2020 12:00 AM.

• #### Author Correction: Earth rotation measured by a chip-scale ring laser gyroscope

Nature Photonics, Published online: 25 March 2020; doi:10.1038/s41566-020-0622-0

Author Correction: Earth rotation measured by a chip-scale ring laser gyroscope

in Nature Photonics - Issue - nature.com science feeds on March 25, 2020 12:00 AM.

• #### A Neuroanatomically Grounded Optimal Control Model of the Compensatory Eye Movement System in Mice

We present a working model of the compensatory eye movement system in mice. We challenge the model with a data set of eye movements in mice (n =34) recorded in 4 different sinusoidal stimulus conditions with 36 different combinations of frequency (0.1–3.2 Hz) and amplitude (0.5–8°) in each condition. The conditions included vestibular stimulation in the dark (vestibular-ocular reflex, VOR), optokinetic stimulation (optokinetic reflex, OKR), and two combined visual/vestibular conditions (the visual-vestibular ocular reflex, vVOR, and visual suppression of the VOR, sVOR). The model successfully reproduced the eye movements in all conditions, except for minor failures to predict phase when gain was very low. Most importantly, it could explain the interaction of VOR and OKR when the two reflexes are activated simultaneously during vVOR stimulation. In addition to our own data, we also reproduced the behavior of the compensatory eye movement system found in the existing literature. These include its response to sum-of-sines stimuli, its response after lesions of the nucleus prepositus hypoglossi or the flocculus, characteristics of VOR adaptation, and characteristics of drift in the dark. Our model is based on ideas of state prediction and forward modeling that have been widely used in the study of motor control. However, it represents one of the first quantitative efforts to simulate the full range of behaviors of a specific system. The model has two separate processing loops, one for vestibular stimulation and one for visual stimulation. Importantly, state prediction in the visual processing loop depends on a forward model of residual retinal slip after vestibular processing. In addition, we hypothesize that adaptation in the system is primarily adaptation of this model. In other words, VOR adaptation happens primarily in the OKR loop.

in Frontiers in Systems Neuroscience on March 25, 2020 12:00 AM.

• #### World Statistics Drive Learning of Cerebellar Internal Models in Adaptive Feedback Control: A Case Study Using the Optokinetic Reflex

The cerebellum is widely implicated in having an important role in adaptive motor control. Many of the computational studies on cerebellar motor control to date have focused on the associated architecture and learning algorithms in an effort to further understand cerebellar function. In this paper we switch focus to the signals driving cerebellar adaptation that arise through different motor behavior. To do this, we investigate computationally the contribution of the cerebellum to the optokinetic reflex (OKR), a visual feedback control scheme for image stabilization. We develop a computational model of the adaptation of the cerebellar response to the world velocity signals that excite the OKR (where world velocity signals are used to emulate head velocity signals when studying the OKR in head-fixed experimental laboratory conditions). The results show that the filter learnt by the cerebellar model is highly dependent on the power spectrum of the colored noise world velocity excitation signal. Thus, the key finding here is that the cerebellar filter is determined by the statistics of the OKR excitation signal.

in Frontiers in Systems Neuroscience on March 25, 2020 12:00 AM.

• #### Stereotactically Injected Kv1.2 and CASPR2 Antisera Cause Differential Effects on CA1 Synaptic and Cellular Excitability, but Both Enhance the Vulnerability to Pro-epileptic Conditions

Purpose

We present a case of voltage-gated potassium channel (VGKC) complex antibody-positive limbic encephalitis (LE) harboring autoantibodies against Kv1.2. Since the patient responded well to immunotherapy, the autoantibodies were regarded as pathogenic. We aimed to characterize the pathophysiological role of this antibody in comparison to an antibody against the VGKC-associated protein contactin-associated protein-2 (CASPR2).

Methods

Stereotactic injection of patient sera (anti-Kv1.2-associated LE or anti-CASPR2 encephalopathy) and a control subject was performed into the hippocampus of the anesthetized rat in vivo, and hippocampal slices were prepared for electrophysiological purposes. Using extra- and intracellular techniques, synaptic transmission, long-term potentiation (LTP) and vulnerability to pro-epileptic conditions were analyzed.

Results

We observed that the slope of the field excitatory postsynaptic potential (fEPSP) was significantly increased at Schaffer collateral-CA1 synapses in anti-Kv1.2-treated and anti-CASPR2-treated rats, but not at medial perforant path-dentate gyrus synapses. The increase of the fEPSP slope in CA1 was accompanied by a decrease of the paired-pulse ratio in anti-Kv1.2, but not in anti-CASPR2 tissue, indicating presynaptic site of anti-Kv1.2. In addition, anti-Kv1.2 tissue showed enhanced LTP in CA1, but dentate gyrus LTP remained unaltered. Importantly, LTP in slices from anti-CASPR2-treated animals did not differ from control values. Intracellular recordings from CA1 neurons revealed that the resting membrane potential and a single action potential were not different between anti-Kv1.2 and control tissue. However, when the depolarization was prolonged, the number of action potentials elicited was reduced in anti-Kv1.2-treated tissue compared to both control and anti-CASPR2 tissue. In contrast, polyspike discharges induced by removal of Mg2+ occurred earlier and more frequently in both patient sera compared to control.

Conclusion

Patient serum containing anti-Kv1.2 facilitates presynaptic transmitter release as well as postsynaptic depolarization at the Schaffer-collateral-CA1 synapse, but not in the dentate gyrus. As a consequence, both synaptic transmission and LTP in CA1 are facilitated and action potential firing is altered. In contrast, anti-CASPR2 leads to increased postsynaptic potentials, but without changing LTP or firing properties suggesting that anti-Kv1.2 and anti-CASPR2 differ in their cellular effects. Both patient sera alter susceptibility to epileptic conditions, but presumably by different mechanisms.

in Frontiers in Synaptic Neuroscience on March 25, 2020 12:00 AM.

• #### CAV-2-Mediated GFP and LRRK2G2019S Expression in the Macaca fascicularis Brain

Parkinson’s disease is characterized by motor and nonmotor symptoms that gradually appear as a consequence of the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Currently, no treatment can slow Parkinson’s disease progression. Inasmuch, there is a need to develop animal models that can be used to understand the pathophysiological mechanisms underlying dopaminergic neuron death. The initial goal of this study was to determine if canine adenovirus type 2 (CAV-2) vectors are effective gene transfer tools in the monkey brain. A second objective was to explore the possibility of developing a large nonhuman primate that expresses one of the most common genetic mutations causing Parkinson’s disease. Our studies demonstrate the neuronal tropism, retrograde transport, biodistribution, and efficacy of CAV-2 vectors expressing GFP and leucine-rich repeat kinase 2 (LRRK2G2019S) in the Macaca fascicularis brain. Our data also suggest that following optimization CAV-2-mediated LRRK2G2019S expression could help us model the neurodegenerative processes of this genetic subtype of Parkinson’s disease in monkeys.

in Frontiers in Molecular Neuroscience on March 25, 2020 12:00 AM.

• #### Fully Integrated PET/MR Imaging for the Assessment of the Relationship Between Functional Connectivity and Glucose Metabolic Rate

In the past, determination of absolute values of cerebral metabolic rate of glucose (CMRGlc) in clinical routine was rarely carried out due to the invasive nature of arterial sampling. With the advent of combined PET/MR imaging technology, CMRGlc values can be obtained non-invasively, thereby providing the opportunity to take advantage of fully quantitative data in clinical routine. However, CMRGlc values display high physiological variability, presumably due to fluctuations in the intrinsic activity of the brain at rest. To reduce CMRGlc variability associated with these fluctuations, the objective of this study was to determine whether functional connectivity measures derived from resting-state fMRI (rs-fMRI) could be used to correct for these fluctuations in intrinsic brain activity. Methods: We studied 10 healthy volunteers who underwent a test-retest dynamic [18F]FDG-PET study using a fully integrated PET/MR system (Siemens Biograph mMR). To validate the non-invasive derivation of an image-derived input function based on combined analysis of PET and MR data, arterial blood samples were obtained. Using the arterial input function (AIF), parametric images representing CMRGlc were determined using the Patlak graphical approach. Both directed functional connectivity (dFC) and undirected functional connectivity (uFC) were determined between nodes in six major networks (Default mode network, Salience, L/R Executive, Attention, and Sensory-motor network) using either a bivariate-correlation (R coefficient) or a Multi-Variate AutoRegressive (MVAR) model. In addition, the performance of a regional connectivity measure, the fractional amplitude of low frequency fluctuations (fALFF), was also investigated. Results: The average intrasubject variability for CMRGlc values between test and retest was determined as (14 ±8%) with an average inter-subject variability of 25% at test and 15% at retest. The average CMRGlc value (umol/100 g/min) across all networks was 39 ±10 at test and increased slightly to 43 ±6 at retest. The R, MVAR and fALFF coefficients showed relatively large test-retest variability in comparison to the inter-subjects variability, resulting in poor reliability (intraclass correlation in the range of 0.11–0.65). More importantly, no significant relationship was found between the R coefficients (for uFC), MVAR coefficients (for dFC) or fALFF and corresponding CMRGlc values for any of the six major networks. Discussion: Measurement of functional connectivity within established brain networks did not provide a means to decrease the inter- or intrasubject variability of CMRGlc values. As such, our results indicate that connectivity measured derived from rs-fMRI acquired contemporaneously with PET imaging are not suited for correction of CMRGlc variability associated with intrinsic fluctuations of resting-state brain activity. Thus, given the observed substantial inter- and intrasubject variability of CMRGlc values, the relevance of absolute quantification for clinical routine is presently uncertain.

in Frontiers in Neuroscience: Brain Imaging Methods on March 25, 2020 12:00 AM.

• #### Twice-Daily Theta Burst Stimulation of the Dorsolateral Prefrontal Cortex Reduces Methamphetamine Craving: A Pilot Study

Objectives

Transcranial magnetic stimulation (TMS) holds potential promise as a therapeutic modality for disorders of addiction. Our previous findings indicate that high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsal–lateral prefrontal cortex (DLPFC) and low-frequency rTMS over the right DLPFC can reduce drug craving for methamphetamine. One major issue with rTMS is the duration of treatment and hence potential dropout rate. Theta burst stimulation (TBS) has been recently shown to be non-inferior relative to repetitive transcranial magnetic stimulation for major depression. Here, we aim to compare the clinical efficacy and tolerability of intermittent and continuous theta burst stimulation protocols targeting left or right dorsolateral prefrontal cortex on methamphetamine craving in abstinent-dependent subjects.

Methods

In this randomized single-blind pilot study, 83 abstinent methamphetamine-dependent subjects from a long-term residential treatment program were randomly allocated into three groups: intermittent theta burst stimulation (iTBS) over the left DLPFC (active group), continuous theta burst stimulation (cTBS) over the left DLPFC (active control group), or cTBS over the right DLPFC (active group) was administered twice daily over 5 days for a total of 10 sessions. We measured the primary outcome of cue-induced craving and secondarily sleep quality, depression, anxiety, impulsivity scores, and adverse effects.

Results

We show a pre- vs. postintervention effect on craving, which, on paired t tests, showed that the effect was driven by iTBS of the left DLPFC and cTBS of the right DLPFC, reducing cue-induced craving but not cTBS of the left DLPFC. We did not show the critical group-by-time interaction. The secondary outcomes of depression, anxiety, and sleep were unrelated to the improvement in craving in the left iTBS and right cTBS group. In the first two sessions, self-reported adverse effects were higher with left iTBS when compared to right cTBS. The distribution of craving change suggested greater clinical response (50% improvement) with right cTBS and a bimodal pattern of effect with left iTBS, suggesting high interindividual variable response in the latter.

Conclusion

Accelerated twice-daily TBS appears feasible and tolerable at modulating craving and mood changes in abstinent methamphetamine dependence critically while reducing session length. We emphasize the need for a larger randomized controlled trial study with a sham control to confirm these findings and longer duration of clinically relevant follow-up.

Clinical Trial Registration

Chinese Clinical Trial Registry number, 17013610.

in Frontiers in Neuroscience: Neural Technology on March 25, 2020 12:00 AM.

• #### Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is an intractable adult-onset neurodegenerative disease that leads to the loss of upper and lower motor neurons (MNs). The long axons of MNs become damaged during the early stages of ALS. Genetic and pathological analyses of ALS patients have revealed dysfunction in the MN axon homeostasis. However, the molecular pathomechanism for the degeneration of axons in ALS has not been fully elucidated. This review provides an overview of the proposed axonal pathomechanisms in ALS, including those involving the neuronal cytoskeleton, cargo transport within axons, axonal energy supply, clearance of junk protein, neuromuscular junctions (NMJs), and aberrant axonal branching. To improve understanding of the global changes in axons, the review summarizes omics analyses of the axonal compartments of neurons in vitro and in vivo, including a motor nerve organoid approach that utilizes microfluidic devices developed by this research group. The review also discusses the relevance of intra-axonal transcription factors frequently identified in these omics analyses. Local axonal translation and the relationship among these pathomechanisms should be pursued further. The development of novel strategies to analyze axon fractions provides a new approach to establishing a detailed understanding of resilience of long MN and MN pathology in ALS.

in Frontiers in Neuroscience: Neurodegeneration on March 25, 2020 12:00 AM.

• #### Finite Element Simulation of Ionic Electrodiffusion in Cellular Geometries

Mathematical models for excitable cells are commonly based on cable theory, which considers a homogenized domain and spatially constant ionic concentrations. Although such models provide valuable insight, the effect of altered ion concentrations or detailed cell morphology on the electrical potentials cannot be captured. In this paper, we discuss an alternative approach to detailed modeling of electrodiffusion in neural tissue. The mathematical model describes the distribution and evolution of ion concentrations in a geometrically-explicit representation of the intra- and extracellular domains. As a combination of the electroneutral Kirchhoff-Nernst-Planck (KNP) model and the Extracellular-Membrane-Intracellular (EMI) framework, we refer to this model as the KNP-EMI model. Here, we introduce and numerically evaluate a new, finite element-based numerical scheme for the KNP-EMI model, capable of efficiently and flexibly handling geometries of arbitrary dimension and arbitrary polynomial degree. Moreover, we compare the electrical potentials predicted by the KNP-EMI and EMI models. Finally, we study ephaptic coupling induced in an unmyelinated axon bundle and demonstrate how the KNP-EMI framework can give new insights in this setting.

in Frontiers in Neuroinformatics on March 25, 2020 12:00 AM.

• #### Establishing a Causal Role for Medial Prefrontal Cortex in Reality Monitoring

Reality monitoring is defined as the ability to distinguish internally self-generated information from externally-derived information. Functional imaging studies have consistently found that the medial prefrontal cortex (mPFC) is a key brain region subserving reality monitoring. This study aimed to determine a causal role for mPFC in reality monitoring using navigated repetitive transcranial magnetic stimulation (nrTMS). In a subject-blinded sham-controlled crossover design, healthy individuals received either active or sham nrTMS targeting mPFC. Active modulation of mPFC using nrTMS at a frequency of 10 Hz, significantly improved identification of both self-generated and externally-derived information during reality monitoring, when compared to sham or baseline. Targeted excitatory modulation of mPFC also improved positive mood, reduced negative mood, and increased overall alertness/arousal. These results establish optimal nrTMS dosing parameters that maximized tolerability/comfort and induced significant neuromodulatory effects in the mPFC target. Importantly, this is a proof-of-concept study that establishes the mPFC as a novel brain target that can be stimulated with nrTMS to causally impact both higher-order reality monitoring and mood.

in Frontiers in Human Neuroscience on March 25, 2020 12:00 AM.

• #### The Adoption of New Treatment Modalities by Health Professionals and the Relative Weight of Empirical Evidence in Favor of Virtual Reality Exposure Versus Mindfulness in the Treatment of Anxiety Disorders

Anxiety disorders are among the most prevalent mental disorders, and cognitive-behavioral therapy (CBT) with exposure exercises is considered as the gold-standard psychological intervention. New psychotherapeutic modalities have emerged in the last decade and, among them, mindfulness has been rapidly adopted by therapists. The adoption rate is slower for the use of virtual reality (VR) to conduct exposure. The goal of the present position paper is to contrast, for the treatment of anxiety disorders, the weight of empirical evidences supporting the use of exposure in VR with the use of mindfulness-based therapy (MBT). Based on the most recent meta-analyses, we found that CBT with exposure conducted in VR was more thoroughly researched and supported than MBT, receiving validation from roughly twice as many studies with high control (i.e., randomized, active controls with clinical samples). However, this conclusion is nuanced by reviewing gaps in the literature for both therapies. Potential factors influencing clinicians’ choice of treatment and suggestions for future research directions are proposed.

in Frontiers in Human Neuroscience on March 25, 2020 12:00 AM.

• #### Off-Target Influences of Arch-Mediated Axon Terminal Inhibition on Network Activity and Behavior

Archaerhodopsin (ArchT)-mediated photoinhibition of axon terminals is commonly used to test the involvement of specific long-range neural projections in behavior. Although sustained activation of this opsin in axon terminals has the unintended consequence of enhancing spontaneous vesicle release, it is unclear whether this desynchronized signaling is consequential for ArchT’s behavioral effects. Here, we compare axon terminal and cell body photoinhibition of nucleus accumbens (NAc) afferents to test the utility of these approaches for uncovering pathway-specific contributions of neural circuits to behavior. First, in brain slice recordings we confirmed that ArchT photoinhibition of glutamatergic axons reduces evoked synaptic currents and increases spontaneous transmitter release. A further consequence was increased interneuron activity, which served to broadly suppress glutamate input via presynaptic GABAB receptors. In vivo, axon terminal photoinhibition increased feeding and reward-seeking behavior irrespective of the afferent pathway targeted. These behavioral effects are comparable to those obtained with broad inhibition of NAc neurons. In contrast, cell body inhibition of excitatory NAc afferents revealed a pathway-specific contribution of thalamic input to feeding behavior and amygdala input to reward-seeking under extinction conditions. These findings underscore the off-target behavioral consequences of ArchT-mediated axon terminal inhibition while highlighting cell body inhibition as a valuable alternative for pathway-specific optogenetic silencing.

in Frontiers in Neural Circuits on March 25, 2020 12:00 AM.

• #### Altered Motoneuron Properties Contribute to Motor Deficits in a Rabbit Hypoxia-Ischemia Model of Cerebral Palsy

Cerebral palsy (CP) is caused by a variety of factors attributed to early brain damage, resulting in permanently impaired motor control, marked by weakness and muscle stiffness. To find out if altered physiology of spinal motoneurons (MNs) could contribute to movement deficits, we performed whole-cell patch-clamp in neonatal rabbit spinal cord slices after developmental injury at 79% gestation. After preterm hypoxia-ischemia (HI), rabbits are born with motor deficits consistent with a spastic phenotype including hypertonia and hyperreflexia. There is a range in severity, thus kits are classified as severely affected, mildly affected, or unaffected based on modified Ashworth scores and other behavioral tests. At postnatal day (P)0–5, we recorded electrophysiological parameters of 40 MNs in transverse spinal cord slices using whole-cell patch-clamp. We found significant differences between groups (severe, mild, unaffected and sham control MNs). Severe HI MNs showed more sustained firing patterns, depolarized resting membrane potential, and fired action potentials at a higher frequency. These properties could contribute to muscle stiffness, a hallmark of spastic CP. Interestingly altered persistent inward currents (PICs) and morphology in severe HI MNs would dampen excitability (depolarized PIC onset and increased dendritic length). In summary, changes we observed in spinal MN physiology likely contribute to the severity of the phenotype, and therapeutic strategies for CP could target the excitability of spinal MNs.

in Frontiers in Cellular Neuroscience on March 25, 2020 12:00 AM.

• #### Publishing in the time of COVID-19

eLife is making changes to its policies on peer review in response to the impact of COVID-19 on the scientific community.

in eLife on March 25, 2020 12:00 AM.

• #### Exerting an influence on evolution

Experiments on mice have shown that developmental processes are influencing the generation of phenotypic variation in a way that shapes evolution.

in eLife on March 25, 2020 12:00 AM.

• #### Building customizable auto-luminescent luciferase-based reporters in plants

Bioluminescence is a powerful biological signal that scientists have repurposed as a reporter for gene expression in plants and animals. However, there are downsides associated with the need to provide a substrate to these reporters, including its high cost and non-uniform tissue penetration. In this work we reconstitute a fungal bioluminescence pathway (FBP) in planta using a composable toolbox of parts. We demonstrate that the FBP can create luminescence across various tissues in a broad range of plants without external substrate addition. We also show how our toolbox can be used to deploy the FBP in planta to build auto-luminescent reporters for the study of gene-expression and hormone fluxes. A low-cost imaging platform for gene expression profiling is also described. These experiments lay the groundwork for future construction of programmable auto-luminescent plant traits, such as light driven plant-pollinator interactions or light emitting plant-based sensors.

in eLife on March 25, 2020 12:00 AM.

• #### UBP12 and UBP13 negatively regulate the activity of the ubiquitin-dependent peptidases DA1, DAR1 and DAR2

Protein ubiquitination is a very diverse post-translational modification leading to protein degradation or delocalization, or altering protein activity. In Arabidopsis thaliana, two E3 ligases, BIG BROTHER (BB) and DA2, activate the latent peptidases DA1, DAR1 and DAR2 by mono-ubiquitination at multiple sites. Subsequently, these activated peptidases destabilize various positive regulators of growth. Here, we show that two ubiquitin-specific proteases, UBP12 and UBP13, deubiquitinate DA1, DAR1 and DAR2, hence reducing their peptidase activity. Overexpression of UBP12 or UBP13 strongly decreased leaf size and cell area, and resulted in lower ploidy levels. Mutants in which UBP12 and UBP13 were downregulated produced smaller leaves that contained fewer and smaller cells. Remarkably, neither UBP12 nor UBP13 were found to be cleavage substrates of the activated DA1. Our results therefore suggest that UBP12 and UBP13 work upstream of DA1, DAR1 and DAR2 to restrict their protease activity and hence fine-tune plant growth and development.

in eLife on March 25, 2020 12:00 AM.

• #### Identification of slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour

To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F3 sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F0 fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F3 fish, one in the slit3 gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human SLIT3 locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of slit3 mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased htr1aa mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans.

in eLife on March 25, 2020 12:00 AM.

• #### Global genome diversity of the Leishmania donovani complex

Protozoan parasites of the Leishmania donovani complex – L. donovani and L. infantum – cause the fatal disease visceral leishmaniasis. We present the first comprehensive genome-wide global study, with 151 cultured field isolates representing most of the geographical distribution. L. donovani isolates separated into five groups that largely coincide with geographical origin but vary greatly in diversity. In contrast, the majority of L. infantum samples fell into one globally-distributed group with little diversity. This picture is complicated by several hybrid lineages. Identified genetic groups vary in heterozygosity and levels of linkage, suggesting different recombination histories. We characterise chromosome-specific patterns of aneuploidy and identified extensive structural variation, including known and suspected drug resistance loci. This study reveals greater genetic diversity than suggested by geographically-focused studies, provides a resource of genomic variation for future work and sets the scene for a new understanding of the evolution and genetics of the Leishmania donovani complex.

in eLife on March 25, 2020 12:00 AM.

• #### An Evolutionary Trace method defines functionally important bases and sites common to RNA families

by Ilya B. Novikov, Angela D. Wilkins, Olivier Lichtarge

Functional non-coding (fnc)RNAs are nucleotide sequences of varied lengths, structures, and mechanisms that ubiquitously influence gene expression and translation, genome stability and dynamics, and human health and disease. Here, to shed light on their functional determinants, we seek to exploit the evolutionary record of variation and divergence read from sequence comparisons. The approach follows the phylogenetic Evolutionary Trace (ET) paradigm, first developed and extensively validated on proteins. We assigned a relative rank of importance to every base in a study of 1070 functional RNAs, including the ribosome, and observed evolutionary patterns strikingly similar to those seen in proteins, namely, (1) the top-ranked bases clustered in secondary and tertiary structures. (2) In turn, these clusters mapped functional regions for catalysis, binding proteins and drugs, post-transcriptional modification, and deleterious mutations. (3) Moreover, the quantitative quality of these clusters correlated with the identification of functional regions. (4) As a result of this correlation, smoother structural distributions of evolutionary important nucleotides improved functional site predictions. Thus, in practice, phylogenetic analysis can broadly identify functional determinants in RNA sequences and functional sites in RNA structures, and reveal details on the basis of RNA molecular functions. As example of application, we report several previously undocumented and potentially functional ET nucleotide clusters in the ribosome. This work is broadly relevant to studies of structure-function in ribonucleic acids. Additionally, this generalization of ET shows that evolutionary constraints among sequence, structure, and function are similar in structured RNA and proteins. RNA ET is currently available as part of the ET command-line package, and will be available as a web-server.

in PLoS Computational Biology on March 24, 2020 09:00 PM.

• #### Bacterially produced metabolites protect <i>C</i>. <i>elegans</i> neurons from degeneration

by Arles Urrutia, Víctor A. García-Angulo, Andrés Fuentes, Mauricio Caneo, Marcela Legüe, Sebastián Urquiza, Scarlett E. Delgado, Juan Ugalde, Paula Burdisso, Andrea Calixto

Caenorhabditis elegans and its cognate bacterial diet comprise a reliable, widespread model to study diet and microbiota effects on host physiology. Nonetheless, how diet influences the rate at which neurons die remains largely unknown. A number of models have been used in C. elegans as surrogates for neurodegeneration. One of these is a C. elegans strain expressing a neurotoxic allele of the mechanosensory abnormality protein 4 (MEC-4d) degenerin/epithelial Na+ (DEG/ENaC) channel, which causes the progressive degeneration of the touch receptor neurons (TRNs). Using this model, our study evaluated the effect of various dietary bacteria on neurodegeneration dynamics. Although degeneration of TRNs was steady and completed at adulthood in the strain routinely used for C. elegans maintenance (Escherichia coli OP50), it was significantly reduced in environmental and other laboratory bacterial strains. Strikingly, neuroprotection reached more than 40% in the E. coli HT115 strain. HT115 protection was long lasting well into old age of animals and was not restricted to the TRNs. Small amounts of HT115 on OP50 bacteria as well as UV-killed HT115 were still sufficient to produce neuroprotection. Early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of DAF-16 (ortholog of the FOXO family of transcription factors), a phenomenon previously reported to underlie neuroprotection caused by down-regulation of the insulin receptor in this system. Moreover, a daf-16 loss-of-function mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics, and metabolomics approaches pinpointed the neurotransmitter γ-aminobutyric acid (GABA) and lactate as metabolites differentially produced between E. coli HT115 and OP50. HT115 mutant lacking glutamate decarboxylase enzyme genes (gad), which catalyze the conversion of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of glutamate decarboxylase in E. coli OP50 conferred neuroprotective activity to this strain. Specific C. elegans GABA transporters and receptors were required for full HT115-mediated neuroprotection. Additionally, lactate supplementation also increased anterior ventral microtubule (AVM) neuron survival in OP50. Together, these results demonstrate that bacterially produced GABA and other metabolites exert an effect of neuroprotection in the host, highlighting the role of neuroactive compounds of the diet in nervous system homeostasis.

in PLoS Biology on March 24, 2020 09:00 PM.

• #### The smell of hunger: Norway rats provision social partners based on odour cues of need

by Karin Schneeberger, Gregory Röder, Michael Taborsky

When individuals exchange helpful acts reciprocally, increasing the benefit of the receiver can enhance its propensity to return a favour, as pay-offs are typically correlated in iterated interactions. Therefore, reciprocally cooperating animals should consider the relative benefit for the receiver when deciding to help a conspecific. Norway rats (Rattus norvegicus) exchange food reciprocally and thereby take into account both the cost of helping and the potential benefit to the receiver. By using a variant of the sequential iterated prisoner’s dilemma paradigm, we show that rats may determine the need of another individual by olfactory cues alone. In an experimental food-exchange task, test subjects were provided with odour cues from hungry or satiated conspecifics located in a different room. Our results show that wild-type Norway rats provide help to a stooge quicker when they receive odour cues from a hungry rather than from a satiated conspecific. Using chemical analysis by gas chromatography-mass spectrometry (GC-MS), we identify seven volatile organic compounds that differ in their abundance between hungry and satiated rats. Combined, this “smell of hunger” can apparently serve as a reliable cue of need in reciprocal cooperation, which supports the hypothesis of honest signalling.

in PLoS Biology on March 24, 2020 09:00 PM.

• #### Correction for Morris et al., Biotic and anthropogenic forces rival climatic/abiotic factors in determining global plant population growth and fitness [Correction]

ECOLOGY Correction for “Biotic and anthropogenic forces rival climatic/abiotic factors in determining global plant population growth and fitness,” by William F. Morris, Johan Ehrlén, Johan P. Dahlgren, Alexander K. Loomis, and Allison M. Louthan, which was first published December 30, 2019; 10.1073/pnas.1918363117 (Proc. Natl. Acad. Sci. U.S.A. 117, 1107–1112). The...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Correction for Xu et al., Structural elements regulating the photochromicity in a cyanobacteriochrome [Correction]

BIOCHEMISTRY Correction for “Structural elements regulating the photochromicity in a cyanobacteriochrome,” by Xiuling Xu, Astrid Port, Christian Wiebeler, Kai-Hong Zhao, Igor Schapiro, and Wolfgang Gärtner, which was first published January 21, 2020; 10.1073/pnas.1910208117 (Proc. Natl. Acad. Sci. U.S.A. 117, 2432–2440). The authors note that the author name Astrid Port should...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Correction for Zhang et al., Tuning friction to a superlubric state via in-plane straining [Correction]

ENGINEERING Correction for “Tuning friction to a superlubric state via in-plane straining,” by Shuai Zhang, Yuan Hou, Suzhi Li, Luqi Liu, Zhong Zhang, Xi-Qiao Feng, and Qunyang Li, which was first published October 28, 2019; 10.1073/pnas.1907947116 (Proc. Natl. Acad. Sci. U.S.A. 116, 24452–24456). The authors wish to note the following:...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### MicroRNAs organize intrinsic variation into stem cell states [Systems Biology]

Pluripotent embryonic stem cells (ESCs) contain the potential to form a diverse array of cells with distinct gene expression states, namely the cells of the adult vertebrate. Classically, diversity has been attributed to cells sensing their position with respect to external morphogen gradients. However, an alternative is that diversity arises...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Brain activity forecasts video engagement in an internet attention market [Psychological and Cognitive Sciences]

The growth of the internet has spawned new “attention markets,” in which people devote increasing amounts of time to consuming online content, but the neurobehavioral mechanisms that drive engagement in these markets have yet to be elucidated. We used functional MRI (FMRI) to examine whether individuals’ neural responses to videos...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Two systems for thinking about others’ thoughts in the developing brain [Psychological and Cognitive Sciences]

Human social interaction crucially relies on the ability to infer what other people think. Referred to as Theory of Mind (ToM), this ability has long been argued to emerge around 4 y of age when children start passing traditional verbal ToM tasks. This developmental dogma has recently been questioned by...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### The Arabidopsis SAFEGUARD1 suppresses singlet oxygen-induced stress responses by protecting grana margins [Plant Biology]

Singlet oxygen (1O2), the major reactive oxygen species (ROS) produced in chloroplasts, has been demonstrated recently to be a highly versatile signal that induces various stress responses. In the fluorescent (flu) mutant, its release causes seedling lethality and inhibits mature plant growth. However, these drastic phenotypes are suppressed when EXECUTER1...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### IPyA glucosylation mediates light and temperature signaling to regulate auxin-dependent hypocotyl elongation in Arabidopsis [Plant Biology]

Auxin is a class of plant hormone that plays a crucial role in the life cycle of plants, particularly in the growth response of plants to ever-changing environments. Since the auxin responses are concentration-dependent and higher auxin concentrations might often be inhibitory, the optimal endogenous auxin level must be closely...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Molecular mechanisms of Evening Complex activity in Arabidopsis [Plant Biology]

The Evening Complex (EC), composed of the DNA binding protein LUX ARRHYTHMO (LUX) and two additional proteins EARLY FLOWERING 3 (ELF3) and ELF4, is a transcriptional repressor complex and a core component of the plant circadian clock. In addition to maintaining oscillations in clock gene expression, the EC also participates...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Spatiotemporal gating of SIRT1 functions by O-GlcNAcylation is essential for liver metabolic switching and prevents hyperglycemia [Physiology]

Inefficient physiological transitions are known to cause metabolic disorders. Therefore, investigating mechanisms that constitute molecular switches in a central metabolic organ like the liver becomes crucial. Specifically, upstream mechanisms that control temporal engagement of transcription factors, which are essential to mediate physiological fed–fast–refed transitions are less understood. SIRT1, a NAD+-dependent...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Distinct signaling and transcriptional pathways regulate peri-weaning development and cold-induced recruitment of beige adipocytes [Physiology]

Adipose tissue provides a defense against starvation and environmental cold. These dichotomous functions are performed by three distinct cell types: energy-storing white adipocytes, and thermogenic beige and brown adipocytes. Previous studies have demonstrated that exposure to environmental cold stimulates the recruitment of beige adipocytes in the white adipose tissue (WAT)...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Indexing brain state-dependent pupil dynamics with simultaneous fMRI and optical fiber calcium recording [Neuroscience]

Pupillometry, a noninvasive measure of arousal, complements human functional MRI (fMRI) to detect periods of variable cognitive processing and identify networks that relate to particular attentional states. Even under anesthesia, pupil dynamics correlate with brain-state fluctuations, and extended dilations mark the transition to more arousable states. However, cross-scale neuronal activation...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Unraveling the complexity of amyloid polymorphism using gold nanoparticles and cryo-EM [Neuroscience]

Increasing evidence suggests that amyloid polymorphism gives rise to different strains of amyloids with distinct toxicities and pathology-spreading properties. Validating this hypothesis is challenging due to a lack of tools and methods that allow for the direct characterization of amyloid polymorphism in hydrated and complex biological samples. Here, we report...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Cerebellar plasticity and associative memories are controlled by perineuronal nets [Neuroscience]

Perineuronal nets (PNNs) are assemblies of extracellular matrix molecules, which surround the cell body and dendrites of many types of neuron and regulate neural plasticity. PNNs are prominently expressed around neurons of the deep cerebellar nuclei (DCN), but their role in adult cerebellar plasticity and behavior is far from clear....

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain [Neuroscience]

Chronic inflammation during Alzheimer’s disease (AD) is most often attributed to sustained microglial activation in response to amyloid-β (Aβ) plaque deposits and cell death. However, cytokine release and microgliosis are consistently observed in AD transgenic animal models devoid of such pathologies, bringing into question the underlying processes that may be...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Central neurogenetic signatures of the visuomotor integration system [Neuroscience]

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader–Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Optofluidic control of rodent learning using cloaked caged glutamate [Chemistry]

Glutamate is the major excitatory neurotransmitter in the brain, and photochemical release of glutamate (or uncaging) is a chemical technique widely used by biologists to interrogate its physiology. A basic prerequisite of these optical probes is bio-inertness before photolysis. However, all caged glutamates are known to have strong antagonism toward...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Exploring histone loading on HIV DNA reveals a dynamic nucleosome positioning between unintegrated and integrated viral genome [Microbiology]

The aim of the present study was to understand the biology of unintegrated HIV-1 DNA and reveal the mechanisms involved in its transcriptional silencing. We found that histones are loaded on HIV-1 DNA after its nuclear import and before its integration in the host genome. Nucleosome positioning analysis along the...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant [Microbiology]

Emerging evidence suggests the Pseudomonas aeruginosa accessory genome is enriched with uncharacterized virulence genes. Identification and characterization of such genes may reveal novel pathogenic mechanisms used by particularly virulent isolates. Here, we utilized a mouse bacteremia model to quantify the virulence of 100 individual P. aeruginosa bloodstream isolates and performed...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Lysosomal degradation products induce Coxiella burnetii virulence [Microbiology]

Coxiella burnetii is an intracellular pathogen that replicates in a lysosome-like vacuole through activation of a Dot/Icm-type IVB secretion system and subsequent translocation of effectors that remodel the host cell. Here a genome-wide small interfering RNA screen and reporter assay were used to identify host proteins required for Dot/Icm effector...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Intestinal bile acids directly modulate the structure and function of C. difficile TcdB toxin [Microbiology]

Intestinal bile acids are known to modulate the germination and growth of Clostridioides difficile. Here we describe a role for intestinal bile acids in directly binding and neutralizing TcdB toxin, the primary determinant of C. difficile disease. We show that individual primary and secondary bile acids reversibly bind and inhibit...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Cryo-EM structure of rhinovirus C15a bound to its cadherin-related protein 3 receptor [Microbiology]

Infection by Rhinovirus-C (RV-C), a species of Picornaviridae Enterovirus, is strongly associated with childhood asthma exacerbations. Cellular binding and entry by all RV-C, which trigger these episodes, is mediated by the first extracellular domain (EC1) of cadherin-related protein 3 (CDHR3), a surface cadherin-like protein expressed primarily on the apical surfaces...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### The Tol-Pal system is required for peptidoglycan-cleaving enzymes to complete bacterial cell division [Microbiology]

Tol-Pal is a multiprotein system present in the envelope of Gram-negative bacteria. Inactivation of this widely conserved machinery compromises the outer membrane (OM) layer of these organisms, resulting in hypersensitivity to many antibiotics. Mutants in the tol-pal locus fail to complete division and form cell chains. This phenotype along with...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection [Microbiology]

The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here,...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Natural diversity in the predatory behavior facilitates the establishment of a robust model strain for nematode-trapping fungi [Microbiology]

Nematode-trapping fungi (NTF) are a group of specialized microbial predators that consume nematodes when food sources are limited. Predation is initiated when conserved nematode ascaroside pheromones are sensed, followed by the development of complex trapping devices. To gain insights into the coevolution of this interkingdom predator–prey relationship, we investigated natural...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Chromosome-free bacterial cells are safe and programmable platforms for synthetic biology [Microbiology]

A type of chromosome-free cell called SimCells (simple cells) has been generated from Escherichia coli, Pseudomonas putida, and Ralstonia eutropha. The removal of the native chromosomes of these bacteria was achieved by double-stranded breaks made by heterologous I-CeuI endonuclease and the degradation activity of endogenous nucleases. We have shown that...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Disruption of cellular proteostasis by H1N1 influenza A virus causes {alpha}-synuclein aggregation [Medical Sciences]

Neurodegenerative diseases feature specific misfolded or misassembled proteins associated with neurotoxicity. The precise mechanisms by which protein aggregates first arise in the majority of sporadic cases have remained unclear. Likely, a first critical mass of misfolded proteins starts a vicious cycle of a prion-like expansion. We hypothesize that viruses, having...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver [Medical Sciences]

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show that Arrdc3 is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Splice variant of growth hormone-releasing hormone receptor drives esophageal squamous cell carcinoma conferring a therapeutic target [Medical Sciences]

The extrahypothalamic growth hormone-releasing hormone (GHRH) and its cognate receptors (GHRH-Rs) and splice variants are expressed in a variety of cancers. It has been shown that the pituitary type of GHRH-R (pGHRH-R) mediates the inhibition of tumor growth induced by GHRH-R antagonists. However, GHRH-R antagonists can also suppress some cancers...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver [Medical Sciences]

Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional β-catenin knockout mouse...

in Proceedings of the National Academy of Sciences Recent Issues on March 24, 2020 05:36 PM.

• #### The Epileptor Model: A Systematic Mathematical Analysis Linked to the Dynamics of Seizures, Refractory Status Epilepticus, and Depolarization Block

Abstract

One characteristic of epilepsy is the variety of mechanisms leading to the epileptic state, which are still largely unknown. Refractory status epilepticus (RSE) and depolarization block (DB) are other pathological brain activities linked to epilepsy, whose patterns are different and whose mechanisms remain poorly understood. In epileptogenic network modeling, the Epileptor is a generic phenomenological model that has been recently developed to describe the dynamics of seizures. Here, we performed a detailed qualitative analysis of the Epileptor model based on dynamical systems theory and bifurcation analysis, and investigate the dynamic evolution of "normal" activity toward seizures and to the pathological RSE and DB states. The mechanisms of the transition between states are called bifurcations. Our detailed analysis demonstrates that the generic model undergoes different bifurcation types at seizure offset, when varying some selected parameters. We show that the pathological and normal activities can coexist within the same model under some conditions, and demonstrate that there are many pathways leading to and away from these activities. We here archive systematically all behaviors and dynamic regimes of the Epileptor model to serve as a resource in the development of patient-specific brain network models, and more generally in epilepsy research.

in eNeuro current issue on March 24, 2020 04:30 PM.

• #### Unique Organization of actin cytoskeleton in magnocellular vasopressin neurons in normal conditions and in response to salt-loading

ABSTRACT

Magnocellular neurosecretory cells are intrinsically osmosensitive and can be activated by increases in blood osmolality, triggering the release of antidiuretic hormone vasopressin (VP) to promote water retention. Hence, the activity of magnocellular VP neurons is one of the key elements contributing to the regulation of body fluid homeostasis in healthy organisms. Chronic exposure to high dietary salt leads to excessive activation of VP neurons, thereby elevating levels of circulating VP, which can cause increases in blood pressure contributing to salt-dependent hypertension. However, the molecular basis underlying high salt diet-induced hyperactivation of magnocellular VP neurons remains not fully understood. Previous studies suggest that magnocellular neurosecretory neurons contain a subcortical layer of actin filaments and pharmacological stabilization of this actin network potentiates osmotically-induced activation of magnocellular neurons. Using super-resolution imaging in situ, we investigated the organization of the actin cytoskeleton in rat magnocellular neurosecretory cells under normal physiological conditions and after a chronic increase in blood osmolality following 7 days of salt-loading. We found that, in addition to the subcortical layer of actin filaments, magnocellular VP neurons are endowed with a unique network of cytoplasmic actin filaments throughout their somata. Moreover, we revealed that the density of both subcortical and cytoplasmic actin networks in magnocellular VP neurons is dramatically increased following salt-loading. These results suggest that increased osmo-responsiveness of VP neurons following chronic exposure to high dietary salt may be mediated by the modulation of unique actin networks in magnocellular VP neurons, possibly contributing to elevated blood pressure in this condition.

Significance statement: Hypothalamic magnocellular neurons secrete antidiuretic hormone vasopressin into the circulation, promoting vasoconstriction and renal water retention. Regulation of vasopressin secretion is a key factor controlling body fluid homeostasis, and excessive vasopressin secretion contributes to fluid balance disorders such as salt-sensitive hypertension. Using super-resolution analysis of different areas of the rat brain, we show that vasopressin neurons feature a unique actin cytoskeleton comprising a subcortical actin layer and an array of cytoplasmic comet-like structures, which are not present in any other neuronal cell type. Moreover, the density of these unique actin structures is increased in a rodent model of salt-sensitive hypertension, and our findings suggest that this modification may contribute to excessive activation of vasopressin neurons in a model salt-sensitive hypertension.

in RSS PAP on March 24, 2020 04:30 PM.

• #### Hemispheric lateralization of arithmetic facts and magnitude processing for two-digit numbers

In the human brain, a (relative) functional asymmetry (i.e., laterality; functional and performance differences between the two cerebral hemispheres) exists for a variety of cognitive domains (e.g., language, visual-spatial processing, etc.). For numerical cognition, both bi-lateral and unilateral processing has been proposed with the retrieval of arithmetic facts postulated as being lateralized to the left hemisphere. In this study, we aimed at evaluating this claim by investigating whether processing of multiplicatively related triplets in a number bisection task (e.g., 12_16_20) in healthy participants (n=23) shows a significant advantage when transmitted to the right hemisphere only as compared to transmission to the left hemisphere. As expected, a control task revealed that stimulus presentation to the left or both visual hemifields did not increase processing disadvantages of unit-decade incompatible number pairs in magnitude comparison. For the number bisection task, we replicated the multiplicativity effect. However, in contrast to the hypothesis deriving from the triple code model, we did not observe significant hemispheric processing asymmetries for multiplicative items. We suggest that participants resorted to keep number triplets in verbal working memory after perceiving them only very briefly for 150ms. Rehearsal of the three numbers was probably slow and time-consuming so allowing for interhemispheric communication in the meantime. We suggest that an effect of lateralized presentation may only be expected for early effects when the task is sufficiently easy.

in Frontiers in Human Neuroscience on March 24, 2020 02:53 PM.

• #### Decoding Imagined Speech using Wavelet Features and Deep Neural Networks. (arXiv:2003.10433v1 [q-bio.NC])

This paper proposes a novel approach that uses deep neural networks for classifying imagined speech, significantly increasing the classification accuracy. The proposed approach employs only the EEG channels over specific areas of the brain for classification, and derives distinct feature vectors from each of those channels. This gives us more data to train a classifier, enabling us to use deep learning approaches. Wavelet and temporal domain features are extracted from each channel. The final class label of each test trial is obtained by applying a majority voting on the classification results of the individual channels considered in the trial. This approach is used for classifying all the 11 prompts in the KaraOne dataset of imagined speech. The proposed architecture and the approach of treating the data have resulted in an average classification accuracy of 57.15%, which is an improvement of around 35% over the state-of-the-art results.

in q-bio.NC updates on arXiv.org on March 24, 2020 01:30 AM.

• #### An Improved EEG Acquisition Protocol Facilitates Localized Neural Activation. (arXiv:2003.10212v1 [q-bio.NC])

This work proposes improvements in the electroencephalogram (EEG) recording protocols for motor imagery through the introduction of actual motor movement and/or somatosensory cues. The results obtained demonstrate the advantage of requiring the subjects to perform motor actions following the trials of imagery. By introducing motor actions in the protocol, the subjects are able to perform actual motor planning, rather than just visualizing the motor movement, thus greatly improving the ease with which the motor movements can be imagined. This study also probes the added advantage of administering somatosensory cues in the subject, as opposed to the conventional auditory/visual cues. These changes in the protocol show promise in terms of the aptness of the spatial filters obtained on the data, on application of the well-known common spatial pattern (CSP) algorithms. The regions highlighted by the spatial filters are more localized and consistent across the subjects when the protocol is augmented with somatosensory stimuli. Hence, we suggest that this may prove to be a better EEG acquisition protocol for detecting brain activation in response to intended motor commands in (clinically) paralyzed/locked-in patients.

in q-bio.NC updates on arXiv.org on March 24, 2020 01:30 AM.

• #### Information-Theoretic Free Energy as Emotion Potential: Emotional Valence as a Function of Complexity and Novelty. (arXiv:2003.10073v1 [q-bio.NC])

This study extends the mathematical model of emotion dimensions that we previously proposed (Yanagisawa, et al. 2019, Front Comput Neurosci) to consider perceived complexity as well as novelty, as a source of arousal potential. Berlyne's hedonic function of arousal potential (or the inverse U-shaped curve, the so-called Wundt curve) is assumed. We modeled the arousal potential as information contents to be processed in the brain after sensory stimuli are perceived (or recognized), which we termed sensory surprisal. We mathematically demonstrated that sensory surprisal represents free energy, and it is equivalent to a summation of information gain (or information from novelty) and perceived complexity (or information from complexity), which are the collative variables forming the arousal potential. We demonstrated empirical evidence with visual stimuli (profile shapes of butterfly) supporting the hypothesis that the summation of perceived novelty and complexity shapes the inverse U-shaped beauty function. We discussed the potential of free energy as a mathematical principle explaining emotion initiators.

in q-bio.NC updates on arXiv.org on March 24, 2020 01:30 AM.

• #### LOOPER: Inferring computational algorithms enacted by neuronal population dynamics. (arXiv:2003.09976v1 [q-bio.NC])

Recording simultaneous activity of hundreds of neurons is now possible. Existing methods can model such population activity, but do not directly reveal the computations used by the brain. We present a fully unsupervised method that models neuronal activity and reveals the computational strategy. The method constructs a topological model of neuronal dynamics consisting of interconnected loops. Transitions between loops mark computationally-salient decisions. We accurately model activation of 100s of neurons in the primate cortex during a working memory task. Dynamics of a recurrent neural network (RNN) trained on the same task are topologically identical suggesting that a similar computational strategy is used. The RNN trained on a modified dataset, however, reveals a different topology. This topology predicts specific novel stimuli that consistently elicit incorrect responses with near perfect accuracy. Thus, our methodology yields a quantitative model of neuronal activity and reveals the computational strategy used to solve the task.

in q-bio.NC updates on arXiv.org on March 24, 2020 01:30 AM.

• #### Representing Attitudes Towards Ambiguity in Hilbert Space: Foundations and Applications. (arXiv:1907.06314v2 [cs.AI] UPDATED)

We provide here a general mathematical framework to model attitudes towards ambiguity which uses the formalism of quantum theory as a `purely mathematical formalism, detached from any physical interpretation''. We show that the quantum-theoretic framework enables modelling of the "Ellsberg paradox", but it also successfully applies to more concrete human decision-making (DM) tests involving financial, managerial and medical decisions. In particular, we elaborate a mathematical representation of various empirical studies which reveal that attitudes of managers towards uncertainty shift from "ambiguity seeking" to "ambiguity aversion", and viceversa, thus exhibiting "hope effects" and "fear effects". The present framework provides a promising direction towards the development of a unified theory of decisions in the presence of uncertainty.

in q-bio.NC updates on arXiv.org on March 24, 2020 01:30 AM.

• #### The MX-Helix of Muscle nAChR Subunits Regulates Receptor Assembly and Surface Trafficking

Nicotinic acetylcholine receptors (AChRs) are pentameric channels that mediate fast transmission at the neuromuscular junction (NMJ) and defects in receptor expression underlie neuromuscular disorders such as myasthenia gravis and congenital myasthenic syndrome (CMS). Nicotinic receptor expression at the NMJ is tightly regulated and we previously identified novel Golgi-retention signals in the β and δ subunit cytoplasmic loops that regulate trafficking of the receptor to the cell surface. Here, we show that the Golgi retention motifs are localized in the MX-helix, a juxta-membrane alpha-helix present in the proximal cytoplasmic loop of receptor subunits, which was defined in recent crystal structures of cys-loop receptor family members. First, mutational analysis of CD4-MX-helix chimeric proteins showed that the Golgi retention signal was dependent on both the amphipathic nature of the MX-helix and on specific lysine residues (βK353 and δK351). Moreover, retention was associated with ubiquitination of the lysines, and βK353R and δK351R mutations reduced ubiquitination and increased surface expression of CD4-β and δ MX-helix chimeric proteins. Second, mutation of these lysines in intact β and δ subunits perturbed Golgi-based glycosylation and surface trafficking of the AChR. Notably, combined βK353R and δK351R mutations increased the amount of surface AChR with immature forms of glycosylation, consistent with decreased Golgi retention and processing. Third, we found that previously identified CMS mutations in the ε subunit MX-helix decreased receptor assembly and surface levels, as did an analogous mutation introduced into the β subunit MX-helix. Together, these findings indicate that the subunit MX-helix contributes to receptor assembly and is required for normal expression of the AChR and function of the NMJ. In addition, specific determinants in the β and δ subunit MX-helix contribute to quality control of AChR expression by intracellular retention and ubiquitination of unassembled subunits, and by facilitating the appropriate glycosylation of assembled surface AChR.

in Frontiers in Molecular Neuroscience on March 24, 2020 12:00 AM.

• #### Interference With Complex IV as a Model of Age-Related Decline in Synaptic Connectivity

Age-related impairment of mitochondrial function may negatively impact energy-demanding processes such as synaptic transmission thereby triggering cognitive decline and processes of neurodegeneration. Here, we present a novel model for age-related mitochondrial impairment based on partial inhibition of cytochrome c oxidase subunit 4 (Cox4) of complex IV of the respiratory chain. miRNA-mediated knockdown of Cox4 correlated with a marked reduction in excitatory and inhibitory synaptic marker densities in vitro and in vivo as well as an impairment of neuronal network activity in primary neuronal cultures. Transcriptome analysis identified the deregulation of gene clusters, which link induced mitochondrial perturbation to impaired synaptic function and plasticity as well as processes of aging. In conclusion, the model of Cox4 deficiency reflects aspects of age-related dementia and might, therefore, serve as a novel test system for drug development.

in Frontiers in Molecular Neuroscience on March 24, 2020 12:00 AM.

• #### NF-κB Inhibitors Attenuate MCAO Induced Neurodegeneration and Oxidative Stress—A Reprofiling Approach

Stroke is the leading cause of morbidity and mortality worldwide. About 87% of stroke cases are ischemic, which disrupt the physiological activity of the brain, thus leading to a series of complex pathophysiological events. Despite decades of research on neuroprotectants to probe for suitable therapies against ischemic stroke, no successful results have been obtained, and new alternative approaches are urgently required in order to combat this pathological torment. To address these problems, drug repositioning/reprofiling is explored extensively. Drug repurposing aims to identify new uses for already established drugs, and this makes it an attractive commercial strategy. Nuclear factor-kappa beta (NF-κB) is reported to be involved in many physiological and pathological conditions, such as neurodegeneration, neuroinflammation, and ischemia/reperfusion (I/R) injury. In this study, we examined the neuroprotective effects of atorvastatin, cephalexin, and mycophenolate against the NF-κB in ischemic stroke, as compared to the standard NF-κB inhibitor caeffic acid phenethyl ester (CAPE). An in-silico docking analysis was performed and their potential neuroprotective activities in the in vivo transient middle cerebral artery occlusion (t-MCAO) rat model was examined. The percent (%) infarct area and 28-point composite neuro score were examined, and an immunohistochemical analysis (IHC) and enzyme-linked immunosorbent assay (ELISA) were further performed to validate the neuroprotective role of these compounds in stroke as well as their potential as antioxidants. Our results demonstrated that these novels NF-κB inhibitors could attenuate ischemic stroke-induced neuronal toxicity by targeting NF-κB, a potential therapeutic approach in ischemic stroke.

in Frontiers in Molecular Neuroscience on March 24, 2020 12:00 AM.

• #### Editorial: The Role of Lipids in the Pathogenesis of Parkinson's Disease

in Frontiers in Neuroscience: Neurodegeneration on March 24, 2020 12:00 AM.

• #### Repeated Paced Mating Increases the Survival of New Neurons in the Accessory Olfactory Bulb

In female rats, the first sexual experience under paced mating conditions increases the number of newborn cells that migrate into the granular layer of the accessory olfactory bulb (AOB). Repeated paced mating has a potentiating effect on the number of new neurons that migrate to the AOB compared with a single session 15 days after paced mating. On the other hand, one paced mating session does no increases the survival of new cells 45 days after mating. In the present study, we evaluated if four paced mating sessions could increase the survival of new neurons in the AOB and main olfactory bulb (MOB) 45 days after females mated. Sexually naive female rats were ovariectomized, hormonally supplemented and randomly assigned to one of five groups: (1) Control, no sexual contact (C); (2) Four sessions in which females were exposed, without mating, to a sexually experience male rat (SE); (3) One session of paced mating (PM1); (4) Four sessions of paced mating (PM4); and (5) Four sessions of non-paced mating (NPM4). In the first behavioral test, females received the DNA synthesis marker 5-bromo-2′deoxyuridine and were euthanized 45 days later. Our data showed that the number of new cells that survived in the mitral cell layer of the AOB decreased when females were exposed to a sexually active male, in comparison to females that mated once pacing the sexual interaction. Repeated sexual behavior in pacing conditions did not increase the survival of new cells in other layers of the MOB and AOB. However, a significant increase in the percentage of new neurons in the granular and glomerular layers of the AOB and granular layer of the MOB was observed in females that mated in four sessions pacing the sexual interaction. In the group that paced the sexual interaction for one session, a significant increase in the percentage of neurons was observed in the glomerular layer of the AOB. Our data suggest that repeated paced mating increases the percentage of new neurons that survive in the olfactory bulb of female rats.

in Frontiers in Neuroscience: Neurogenesis on March 24, 2020 12:00 AM.

• #### Nix Plays a Neuroprotective Role in Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats

Nix is located in the outer membrane of mitochondria, mediates mitochondrial fission and implicated in many neurological diseases. However, the association between Nix and subarachnoid hemorrhage (SAH) has not previously been reported. Therefore, the present study was designed to evaluate the expression of Nix and its role in early brain injury (EBI) after SAH. Adult male Sprague-Dawley (SD) rats were randomly assigned to various time points for investigation after SAH. A rat model of SAH was induced by injecting 0.3 ml of autologous non-heparinized arterial blood into the prechiasmatic cistern. The expression of Nix was investigated by Western blot and immunohistochemistry. Next, Nix-specific overexpression plasmids and small interfering RNAs (siRNAs) were separately administered. Western blot, neurological scoring, Morris water maze, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and fluoro-jade B (FJB) staining were performed to evaluate the role of Nix in EBI following SAH. We found that Nix was expressed in neurons and its expression level in the SAH groups was higher than that in the Sham group, which peaked at 24 h after SAH. Overexpression of Nix following SAH significantly decreased the expression of translocase of outer mitochondrial membrane 20 (TOMM20, a marker of mitochondria), ameliorated neurological/cognitive deficits induced by SAH, and reduced the total number of apoptotic/neurodegenerative cells, whereas siRNA knockdown of Nix yielded opposite effects. Taken together, our findings demonstrated that the expression of Nix is increased in neurons after experimental SAH in rats, and may play a neuroprotective role in EBI following SAH.

in Frontiers in Neuroscience: Neurodegeneration on March 24, 2020 12:00 AM.

• #### Model-Based and Model-Free Analyses of the Neural Correlates of Tongue Movements

The tongue performs movements in all directions to subserve its diverse functions in chewing, swallowing, and speech production. Using task-based functional MRI in a group of 17 healthy young participants, we studied (1) potential differences in the cerebral control of frontal (protrusion), horizontal (side to side), and vertical (elevation) tongue movements and (2) inter-individual differences in tongue motor control. To investigate differences between different tongue movements, we performed voxel-wise multiple linear regressions. To investigate inter-individual differences, we applied a novel approach, spatio-temporal filtering of independent components. For this approach, individual functional data were decomposed into spatially independent components and corresponding time courses using independent component analysis. A temporal filter (correlation with the expected brain response) was used to identify independent components time-locked to the tongue motor tasks. A spatial filter (cross-correlation with established neurofunctional systems) was used to identify brain activity not time-locked to the tasks. Our results confirm the importance of an extended bilateral cortical and subcortical network for the control of tongue movements. Frontal (protrusion) tongue movements, highly overlearned movements related to speech production, showed less activity in the frontal and parietal lobes compared to horizontal (side to side) and vertical (elevation) movements and greater activity in the left frontal and temporal lobes compared to vertical movements (cluster-forming threshold of Z > 3.1, cluster significance threshold of p < 0.01, corrected for multiple comparisons). The investigation of inter-individual differences revealed a component representing the tongue primary sensorimotor cortex time-locked to the task in all participants. Using the spatial filter, we found the default mode network in 16 of 17 participants, the left fronto-parietal network in 16, the right fronto-parietal network in 8, and the executive control network in four participants (Pearson's r > 0.4 between neurofunctional systems and individual components). These results demonstrate that spatio-temporal filtering of independent components allows to identify individual brain activity related to a specific task and also structured spatiotemporal processes representing known neurofunctional systems on an individual basis. This novel approach may be useful for the assessment of individual patients and results may be related to individual clinical, behavioral, and genetic information.

in Frontiers in Neuroscience: Brain Imaging Methods on March 24, 2020 12:00 AM.

• #### Neuronal CXCL10/CXCR3 Axis Mediates the Induction of Cerebral Hyperexcitability by Peripheral Viral Challenge

Peripheral infections can potently exacerbate neuropathological conditions, though the underlying mechanisms are poorly understood. We have previously demonstrated that intraperitoneal (i.p.) injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC) induces a robust generation of CXCL10 chemokine in the hippocampus. The hippocampus also features hyperexcitability of neuronal circuits following PIC challenge. The present study was undertaken to determine the role of CXCL10 in mediating the development of hyperexcitability in response to PIC challenge. Briefly, young female C57BL/6 mice were i.p. injected with PIC, and after 24 h, the brains were analyzed by confocal microscopy. CXCL10 staining of neuronal perikarya and a less intense staining of the neuropil was observed in the hippocampus and cortex. CXCL10 staining was also evident in a subpopulation of astrocytes, whereas microglia were CXCL10 negative. CXCR3, the cognate receptor of CXCL10 was present exclusively on neurons, indicating that the CXCL10/CXCR3 axis operates through an autocrine/paracrine neuronal signaling. Blocking cerebral CXCR3 through intracerebroventricular injection of a specific inhibitor, AMG487, abrogated PIC challenge-induced increase in basal synaptic transmission and long-term potentiation (LTP), as well as the reduction of paired-pulse facilitation (PPF), in the hippocampus. The PIC-mediated abolishment of hippocampal long-term depression (LTD) was also restored after administration of AMG487. Moreover, CXCR3 inhibition attenuated seizure hypersensitivity induced by PIC challenge. The efficacy of AMG487 strongly strengthens the notion that CXCL10/CXCR3 axis mediates the induction of cerebral hyperexcitability by PIC challenge.

in Frontiers in Neuroscience: Neurodegeneration on March 24, 2020 12:00 AM.

• #### MicroRNA Let-7i Is a Promising Serum Biomarker for Post-stroke Cognitive Impairment and Alleviated OGD-Induced Cell Damage in vitro by Regulating Bcl-2

Background

The mechanism of post-stroke cognitive impairment (PSCI) has not been explained. We aimed to investigate whether miR-let-7i participates in the PSCI and illuminates its underlying role in oxygen–glucose deprivation (OGD)-induced cell apoptosis.

Methods

Blood samples from 36 subjects with PSCI and 38 with post-stroke cognitive normality (Non-PSCI) were collected to evaluate the differential expression of miR-let-7 family members, using qRT-PCT analysis. Spearman correlation was performed to estimate the correlation between the miR-1et-7i level and Montreal Cognitive Assessment (MoCA) score. Treatment of SH-SY5Y cells with OGD was used to induce cell apoptosis in vitro. Effects of miR-let-7i on OGD-induced cell apoptosis was estimated after transfection. The target gene of miR-let-7i was analyzed by dual luciferase reporter gene assay.

Results

The expression of miR-let-7i was up-regulated in PSCI patients compared with Non-PSCI (p < 0.001) and negatively correlated with MoCA score (r = −0.643, p < 0.001). When exposed to OGD, SH-SY5Y cells showed significant apoptosis accompanied by miR-let-7i up-regulation. In OGD-treated cells, miR-let-7i up-regulation was accompanied by cell apoptosis, while down-regulation showed the opposite effect. Luciferase reporter assay showed that Bcl-2 was a target gene of miR-let-7i. Western blot showed that miR-let-7i up-regulation promoted Bcl-2 expression, while qRT-PCR showed that miR-let-7i had no effect on Bcl-2 expression.

Conclusion

miR-let-7i was overexpressed in PSCI patients and it could be used as a diagnostic biomarker for PSCI. We illuminated the potential mechanism that miR-let-7i alleviated OGD-induced cell damage by targeting Bcl-2 at the post-transcriptional level.

in Frontiers in Neuroscience: Neurodegeneration on March 24, 2020 12:00 AM.

• #### Intramuscular Injection of Bone Marrow Stem Cells in Amyotrophic Lateral Sclerosis Patients: A Randomized Clinical Trial

Background

Preclinical studies suggest that stem cells may be a valuable therapeutic tool in amyotrophic lateral sclerosis (ALS). As it has been demonstrated that there are molecular changes at the end-plate during the early stages of motorneuron degeneration in animal models, we hypothesize that the local effect of this stem cell delivery method could slow the progressive loss of motor units (MUs) in ALS patients.

Methods

We designed a Phase I/II clinical trial to study the safety of intramuscularly implanting autologous bone marrow mononuclear cells (BMMCs), including stem cells, in ALS patients and their possible effects on the MU of the tibialis anterior (TA) muscle. Twenty-two patients participated in a randomized, double-blind, placebo-controlled trial that consisted of a baseline visit followed by one intramuscular injection of BMNCs, follow-up visits at 30, 90, 180, and 360 days, and an additional year of clinical follow-up. In each patient, one TA muscle was injected with a single dose of BMMCs while the contralateral muscle was given a placebo; the sides were selected randomly. All visits included a complete EMG study of both TA muscles.

Results

Our results show that (1) the intramuscular injection of BMMCs is a safe procedure; (2) ALS patients show heterogeneities in the degree of TA injury; (3) a comparison of placebo-injected muscles with BMMC-injected muscles showed significant differences in only one parameter, the D50 index used to quantify the Compound Muscle Action Potential (CMAP) scan curve. This parameter was higher in the BMMC-injected TA muscle at both 90 days (placebo side: 29.55 ± 2.89, n = 20; experimental side: 39.25 ± 3.21, n = 20; p < 0.01) and 180 days (placebo side: 29.35 ± 3.29, n = 17; experimental side: 41.24 ± 3.34, n = 17; p < 0.01).

Conclusion

This procedure had no effect on the TA muscle MU properties, with the exception of the D50 index. Finding differences in just this index supports the fact that it may be much more sensitive than other electrophysiological parameters when studying treatment effects. Given the low number of patients and their heterogeneity, these results justify exploring the efficacy of this procedure in further patients and other muscles, through Phase II trials.

Clinical Trial Registration

www.clinicaltrials.gov (identifier NCT02286011); EudraCT number 2011-004801-25.

in Frontiers in Neuroscience: Neurodegeneration on March 24, 2020 12:00 AM.

• #### The Brief Form of the California Odor Learning Test 3

This study explored whether a Brief Form of the California Odor Learning Test 3 (COLT), an olfactory analog of the newly released Brief Form of the California Verbal Learning Test (CVLT 3), could retain the ability of the COLT to detect odor memory dysfunctions observed in normal aging. 52 participants, 28 young (18–30 years old) and 24 old (65 years of age and older), were administered the Brief Forms of the CVLT 3 and the COLT 3. Results indicated poorer performance in immediate and delayed odor recall in older than in younger adults. Poorer odor recognition memory performance in older adults than in younger adults was detected. This study suggests that the Brief Form of the COLT can detect differential odor learning and memory between young and older adults. Thus, the current brief test holds promise as a measure that can be incorporated into studies that demand a brief, non-invasive test capable of detecting impairment in olfactory function.

in Frontiers in Neuroscience: Neurodegeneration on March 24, 2020 12:00 AM.

• #### Automated Hierarchy Evaluation System of Large Vessel Occlusion in Acute Ischemia Stroke

Background

The detection of large vessel occlusion (LVO) plays a critical role in the diagnosis and treatment of acute ischemic stroke (AIS). Identifying LVO in the pre-hospital setting or early stage of hospitalization would increase the patients’ chance of receiving appropriate reperfusion therapy and thereby improve neurological recovery.

Methods

To enable rapid identification of LVO, we established an automated evaluation system based on all recorded AIS patients in Hong Kong Hospital Authority’s hospitals in 2016. The 300 study samples were randomly selected based on a disproportionate sampling plan within the integrated electronic health record system, and then separated into a group of 200 patients for model training, and another group of 100 patients for model performance evaluation. The evaluation system contained three hierarchical models based on patients’ demographic data, clinical data and non-contrast CT (NCCT) scans. The first two levels of modeling utilized structured demographic and clinical data, while the third level involved additional NCCT imaging features obtained from deep learning model. All three levels’ modeling adopted multiple machine learning techniques, including logistic regression, random forest, support vector machine (SVM), and eXtreme Gradient Boosting (XGboost). The optimal cut-off for the likelihood of LVO was determined by the maximal Youden index based on 10-fold cross-validation. Comparisons of performance on the testing group were made between these techniques.

Results

Among the 300 patients, there were 160 women and 140 men aged from 27 to 104 years (mean 76.0 with standard deviation 13.4). LVO was present in 130 (43.3%) patients. Together with clinical and imaging features, the XGBoost model at the third level of evaluation achieved the best model performance on testing group. The Youden index, accuracy, sensitivity, specificity, F1 score, and area under the curve (AUC) were 0.638, 0.800, 0.953, 0.684, 0.804, and 0.847, respectively.

Conclusion

To the best of our knowledge, this is the first study combining both structured clinical data with non-structured NCCT imaging data for the diagnosis of LVO in the acute setting, with superior performance compared to previously reported approaches. Our system is capable of automatically providing preliminary evaluations at different pre-hospital stages for potential AIS patients.

in Frontiers in Neuroinformatics on March 24, 2020 12:00 AM.

• #### A Minimal Turing Test: Reciprocal Sensorimotor Contingencies for Interaction Detection

In the classical Turing test, participants are challenged to tell whether they are interacting with another human being or with a machine. The way the interaction takes place is not direct, but a distant conversation through computer screen messages. Basic forms of interaction are face-to-face and embodied, context-dependent and based on the detection of reciprocal sensorimotor contingencies. Our idea is that interaction detection requires the integration of proprioceptive and interoceptive patterns with sensorimotor patterns, within quite short time lapses, so that they appear as mutually contingent, as reciprocal. In other words, the experience of interaction takes place when sensorimotor patterns are contingent upon one’s own movements, and vice versa. I react to your movement, you react to mine. When I notice both components, I come to experience an interaction. Therefore, we designed a “minimal” Turing test to investigate how much information is required to detect these reciprocal sensorimotor contingencies. Using a new version of the perceptual crossing paradigm, we tested whether participants resorted to interaction detection to tell apart human from machine agents in repeated encounters with these agents. In two studies, we presented participants with movements of a human agent, either online or offline, and movements of a computerized oscillatory agent in three different blocks. In each block, either auditory or audiovisual feedback was provided along each trial. Analysis of participants’ explicit responses and of the implicit information subsumed in the dynamics of their series will reveal evidence that participants use the reciprocal sensorimotor contingencies within short time windows. For a machine to pass this minimal Turing test, it should be able to generate this sort of reciprocal contingencies.

in Frontiers in Human Neuroscience on March 24, 2020 12:00 AM.

• #### Commentary: A mental number line in human newborns

in Frontiers in Human Neuroscience on March 24, 2020 12:00 AM.

• #### Effects of Visual Scene Complexity on Neural Signatures of Spatial Attention

Spatial selective attention greatly affects our processing of complex visual scenes, yet the way in which the brain selects relevant objects while suppressing irrelevant objects is still unclear. Evidence of these processes has been found using non-invasive electroencephalography (EEG). However, few studies have characterized these measures during attention to dynamic stimuli, and little is known regarding how these measures change with increased scene complexity. Here, we compared attentional modulation of the EEG N1 and alpha power (oscillations between 8–14 Hz) across three visual selective attention tasks. The tasks differed in the number of irrelevant stimuli presented, but all required sustained attention to the orientation trajectory of a lateralized stimulus. In scenes with few irrelevant stimuli, top-down control of spatial attention is associated with strong modulation of both the N1 and alpha power across parietal-occipital channels. In scenes with many irrelevant stimuli in both hemifields, however, top-down control is no longer represented by strong modulation of alpha power, and N1 amplitudes are overall weaker. These results suggest that as a scene becomes more complex, requiring suppression in both hemifields, the neural signatures of top-down control degrade, likely reflecting some limitation in EEG to represent this suppression.

in Frontiers in Human Neuroscience on March 24, 2020 12:00 AM.

• #### High Gamma Band EEG Closely Related to Emotion: Evidence From Functional Network

High-frequency electroencephalography (EEG) signals play an important role in research on human emotions. However, the different network patterns under different emotional states in the high gamma band (50–80 Hz) remain unclear. In this paper, we investigate different emotional states using functional network analysis on various frequency bands. We constructed multiple functional networks on different frequency bands and performed functional network analysis and time–frequency analysis on these frequency bands to determine the significant features that represent different emotional states. Furthermore, we verified the effectiveness of these features by using them in emotion recognition. Our experimental results revealed that the network connections in the high gamma band with significant differences among the positive, neutral, and negative emotional states were much denser than the network connections in the other frequency bands. The connections mainly occurred in the left prefrontal, left temporal, parietal, and occipital regions. Moreover, long-distance connections with significant differences among the emotional states were observed in the high frequency bands, particularly in the high gamma band. Additionally, high gamma band fusion features derived from the global efficiency, network connections, and differential entropies achieved the highest classification accuracies for both our dataset and the public dataset. These results are consistent with literature and provide further evidence that high gamma band EEG signals are more sensitive and effective than the EEG signals in other frequency bands in studying human affective perception.

in Frontiers in Human Neuroscience on March 24, 2020 12:00 AM.

• #### Developmental Dynamic Dysphasia: Are Bilateral Brain Abnormalities a Signature of Inefficient Neural Plasticity?

The acquisition and evolution of speech production, discourse and communication can be negatively impacted by brain malformations. We describe, for the first time, a case of developmental dynamic dysphasia (DDD) in a right-handed adolescent boy (subject D) with cortical malformations involving language-eloquent regions (inferior frontal gyrus) in both the left and the right hemispheres. Language evaluation revealed a markedly reduced verbal output affecting phonemic and semantic fluency, phrase and sentence generation and verbal communication in everyday life. Auditory comprehension, repetition, naming, reading and spelling were relatively preserved, but executive function was impaired. Multimodal neuroimaging showed a malformed cerebral cortex with atypical configuration and placement of white matter tracts bilaterally and abnormal callosal fibers. Dichotic listening showed right hemisphere dominance for language, and functional magnetic resonance imaging (fMRI) additionally revealed dissociated hemispheric language representation with right frontal activation for phonology and bilateral dominance for semantic processing. Moreover, subject D also had congenital mirror movements (CMM), defined as involuntary movements of one side of the body that mirror intentional movements of the other side. Transcranial magnetic stimulation and fMRI during voluntary unimanual (left and right) hand movements showed bilateral motor cortex recruitment and tractography revealed a lack of decussation of bilateral corticospinal tracts. Genetic testing aimed to detect mutations that disrupt the development of commissural tracts correlating with CMM (e.g., Germline DCC mutations) was negative. Overall, our findings suggest that DDD in subject D resulted from the underdevelopment of the left inferior frontal gyrus with limited capacity for plastic reorganization by its homologous counterpart in the right hemisphere. Corpus callosum anomalies probably contributed to hinder interhemispheric connectivity necessary to compensate language and communication deficits after left frontal involvement.

in Frontiers in Human Neuroscience on March 24, 2020 12:00 AM.

• #### Combined Transplantation of Olfactory Ensheathing Cells With Rat Neural Stem Cells Enhanced the Therapeutic Effect in the Retina of RCS Rats

Retinal degenerative diseases (RDDs) are the leading causes of blindness and currently lack effective treatment. Cytotherapy has become a promising strategy for RDDs. The transplantation of olfactory ensheathing cells (OECs) or neural stem cells (NSCs) has recently been applied for the experimental treatment of RDDs. However, the long-term outcomes of single-cell transplantation are poor. The combined transplantation of multiple types of cells might achieve better effects. In the present study, OECs [containing olfactory nerve fibroblasts (ONFs)] and NSCs were cotransplanted into the subretinal space of Royal College of Surgeons (RCS) rats. Using electroretinogram (ERG), immunofluorescence, Western blot, and in vitro Transwell system, the differences in the electrophysiological and morphological changes of single and combined transplantation as well as the underlying mechanisms were explored at 4, 8, and 12 weeks postoperation. In addition, using the Transwell system, the influence of OECs on the stemness of NSCs was discovered. Results showed that, compared to the single transplantation of OECs or NSCs, the combined transplantation of OECs and NSCs produced greater improvements in b-wave amplitudes in ERGs and the thickness of the outer nuclear layer at all three time points. More endogenous stem cells were found within the retina after combined transplantation. Glial fibrillary acidic protein (GFAP) expression decreased significantly when NSCs were cotransplanted with OECs. Both the vertical and horizontal migration of grafted cells were enhanced in the combined transplantation group. Meanwhile, the stemness of NSCs was also better maintained after coculture with OECs. Taken together, the results suggested that the combined transplantation of NSCs and OECs enhanced the improvement in retinal protection in RCS rats, providing a new strategy to treat RDDs in the future.

in Frontiers in Cellular Neuroscience on March 24, 2020 12:00 AM.

• #### Reduced Retinal Thickness Predicts Age-Related Changes in Cognitive Function

Currently, there is a lack of biomarkers to identify individuals in the early stages of Alzheimer’s disease (AD). A preponderance of evidence suggests that neurodegenerative processes that affect the brain, may also affect the retina. Using optical coherence tomography (OCT), a non-invasive approach, many have shown thinning of the retina in AD and the developmental precursor to AD, mild cognitive impairment (MCI). However, the relationship between retinal thickness and cognitive function is not entirely clear. This is likely due to the disparity in diagnostic criteria used to determine MCI that does not fully probe the cognitive domains that are particularly vulnerable to aging. This study used a comprehensive neuropsychological assessment involving multiple domains of cognition to determine if retinal thickness correlates with cognitive performance in a normal aged population. In this study, 20 healthy individuals between 60 and 90 years of age were administered neuropsychological assessments probing various domains of cognitive function, and OCT to measure peripapillary retinal nerve fiber layer (RNFL) thickness. We found that RNFL thickness is correlated with neuropsychological performance in multiple cognitive domains (e.g., working memory, psychomotor speed, and executive function). Our work demonstrates a positive correlation between RNFL thickness and several, but not all, domains of cognitive function in a normative aging population. By determining which cognitive domains retinal thickness can predict, this work can help identify individuals at risk or in preclinical stages of AD and other neurodegenerative diseases.

in Frontiers in Ageing Neuroscience on March 24, 2020 12:00 AM.

• #### Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson’s disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

in Frontiers in Ageing Neuroscience on March 24, 2020 12:00 AM.

• #### A roadmap for gene functional characterisation in crops with large genomes: Lessons from polyploid wheat

Understanding the function of genes within staple crops will accelerate crop improvement by allowing targeted breeding approaches. Despite their importance, a lack of genomic information and resources has hindered the functional characterisation of genes in major crops. The recent release of high-quality reference sequences for these crops underpins a suite of genetic and genomic resources that support basic research and breeding. For wheat, these include gene model annotations, expression atlases and gene networks that provide information about putative function. Sequenced mutant populations, improved transformation protocols and structured natural populations provide rapid methods to study gene function directly. We highlight a case study exemplifying how to integrate these resources. This review provides a helpful guide for plant scientists, especially those expanding into crop research, to capitalise on the discoveries made in Arabidopsis and other plants. This will accelerate the improvement of crops of vital importance for food and nutrition security.

in eLife on March 24, 2020 12:00 AM.

• #### Site-directed MT1-MMP trafficking and surface insertion regulate AChR clustering and remodeling at developing NMJs

At vertebrate neuromuscular junctions (NMJs), the synaptic basal lamina contains different extracellular matrix (ECM) proteins and synaptogenic factors that induce and maintain synaptic specializations. Here, we report that podosome-like structures (PLSs) induced by ubiquitous ECM proteins regulate the formation and remodeling of acetylcholine receptor (AChR) clusters via focal ECM degradation. Mechanistically, ECM degradation is mediated by PLS-directed trafficking and surface insertion of membrane-type 1 matrix metalloproteinase (MT1-MMP) to AChR clusters through microtubule-capturing mechanisms. Upon synaptic induction, MT1-MMP plays a crucial role in the recruitment of aneural AChR clusters for the assembly of postsynaptic specializations. Lastly, the structural defects of NMJs in embryonic MT1-MMP-/- mice further demonstrate the physiological role of MT1-MMP in normal NMJ development. Collectively, this study suggests that postsynaptic MT1-MMP serves as a molecular switch to synaptogenesis by modulating local ECM environment for the deposition of synaptogenic signals that regulate postsynaptic differentiation at developing NMJs.

in eLife on March 24, 2020 12:00 AM.

• #### Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria

By sequencing autozygous human populations we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n=67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5sd outliers versus n=25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.

in eLife on March 24, 2020 12:00 AM.

• #### Cerebellar modulation of synaptic input to freezing-related neurons in the periaqueductal gray

Innate defensive behaviors, such as freezing, are adaptive for avoiding predation. Freezing-related midbrain regions project to the cerebellum, which is known to regulate rapid sensorimotor integration, raising the question of cerebellar contributions to freezing. Here, we find that neurons of the mouse medial (fastigial) cerebellar nuclei (mCbN), which fire spontaneously with wide dynamic ranges, send glutamatergic projections to the ventrolateral periaqueductal gray (vlPAG), which contains diverse cell types. In freely moving mice, optogenetically stimulating glutamatergic vlPAG neurons that express Chx10 reliably induces freezing. In vlPAG slices, mCbN terminals excite ~20% of neurons positive for Chx10 or GAD2 and ~70% of dopaminergic TH-positive neurons. Stimulating either mCbN afferents or TH neurons augments IPSCs and suppresses EPSCs in Chx10 neurons by activating postsynaptic D2 receptors. The results suggest that mCbN activity regulates dopaminergic modulation of the vlPAG, favoring inhibition of Chx10 neurons. Suppression of cerebellar output may therefore facilitate freezing.

in eLife on March 24, 2020 12:00 AM.

• #### CCR4, a RNA decay factor, is hijacked by a plant cytorhabdovirus phosphoprotein to facilitate virus replication

Carbon catabolite repression 4 (CCR4) is a conserved mRNA deadenylase regulating posttranscriptional gene expression. However, regulation of CCR4 in virus infections is less understood. Here, we characterized a pro-viral role of CCR4 in replication of a plant cytorhabdovirus, Barley yellow striate mosaic virus (BYSMV). The barley (Hordeum vulgare) CCR4 protein (HvCCR4) was identified to interact with the BYSMV phosphoprotein (P). The BYSMV P protein recruited HvCCR4 from processing bodies (PBs) into viroplasm-like bodies. Overexpression of HvCCR4 promoted BYSMV replication in plants. Conversely, knockdown of the small brown planthopper CCR4 inhibited viral accumulation in the insect vector. Biochemistry experiments revealed that HvCCR4 was recruited into N–RNA complexes by the BYSMV P protein and triggered turnover of N-bound cellular mRNAs, thereby releasing RNA-free N protein to bind viral genomic RNA for optimal viral replication. Our results demonstrate that the co-opted the CCR4-mediated RNA decay facilitates cytorhabdovirus replication in plants and insects.

in eLife on March 24, 2020 12:00 AM.

• #### Correcting for physical distortions in visual stimuli improves reproducibility in zebrafish neuroscience

Breakthrough technologies for monitoring and manipulating single-neuron activity provide unprecedented opportunities for whole-brain neuroscience in larval zebrafish1–9. Understanding the neural mechanisms of visually guided behavior also requires precise stimulus control, but little prior research has accounted for physical distortions that result from refraction and reflection at an air-water interface that usually separates the projected stimulus from the fish10–12. Here we provide a computational tool that transforms between projected and received stimuli in order to detect and control these distortions. The tool considers the most commonly encountered interface geometry, and we show that this and other common configurations produce stereotyped distortions. By correcting these distortions, we reduced discrepancies in the literature concerning stimuli that evoke escape behavior13,14, and we expect this tool will help reconcile other confusing aspects of the literature. This tool also aids experimental design, and we illustrate the dangers that uncorrected stimuli pose to receptive field mapping experiments.

in eLife on March 24, 2020 12:00 AM.

• #### Delayed antibiotic exposure induces population collapse in enterococcal communities with drug-resistant subpopulations

The molecular underpinnings of antibiotic resistance are increasingly understood, but less is known about how these molecular events influence microbial dynamics on the population scale. Here we show that the dynamics of E. faecalis communities exposed to antibiotics can be surprisingly rich, revealing scenarios where increasing population size or delaying drug exposure can promote population collapse. Specifically, we demonstrate how density-dependent feedback loops couple population growth and antibiotic efficacy when communities include drug-resistant subpopulations, leading to a wide range of behavior, including population survival, collapse, or one of two qualitatively distinct bistable behaviors where survival is favored in either small or large populations. These dynamics reflect competing density-dependent effects of different subpopulations, with growth of drug-sensitive cells increasing but growth of drug-resistant cells decreasing effective drug inhibition. Finally, we demonstrate how populations receiving immediate drug influx may sometimes thrive, while identical populations exposed to delayed drug influx collapse.

in eLife on March 24, 2020 12:00 AM.

• #### Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

Rett syndrome is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. Herein, we use the AAV-PHP.eB to deliver an instability-prone Mecp2 (iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic Mecp2 mutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eB-iMecp2 administration was well tolerated in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of iMecp2 provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.

in eLife on March 24, 2020 12:00 AM.

• #### Cooperative interactions facilitate stimulation of Rad51 by the Swi5-Sfr1 auxiliary factor complex

in eLife on March 24, 2020 12:00 AM.

• #### Rejuvenating conventional dendritic cells and T follicular helper cell formation after vaccination

Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals.

in eLife on March 24, 2020 12:00 AM.

• #### Deciphering anomalous heterogeneous intracellular transport with neural networks

Intracellular transport is predominantly heterogeneous in both time and space, exhibiting varying non-Brownian behavior. Characterization of this movement through averaging methods over an ensemble of trajectories or over the course of a single trajectory often fails to capture this heterogeneity. Here, we developed a deep learning feedforward neural network trained on fractional Brownian motion, providing a novel, accurate and efficient method for resolving heterogeneous behavior of intracellular transport in space and time. The neural network requires significantly fewer data points compared to established methods. This enables robust estimation of Hurst exponents for very short time series data, making possible direct, dynamic segmentation and analysis of experimental tracks of rapidly moving cellular structures such as endosomes and lysosomes. By using this analysis, fractional Brownian motion with a stochastic Hurst exponent was used to interpret, for the first time, anomalous intracellular dynamics, revealing unexpected differences in behavior between closely related endocytic organelles.

in eLife on March 24, 2020 12:00 AM.

• #### Polyunsaturated fatty acid analogues differentially affect cardiac Nav, Cav, and Kv channels through unique mechanisms

The cardiac ventricular action potential depends on several voltage-gated ion channels, including Nav, Cav, and Kv channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (Nav, Cav, and KV). In addition, a PUFA analogue selective for the cardiac IKs channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.

in eLife on March 24, 2020 12:00 AM.

• #### The hazards of smoking and the benefits of cessation: a critical summation of the epidemiological evidence in high-income countries

In high-income countries, the biggest cause of premature death, defined as death before 70 years, is smoking of manufactured cigarettes. Smoking-related disease was responsible for about 41 million deaths in the United States, United Kingdom and Canada, cumulatively, from 1960 to 2020. Every million cigarettes smoked leads to one death in the US and Canada, but slightly more than one death in the UK. The 21st century hazards reveal that smokers who start smoking early in adult life and do not quit lose a decade of life expectancy versus non-smokers. Cessation, particularly before age 40 years, yields large reductions in mortality risk. Up to two-thirds of deaths among smokers are avoidable at non-smoking death rates, and former smokers have about only a quarter of the excess risk of death compared to current smokers. The gap between scientific and popular understanding of smoking hazards is surprisingly large.

in eLife on March 24, 2020 12:00 AM.

• #### BMP Signaling Gradient Scaling in the Zebrafish Pectoral Fin

The control of organ growth is essential for embryonic development. Mateus et al. show that during zebrafish pectoral fin development, two BMP morphogen signaling gradients form and expand proportionally to fin size, regulating growth. A feedback loop between Smoc1 (a conserved secreted factor) and BMP signaling mediates BMP gradient scaling.

in Cell Reports on March 24, 2020 12:00 AM.

• #### Dissecting the Single-Cell Transcriptome Network Underlying Gastric Premalignant Lesions and Early Gastric Cancer

(Cell Reports 27, 1934–1947.e1–e5; May 7, 2019)

in Cell Reports on March 24, 2020 12:00 AM.

• #### Cardiolipin’s Remodeling Rules Revealed: The Role of the Cellular Lipidome

In this issue of Cell Reports, Oemer et al. (2020) define the acyl chain composition of cardiolipin and other lipid classes in murine tissues. They then employ artificial neural networks to predict mechanisms that govern cardiolipin tissue specificity, with implications for understanding cellular pathogenesis in human disease.

in Cell Reports on March 24, 2020 12:00 AM.

• #### TLR4-Mediated Pathway Triggers Interferon-Independent G0 Arrest and Antiviral SAMHD1 Activity in Macrophages

Mlcochova et al. demonstrate that TLR4 activation regulates the cell cycle in human primary macrophages. This culminates in G0 arrest and activation of the antiviral protein SAMHD1, suggesting that macrophages can achieve a heightened state of alert in response to pathogen-associated danger signals in macrophages prior to type I IFN secretion.

in Cell Reports on March 24, 2020 12:00 AM.

• #### Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses

Lymph node stromal cells influence adaptive immune cells in various ways. Nadafi et al. show that by presenting self-antigens on MHC class II, lymph node stromal cells promote the differentiation of CD4+ T cells into regulatory T cells, which are able to prevent the generation of follicular T helper cells and germinal center B cells directed against the same self-antigen.

in Cell Reports on March 24, 2020 12:00 AM.

• #### An mRNA-mRNA Interaction Couples Expression of a Virulence Factor and Its Chaperone in Listeria monocytogenes

By using a comparative structural analysis method targeting 5′ untranslated regions, Ignatov et al. identify different RNA-based regulatory mechanisms such as an RNA thermoswitch, a small RNA (sRNA)-mRNA interaction, and strikingly, an mRNA-mRNA interaction.

in Cell Reports on March 24, 2020 12:00 AM.

• #### c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3

Ma et al. identify a mechanism of c-Src in promoting tumorigenesis and progression by phosphorylating and activating PFKFB3, an indispensable activator of the rate-limiting enzyme PFK1. PFKFB3 activation further stimulates glycolysis that provides precursors for biosynthesis of proliferating tumor cells.

in Cell Reports on March 24, 2020 12:00 AM.

• #### Platform Effects on Regeneration by Pulmonary Basal Cells as Evaluated by Single-Cell RNA Sequencing

Greaney et al. compare pulmonary epithelial regeneration across multiple modalities in vitro, finding that decellularized scaffolds achieved the most physiologic differentiation over more artificial platforms. scRNA-seq enables high-resolution comparison between engineered and native cell populations, thereby better gauging progress toward the generation of a tissue that may function on implantation.

in Cell Reports on March 24, 2020 12:00 AM.

• #### Structural Basis for EPC1-Mediated Recruitment of MBTD1 into the NuA4/TIP60 Acetyltransferase Complex

EPC1 is a critical component of the NuA4/TIP60 acetyltransferase complex involved in gene expression and genome maintenance. Zhang et al. illuminate the structural and molecular basis for EPC1 bound to the H4K20me reader MBTD1, highlighting the important role of their association in gene transcription and DNA repair.

in Cell Reports on March 24, 2020 12:00 AM.

• #### IQGAP1 Negatively Regulates HIV-1 Gag Trafficking and Virion Production

IQGAP1 is a ubiquitously expressed master regulator of many cellular processes, including intracellular trafficking. Sabo et al. demonstrate that in a variety of cell types, IQGAP1 acts as a negative regulator of HIV-1 viral particle release by reducing accumulation of the Gag viral structural protein at the plasma membrane.

in Cell Reports on March 24, 2020 12:00 AM.

• #### Histone H4K20 Demethylation by Two hHR23 Proteins

Cao et al. screen 2,500 nuclear proteins and find that hHR23A/B are histone H4K20 demethylases. They also show that hHR23A/B activate transcription via demethylation.

in Cell Reports on March 24, 2020 12:00 AM.

• #### Chromatin Remodeling and Immediate Early Gene Activation by SLFN11 in Response to Replication Stress

Schlafen 11 (SLFN11), a promising therapeutic biomarker, binds chromatin and sensitizes cancer cells to DNA-targeting agents by blocking DNA replication. Murai et al. show that, in response to replication stress, SLFN11 selectively increases chromatin accessibility at promoters and activates a subset of genes known as the immediate early genes (IEGs).

in Cell Reports on March 24, 2020 12:00 AM.

• #### Streptococcus pneumoniae Infection Promotes Histone H3 Dephosphorylation by Modulating Host PP1 Phosphatase

Dong et al. show that Streptococcus pneumoniae infection induces histone H3 dephosphorylation in lung epithelial cells, through two bacterial factors, PLY and SpxB. Infection-triggered activation of the host phosphatase PP1 is required for this histone modification and efficient intracellular infection.

in Cell Reports on March 24, 2020 12:00 AM.

• #### Phospholipid Acyl Chain Diversity Controls the Tissue-Specific Assembly of Mitochondrial Cardiolipins

The lipid architecture of biomembranes is crucial for their cellular functions. The regulatory origins of the strong tissue specificity of cardiolipins, a vital mitochondrial phospholipid class, were so far largely unresolved. Oemer et al. find that a single mechanism explains cardiolipin diversity across tissues on basis of the phospholipid environment.

in Cell Reports on March 24, 2020 12:00 AM.

• #### Transcription Factor Binding to Replicated DNA

During genome replication, mRNA synthesis from replicated genes is inhibited. Bar-Ziv et al. find that transcription factors (TFs) are recruited to replicated promoters but RNA polymerase II (Pol II) binding is buffered. Their work suggests that the unique chromatin environment during DNA replication limits the ability of TFs to recruit Pol II.

in Cell Reports on March 24, 2020 12:00 AM.

• #### Vitamin B12 Regulates Glial Migration and Synapse Formation through Isoform-Specific Control of PTP-3/LAR PRTP Expression

Zhang et al. describe glial migration and synapse formation defects stemming from vitamin B12 deficiency. Their study identifies a cell-autonomous mechanism regulating glial migration, where vitamin B12 regulates expression of the cell adhesion molecule PTP-3/LAR PRTP in an isoform-specific manner.

in Cell Reports on March 24, 2020 12:00 AM.

• #### SPHK2-Generated S1P in CD11b+ Macrophages Blocks STING to Suppress the Inflammatory Function of Alveolar Macrophages

Joshi et al. demonstrate an essential role of SPHK2+ monocyte-derived CD11b+ macrophages, which are recruited to the airspace, in promoting anti-inflammatory function of alveolar macrophages during lung injury. They show that S1P generated by recruited SPHK2+-CD11b+ macrophages suppresses STING signaling in alveolar macrophages to resolve inflammatory injury.

in Cell Reports on March 24, 2020 12:00 AM.

• #### Route of Vaccine Administration Alters Antigen Trafficking but Not Innate or Adaptive Immunity

Route of immunization, especially intramuscular versus subcutaneous administration, is often debated. Ols et al. use a rhesus macaque model to determine the tissues targeted by a nanoparticle vaccine administered by either route. The authors demonstrate that tissue dissemination is route dependent, but innate and adaptive immune responses develop comparably.

in Cell Reports on March 24, 2020 12:00 AM.

• #### The Zonal Organization of Odorant Receptor Gene Choice in the Main Olfactory Epithelium of the Mouse

Zapiec and Mombaerts report a multiplex method to map the expression areas of odorant receptor genes in individual, non-genetically modified mice. They classify the expression areas of 68 odorant receptor genes into 9 zones. These zones are highly overlapping and strikingly complex when viewed in 3D reconstructions.

in Cell Reports on March 24, 2020 12:00 AM.