• #### How data, synapses and neurons interact with each other: a variational principle marrying gradient ascent and message passing. (arXiv:1911.07662v1 [stat.ML])

Unsupervised learning requiring only raw data is not only a fundamental function of the cerebral cortex, but also a foundation for a next generation of artificial neural networks. However, a unified theoretical framework to treat sensory inputs, synapses and neural activity together is still lacking. The computational obstacle originates from the discrete nature of synapses, and complex interactions among these three essential elements of learning. Here, we propose a variational mean-field theory in which only the distribution of synaptic weight is considered. The unsupervised learning can then be decomposed into two interwoven steps: a maximization step is carried out as a gradient ascent of the lower-bound on the data log-likelihood, and an expectation step is carried out as a message passing procedure on an equivalent or dual neural network whose parameter is specified by the variational parameter of the weight distribution. Therefore, our framework explains how data (or sensory inputs), synapses and neural activities interact with each other to achieve the goal of extracting statistical regularities in sensory inputs. This variational framework is verified in restricted Boltzmann machines with planted synaptic weights and learning handwritten digits.

in q-bio.NC updates on arXiv.org on November 19, 2019 01:30 AM.

• #### Spatial Resolution of Local Field Potential Signals in Macaque V4. (arXiv:1911.07388v1 [q-bio.NC])

A main challenge for the development of cortical visual prostheses is to spatially localize individual spots of light, called phosphenes, by assigning appropriate stimulating parameters to implanted electrodes. Imitating the natural responses to phosphene-like stimuli at different positions can help in designing a systematic procedure to determine these parameters. The key characteristic of such a system is the ability to discriminate between responses to different positions in the visual field. While most previous prosthetic devices have targeted the primary visual cortex, the extrastriate cortex has the advantage of covering a large part of the visual field with a smaller amount of cortical tissue, providing the possibility of a more compact implant. Here, we studied how well ensembles of Multiunit activity (MUA) and Local Field Potentials (LFPs) responses from extrastriate cortical visual area V4 of a behaving macaque monkey can discriminate between two-dimensional spatial positions. We found that despite the large receptive field sizes in V4, the combined responses from multiple sites, whether MUA or LFP, has the capability for fine and coarse discrimination of positions. We identified a selection procedure that could significantly increase the discrimination performance while reducing the required number of electrodes. Analysis of noise correlation in MUA and LFP responses showed that noise correlations in LFP responses carry more information about the spatial positions. Overall, these findings suggest that spatial positions could be localized with patterned stimulation in extrastriate area V4.

in q-bio.NC updates on arXiv.org on November 19, 2019 01:30 AM.

• #### Quantum Computing at the Frontiers of Biological Sciences. (arXiv:1911.07127v1 [quant-ph])

The search for meaningful structure in biological data has relied on cutting-edge advances in computational technology and data science methods. However, challenges arise as we push the limits of scale and complexity in biological problems. Innovation in massively parallel, classical computing hardware and algorithms continues to address many of these challenges, but there is a need to simultaneously consider new paradigms to circumvent current barriers to processing speed. Accordingly, we articulate a view towards quantum computation and quantum information science, where algorithms have demonstrated potential polynomial and exponential computational speedups in certain applications, such as machine learning. The maturation of the field of quantum computing, in hardware and algorithm development, also coincides with the growth of several collaborative efforts to address questions across length and time scales, and scientific disciplines. We use this coincidence to explore the potential for quantum computing to aid in one such endeavor: the merging of insights from genetics, genomics, neuroimaging and behavioral phenotyping. By examining joint opportunities for computational innovation across fields, we highlight the need for a common language between biological data analysis and quantum computing. Ultimately, we consider current and future prospects for the employment of quantum computing algorithms in the biological sciences.

in q-bio.NC updates on arXiv.org on November 19, 2019 01:30 AM.

• #### Evaluation of techniques for predicting seizure Build up. (arXiv:1911.07081v1 [eess.SP])

The analysis of electrophysiological signal of scalp: EEG (electroencephalography), MEG (magnetoencephalography) and depth (intracerebral EEG) IEEG is a way to delimit epileptogenic zone (EZ). These epileptic signals present two different activities (oscillations and spikes) which can be overlapped in the time frequency plane. Automatic recognition of epileptic seizure occurrence needs several preprocessing steps. In this study, we evaluated two filtering techniques: the stationary wavelet transforms (SWT) and the Despikifying in order to extract pre ictal gamma oscillations (bio markers of seizure build up). Then, we used a temporal basis set of Jmail et al 2017 as a preprocessing step to evaluate the performance of both technique. Moreover, we used time-frequency and spatio-temporal mapping of simulated and real data for both techniques in order to predict seizure build up (in time and space). We concluded that SWT can detect the oscillations, but Despikyfying is more robust than SWT in reconstructing pure pre ictal gamma oscillations and hence in predicting seizure build up.

in q-bio.NC updates on arXiv.org on November 19, 2019 01:30 AM.

• #### Three cooperative mechanisms required for recovery after brain damage. (arXiv:1911.07012v1 [q-bio.NC])

Stroke is one of the main causes of human disabilities. Experimental observations indicate that several mechanisms are activated during the recovery of functional activity after a stroke. Here we unveil how the brain recovers by explaining the role played by three mechanisms: Plastic adaptation, hyperexcitability and synaptogenesis. We consider two different damages in a neural network: A diffuse damage that simply causes the reduction of the effective system size and a localized damage, a stroke, that strongly alters the spontaneous activity of the system. Recovery mechanisms observed experimentally are implemented both separately and in a combined way. Interestingly, each mechanism contributes to the recovery to a limited extent. Only the combined application of all three together is able to recover the spontaneous activity of the undamaged system. This explains why the brain triggers independent mechanisms, whose cooperation is the fundamental ingredient for the system recovery.

in q-bio.NC updates on arXiv.org on November 19, 2019 01:30 AM.

• #### Precise Spatial Memory in Local Random Networks. (arXiv:1911.06921v1 [q-bio.NC])

Self-sustained, elevated neuronal activity persisting on time scales of ten seconds or longer is thought to be vital for aspects of working memory, including brain representations of real space. Continuous-attractor neural networks, one of the most well-known modeling frameworks for persistent activity, have been able to model crucial aspects of such spatial memory. These models tend to require highly structured or regular synaptic architectures. In contrast, we elaborate a geometrically-embedded model with a local but otherwise random connectivity profile which, combined with a global regulation of the mean firing rate, produces localized, finely spaced discrete attractors that effectively span a 2D manifold. We demonstrate how the set of attracting states can reliably encode a representation of the spatial locations at which the system receives external input, thereby accomplishing spatial memory via attractor dynamics without synaptic fine-tuning or regular structure. We measure the network's storage capacity and find that the statistics of retrievable positions are also equivalent to a full tiling of the plane, something hitherto achievable only with (approximately) translationally invariant synapses, and which may be of interest in modeling such biological phenomena as visuospatial working memory in two dimensions.

in q-bio.NC updates on arXiv.org on November 19, 2019 01:30 AM.

• #### Exponential Time Differencing Algorithm For Pulse-coupled Hodgkin-Huxley Neuronal Networks. (arXiv:1910.08724v2 [q-bio.NC] UPDATED)

The exponential time differencing (ETD) method allows using a large time step to efficiently evolve the stiff system such as Hodgkin-Huxley (HH) neural networks.

For pulse-coupled HH networks, the synaptic spike times cannot be predetermined and are convoluted with neuron's trajectory itself.

This presents a challenging issue for the design of an efficient numerical simulation algorithm.

The stiffness in the HH equations are quite different between the spike and non-spike regions. Here, we design a second-order adaptive exponential time differencing algorithm (AETD2) for the numerical evolution of HH neural networks.

Compared with the regular second-order Runge-Kutta method (RK2), our AETD2 method can use time steps one order of magnitude larger and improve computational efficiency more than ten times while excellently capturing accurate traces of membrane potentials of HH neurons. This high accuracy and efficiency can be robustly obtained and do not depend on the dynamical regimes, connectivity structure or the network size.

in q-bio.NC updates on arXiv.org on November 19, 2019 01:30 AM.

• #### Modeling Bottom-Up and Top-Down Attention with a Neurodynamic Model of V1. (arXiv:1904.02741v3 [q-bio.NC] UPDATED)

Previous studies suggested that lateral interactions of V1 cells are responsible, among other visual effects, of bottom-up visual attention (alternatively named visual salience or saliency). Our objective is to mimic these connections with a neurodynamic network of firing-rate neurons in order to predict visual attention. Early visual subcortical processes (i.e. retinal and thalamic) are functionally simulated. An implementation of the cortical magnification function is included to define the retinotopical projections towards V1, processing neuronal activity for each distinct view during scene observation. Novel computational definitions of top-down inhibition (in terms of inhibition of return and selection mechanisms), are also proposed to predict attention in Free-Viewing and Visual Search tasks. Results show that our model outpeforms other biologically-inpired models of saliency prediction while predicting visual saccade sequences with the same model. We also show how temporal and spatial characteristics of inhibition of return can improve prediction of saccades, as well as how distinct search strategies (in terms of feature-selective or category-specific inhibition) can predict attention at distinct image contexts.

in q-bio.NC updates on arXiv.org on November 19, 2019 01:30 AM.

• #### Critical synchronization dynamics of the Kuramoto model on connectome and small world graphs. (arXiv:1903.00385v3 [cond-mat.dis-nn] UPDATED)

The hypothesis, that cortical dynamics operates near criticality also suggests, that it exhibits universal critical exponents which marks the Kuramoto equation, a fundamental model for synchronization, as a prime candidate for an underlying universal model. Here, we determined the synchronization behavior of this model by solving it numerically on a large, weighted human connectome network, containing 804092 nodes, in an assumed homeostatic state. Since this graph has a topological dimension $d < 4$, a real synchronization phase transition is not possible in the thermodynamic limit, still we could locate a transition between partially synchronized and desynchronized states. At this crossover point we observe power-law--tailed synchronization durations, with $\tau_t \simeq 1.2(1)$, away from experimental values for the brain. For comparison, on a large two-dimensional lattice, having additional random, long-range links, we obtain a mean-field value: $\tau_t \simeq 1.6(1)$. However, below the transition of the connectome we found global coupling control-parameter dependent exponents $1 < \tau_t \le 2$, overlapping with the range of human brain experiments. We also studied the effects of random flipping of a small portion of link weights, mimicking a network with inhibitory interactions, and found similar results. The control-parameter dependent exponent suggests extended dynamical criticality below the transition point.

in q-bio.NC updates on arXiv.org on November 19, 2019 01:30 AM.

• #### Sleep-like slow oscillations improve visual classification through synaptic homeostasis and memory association in a thalamo-cortical model. (arXiv:1810.10498v5 [q-bio.NC] UPDATED)

The occurrence of sleep passed through the evolutionary sieve and is widespread in animal species. Sleep is known to be beneficial to cognitive and mnemonic tasks, while chronic sleep deprivation is detrimental. Despite the importance of the phenomenon, a complete understanding of its functions and underlying mechanisms is still lacking. In this paper, we show interesting effects of deep-sleep-like slow oscillation activity on a simplified thalamo-cortical model which is trained to encode, retrieve and classify images of handwritten digits. During slow oscillations, spike-timing-dependent-plasticity (STDP) produces a differential homeostatic process. It is characterized by both a specific unsupervised enhancement of connections among groups of neurons associated to instances of the same class (digit) and a simultaneous down-regulation of stronger synapses created by the training. This hierarchical organization of post-sleep internal representations favours higher performances in retrieval and classification tasks. The mechanism is based on the interaction between top-down cortico-thalamic predictions and bottom-up thalamo-cortical projections during deep-sleep-like slow oscillations. Indeed, when learned patterns are replayed during sleep, cortico-thalamo-cortical connections favour the activation of other neurons coding for similar thalamic inputs, promoting their association. Such mechanism hints at possible applications to artificial learning systems.

in q-bio.NC updates on arXiv.org on November 19, 2019 01:30 AM.

• #### Imaging and Quantification of Myelin Integrity After Injury With Spectral Confocal Reflectance Microscopy

Developing a high-throughput approach to quantify the extent of myelin integrity in preclinical models of demyelinating diseases will enhance our capacity to identify novel therapies for myelin repair. In light of the technical limitations of electron microscopy and immunohistochemical analyses of myelination, we have utilized a novel imaging technique, spectral confocal reflectance (SCoRe) microscopy. SCoRe takes advantage of the optically reflective properties of compact myelin, allowing the integrity of compact myelin to be quantified over the course of the cuprizone-induced model of central demyelination. We applied SCoRe imaging on fixed frozen brain sections. SCoRe analysis of control mice identified an increase in corpus callosum myelination during the period of cuprizone administration and recovery, suggesting that the normal developmental processes of myelination are ongoing at this time. Importantly, analysis of mice subjected to cuprizone identified a significant reduction in compact myelin in both rostral and caudal corpus callosum compared to age-matched control mice. SCoRe microscopy also allowed the visualization and quantification of the amount of myelin debris in demyelinating lesions. Combining SCoRe imaging with immunohistochemistry, we quantified the amount of myelin debris within IBA-1+ microglia and found that 11% of myelin debris colocalized in microglia irrespective of the callosal regions, with the vast majority of debris outside of microglia. In summary, we have demonstrated that SCoRe microscopy is an effective and powerful tool to perform both quantitative and qualitative analyses of compact myelin integrity in health or after injury in vivo, demonstrating its future application in high-throughput assessments and screening of the therapeutic efficacy of myelin repair therapies in preclinical animal models of demyelinating diseases.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Design of a New [PSI+]-No-More Mutation in SUP35 With Strong Inhibitory Effect on the [PSI+] Prion Propagation

A number of [PSI+]-no-more (PNM) mutations, eliminating [PSI+] prion, were previously described in SUP35. In this study, we designed and analyzed a new PNM mutation based on the parallel in-register β-structure of Sup35 prion fibrils suggested by the known experimental data. In such an arrangement, substitution of non-charged residues by charged ones may destabilize the fibril structure. We introduced Q33K/A34K amino acid substitutions into the Sup35 protein, corresponding allele was called sup35-M0. The mutagenized residues were chosen based on ArchCandy in silico prediction of high inhibitory effect on the amyloidogenic potential of Sup35. The experiments confirmed that Sup35-M0 leads to the elimination of [PSI+] with high efficiency. Our data suggested that the elimination of the [PSI+] prion is associated with the decreased aggregation properties of the protein. The new mutation can induce the prion with very low efficiency and is able to propagate only weak [PSI+] prion variants. We also showed that Sup35-M0 protein co-aggregates with the wild-type Sup35 in vivo. Moreover, our data confirmed the utility of the strategy of substitution of non-charged residues by charged ones to design new mutations to inhibit a prion formation.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Optimized Configuration of Functional Brain Network for Processing Semantic Audiovisual Stimuli Underlying the Modulation of Attention: A Graph-Based Study

Semantic audiovisual stimuli have a facilitatory effect on behavioral performance and influence the integration of multisensory inputs across sensory modalities. Many neuroimaging and electrophysiological studies investigated the neural mechanisms of multisensory semantic processing and reported that attention modulates the response to multisensory semantic inputs. In the present study, we designed an functional magnetic resonance imaging (fMRI) experiment of semantic discrimination using the unimodal auditory, unimodal visual and bimodal audiovisual stimuli with semantic information. By manipulating the stimuli present on attended and unattended position, we recorded the task-related fMRI data corresponding to the unimodal auditory, unimodal visual and bimodal audiovisual stimuli in attended and unattended conditions. We also recorded the fMRI data in resting state. Then the fMRI method was used together with a graph theoretical analysis to construct the functional brain networks in task-related and resting states and quantitatively characterize the topological network properties. The aim of our present study is to explore the characteristics of functional brain networks that process semantic audiovisual stimuli in attended and unattended conditions, revealing the neural mechanism of multisensory processing and the modulation of attention. The behavioral results showed that the audiovisual stimulus presented simultaneously promoted the performance of semantic discrimination task. And the analyses of network properties showed that compared with the resting-state condition, the functional networks of processing semantic audiovisual stimuli (both in attended and unattended conditions) had greater small-worldness, global efficiency, and lower clustering coefficient, characteristic path length, global efficiency and hierarchy. In addition, the hubs were concentrated in the bilateral temporal lobes, especially in the anterior temporal lobes (ATLs), which were positively correlated to reaction time (RT). Moreover, attention significantly altered the degree of small-worldness and the distribution of hubs in the functional network for processing semantic audiovisual stimuli. Our findings suggest that the topological structure of the functional brain network for processing semantic audiovisual stimulus is modulated by attention, and has the characteristics of high efficiency and low wiring cost, which maintains an optimized balance between functional segregation and integration for multisensory processing efficiently.

in Frontiers in Integrative Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Association Between BDNF Val66Met Polymorphism and Optic Neuritis Damage in Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS). The purpose of the study was to examine the association between the brain-derived neurotrophic factor (BDNF) Val66Met genotype and structural and functional optic nerve damage in the eyes of NMOSD patients. A total of 17 NMOSD subjects (34 eyes) were included in the study and were divided into subgroups based on optic neuritis (ON) history and BDNF Val66Met polymorphisms. The mean (range) age was 47.8 (23–78) years, and the mean (SD) disease duration was 7.4 (2–39) years. All participants had undergone optical coherence tomography (OCT) scans for global retinal nerve fiber layer (gRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness and multifocal visual evoked potential (mfVEP) test for amplitude and latency. BDNF Val66Met polymorphisms were genotyped in all participants. OCT and mfVEP changes were compared between two genotype groups (Met carriers vs. Val homozygotes) by using the generalised estimating equation (GEE) models. The BDNF Val66Met polymorphism was significantly associated with more severe nerve fiber layer damage and axonal loss in ON eyes of NMOSD subjects. Met carriers had more significantly reduced GCIPL (P = 0.002) and gRNFL (P < 0.001) thickness as well as more delayed mfVEP latency (P = 0.008) in ON eyes. No association was found between Val66Met variants and non-ON (NON)-eye of the participants. These findings suggest that the BDNF Val66Met polymorphism may be associated with optic nerve damage caused by acute ON attacks in NMOSD patients.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Lowering EphA4 Does Not Ameliorate Disease in a Mouse Model for Severe Spinal Muscular Atrophy

EphA4 is a receptor of the Eph-ephrin system, which plays an important role in axon guidance during development. Previously, we identified EphA4 as a genetic modifier of amyotrophic lateral sclerosis (ALS) in both zebrafish and rodent models, via modulation of the intrinsic vulnerability, and re-sprouting capacity of motor neurons. Moreover, loss of EphA4 rescued the motor axon phenotype in a zebrafish model of spinal muscular atrophy (SMA). Similar to ALS, SMA is a neurodegenerative disorder affecting spinal motor neurons resulting in neuromuscular junction (NMJ) denervation, muscle atrophy and paralysis. In this study, we investigated the disease modifying potential of reduced EphA4 protein levels in the SMNΔ7 mouse model for severe SMA. Reduction of EphA4 did not improve motor function, survival, motor neuron survival or NMJ innervation. Our data suggest that either lowering EphA4 has limited therapeutic potential in SMA or that the clinical severity hampers the potential beneficial role of EphA4 reduction in this mouse model for SMA.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Naringenin Ameliorates Drosophila ReepA Hereditary Spastic Paraplegia-Linked Phenotypes

Defects in the endoplasmic reticulum (ER) membrane shaping and interaction with other organelles seem to be a crucial mechanism underlying Hereditary Spastic Paraplegia (HSP) neurodegeneration. REEP1, a transmembrane protein belonging to TB2/HVA22 family, is implicated in SPG31, an autosomal dominant form of HSP, and its interaction with Atlastin/SPG3A and Spastin/SPG4, the other two major HSP linked proteins, has been demonstrated to play a crucial role in modifying ER architecture. In addition, the Drosophila ortholog of REEP1, named ReepA, has been found to regulate the response to ER neuronal stress. Herein we investigated the role of ReepA in ER morphology and stress response. ReepA is upregulated under stress conditions and aging. Our data show that ReepA triggers a selective activation of Ire1 and Atf6 branches of Unfolded Protein Response (UPR) and modifies ER morphology. Drosophila lacking ReepA showed Atf6 and Ire1 activation, expansion of ER sheet-like structures, locomotor dysfunction and shortened lifespan. Furthermore, we found that naringenin, a flavonoid that possesses strong antioxidant and neuroprotective activity, can rescue the cellular phenotypes, the lifespan and locomotor disability associated with ReepA loss of function. Our data highlight the importance of ER homeostasis in nervous system functionality and HSP neurodegenerative mechanisms, opening new opportunities for HSP treatment.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Successes and Hurdles in Stem Cells Application and Production for Brain Transplantation

Brain regenerative strategies through the transplantation of stem cells hold the potential to promote functional rescue of brain lesions caused either by trauma or neurodegenerative diseases. Most of the positive modulations fostered by stem cells are fueled by bystander effects, namely increase of neurotrophic factors levels and reduction of neuroinflammation. Nevertheless, the ultimate goal of cell therapies is to promote cell replacement. Therefore, the ability of stem cells to migrate and differentiate into neurons that later become integrated into the host neuronal network replacing the lost neurons has also been largely explored. However, as most of the preclinical studies demonstrate, there is a small functional integration of graft-derived neurons into host neuronal circuits. Thus, it is mandatory to better study the whole brain cell therapy approach in order to understand what should be better comprehended concerning graft-derived neuronal and glial cells migration and integration before we can expect these therapies to be ready as a viable solution for brain disorder treatment. Therefore, this review discusses the positive mechanisms triggered by cell transplantation into the brain, the limitations of adult brain plasticity that might interfere with the neuroregeneration process, as well as some strategies tested to overcome some of these limitations. It also considers the efforts that have been made by the regulatory authorities to lead to better standardization of preclinical and clinical studies in this field in order to reduce the heterogeneity of the obtained results.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Editorial: Psychophysiological Contributions to Traffic Safety

in Frontiers in Human Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Individual Differences in Verb Bias Sensitivity in Children and Adults With Developmental Language Disorder

A number of experiments support the hypothetical utility of statistical information for language learning and processing among both children and adults. However, tasks in these studies are often very general, and only a few include populations with developmental language disorder (DLD). We wanted to determine whether a stronger relationship might be shown when the measure of statistical learning is chosen for its relevance to the language task when including a substantial number of participants with DLD. The language ability we measured was sensitivity to verb bias – the likelihood of a verb to appear with a certain argument or interpretation. A previous study showed adults with DLD were less sensitive to verb bias than their typical peers. Verb bias sensitivity had not yet been tested in children with DLD. In Study 1, 49 children, ages 7–9 years, 17 of whom were classified as having DLD, completed a task designed to measure sensitivity to verb bias through implicit and explicit measures. We found children with and without DLD showed sensitivity to verb bias in implicit but not explicit measures, with no differences between groups. In Study 2, we used a multiverse approach to investigate whether individual differences in statistical learning predicted verb bias sensitivity in these participants as well as in a dataset of adult participants. Our analysis revealed no evidence of a relationship between statistical learning and verb bias sensitivity in children, which was not unexpected given we found no group differences in Study 1. Statistical learning predicted sensitivity to verb bias as measured through explicit measures in adults, though results were not robust. These findings suggest that verb bias may still be relatively unstable in school age children, and thus may not play the same role in sentence processing in children as in adults. It would also seem that individuals with DLD may not be using the same mechanisms during processing as their typically developing (TD) peers in adulthood. Thus, statistical information may differ in relevance for language processing in individuals with and without DLD.

in Frontiers in Human Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Optogenetic/Chemogenetic Activation of GABAergic Neurons in the Ventral Tegmental Area Facilitates General Anesthesia via Projections to the Lateral Hypothalamus in Mice

The ventral tegmental area (VTA) reportedly regulates sleep and wakefulness through communication with the lateral hypothalamus (LH). It has also been suggested that adequate anesthesia produced by administration of chloral hydrate, ketamine, or halothane significantly reduces the GABAergic neuronal firing rate within the VTA. However, the exact effects on GABAergic neurons in the VTA and the mechanisms through which these neurons modulate anesthesia through associated neural circuits is still unclear. Here, we used optogenetic and chemogenetic methods to specifically activate or inhibit GABAergic neuronal perikarya in the VTA or their projections to the LH in Vgat-Cre mice. Electroencephalogram (EEG) spectral analyses and burst suppression ratio (BSR) calculations were conducted following administration of 0.8 or 1.0% isoflurane, respectively; and loss of righting reflex (LORR), recovery of righting reflex (RORR), and anesthesia sensitivity were assessed under 1.4% isoflurane anesthesia. The results showed that activation of GABAergic neurons in the VTA increased delta wave power from 40.0 to 46.4% (P = 0.006) and decreased gamma wave power from 15.2 to 11.5% (P = 0.017) during anesthesia maintenance. BSR was increased from 51.8 to 68.3% (P = 0.017). Induction time (LORR) was reduced from 333 to 290 s (P = 0.019), whereas arousal time (RORR) was prolonged from 498 to 661 s (P = 0.007). Conversely, inhibition of VTA GABAergic neurons led to opposite effects. In contrast, optical activation of VTA–LH GABAergic projection neurons increased power of slow delta waves from 44.2 to 48.8% (P = 0.014) and decreased that of gamma oscillations from 10.2 to 8.0%. BSR was increased from 39.9 to 60.2% (P = 0.0002). LORR was reduced from 330 to 232 s (P = 0.002), and RORR increased from 396 to 565 s (P = 0.007). Optical inhibition of the projection neurons caused opposite effects in terms of both the EEG spectrum and the BSR, except that inhibition of this projection did not accelerate arousal time. These results indicate that VTA GABAergic neurons could facilitate the anesthetic effects of isoflurane during induction and maintenance while postponing anesthetic recovery, at least partially, through modulation of their projections to the LH.

in Frontiers in Neural Circuits | New and Recent Articles on November 19, 2019 12:00 AM.

• #### GABA-Glycine Cotransmitting Neurons in the Ventrolateral Medulla: Development and Functional Relevance for Breathing

Inhibitory neurons crucially contribute to shaping the breathing rhythm in the brain stem. These neurons use GABA or glycine as neurotransmitter; or co-release GABA and glycine. However, the developmental relationship between GABAergic, glycinergic and cotransmitting neurons, and the functional relevance of cotransmitting neurons has remained enigmatic. Transgenic mice expressing fluorescent markers or the split-Cre system in inhibitory neurons were developed to track the three different interneuron phenotypes. During late embryonic development, the majority of inhibitory neurons in the ventrolateral medulla are cotransmitting cells, most of which differentiate into GABAergic and glycinergic neurons around birth and around postnatal day 4, respectively. Functional inactivation of cotransmitting neurons revealed an increase of the number of respiratory pauses, the cycle-by-cycle variability, and the overall variability of breathing. In summary, the majority of cotransmitting neurons differentiate into GABAergic or glycinergic neurons within the first 2 weeks after birth and these neurons contribute to fine-tuning of the breathing pattern.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Pharmacological Targeting of Microglial Activation: New Therapeutic Approach

Mounting evidence suggests that neuroinflammation is not just a consequence but a vital contributor to the development and progression of Parkinson’s disease (PD). Microglia in particular, may contribute to the induction and modulation of inflammation in PD. Upon stimulation, microglia convert into activated phenotypes, which exist along a dynamic continuum and bear different immune properties depending on the disease stage and severity. Activated microglia release various factors involved in neuroinflammation, such as cytokines, chemokines, growth factors, reactive oxygen species (ROS), reactive nitrogen species (RNS), and prostaglandins (PGs). Further, activated microglia interact with other cell types (e.g., neurons, astrocytes and mast cells) and are closely associated with α-synuclein (α-syn) pathophysiology and iron homeostasis disturbance. Taken together, microglial activation and microglia-mediated inflammatory responses play essential roles in the pathogenesis of PD and elucidation of the complexity and imbalance of microglial activation may shed light on novel therapeutic approaches for PD.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Intra- and Extracellular Pillars of a Unifying Framework for Homeostatic Plasticity: A Crosstalk Between Metabotropic Receptors and Extracellular Matrix

In the face of chronic changes in incoming sensory inputs, neuronal networks are capable of maintaining stable conditions of electrical activity over prolonged periods of time by adjusting synaptic strength, to amplify or dampen incoming inputs [homeostatic synaptic plasticity (HSP)], or by altering the intrinsic excitability of individual neurons [homeostatic intrinsic plasticity (HIP)]. Emerging evidence suggests a synergistic interplay between extracellular matrix (ECM) and metabotropic receptors in both forms of homeostatic plasticity. Activation of dopaminergic, serotonergic, or glutamate metabotropic receptors stimulates intracellular signaling through calmodulin-dependent protein kinase II, protein kinase A, protein kinase C, and inositol trisphosphate receptors, and induces changes in expression of ECM molecules and proteolysis of both ECM molecules (lecticans) and ECM receptors (NPR, CD44). The resulting remodeling of perisynaptic and synaptic ECM provides permissive conditions for HSP and plays an instructive role by recruiting additional signaling cascades, such as those through metabotropic glutamate receptors and integrins. The superimposition of all these signaling events determines intracellular and diffusional trafficking of ionotropic glutamate receptors, resulting in HSP and modulation of conditions for inducing Hebbian synaptic plasticity (i.e., metaplasticity). It also controls cell-surface delivery and activity of voltage- and Ca2+-gated ion channels, resulting in HIP. These mechanisms may modify epileptogenesis and become a target for therapeutic interventions.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Brainstem-Evoked Transcription of Defensive Genes After Spinal Cord Injury

The spinal cord after injury shows altered transcription in numerous genes. We tested in a pilot study whether the nucleus raphé magnus, a descending serotonergic brainstem region whose stimulation improves recovery after incomplete spinal cord injury (SCI), can influence these transcriptional changes. Rats received 2 h of low-frequency electrical stimulation in the raphé magnus 3 days after an impact contusion at segment T8. Comparison groups lacked injuries or activated stimulators or both. Immediately following stimulation, spinal cords were extracted, their RNA transcriptome sequenced, and differential gene expression quantified. Confirming many previous studies, injury primarily increased inflammatory and immune transcripts and decreased those related to lipid and cholesterol synthesis and neuronal signaling. Stimulation plus injury, contrasted with injury alone, caused significant changes in 43 transcripts (39 increases, 4 decreases), all protein-coding. Injury itself decreased only four of these 43 transcripts, all reversed by stimulation, and increased none of them. The non-specific 5-HT7 receptor antagonist pimozide reversed 25 of the 43 changes. Stimulation in intact rats principally caused decreases in transcripts related to oxidative phosphorylation, none of which were altered by stimulation in injury. Gene ontology (biological process) annotations comparing stimulation with either no stimulation or pimozide treatment in injured rats highlighted defense responses to lipopolysaccharides and microorganisms, and also erythrocyte development and oxygen transport (possibly yielding cellular oxidant detoxification). Connectivity maps of human orthologous genes generated in the CLUE database of perturbagen-response transcriptional signatures showed that drug classes whose effects in injured rats most closely resembled stimulation without pimozide include peroxisome proliferator-activated receptor agonists and angiotensin receptor blockers, which are reportedly beneficial in SCI. Thus the initial transcriptional response of the injured spinal cord to raphé magnus stimulation is upregulation of genes that in various ways are mostly protective, some probably located in recently arrived myeloid cells.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Th17 and Cognitive Impairment: Possible Mechanisms of Action

T helper 17 (Th17) cells represent a distinct population of immune cells, important in the defense of the organism against extracellular infectious agents. Because of their cytokine profile and ability to recruit other immune cell types, they are highly pro-inflammatory and are involved in the induction of several autoimmune disorders. Recent studies show that Th17 cells and their signature cytokine IL-17 have also a role in a wide variety of neurological diseases. This review article will briefly summarize the evidence linking Th17 cells to brain diseases associated with cognitive impairment, including multiple sclerosis (MS), ischemic brain injury and Alzheimer’s disease (AD). We will also investigate the mechanisms by which these cells enter the brain and induce brain damage, including direct effects of IL-17 on brain cells and indirect effects mediated through disruption of the blood-brain barrier (BBB), neurovascular dysfunction and gut-brain axis. Finally, therapeutic prospects targeting Th17 cells and IL-17 will be discussed.

in Frontiers in Neuroanatomy | New and Recent Articles on November 19, 2019 12:00 AM.

• #### The Golgi Apparatus of Neocortical Glial Cells During Hibernation in the Syrian Hamster

Hibernating mammals undergo torpor periods characterized by a general decrease in body temperature, metabolic rate, and brain activity accompanied by complex adaptive brain changes that appear to protect the brain from extreme conditions of hypoxia and low temperatures. These processes are accompanied by morphological and neurochemical changes in the brain including those in cortical neurons such as the fragmentation and reduction of the Golgi apparatus (GA), which both reverse a few hours after arousal from the torpor state. In the present study, we characterized – by immunofluorescence and confocal microscopy – the GA of cortical astrocytes, oligodendrocytes, and microglial cells in the Syrian hamster, which is a facultative hibernator. We also show that after artificial induction of hibernation, in addition to neurons, the GA of glia in the Syrian hamster undergoes important structural changes, as well as modifications in the intensity of immunostaining and distribution patterns of Golgi structural proteins at different stages of the hibernation cycle.

in Frontiers in Neuroanatomy | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Melatonin and Rapamycin Attenuate Isoflurane-Induced Cognitive Impairment Through Inhibition of Neuroinflammation by Suppressing the mTOR Signaling in the Hippocampus of Aged Mice

Melatonin exerts neuroprotective effects on isoflurane-induced cognitive impairment. However, the underlying mechanism has yet to be elucidated. The present study sought to determine if melatonin confers its beneficial effects by acting on mammalian target of rapamycin (mTOR) and attenuates the neuroinflammation in the hippocampus of aged mice. A total of 72 male C57BL/6 mice, 16-month-old, were randomly and equally divided into six groups: (1) the control group (CON); (2) the rapamycin group (RAP); (3) the melatonin group (MEL); (4) the isoflurane group (ISO); (5) the rapamycin + isoflurane group (RAP + ISO); and (6) the melatonin + isoflurane group (MEL + ISO). RAP, RAP + ISO, MEL, MEL + ISO groups received 1 mg/kg/day mTOR inhibitor rapamycin solution or 10 mg/kg/day melatonin solution, respectively, intraperitoneally at 5:00 p.m. for 14 days consecutively. Mice in the CON and ISO groups were administered an equivalent volume of saline. Subsequently, ISO, RAP + ISO, and MEL + ISO groups were exposed to inhale 2% isoflurane for 4 h; the CON, RAP, and MEL mice received only the vehicle gas. Then, the memory function and spatial learning of the mice were examined via the Morris water maze (MWM) test. mTOR expression was detected via Western blot, whereas the concentration of inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and that of melatonin was quantified with enzyme-linked immunosorbent assay (ELISA). Melatonin and rapamycin significantly ameliorated the isoflurane-induced cognitive impairment and also led to a decrease in the melatonin levels as well as the expression levels of TNF-α, IL-1β, IL-6, and p-mTOR in the hippocampus. In conclusion, these results showed that melatonin and rapamycin attenuates mTOR expression while affecting the downstream proinflammatory cytokines. Thus, these molecular findings could be associated with an improved cognitive function in mice exposed to isoflurane.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Inhibition of AMD-Like Pathology With a Neurotrophic Compound in Aged Rats and 3xTg-AD Mice

Age-associated macular degeneration (AMD), which leads to loss of vision at its end stage, is one of the most common neurodegenerative diseases among the elderly. However, to date, no effective drug therapy is available for the prevention of AMD. Here, we report the occurrence of AMD pathology and its prevention by chronic treatment with the neurotrophic peptidergic compound P021, in aged rats and 3xTg-AD mice. We found photoreceptor degeneration, lipofuscin granules, vacuoles, and atrophy in retinal pigment epithelium (RPE) as well as Bruch’s membrane (BM) thickening; in aged rats, we even found rosette-like structure formation. Microgliosis and astrogliosis were observed in different retinal layers. In addition, we also found that total tau, phosphorylated tau, Aβ/APP, and VEGF were widely distributed in the sub-retina of aged rats and 3xTg mice. Importantly, chronic treatment with P021 for 3 months in rats and for 18 months in 3xTg mice ameliorated the pathological changes above. These findings indicate the therapeutic potential of P021 for prevention and treatment of AMD and retinal changes associated with aging and Alzheimer’s disease.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 19, 2019 12:00 AM.

• #### Contrasting the impact of cytotoxic and cytostatic drug therapies on tumour progression

by Jani V. Anttila, Mikhail Shubin, Johannes Cairns, Florian Borse, Qingli Guo, Tommi Mononen, Ignacio Vázquez-García, Otto Pulkkinen, Ville Mustonen

A tumour grows when the total division (birth) rate of its cells exceeds their total mortality (death) rate. The capability for uncontrolled growth within the host tissue is acquired via the accumulation of driver mutations which enable the tumour to progress through various hallmarks of cancer. We present a mathematical model of the penultimate stage in such a progression. We assume the tumour has reached the limit of its present growth potential due to cell competition that either results in total birth rate reduction or death rate increase. The tumour can then progress to the final stage by either seeding a metastasis or acquiring a driver mutation. We influence the ensuing evolutionary dynamics by cytotoxic (increasing death rate) or cytostatic (decreasing birth rate) therapy while keeping the effect of the therapy on net growth reduction constant. Comparing the treatments head to head we derive conditions for choosing optimal therapy. We quantify how the choice and the related gain of optimal therapy depends on driver mutation, metastasis, intrinsic cell birth and death rates, and the details of cell competition. We show that detailed understanding of the cell population dynamics could be exploited in choosing the right mode of treatment with substantial therapy gains.

in PLOS Computational Biology: New Articles on November 18, 2019 10:00 PM.

• #### A mechanistic integrative computational model of macrophage polarization: Implications in human pathophysiology

by Chen Zhao, Adam C. Mirando, Richard J. Sové, Thalyta X. Medeiros, Brian H. Annex, Aleksander S. Popel

Macrophages respond to signals in the microenvironment by changing their functional phenotypes, a process known as polarization. Depending on the context, they acquire different patterns of transcriptional activation, cytokine expression and cellular metabolism which collectively constitute a continuous spectrum of phenotypes, of which the two extremes are denoted as classical (M1) and alternative (M2) activation. To quantitatively decode the underlying principles governing macrophage phenotypic polarization and thereby harness its therapeutic potential in human diseases, a systems-level approach is needed given the multitude of signaling pathways and intracellular regulation involved. Here we develop the first mechanism-based, multi-pathway computational model that describes the integrated signal transduction and macrophage programming under M1 (IFN-γ), M2 (IL-4) and cell stress (hypoxia) stimulation. Our model was calibrated extensively against experimental data, and we mechanistically elucidated several signature feedbacks behind the M1-M2 antagonism and investigated the dynamical shaping of macrophage phenotypes within the M1-M2 spectrum. Model sensitivity analysis also revealed key molecular nodes and interactions as targets with potential therapeutic values for the pathophysiology of peripheral arterial disease and cancer. Through simulations that dynamically capture the signal integration and phenotypic marker expression in the differential macrophage polarization responses, our model provides an important computational basis toward a more quantitative and network-centric understanding of the complex physiology and versatile functions of macrophages in human diseases.

in PLOS Computational Biology: New Articles on November 18, 2019 10:00 PM.

• #### Erratum: Weible et al., Differential Involvement of Three Brain Regions during Mouse Skill Learning

in eNeuro current issue on November 18, 2019 05:30 PM.

• #### Erratum: Gupta et al., Restrained Dendritic Growth of Adult-Born Granule Cells Innervated by Transplanted Fetal GABAergic Interneurons in Mice with Temporal Lobe Epilepsy

in eNeuro current issue on November 18, 2019 05:30 PM.

• #### MicroRNA-137 drives epigenetic reprogramming in the adult amygdala and behavioral changes after adolescent alcohol exposure

Abstract

Significance Statement Adolescent alcohol exposure is a serious public health problem and contributes to alcohol use and anxiety disorders later in life. In this study, we identify microRNA-137, a small non-coding RNA, in the central nucleus of amygdala (CeA) as a crucial regulator of increased alcohol consumption and anxiety-like behavior in adult rats after adolescent intermittent ethanol (AIE) exposure. Inhibition of microRNA-137 in the CeA reverses increased alcohol intake and anxiety-like behavior, and this effect is mediated by lysine-specific demethylase 1 (LSD1), a microRNA-137 target gene that regulates epigenetic programming. Thus, we have identified microRNA-137 and its target LSD1, in the CeA that play a mechanistic role in the pathogenesis of increased adult anxiety and alcohol consumption after adolescent alcohol exposure.

in RSS PAP on November 18, 2019 05:29 PM.

• #### Sex and individual differences in alcohol intake are associated with differences in ketamine self-administration behaviors and nucleus accumbens dendritic spine density

Abstract

Clinical and preclinical studies have shown that ketamine, an NMDA-receptor antagonist, has promising therapeutic value for the treatment of alcohol use disorder (AUD). However, maintenance of remission will ultimately require repeated infusions of ketamine which may lead to abuse potential and may hinder its therapeutic benefits. It is therefore crucial to assess the effects of repeated treatments with ketamine on alcohol intake. Accordingly, this study aimed to examine in both sexes how individual differences in alcohol intake alter ketamine self-administration and how ketamine self-administration will alter subsequent alcohol drinking behaviors. Male and female rats intermittently drank alcohol or water for 10-weeks and were divided into high- or low-alcohol intake groups prior to ketamine self-administration. Rats self-administered ketamine under fixed and progressive ratios schedules of reinforcement from weeks 4-7, and incubation of ketamine craving was examined from weeks 8-10. To investigate structural plasticity in a brain region involved in reward, nucleus accumbens (NAc) dendritic spine morphology was examined. Our results show that high-alcohol intake in male rats attenuated ketamine self-administration whereas in female rats, high-alcohol intake enhanced motivation to self-administer ketamine. Ketamine reduced alcohol intake in high-alcohol male rats but increased it in low-alcohol female rats. Incubation of ketamine craving developed in all groups except low-alcohol females. 3-weeks abstinence from ketamine was associated with increased mushroom spines in all groups except the high-alcohol male group. Overall, these data suggest that ketamine as a treatment for AUD may benefit male but not female subjects and warrants further investigation before use as a therapeutic agent.

Significance statement: Alcohol use disorder (AUD) is one of the most prevalent forms of addiction yet effective treatment options are lacking. Preclinical and clinical data suggest that ketamine is a potential AUD treatment option. Since ketamine is also an addictive drug, we investigated here the relationship between alcohol and ketamine in both sexes and examined morphological changes in nucleus accumbens (NAc) medium spiny neurons, which are involved in mediating addiction related plasticity. We showed clear individual and sex differences in the interactions between alcohol and ketamine, which were reflected with structural plasticity alterations in the NAc of both sexes. Our data suggest that ketamine could be further investigated in humans as a viable treatment for AUD in male but not female subjects.

in RSS PAP on November 18, 2019 05:29 PM.

## Objective

The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome‐wide association studies of Parkinson disease (PD). We aimed to identify the specific disease‐associated variants in this locus, and their potential implications.

## Methods

Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta‐analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function.

## Results

Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side‐chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants.

## Interpretation

Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2019

## Objective

Previous studies have observed that epilepsy risk is higher among offspring of affected women than offspring of affected men. We tested whether this “maternal effect” was present in familial epilepsies, which are enriched for genetic factors that contribute to epilepsy risk.

## Methods

We assessed evidence of a maternal effect in a cohort of families containing ≥3 persons with epilepsy using 3 methods: (1) “downward‐looking” analysis, comparing the rate of epilepsy in offspring of affected women versus men; (2) “upward‐looking” analysis, comparing the rate of epilepsy among mothers versus fathers of affected individuals; and (3) lineage analysis, comparing the proportion of affected individuals with family history of epilepsy on the maternal versus paternal side.

## Results

Downward‐looking analysis revealed no difference in epilepsy rates among offspring of affected mothers versus fathers (prevalence ratio = 1.0, 95% confidence interval [CI] = 0.8–1.2). Upward‐looking analysis revealed more affected mothers than affected fathers; this effect was similar for affected and unaffected sibships (odds ratio = 0.8, 95% CI = 0.5–1.2) and was explained by a combination of differential fertility and participation rates. Lineage analysis revealed no significant difference in the likelihood of maternal versus paternal family history of epilepsy.

## Interpretation

We found no evidence of a maternal effect on epilepsy risk in this familial epilepsy cohort. Confounding sex imbalances can create the appearance of a maternal effect in upward‐looking analyses and may have impacted prior studies. We discuss possible explanations for the lack of evidence, in familial epilepsies, of the maternal effect observed in population‐based studies. ANN NEUROL 2019

• #### A crossover code for high-dimensional composition. (arXiv:1911.06775v1 [q-bio.NC])

We present a novel way to encode compositional information in high-dimensional (HD) vectors. Inspired by chromosomal crossover, random HD vectors are recursively interwoven, with a fraction of one vector's components masked out and replaced by those from another using a context-dependent mask. Unlike many HD computing schemes, "crossover" codes highly overlap with their base elements' and sub-structures' codes without sacrificing relational information, allowing fast element readout and decoding by greedy reconstruction. Crossover is mathematically tractable and has several properties desirable for robust, flexible representation.

in q-bio.NC updates on arXiv.org on November 18, 2019 01:30 AM.

• #### Radically Compositional Cognitive Concepts. (arXiv:1911.06602v1 [q-bio.NC])

Despite ample evidence that our concepts, our cognitive architecture, and mathematics itself are all deeply compositional, few models take advantage of this structure. We therefore propose a radically compositional approach to computational neuroscience, drawing on the methods of applied category theory. We describe how these tools grant us a means to overcome complexity and improve interpretability, and supply a rigorous common language for scientific modelling, analogous to the type theories of computer science. As a case study, we sketch how to translate from compositional narrative concepts to neural circuits and back again.

in q-bio.NC updates on arXiv.org on November 18, 2019 01:30 AM.

• #### Improvement of the Izhikevich model based on the rat basolateral amygdala and hippocampus neurons, and recognition of their possible firing patterns. (arXiv:1910.11380v2 [cs.NE] UPDATED)

Introduction: Identifying the potential firing patterns following by different brain regions under normal and abnormal conditions increases our understanding of what is happening in the level of neural interactions in the brain. On the other hand, it is important to be capable of modeling the potential neural activities, in order to build precise artificial neural networks. The Izhikevich model is one of the simple biologically plausible models that is capable of capturing the most known firing patterns of neurons. This property makes the model efficient in simulating large-scale networks of neurons. Improving the Izhikevich model for adapting with the neuronal activity of rat brain with great accuracy would make the model effective for future neural network implementations. Methods: Data sampling from two brain regions, the HIP and BLA, is performed by extracellular recordings of male Wistar rats and spike sorting is done using Plexon offline sorter. Further data analyses are done through NeuroExplorer and MATLAB software. In order to optimize the Izhikevich model parameters, the genetic algorithm is used. Results: In the present study, the possible firing patterns of the real single neurons of the HIP and BLA are identified. Additionally, improvement of the Izhikevich model is achieved. As a result, the real neuronal spiking pattern of these regions neurons, and the corresponding cases of the Izhikevich neuron spiking pattern are adjusted with great accuracy. Conclusion: This study is conducted to elevate our knowledge of neural interactions in different structures of the brain and accelerate the quality of future large scale neural networks simulations, as well as reducing the modeling complexity. This aim is achievable by performing the improved Izhikevich model, and inserting only the plausible firing patterns and eliminating unrealistic ones, as the results of this study.

in q-bio.NC updates on arXiv.org on November 18, 2019 01:30 AM.

• #### Neurobiological functions of transcriptional enhancers

Nature Neuroscience, Published online: 18 November 2019; doi:10.1038/s41593-019-0538-5

This paper offers a primer on transcriptional enhancers in the CNS, using examples of enhancer regulation in the maturing brain and the role of non-coding variation in brain disorders to explain the concepts emerging from functional neurogenomics.

in Nature Neuroscience - Issue - nature.com science feeds on November 18, 2019 12:00 AM.

• #### Sensory cortical control of movement

Nature Neuroscience, Published online: 18 November 2019; doi:10.1038/s41593-019-0536-7

Walking requires continual integrated information about the dynamic internal and external environment. This study reveals a pathway whereby the somatosensory cortex directly influences motor behavior based on integrated spatiotemporal information.

in Nature Neuroscience - Issue - nature.com science feeds on November 18, 2019 12:00 AM.

• #### Mapping microglia states in the human brain through the integration of high-dimensional techniques

Nature Neuroscience, Published online: 18 November 2019; doi:10.1038/s41593-019-0532-y

Sankowski et al. have combined high-throughput techniques to characterize human microglia, identifying a spectrum of microglia phenotypes that are determined by localization, aging and glioblastoma.

in Nature Neuroscience - Issue - nature.com science feeds on November 18, 2019 12:00 AM.

• #### A stochastic framework of neurogenesis underlies the assembly of neocortical cytoarchitecture

The cerebral cortex contains multiple areas with distinctive cytoarchitectonical patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have investigated the neuronal output of individual progenitor cells in the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. Our experimental results indicate that progenitor cells generate pyramidal cell lineages with a wide range of sizes and laminar configurations. Mathematical modelling indicates that these outcomes are compatible with a stochastic model of cortical neurogenesis in which progenitor cells undergo a series of probabilistic decisions that lead to the specification of very heterogeneous progenies. Our findings support a mechanism for cortical neurogenesis whose flexibility would make it capable to generate the diverse cytoarchitectures that characterize distinct neocortical areas.

in eLife: latest articles on November 18, 2019 12:00 AM.

• #### Structure of a mitochondrial ATP synthase with bound native cardiolipin

The mitochondrial ATP synthase fuels eukaryotic cells with chemical energy. Here we report the cryo-EM structure of a divergent ATP synthase dimer from mitochondria of Euglena gracilis, a member of the phylum Euglenozoa that also includes human parasites. It features 29 different subunits, 8 of which are newly identified. The membrane region was determined to 2.8 Å resolution, enabling the identification of 37 associated lipids, including 25 cardiolipins, which provides insight into protein-lipid interaction and their functional roles. The rotor-stator interface comprises four membrane-embedded horizontal helices, including a distinct subunit a. The dimer interface is formed entirely by phylum-specific components, and a peripherally associated subcomplex contributes to the membrane curvature. The central and peripheral stalks directly interact with each other. Last, the ATPase inhibitory factor 1 (IF1) binds in a mode that is different from human, but conserved in Trypanosomatids.

in eLife: latest articles on November 18, 2019 12:00 AM.

• #### Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy

Two crucial questions in neuroscience are how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. In the central nervous system, spinal motor neurons serve as one of the best-characterized cell types for addressing these two questions. In this review, we dissect these questions by evaluating the emerging role of regulatory microRNAs in motor neuron generation in developing embryos and their potential contributions to neurodegenerative diseases such as spinal muscular atrophy (SMA). Given recent promising results from novel microRNA-based medicines, we discuss the potential applications of microRNAs for clinical assessments of SMA disease progression and treatment.

in eLife: latest articles on November 18, 2019 12:00 AM.

• #### Spatiotemporal constraints on optogenetic inactivation in cortical circuits

Optogenetics allows manipulations of genetically and spatially defined neuronal populations with excellent temporal control. However, neurons are coupled with other neurons over multiple length scales, and the effects of localized manipulations thus spread beyond the targeted neurons. We benchmarked several optogenetic methods to inactivate small regions of neocortex. Optogenetic excitation of GABAergic neurons produced more effective inactivation than light-gated ion pumps. Transgenic mice expressing the light-dependent chloride channel GtACR1 produced the most potent inactivation. Generally, inactivation spread substantially beyond the photostimulation light, caused by strong coupling between cortical neurons. Over some range of light intensity, optogenetic excitation of inhibitory neurons reduced activity in these neurons, together with pyramidal neurons, a signature of inhibition-stabilized neural networks ('paradoxical effect'). The offset of optogenetic inactivation was followed by rebound excitation in a light dose-dependent manner, limiting temporal resolution. Our data offer guidance for the design of in vivo optogenetics experiments.

in eLife: latest articles on November 18, 2019 12:00 AM.

• #### Neural representation of newly instructed rule identities during early implementation trials

By following explicit instructions, humans instantaneously get the hang of tasks they have never performed before. We used a specially calibrated multivariate analysis technique to uncover the elusive representational states during the first few implementations of arbitrary rules such as 'for coffee, press red button' following their first-time instruction. Distributed activity patterns within the ventrolateral prefrontal cortex (VLPFC) indicated the presence of neural representations specific of individual stimulus-response (S-R) rule identities, preferentially for conditions requiring the memorization of instructed S-R rules for correct performance. Identity-specific representations were detectable starting from the first implementation trial and continued to be present across early implementation trials. The increasingly fluent application of novel rule representations was channelled through increasing cooperation between VLPFC and anterior striatum. These findings inform representational theories on how the prefrontal cortex supports behavioural flexibility specifically by enabling the ad-hoc coding of newly instructed individual rule identities during their first-time implementation.

in eLife: latest articles on November 18, 2019 12:00 AM.

• #### Brain clusterin protein isoforms and mitochondrial localization

Clusterin (CLU), or apolipoprotein J (ApoJ), is the third most predominant genetic risk factor associated with late-onset Alzheimer’s disease (LOAD). In this study, we use multiple rodent and human brain tissue and neural cell models to demonstrate that CLU is expressed as multiple isoforms that have distinct cellular or subcellular localizations in the brain. Of particular significance, we identify a non-glycosylated 45 kDa CLU isoform (mitoCLU) that is localized to the mitochondrial matrix and expressed in both rodent and human neurons and astrocytes. In addition, we show that rodent mitoCLU is translated from a non-canonical CUG (Leu) start site in Exon 3, a site that coincides with an AUG (Met) in human CLU. Last, we reveal that mitoCLU is present at the gene and protein level in the currently available CLU–/– mouse model. Collectively, these data provide foundational knowledge that is integral in elucidating the relationship between CLU and the development of LOAD.

in eLife: latest articles on November 18, 2019 12:00 AM.

• #### Persistent epigenetic memory impedes rescue of the telomeric phenotype in human ICF iPSCs following DNMT3B correction

DNA methyltransferase 3B (DNMT3B) is the major DNMT that methylates mammalian genomes during early development. Mutations in human DNMT3B disrupt genome-wide DNA methylation patterns and result in ICF syndrome type 1 (ICF1). To study whether normal DNA methylation patterns may be restored in ICF1 cells, we corrected DNMT3B mutations in induced pluripotent stem cells from ICF1 patients. Focusing on repetitive regions, we show that in contrast to pericentromeric repeats, which reacquire normal methylation, the majority of subtelomeres acquire only partial DNA methylation and, accordingly, the ICF1 telomeric phenotype persists. Subtelomeres resistant to de novo methylation were characterized by abnormally high H3K4 trimethylation (H3K4me3), and short-term reduction of H3K4me3 by pharmacological intervention partially restored subtelomeric DNA methylation. These findings demonstrate that the abnormal epigenetic landscape established in ICF1 cells restricts the recruitment of DNMT3B, and suggest that rescue of epigenetic diseases with genome-wide disruptions will demand further manipulation beyond mutation correction.

in eLife: latest articles on November 18, 2019 12:00 AM.

• #### In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation

Recent evidence has determined that the conserved X chromosome mega-structures controlled by the Firre and Dxz4 loci are not required for X chromosome inactivation (XCI) in cell lines. Here, we examined the in vivo contribution of these loci by generating mice carrying a single or double deletion of Firre and Dxz4. We found that these mutants are viable, fertile and show no defect in random or imprinted XCI. However, the lack of these elements results in many dysregulated genes on autosomes in an organ-specific manner. By comparing the dysregulated genes between the single and double deletion, we identified superloop, megadomain, and Firre locus-dependent gene sets. The largest transcriptional effect was observed in all strains lacking the Firre locus, indicating that this locus is the main driver for these autosomal expression signatures. Collectively, these findings suggest that these X-linked loci are involved in autosomal gene regulation rather than XCI biology.

in eLife: latest articles on November 18, 2019 12:00 AM.

• #### Replay as wavefronts and theta sequences as bump oscillations in a grid cell attractor network

Grid cells fire in sequences that represent rapid trajectories in space. During locomotion, theta sequences encode sweeps in position starting slightly behind the animal and ending ahead of it. During quiescence and slow wave sleep, bouts of synchronized activity represent long trajectories called replays, which are well-established in place cells and have been recently reported in grid cells. Theta sequences and replay are hypothesized to facilitate many cognitive functions, but their underlying mechanisms are unknown. One mechanism proposed for grid cell formation is the continuous attractor network. We demonstrate that this established architecture naturally produces theta sequences and replay as distinct consequences of modulating external input. Driving inhibitory interneurons at the theta frequency causes attractor bumps to oscillate in speed and size, which gives rise to theta sequences and phase precession, respectively. Decreasing input drive to all neurons produces traveling wavefronts of activity that are decoded as replays.

in eLife: latest articles on November 18, 2019 12:00 AM.

• #### Rapid learning and unlearning of predicted sensory delays in self-generated touch

Self-generated touch feels less intense and less ticklish than identical externally generated touch. This somatosensory attenuation occurs because the brain predicts the tactile consequences of our self-generated movements. To produce attenuation, the tactile predictions need to be time-locked to the movement, but how the brain maintains this temporal tuning remains unknown. Using a bimanual self-touch paradigm, we demonstrate that people can rapidly unlearn to attenuate touch immediately after their movement and learn to attenuate delayed touch instead, after repeated exposure to a systematic delay between the movement and the resulting touch. The magnitudes of the unlearning and learning effects are correlated and dependent on the number of trials that participants have been exposed to. We further show that delayed touches feel less ticklish and non-delayed touches more ticklish after exposure to the systematic delay. These findings demonstrate that the attenuation of self-generated touch is adaptive.

in eLife: latest articles on November 18, 2019 12:00 AM.

• #### Unravelling the modulation of intracortical inhibition during motor imagery: An adaptive threshold-hunting study

Motor imagery (MI) is the mental simulation of an action without any apparent muscular contraction. By means of transcranial magnetic stimulation, few studies revealed a decrease of short-interval intracortical inhibition (SICI) within the primary motor cortex. However, this decrease is ambiguous, as one would expect greater inhibition during MI to prevent overt motor output. The current study investigated the extent of SICI modulation during MI through a methodological and a conceptual reconsideration of i) the importance of parameters to assess SICI (Exp.1) and ii) the inhibitory process within the primary motor cortex as an inherent feature of MI (Exp.2). Participants performed two tasks: 1) rest and 2) imagery of isometric abduction of the right index finger. Using transcranial magnetic stimulation, motor evoked potentials were elicited in the right first dorsal interosseous muscle. An adaptive threshold-hunting paradigm was used, where the stimulus intensity required to maintain a fixed motor evoked potential amplitude was quantified. To test SICI, we conditioned the test stimulus with a conditioning stimulus (CS) of different intensities. Results revealed an Intensity by Task interaction showing that SICI decreased during MI as compared to rest only for the higher CS intensity (Exp.1). At the lowest CS intensities, a Task main effect revealed that SICI increased during MI (Exp.2). SICI modulation during MI depends critically on the CS intensity. By optimising CS intensity, we have shown that SICI circuits may increase during MI, revealing a potential mechanism to prevent the production of a movement while the motor system is activated.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Mapping the cell-surface proteome underlying hippocampal mossy fiber synapse identity

Synaptic diversity is a key feature of neural circuits. Its underlying molecular basis is largely unknown, due to the challenge of analyzing the protein composition of specific synapse types. Here, we isolate the hippocampal mossy fiber (MF) synapse, taking advantage of its unique size and architecture, and dissect its proteome. We identify a rich cell-surface repertoire that includes adhesion proteins, guidance cue receptors, extracellular matrix (ECM) proteins, and proteins of unknown function. Among the latter, we find IgSF8, a previously uncharacterized neuronal receptor, and uncover its role in regulating MF synapse architecture and feedforward inhibition on CA3 pyramidal neurons. Our findings reveal a diverse MF synapse surface proteome and highlight the role of neuronal surface-ECM interactions in the specification of synapse identity and circuit formation.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Flexible working memory through selective gating and attentional tagging

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Dynamical informational structures characterize the different human brain states of wakefulness and deep sleep

The dynamical activity of the human brain describes an extremely complex energy landscape changing over time and its characterisation is central unsolved problem in neuroscience. We propose a novel mathematical formalism for characterizing how the landscape of attractors sustained by a dynamical system evolves in time. This mathematical formalism is used to distinguish quantitatively and rigorously between the different human brain states of wakefulness and deep sleep. In particular, by using a whole-brain dynamical ansatz integrating the underlying anatomical structure with the local node dynamics based on a Lotka-Volterra description, we compute analytically the global attractors of this cooperative system and their associated directed graphs, here called the informational structures. The informational structure of the global attractor of a dynamical system describes precisely the past and future behaviour in terms of a directed graph composed of invariant sets (nodes) and their corresponding connections (links). We characterize a brain state by the time variability of these informational structures. This theoretical framework is potentially highly relevant for developing reliable biomarkers of patients with e.g. neuropsychiatric disorders or different levels of coma.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Hubs of long-distance co-alteration in brain pathology

The exact mechanisms at the root of pathologic anatomical covariances are still unknown. It is nonetheless becoming clearer that the impact of brain diseases is more convincingly represented in terms of co-alterations rather than in terms of localization of alterations. According to this view, neurological and psychiatric conditions might be seen as whole-brain patterns of modifications. In this context, the physical distance between two co-altered areas may provide insightful information about how pathology develops across the brain, assuming that long-range co-alterations might be relevant features of pathological networks. To demonstrate this hypothesis, we calculated the probability of co-alteration between brain areas across a large database of voxel-based morphometry studies of psychiatric and neurological disorders, and we investigated the physical (Euclidean) distance of the edges of the resulting network. Such analysis produced a series of observations relevant for the understanding of pathology, which range from unanticipated results to the recognition of regions of well-known functional and clinical relevance. For instance, it emphasizes the importance of the anterior and dorsal prefrontal cortices in the distribution of the disease-related alterations, as well as a specular asymmetry of gray matter decreases and increases between the hemispheres. Also, the analyses of schizophrenia and Alzheimer's disease show that long-distance co-alterations are able to identify areas involved in pathology and symptomatology. Moreover, the good concordance between the measure of the mean physical distance and that of functional degree centrality suggests that co-alterations and connectivity are intimately related. These findings highlight the importance of analyzing the physical distance in pathology, as the areas characterized by a long mean distance may be considered as hubs with a crucial role in the systems of alterations induced by brain diseases.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### The Human Brain encodes a Chronicle of Visual Events at each Instant of Time

The human brain continuously processes streams of visual input. Yet, a single image typically triggers neural responses that extend beyond one second. To understand how such a slow computation copes with real-time processing, we recorded subjects' electrical brain activity, while they watched ~5,000 rapidly-changing images. First, we show that each image can be decoded from brain activity for ~1 sec, and demonstrate that the brain simultaneously represents multiple images at each time instant. Second, dynamical system modeling reveals that these sustained representations can be explained by a specific chain of neural circuits, which consist of (i) a hidden maintenance mechanism, and (ii) an observable update mechanism. Third, this neural architecture is localized along the expected visual pathways. Finally, we show that the propagation of low-level representations across the visual hierarchy is a principle shared with deep convolutional networks. Together, these findings provide a general neural mechanism to simultaneously represent successive visual events.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Quantitative analysis of 1300-nm three-photon calcium imaging in the mouse brain

1300-nm three-photon calcium imaging has emerged as a useful technique to allow calcium imaging in deep brain regions. Application to large-scale neural activity imaging entails a careful balance between recording fidelity and tissue heating. We calculated and experimentally verified the excitation pulse energy to achieve the minimum photon count required for the detection of calcium transients in GCaMP6s-expressing neurons for 920-nm two-photon and 1320-nm three-photon excitation, respectively. Brain tissue heating by continuous three-photon imaging was simulated with Monte Carlo method and experimentally validated with immunohistochemistry. We observed increased immunoreactivity with 150 mW excitation power at 1.0- and 1.2-mm imaging depths. Based on the data, we explained how three-photon excitation achieves better calcium imaging fidelity than two-photon excitation in the deep brain and quantified the imaging depth where three-photon microscopy should be applied. Our analysis presents a translatable model for the optimization of three-photon calcium imaging based on experimentally tractable parameters.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Enhanced representation of natural sound sequences in the ventral auditory midbrain

The auditory midbrain (inferior colliculus, IC) plays an important role in sound processing, acting as hub for acoustic information extraction and for the implementation of fast audio-motor behaviors. IC neurons are topographically organized according to their sound frequency preference: dorsal IC regions encode low frequencies while ventral areas respond best to high frequencies, a type of sensory map defined as tonotopy. Tonotopic maps have been studied extensively using artificial stimuli (pure tones) but our knowledge of how these maps represent information about sequences of natural, spectro-temporally rich sounds is sparse. We studied this question by conducting simultaneous extracellular recordings across IC depths in awake bats (Carollia perspicillata) that listened to sequences of natural communication and echolocation sounds. The hypothesis was that information about these two types of sound streams is represented at different IC depths since they exhibit large differences in spectral composition, i.e. echolocation covers the high frequency portion of the bat soundscape (> 45 kHz), while communication sounds are broadband and carry most power at low frequencies (20-25 kHz). Our results showed that mutual information between neuronal responses and acoustic stimuli, as well as response redundancy in pairs of neurons recorded simultaneously, increase exponentially with IC depth. The latter occurs regardless of the sound type presented to the bats (echolocation or communication). Taken together, our results indicate the existence of mutual information and redundancy maps at the midbrain level whose response cannot be predicted based on the frequency composition of natural sounds and classic neuronal tuning curves.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Decentralized multi-site VBM analysis during adolescence shows structural changes linked to age, body mass index, and smoking: A COINSTAC analysis

In the recent past, there has been an upward trend in developing frameworks that enable neuroimaging researchers to address challenging questions by leveraging data across multiple sites all over the world. One such framework, Collaborative Informatics and Neuroimaging Suite Toolkit for Anonymous Computation (COINSTAC), provides a platform to analyze neuroimaging data stored locally across multiple organizations without the need for pooling the data at any point during the analysis. In this paper, we perform a decentralized voxel-based morphometry analysis of structural magnetic resonance imaging data across two different sites to understand the structural changes in the brain as linked to age, body mass index and smoking. Results produced by the decentralized analysis are contrasted with similar findings in literature. This work showcases the potential benefits of performing multi-voxel and multivariate analyses of large-scale neuroimaging data located at multiple sites.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Rapid acquisition of near optimal stopping using Bayesian by-products

Prior to any decision, animals (including humans) must stop deliberating. Both accumulating evidence for too little or too long can be costly. In contrast to accounts of decision making, accounts of stopping do not typically claim that animals use Bayesian posteriors. Considering a generic perceptual decision making task we show that, under approximation, only two variables are relevant to the question of when to stop evidence accumulation; time and the maximum posterior probability. We explored the rate at which stopping rules are learned using deep neural networks as model learners. A network which only used time and the maximum posterior probability learned faster than any other network considered. Therefore, such an approach may be highly adaptive, and animals may be able to reuse the same neural machinery they use for decisions for stopping. These results suggest that Bayesian inference may be even more important for animals than previously thought.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Temporally-precise disruption of prefrontal cortex informed by the timing of beta bursts impairs human action-stopping

Human action-stopping is widely considered to rely on a prefronto-basal ganglia-thalamocortical network, with right inferior frontal cortex (rIFC) posited to play a critical role in the early stage of implementation. Here we sought causal evidence for this idea in experiments involving healthy human participants (male/female). We first show that action-stopping is preceded by bursts of electroencephalographic activity in the beta band over prefrontal electrodes, putatively rIFC, and that the timing of these bursts correlates with the latency of stopping at a single-trial level: earlier bursts are associated with faster stopping. From this we reasoned that the integrity of rIFC at the time of beta bursts might be critical to the successful implementation of the stop process. We then used fMRI-guided transcranial magnetic stimulation (TMS) to disrupt rIFC at the approximate time of beta bursting. Stimulation prolonged stopping latencies and, moreover, the prolongation was most pronounced in individuals for whom the pulse appeared closer to the presumed time of beta bursting. These results help validate a prominent model of the neural architecture of action stopping, whereby the process is initiated early by the rIFC (~80-120 ms after a stop signal) and is then implemented via basal ganglia and primary motor cortex, before affecting the muscle at about 160 ms. The results also highlight the usefulness of prefrontal beta bursts to index an apparently important sub-process of stopping, the timing of which might help explain within- and between-individual variation in impulse control.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Predictive Coding Models for Pain Perception

Pain is a complex, multidimensional experience that involves dynamic interactions between sensory-discriminative and affective-emotional processes. Pain experiences have a high degree of variability depending on their context and prior anticipation. Viewing pain perception as a perceptual inference problem, we use a predictive coding paradigm to characterize both evoked and spontaneous pain. We record the local field potentials (LFPs) from the primary somatosensory cortex (S1) and the anterior cingulate cortex (ACC) of freely behaving rats---two regions known to encode the sensory-discriminative and affective-emotional aspects of pain, respectively. We further propose a framework of predictive coding to investigate the temporal coordination of oscillatory activity between the S1 and ACC. Specifically, we develop a high-level, empirical and phenomenological model to describe the macroscopic dynamics of bottom-up and top-down activity. Supported by recent experimental data, we also develop a mechanistic mean-field model to describe the mesoscopic population neuronal dynamics in the S1 and ACC populations, in both naive and chronic pain- treated animals. Our proposed predictive coding models not only replicate important experimental findings, but also provide new mechanistic insight into the uncertainty of expectation, placebo or nocebo effect, and chronic pain.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Neural correlates of episodic memory modulated by temporally delayed rewards

When a stimulus is associated with an external reward, its chance of being consolidated into long-term memory is boosted via dopaminergic facilitation of long-term potentiation in the hippocampus. Given that higher temporal distance has been found to discount the subjective value of a reward, we hypothesized that memory performance associated with a more immediate reward will result in better memory performance. We tested this hypothesis by measuring both behavioral memory performance and brain activation using functional magnetic resonance imaging (fMRI) during memory encoding and retrieval tasks. Contrary to our hypothesis, both behavioral and fMRI results suggest that the temporal distance of rewards might enhance the chance of the associated stimulus being remembered. The fMRI data demonstrate that lateral prefrontal cortex, which show encoding-related activation proportional to the temporal distance, is reactivated when searching for regions that show activation proportional to the temporal distance during retrieval. This is not surprising given that this region is not only activated to discriminate between future vs. immediate rewards, it is also a part of the retrieval-success network. We conclude by assuming that the encoding-retrieval overlap provoked by the temporal distance of rewards will have yielded better memory performance.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Cell-type specificity of neuronal excitability and morphology in the central amygdala

Central amygdala (CeA) neurons expressing protein kinase C delta (PKC{delta}+) or Somatostatin (Som+) differentially modulate diverse behaviors. The underlying features supporting cell-type-specific function in the CeA, however, remain unknown. Using whole-cell patch-clamp electrophysiology in acute mouse brain slices and biocytin-based neuronal reconstructions, we demonstrate that neuronal morphology and relative excitability are two distinguishing features between Som+ and PKC{delta}+ CeLC neurons. Som+ neurons, for example, are more excitable, compact and with more complex dendritic arborizations than PKC{delta}+ neurons. Cell size, intrinsic membrane properties, and anatomical localization were further shown to correlate with cell-type-specific differences in excitability. Lastly, in the context of neuropathic pain, we show a shift in the excitability equilibrium between PKC{delta}+ and Som+ neurons, suggesting that imbalances in the relative output of these cells underlie maladaptive changes in behaviors. Together, our results identify fundamentally important distinguishing features of PKC{delta}+ and Som+ cells that support cell-type-specific function in the CeA.

in bioRxiv Subject Collection: Neuroscience on November 18, 2019 12:00 AM.

• #### Different mechanisms for modulation of the initiation and steady-state of smooth pursuit eye movements

Smooth pursuit eye movements are used by primates to track moving objects. They are initiated by sensory estimates of target speed represented in the middle temporal (MT) area of extrastriate visual cortex and then supported by motor feedback to maintain steady-state eye speed at target speed. Here, we show that reducing the coherence in a patch of dots for a tracking target degrades the eye speed both at the initiation of pursuit and during steady-state tracking, when eye speed reaches an asymptote well below target speed. The deficits are quantitatively different between the motor-supported steady-state of pursuit and the sensory-driven initiation of pursuit, suggesting separate mechanisms. The deficit in visually-guided pursuit initiation could not explain the deficit in steady-state tracking. Pulses of target speed during steady-state tracking revealed lower sensitivities to image motion across the retina for lower values of dot coherence. However, sensitivity was not zero, implying that visual motion should still be driving eye velocity towards target velocity. When we changed dot coherence from 100% to lower values during accurate steady-state pursuit, we observed larger eye decelerations for lower coherences, as expected if motor feedback was reduced in gain. A simple pursuit model accounts for our data based on separate modulation of the strength of visual-motor transmission and motor feedback. We suggest that reduced dot coherence creates less reliable target motion that impacts pursuit initiation by changing the gain of visual-motor transmission and perturbs steady-state tracking by modulation of the motor corollary discharges that comprise eye velocity memory.

in bioRxiv Subject Collection: Neuroscience on November 17, 2019 12:00 AM.

• #### A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol

Aggregation and spreading of -Synuclein (Syn) are hallmarks of several neurodegenerative diseases, thus monitoring human Syn (hSyn) in animal models or cell cultures is vital for the field. However, the detection of native hSyn in such systems is challenging. We found that the nanobody NbSyn87, previously-described to bind hSyn, also shows cross-reactivity for the proteasomal subunit Rpn10. As such, when the NbSyn87 is expressed in the absence of hSyn, it is continuously degraded by the proteasome, while it is stabilized when it binds to hSyn. Here, we exploited this feature to design a new Fluorescent Reporter for hSyn (FluoReSyn) by coupling NbSyn87 to fluorescent proteins, which results in fluorescence signal fluctuations depending on the presence and amounts of intracellular hSyn. We characterized this biosensor in cells and tissues, and finally, revealed the presence of transmittable Syn in human cerebrospinal fluid demonstrating the potential of FluoReSyn for clinical research and diagnostics.

in bioRxiv Subject Collection: Neuroscience on November 17, 2019 12:00 AM.

• #### Motor learning and transfer: from feedback to feedforward control

Previous work has demonstrated that when learning a new motor task, the nervous system modifies feedforward (ie. voluntary) motor commands and that such learning transfers to fast feedback (ie. reflex) responses evoked by mechanical perturbations. Here we show the inverse, that learning new feedback responses transfers to feedforward motor commands. Sixty human participants (34 females) used a robotic exoskeleton and either 1) received short duration mechanical perturbations (20 ms) that created pure elbow rotation or 2) generated self-initiated pure elbow rotations. They did so with the shoulder joint free to rotate (normal arm dynamics) or locked (altered arm dynamics) by the robotic manipulandum. With the shoulder unlocked, the perturbation evoked clear shoulder muscle activity in the long-latency stretch reflex epoch (50-100ms post-perturbation), as required for countering the imposed joint torques, but little muscle activity thereafter in the so-called voluntary response. After locking the shoulder joint, which alters the required joint torques to counter pure elbow rotation, we found a reliable reduction in the long-latency stretch reflex over many trials. This reduction transferred to feedforward control as we observed 1) a reduction in shoulder muscle activity during self-initiated pure elbow rotation trials and 2) kinematic errors (ie. aftereffects) in the direction predicted when failing to compensate for normal arm dynamics, even though participants never practiced self-initiated movements with the shoulder locked. Taken together, our work shows that transfer between feedforward and feedback control is bidirectional, furthering the notion that these processes share common neural circuits that underlie motor learning and transfer.

in bioRxiv Subject Collection: Neuroscience on November 17, 2019 12:00 AM.

• #### Effects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice

Background: Older-age individuals are at the highest risk for disability from a traumatic brain injury (TBI). Astrocytes are the most numerous glia in the brain, necessary for brain function, yet there is little known about unique responses of astrocytes in the aged-brain following TBI. Methods: Our approach examined astrocytes in young adult, 4 month old, versus aged, 18 month old mice, at 1, 3, and 7 days post-TBI. We selected these time points to span the critical period in the transition from acute injury to presumably irreversible tissue damage and disability. Two approaches were used to define the astrocyte contribution to TBI by age interaction: 1) tissue histology and morphological phenotyping, and 2) transcriptomics on enriched astrocytes from the injured brain. Results: Aging was found to have a profound effect on the TBI-induced loss of homeostatic astrocyte function needed for maintaining water transport and edema namely, aquaporin-4. The loss of homoeostatic responses was coupled with a progressive exacerbation of astrogliosis in the aged brain as a function of time after injury. Moreover, clasmatodendrosis, an underrecognized astrogliopathy, was found to be significantly increased in the aged brain, but not in the young brain. As a function of TBI, we observed a transitory refraction in the number of these astrocytes, which rebounded by 7 days post-injury in the aged brain. The transcriptomics found disproportionate changes in genes attributed to reactive astrocytes, inflammatory response, complement pathway, and synaptic support in aged mice following TBI compared to young mice. Additionally, our data highlight that TBI did not evoke a clear alignment with previously defined A1/A2 dichotomy of reactive astrogliosis. Conclusions: Overall, our findings point toward a progressive phenotype of aged astrocytes following TBI that we hypothesize to be maladaptive, shedding new insights into potentially modifiable astrocyte-specific mechanisms that may underlie increased fragility of the aged brain to trauma.

in bioRxiv Subject Collection: Neuroscience on November 17, 2019 12:00 AM.

• #### ExploreASL: an image processing pipeline for multi-center ASL perfusion MRI studies

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. The toolbox adheres to previously defined international standards for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts to increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

in bioRxiv Subject Collection: Neuroscience on November 17, 2019 12:00 AM.

• #### Emergence of opposite neurons in a decentralized firing-rate model of multisensory integration

Multisensory integration areas such as dorsal medial superior temporal (MSTd) andventral intraparietal (VIP) areas in macaques combine visual and vestibular cues ofself-motion to produce better estimates of self-motion. Congruent and opposite neurons,two types of neurons found in these areas, combine congruent inputs and oppositeinputs respectively. A recently proposed computational model of congruent andopposite neurons reproduces their tuning properties and shows that congruent neuronsoptimally integrate information while opposite neurons compute disparity information.However, the connections in the network are fixed rather than learned, and in fact theconnections of opposite neurons, as we will show, cannot arise from Hebbian learningrules. We therefore propose a new model of multisensory integration in which congruentneurons and opposite neurons emerge through Hebbian and anti-Hebbian learning rules,and show that these neurons exhibit experimentally observed tuning properties.

in bioRxiv Subject Collection: Neuroscience on November 17, 2019 12:00 AM.

• #### An <i>in silico</i> analysis of robust but fragile gene regulation links enhancer length to robustness

by Kenneth Barr, John Reinitz, Ovidiu Radulescu

Organisms must ensure that expression of genes is directed to the appropriate tissues at the correct times, while simultaneously ensuring that these gene regulatory systems are robust to perturbation. This idea is captured by a mathematical concept called r-robustness, which says that a system is robust to a perturbation in up to r − 1 randomly chosen parameters. r-robustness implies that the biological system has a small number of sensitive parameters and that this number can be used as a robustness measure. In this work we use this idea to investigate the robustness of gene regulation using a sequence level model of the Drosophila melanogaster gene even-skipped. We consider robustness with respect to mutations of the enhancer sequence and with respect to changes of the transcription factor concentrations. We find that gene regulation is r-robust with respect to mutations in the enhancer sequence and identify a number of sensitive nucleotides. In both natural and in silico predicted enhancers, the number of nucleotides that are sensitive to mutation correlates negatively with the length of the sequence, meaning that longer sequences are more robust. The exact degree of robustness obtained is dependent not only on DNA sequence, but also on the local concentration of regulatory factors. We find that gene regulation can be remarkably sensitive to changes in transcription factor concentrations at the boundaries of expression features, while it is robust to perturbation elsewhere.

in PLOS Computational Biology: New Articles on November 15, 2019 10:00 PM.

• #### Large-scale cortical travelling waves predict localized future cortical signals

by David M. Alexander, Tonio Ball, Andreas Schulze-Bonhage, Cees van Leeuwen

Predicting future brain signal is highly sought-after, yet difficult to achieve. To predict the future phase of cortical activity at localized ECoG and MEG recording sites, we exploit its predominant, large-scale, spatiotemporal dynamics. The dynamics are extracted from the brain signal through Fourier analysis and principal components analysis (PCA) only, and cast in a data model that predicts future signal at each site and frequency of interest. The dominant eigenvectors of the PCA that map the large-scale patterns of past cortical phase to future ones take the form of smoothly propagating waves over the entire measurement array. In ECoG data from 3 subjects and MEG data from 20 subjects collected during a self-initiated motor task, mean phase prediction errors were as low as 0.5 radians at local sites, surpassing state-of-the-art methods of within-time-series or event-related models. Prediction accuracy was highest in delta to beta bands, depending on the subject, was more accurate during episodes of high global power, but was not strongly dependent on the time-course of the task. Prediction results did not require past data from the to-be-predicted site. Rather, best accuracy depended on the availability in the model of long wavelength information. The utility of large-scale, low spatial frequency traveling waves in predicting future phase activity at local sites allows estimation of the error introduced by failing to account for irreducible trajectories in the activity dynamics.

in PLOS Computational Biology: New Articles on November 15, 2019 10:00 PM.

• #### Developmental Nicotine Exposure Alters Synaptic Input to Hypoglossal Motoneurons and Is Associated with Altered Function of Upper Airway Muscles

Abstract

Nicotine exposure during the fetal and neonatal periods [developmental nicotine exposure (DNE)] is associated with ineffective upper airway protective reflexes in infants. This could be explained by desensitized chemoreceptors and/or mechanoreceptors, diminished neuromuscular transmission or altered synaptic transmission among central neurons, as each of these systems depend in part on cholinergic signaling through nicotinic AChRs (nAChRs). Here, we showed that DNE blunts the response of the genioglossus (GG) muscle to nasal airway occlusion in lightly anesthetized rat pups. The GG muscle helps keep the upper airway open and is innervated by hypoglossal motoneurons (XIIMNs). Experiments using the phrenic nerve-diaphragm preparation showed that DNE does not alter transmission across the neuromuscular junction. Accordingly, we used whole cell recordings from XIIMNs in brainstem slices to examine the influence of DNE on glutamatergic synaptic transmission under baseline conditions and in response to an acute nicotine challenge. DNE did not alter excitatory transmission under baseline conditions. Analysis of cumulative probability distributions revealed that acute nicotine challenge of P1–P2 preparations resulted in an increase in the frequency of nicotine-induced glutamatergic inputs to XIIMNs in both control and DNE. By contrast, P3–P5 DNE pups showed a decrease, rather than an increase in frequency. We suggest that this, together with previous studies showing that DNE is associated with a compensatory increase in inhibitory synaptic input to XIIMNs, leads to an excitatory-inhibitory imbalance. This imbalance may contribute to the blunting of airway protective reflexes observed in nicotine exposed animals and human infants.

in eNeuro current issue on November 15, 2019 05:30 PM.

• #### Compound Stimuli Reveal the Structure of Visual Motion Selectivity in Macaque MT Neurons

Abstract

Motion selectivity in primary visual cortex (V1) is approximately separable in orientation, spatial frequency, and temporal frequency ("frequency-separable"). Models for area MT neurons posit that their selectivity arises by combining direction-selective V1 afferents whose tuning is organized around a tilted plane in the frequency domain, specifying a particular direction and speed ("velocity-separable"). This construction explains "pattern direction-selective" MT neurons, which are velocity-selective but relatively invariant to spatial structure, including spatial frequency, texture and shape. We designed a set of experiments to distinguish frequency-separable and velocity-separable models and executed them with single-unit recordings in macaque V1 and MT. Surprisingly, when tested with single drifting gratings, most MT neurons’ responses are fit equally well by models with either form of separability. However, responses to plaids (sums of two moving gratings) tend to be better described as velocity-separable, especially for pattern neurons. We conclude that direction selectivity in MT is primarily computed by summing V1 afferents, but pattern-invariant velocity tuning for complex stimuli may arise from local, recurrent interactions.

in eNeuro current issue on November 15, 2019 05:30 PM.

• #### Functional Dissociation of {theta} Oscillations in the Frontal and Visual Cortices and Their Long-Range Network during Sustained Attention

Abstract

-Band (4–12 Hz) activities in the frontal cortex have been thought to be a key mechanism of sustained attention and goal-related behaviors, forming a phase-coherent network with task-related sensory cortices for integrated neuronal ensembles. However, recent visual task studies found that selective attention attenuates stimulus-related power in the visual cortex, suggesting a functional dissociation of cortical oscillations. To investigate this contradictory behavior of cortical , a visual Go/No-Go task was performed with electroencephalogram (EEG) recording in C57BL/6J mice. During the No-Go period, transient oscillations were observed in both the frontal and visual cortices, but oscillations of the two areas were prominent in different trial epochs. By separating trial epochs based on subjects’ short-term performance, we found that frontal was prominent in good-performance epochs, while visual was prominent in bad-performance epochs, exhibiting a functional dissociation of cortical rhythms. Furthermore, the two rhythms also showed a heterogeneous pattern of phase-amplitude coupling with fast oscillations, reflecting their distinct architecture in underlying neuronal circuitry. Interestingly, in good-performance epochs, where visual was relatively weak, stronger fronto-visual long-range synchrony and shorter posterior-to-anterior temporal delay were found. These findings highlight a previously overlooked aspect of long-range synchrony between distinct oscillatory entities in the cerebral cortex and provide empirical evidence of a functional dissociation of cortical rhythms.

in eNeuro current issue on November 15, 2019 05:30 PM.

• #### The Effects of Acute Neonatal Pain on Expression of Corticotropin-Releasing Hormone and Juvenile Anxiety in a Rodent Model

Abstract

Premature infants in the neonatal intensive care unit (NICU) may be subjected to numerous painful procedures without analgesics. One necessary, though acutely painful, procedure is the use of heel lances to monitor blood composition. The current study examined the acute effects of neonatal pain on maternal behavior as well as amygdalar and hypothalamic activation, and the long-term effects of neonatal pain on later-life anxiety-like behavior, using a rodent model. Neonatal manipulations consisted of either painful needle pricks or non-painful tactile stimulation in subjects’ left plantar paw surface which occurred four times daily during the first week of life [postnatal day (PND)1–PND7]. Additionally, maternal behaviors in manipulated litters were compared against undisturbed litters via scoring of videotaped interactions to examine the long-term effects of pain on dam-pup interactions. Select subjects underwent neonatal brain collection (PND6) and fluorescent in situ hybridization (FISH) for corticotropin-releasing hormone (CRH) and the immediate early gene c-fos. Other subjects were raised to juvenile age (PND24 and PND25) and underwent innate anxiety testing utilizing an elevated plus maze (EPM) protocol. FISH indicated that neonatal pain influenced amygdalar CRH and c-fos expression, predominately in males. No significant increase in c-fos or CRH expression was observed in the hypothalamus. Additionally, neonatal pain altered anxiety behaviors independent of sex, with neonatal pain subjects showing the highest frequency of exploratory behavior. Neonatal manipulations did not alter maternal behaviors. Overall, neonatal pain drives CRH expression and produces behavioral changes in anxiety that persist until the juvenile stage.

in eNeuro current issue on November 15, 2019 05:30 PM.

• #### Synaptic Plasticity at Inhibitory Synapses in the Ventral Tegmental Area Depends upon Stimulation Site

Abstract

Drug exposure induces cell and synaptic plasticity within the brain reward pathway that could be a catalyst for progression to addiction. Several cellular adaptations have been described in the ventral tegmental area (VTA), a central component of the reward pathway that is the major source of dopamine release. For example, administration of morphine induces long-term potentiation (LTP) of excitatory synapses on VTA dopamine cells and blocks LTP at inhibitory synapses. Drug-induced synaptic changes have a common endpoint of increasing dopamine cell firing and dopamine release. However, gaining a complete picture of synaptic plasticity in the VTA is hindered by its complex circuitry of efferents and afferents. Most studies of synaptic plasticity in the VTA activated a mixed population of afferents, potentially yielding an incomplete and perhaps misleading view of how drugs of abuse modify VTA synapses. Here, we use midbrain slices from mice and find that electrical stimulation in two different regions induces different forms of plasticity, including two new forms of LTP at inhibitory synapses. High-frequency stimulation (HFS) induces LTP independently of NMDA receptor (NMDAR) activation, and surprisingly, some inhibitory inputs to the VTA also undergo NMDAR-independent LTP after a low-frequency stimulation (LFS) pairing protocol.

in eNeuro current issue on November 15, 2019 05:30 PM.

• #### Chemogenetic Activation of Excitatory Neurons Alters Hippocampal Neurotransmission in a Dose-Dependent Manner

Abstract

Designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tools are extensively used to manipulate neuronal activity in a cell type-specific manner. Whole-cell patch-clamp recordings indicate membrane depolarization, coupled with increased neuronal firing rate, following administration of the DREADD ligand, clozapine-N-oxide (CNO) to activate the Gq-coupled DREADD, hM3Dq. Although hM3Dq has been used to enhance neuronal firing in order to manipulate diverse behaviors, often within 30 min to 1 h after CNO administration, the physiological effects on excitatory neurotransmission remain poorly understood. We investigated the influence of CNO-mediated hM3Dq DREADD activation on distinct aspects of hippocampal excitatory neurotransmission at the Schaffer collateral-CA1 synapse in hippocampal slices derived from mice expressing hM3Dq in Ca2+/calmodulin-dependent protein kinase α (CamKIIα)-positive excitatory neurons. Our results indicate a clear dose-dependent effect on field EPSP (fEPSP) slope, with no change noted at the lower dose of CNO (1 µM) and a significant, long-term decline in fEPSP slope observed at higher doses (5–20 µM). Further, we noted a robust burst stimulus (TBS) induced long-term potentiation (LTP) in the presence of the lower CNO (1 µM) dose, which was significantly attenuated at the higher CNO (20 µM) dose. Whole-cell patch-clamp recording revealed both complex dose-dependent regulation of excitability, and spontaneous and evoked activity of CA1 pyramidal neurons in response to hM3Dq activation across CNO concentrations. Our data indicate that CNO-mediated activation of the hM3Dq DREADD results in dose-dependent regulation of excitatory hippocampal neurotransmission and highlight the importance of careful interpretation of behavioral experiments involving chemogenetic manipulation.

in eNeuro current issue on November 15, 2019 05:30 PM.

• #### Dexamethasone Attenuates Hyperexcitability Provoked by Experimental Febrile Status Epilepticus

Abstract

The role of neuroinflammation in the mechanisms of epilepsy development is important because inflammatory mediators provide tractable targets for intervention. Inflammation is intrinsically involved in the generation of childhood febrile seizures (FSs), and prolonged FS [febrile status epilepticus (FSE)] precedes a large proportion of adult cases of temporal lobe epilepsy (TLE). As TLE is often refractory to therapy and is associated with serious cognitive and emotional problems, we investigated whether its development can be prevented using anti-inflammatory strategies. Using an immature rat model of FSE [experimental FSE (eFSE)], we administered dexamethasone (DEX), a broad anti-inflammatory agent, over 3 d following eFSE. We assessed eFSE-provoked hippocampal network hyperexcitability by quantifying the presence, frequency, and duration of hippocampal spike series, as these precede and herald the development of TLE-like epilepsy. We tested whether eFSE provoked hippocampal microgliosis, astrocytosis, and proinflammatory cytokine production in male and female rats and investigated blood–brain barrier (BBB) breaches as a potential contributor. We then evaluated whether DEX attenuated these eFSE sequelae. Spike series were not observed in control rats given vehicle or DEX, but occurred in 41.6% of eFSE-vehicle rats, associated with BBB leakage and elevated hippocampal cytokines. eFSE did not induce astrocytosis or microgliosis but provoked BBB disruption in 60% of animals. DEX significantly reduced spike series prevalence (to 7.6%) and frequency, and abrogated eFSE-induced cytokine production and BBB leakage (to 20%). These findings suggest that a short, postinsult intervention with a clinically available anti-inflammatory agent potently attenuates epilepsy-predicting hippocampal hyperexcitability, potentially by minimizing BBB disruption and related neuroinflammation.

in eNeuro current issue on November 15, 2019 05:30 PM.

• #### Pushing the Boundaries of Psychiatric Neuroimaging to Ground Diagnosis in Biology

Abstract

To accurately detect, track progression of, and develop novel treatments for mental illnesses, a diagnostic framework is needed that is grounded in biological features. Here, we present the case for utilizing personalized neuroimaging, computational modeling, standardized computing, and ecologically valid neuroimaging to anchor psychiatric nosology in biology.

in eNeuro current issue on November 15, 2019 05:30 PM.

• #### Cognitive Workload and Workload Transitions Elicit Curvilinear Hemodynamics During Spatial Working Memory.

in Frontiers in Human Neuroscience | New and Recent Articles on November 15, 2019 01:15 PM.

• #### Editorial Board

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s):

in ScienceDirect Publication: Current Opinion in Neurobiology on November 15, 2019 08:00 AM.

• #### LGN-CNN: a biologically inspired CNN architecture. (arXiv:1911.06276v1 [cs.NE])

In this paper we introduce a biologically inspired CNN architecture that has a first convolutional layer that mimics the role of the LGN. The first layer of the net shows a rotationally symmetric pattern justified by the structure of the net itself that turns up to be an approximation of a Laplacian of Gaussian. The latter function is in turn a good approximation of the receptive profiles of the cells in the LGN. The analogy with respect to the visual system structure is established, emerging directly from the architecture of the net.

in q-bio.NC updates on arXiv.org on November 15, 2019 01:30 AM.

• #### Task-dependence in scene perception: Head unrestrained viewing using mobile eye-tracking. (arXiv:1911.06085v2 [q-bio.NC] UPDATED)

Real-world scene perception is typically studied in the laboratory using static picture viewing with restrained head position. Consequently, the transfer of results obtained in this paradigm to real-word scenarios has been questioned. The advancement of mobile eye-trackers and the progress in image processing, however, permit a more natural experimental setup that, at the same time, maintains the high experimental control from the standard laboratory setting. We investigated eye movements while participants were standing in front of a projector screen and explored images under four specific task instructions. Eye movements were recorded with a mobile eye-tracking device and raw gaze data was transformed from head-centered into image-centered coordinates. We observed differences between tasks in temporal and spatial eye-movement parameters and found that the bias to fixate images near the center differed between tasks. Our results demonstrate that current mobile eye-tracking technology and a highly controlled design support the study of fine-scaled task dependencies in an experimental setting that permits more natural viewing behavior than the static picture viewing paradigm.

in q-bio.NC updates on arXiv.org on November 15, 2019 01:30 AM.

• #### Structured Mean-field Variational Inference and Learning in Winner-take-all Spiking Neural Networks. (arXiv:1911.05943v1 [q-bio.NC])

The Bayesian view of the brain hypothesizes that the brain constructs a generative model of the world, and uses it to make inferences via Bayes' rule. Although many types of approximate inference schemes have been proposed for hierarchical Bayesian models of the brain, the questions of how these distinct inference procedures can be realized by hierarchical networks of spiking neurons remains largely unresolved. Based on a previously proposed multi-compartment neuron model in which dendrites perform logarithmic compression, and stochastic spiking winner-take-all (WTA) circuits in which firing probability of each neuron is normalized by activities of other neurons, here we construct Spiking Neural Networks that perform \emph{structured} mean-field variational inference and learning, on hierarchical directed probabilistic graphical models with discrete random variables. In these models, we do away with symmetric synaptic weights previously assumed for \emph{unstructured} mean-field variational inference by learning both the feedback and feedforward weights separately. The resulting online learning rules take the form of an error-modulated local Spike-Timing-Dependent Plasticity rule. Importantly, we consider two types of WTA circuits in which only one neuron is allowed to fire at a time (hard WTA) or neurons can fire independently (soft WTA), which makes neurons in these circuits operate in regimes of temporal and rate coding respectively. We show how the hard WTA circuits can be used to perform Gibbs sampling whereas the soft WTA circuits can be used to implement a message passing algorithm that computes the marginals approximately. Notably, a simple change in the amount of lateral inhibition realizes switching between the hard and soft WTA spiking regimes. Hence the proposed network provides a unified view of the two previously disparate modes of inference and coding by spiking neurons.

in q-bio.NC updates on arXiv.org on November 15, 2019 01:30 AM.

• #### Differential Effect on Hippocampal Synaptic Facilitation by the Presynaptic Protein Mover

Neurotransmitter release relies on an evolutionarily conserved presynaptic machinery. Nonetheless, some proteins occur in certain species and synapses, and are absent in others, indicating that they may have modulatory roles. How such proteins expand the power or versatility of the core release machinery is unclear. The presynaptic protein Mover/TPRGL/SVAP30 is heterogeneously expressed among synapses of the rodent brain, suggesting that it may add special functions to subtypes of presynaptic terminals. Mover is a synaptic vesicle-attached phosphoprotein that binds to Calmodulin and the active zone scaffolding protein Bassoon. Here we use a Mover knockout mouse line to investigate the role of Mover in the hippocampal mossy fiber (MF) to CA3 pyramidal cell synapse and Schaffer collateral to CA1. While Schaffer collateral synapses were unchanged by the knockout, the MFs showed strongly increased facilitation. The effect of Mover knockout in facilitation was both calcium- and age-dependent, having a stronger effect at higher calcium concentrations and in younger animals. Increasing cyclic adenosine monophosphate (cAMP) levels by forskolin equally potentiated both wildtype and knockout MF synapses, but occluded the increased facilitation observed in the knockout. These discoveries suggest that Mover has distinct roles at different synapses. At MF terminals, it acts to constrain the extent of presynaptic facilitation.

in Frontiers in Synaptic Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Editorial: Neuronal Calcium Sensors in Health and Disease

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### MIM-Deficient Mice Exhibit Anatomical Changes in Dendritic Spines, Cortex Volume and Brain Ventricles, and Functional Changes in Motor Coordination and Learning

In this study, we performed a comprehensive behavioral and anatomical analysis of the Missing in Metastasis (Mtss1/MIM) knockout (KO) mouse brain. We also analyzed the expression of MIM in different brain regions at different ages. MIM is an I-BAR containing membrane curving protein, shown to be involved in dendritic spine initiation and dendritic branching in Purkinje cells in the cerebellum. Behavioral analysis of MIM KO mice revealed defects in both learning and reverse-learning, alterations in anxiety levels and reduced dominant behavior, and confirmed the previously described deficiency in motor coordination and pre-pulse inhibition. Anatomically, we observed enlarged brain ventricles and decreased cortical volume. Although MIM expression was relatively low in hippocampus after early development, hippocampal pyramidal neurons exhibited reduced density of thin and stubby dendritic spines. Learning deficiencies can be connected to all detected anatomical changes. Both behavioral and anatomical findings are typical for schizophrenia mouse models.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### DYRK1A Overexpression Alters Cognition and Neural-Related Proteomic Pathways in the Hippocampus That Are Rescued by Green Tea Extract and/or Environmental Enrichment

Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. We recently discovered that green tea extracts containing epigallocatechin-3-gallate (EGCG) improve cognition in mice transgenic for Dyrk1a (TgDyrk1A) and in a trisomic DS mouse model (Ts65Dn). Interestingly, paired with cognitive stimulation, green tea has beneficial pro-cognitive effects in DS individuals. Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A (DYRK1A) is a major candidate to explain the cognitive phenotypes of DS, and inhibiting its activity is a promising pro-cognitive therapy. DYRK1A kinase activity can be normalized in the hippocampus of transgenic DYRK1A mice administering green tea extracts, but also submitting the animals to environmental enrichment (EE). However, many other mechanisms could also explain the pro-cognitive effects of green tea extracts and EE. To underpin the overall alterations arising upon DYRK1A overexpression and the molecular processes underneath the pro-cognitive effects, we used quantitative proteomics. We investigated the hippocampal (phospho)proteome in basal conditions and after treatment with a green tea extract containing EGCG and/or EE in TgDyrk1A and control mice. We found that Dyrk1A overexpression alters protein and phosphoprotein levels of key postsynaptic and plasticity-related pathways and that these alterations were rescued upon the cognitive enhancer treatments.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Commentary: Deficient inhibition in alcohol-dependence: let's consider the role of the motor system!

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Investigations Into Bioenergetic Neuroprotection of Cone Photoreceptors: Relevance to Retinitis Pigmentosa

Recent studies suggest cone degeneration in retinitis pigmentosa (RP) may result from intracellular energy depletion. We tested the hypothesis that cones die when depleted of energy by examining the effect of two bioenergetic, nutraceutical agents on cone survival. The study had three specific aims: firstly, we, studied the neuroprotective efficacies of glucose and creatine in an in vitro model of RP. Next, we utilized a well-characterized mouse model of RP to examine whether surviving cones, devoid of their inner segments, continue to express genes vital for glucose, and creatine utilization. Finally, we analyzed the neuroprotective properties of glucose and creatine on cone photoreceptors in a mouse model of RP. Two different bioenergy-based therapies were tested in rd1 mice: repeated local delivery of glucose and systemic creatine. Optomotor responses were tested and cone density was quantified on retinal wholemounts. The results showed that glucose supplementation increased survival of cones in culture subjected to mitochondrial stress or oxidative insult. Despite losing their inner segments, surviving cones in the rd1 retina continued to express the various glycolytic enzymes. Following a single subconjunctival injection, the mean vitreous glucose concentration was significantly elevated at 1 and 8 h, but not at 16 h after injection; however, daily subconjunctival injection of glucose neither enhanced spatial visual performance nor slowed cone cell degeneration in rd1 mice relative to isotonic saline. Creatine dose-dependently increased survival of cones in culture subjected to mitochondrial dysfunction, but not to oxidative stress. Despite the loss of their mitochondrial-rich inner segments, cone somas and axonal terminals in the rd1 retina were strongly positive for both the mitochondrial and cytosolic forms of creatine kinase at each time point examined. Creatine-fed rd1 mice displayed enhanced optomotor responses compared to mice fed normal chow. Moreover, cone density was significantly greater in creatine-treated mice compared to controls. The overall results of this study provide tentative support for the hypothesis that creatine supplementation may delay secondary degeneration of cones in individuals with RP.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Amyloid Load, Hippocampal Volume Loss, and Diffusion Tensor Imaging Changes in Early Phases of Brain Aging

Background and Purpose

Amyloid imaging, gray matter (GM) morphometry and diffusion tensor imaging (DTI) have all been used as predictive biomarkers in dementia. Our objective was to define the imaging profile of healthy elderly controls as a function of their cognitive trajectories and explore whether amyloid burden and white matter (WM) microstructure changes are associated with subtle decrement of neuropsychological performances in old age.

Materials and Methods

We performed a 4.5-year longitudinal study in 133 elderly individuals who underwent cognitive testing at inclusion and follow-up, amyloid PET, MRI including DTI sequences at inclusion, and APOE epsilon 4 genotyping. All cases were assessed using a continuous cognitive score (CCS) taking into account the global evolution of neuropsychological performances. Data processing included region of interest analysis of amyloid PET analysis, GM densities and tract-based spatial statistics (TBSS)-DTI. Regression models were built to explore the association between the CCS and imaging parameters controlling for significant demographic and clinical covariates.

Results

Amyloid uptake was not related to the cognitive outcome. In contrast, GM densities in bilateral hippocampus were associated with worst CCS at follow-up. In addition, radial and axial diffusivities in left hippocampus were negatively associated with CCS. Amyloid load was associated with decreased VBM and increased radial and axial diffusivity in the same area. These associations persisted when adjusting for gender and APOE4 genotype. Importantly, they were absent in amygdala and neocortical areas studied.

Conclusion

The progressive decrement of neuropsychological performances in normal aging is associated with volume loss and WM microstructure changes in hippocampus long before the emergence of clinically overt symptoms. Higher amyloid load in hippocampus is compatible with cognitive preservation in cases with better preservation of GM densities and WM microstructure in this area.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 15, 2019 12:00 AM.

• #### The Impact of Transcranial Direct Current Stimulation on Upper-Limb Motor Performance in Healthy Adults: A Systematic Review and Meta-Analysis

Background: Transcranial direct current stimulation (tDCS) has previously been reported to improve facets of upper limb motor performance such as accuracy and strength. However, the magnitude of motor performance improvement has not been reviewed by contemporaneous systematic review or meta-analysis of sham vs. active tDCS.

Objective: To systematically review and meta-analyse the existing evidence regarding the benefits of tDCS on upper limb motor performance in healthy adults.

Methods: A systematic search was conducted to obtain relevant articles from three databases (MEDLINE, EMBASE, and PsycINFO) yielding 3,200 abstracts. Following independent assessment by two reviewers, a total of 86 articles were included for review, of which 37 were deemed suitable for meta-analysis.

Results: Meta-analyses were performed for four outcome measures, namely: reaction time (RT), execution time (ET), time to task failure (TTF), and force. Further qualitative review was performed for accuracy and error. Statistically significant improvements in RT (effect size −0.01; 95% CI −0.02 to 0.001, p = 0.03) and ET (effect size −0.03; 95% CI −0.05 to −0.01, p = 0.017) were demonstrated compared to sham. In exercise tasks, increased force (effect size 0.10; 95% CI 0.08 to 0.13, p < 0.001) and a trend towards improved TTF was also observed.

Conclusions: This meta-analysis provides evidence attesting to the impact of tDCS on upper limb motor performance in healthy adults. Improved performance is demonstrable in reaction time, task completion time, elbow flexion tasks and accuracy. Considerable heterogeneity exists amongst the literature, further confirming the need for a standardised approach to reporting tDCS studies.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Deep Feature Selection and Causal Analysis of Alzheimer’s Disease

Deep convolutional neural networks (DCNNs) have achieved great success for image classification in medical research. Deep learning with brain imaging is the imaging method of choice for the diagnosis and prediction of Alzheimer’s disease (AD). However, it is also well known that DCNNs are “black boxes” owing to their low interpretability to humans. The lack of transparency of deep learning compromises its application to the prediction and mechanism investigation in AD. To overcome this limitation, we develop a novel general framework that integrates deep leaning, feature selection, causal inference, and genetic-imaging data analysis for predicting and understanding AD. The proposed algorithm not only improves the prediction accuracy but also identifies the brain regions underlying the development of AD and causal paths from genetic variants to AD via image mediation. The proposed algorithm is applied to the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset with diffusion tensor imaging (DTI) in 151 subjects (51 AD and 100 non-AD) who were measured at four time points of baseline, 6 months, 12 months, and 24 months. The algorithm identified brain regions underlying AD consisting of the temporal lobes (including the hippocampus) and the ventricular system.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Proteostasis in Cerebral Small Vessel Disease

Maintaining the homeostasis of proteins (proteostasis) by controlling their synthesis, folding and degradation is a central task of cells and tissues. The gradual decline of the capacity of the various proteostasis machineries, frequently in combination with their overload through mutated, aggregation-prone proteins, is increasingly recognized as an important catalyst of age-dependent pathologies in the brain, most prominently neurodegenerative disorders. A dysfunctional proteostasis might also contribute to neurovascular disease as indicated by the occurrence of excessive protein accumulation or massive extracellular matrix expansion within vessel walls in conditions such as cerebral small vessel disease (SVD), a major cause of ischemic stroke, and cerebral amyloid angiopathy. Recent advances in brain vessel isolation techniques and mass spectrometry methodology have facilitated the analysis of cerebrovascular proteomes and fueled efforts to determine the proteomic signatures associated with neurovascular disease. In several studies in humans and mice considerable differences between healthy and diseased vessel proteomes were observed, emphasizing the critical contribution of an impaired proteostasis to disease pathogenesis. These findings highlight the important role of a balanced proteostasis for cerebrovascular health.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Enabling Large-Scale Simulations With the GENESIS Neuronal Simulator

In this paper, we evaluate the computational performance of the GEneral NEural SImulation System (GENESIS) for large scale simulations of neural networks. While many benchmark studies have been performed for large scale simulations with leaky integrate-and-fire neurons or neuronal models with only a few compartments, this work focuses on higher fidelity neuronal models represented by 50–74 compartments per neuron. After making some modifications to the source code for GENESIS and its parallel implementation, PGENESIS, particularly to improve memory usage, we find that PGENESIS is able to efficiently scale on supercomputing resources to network sizes as large as 9 × 106 neurons with 18 × 109 synapses and 2.2 × 106 neurons with 45 × 109 synapses. The modifications to GENESIS that enabled these large scale simulations have been incorporated into the May 2019 Official Release of PGENESIS 2.4 available for download from the GENESIS web site (genesis-sim.org).

in Frontiers in Neuroinformatics | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Dissociating Sensory and Cognitive Biases in Human Perceptual Decision-Making: A Re-evaluation of Evidence From Reference Repulsion

Our perception of the world is governed by a combination of bottom-up sensory and top-down cognitive processes. This often begs the question whether a perceptual phenomenon originates from sensory or cognitive processes in the brain. For instance, reference repulsion, a compelling visual illusion in which the subjective estimates about the direction of a motion stimulus are biased away from a reference boundary, is previously thought to be originated at the sensory level. Recent studies, however, suggest that the misperception is not sensory in nature but rather reflects post-perceptual cognitive biases. Here I challenge the post-perceptual interpretations on both empirical and conceptual grounds. I argue that these new findings are not incompatible with the sensory account and can be more parsimoniously explained as reflecting the consequences of motion representations in different reference frames. Finally, I will propose one concrete experiment with testable predictions to shed more insights on the sensory vs. cognitive nature of this visual illusion.

in Frontiers in Human Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Commentary: The Human Default Consciousness and Its Disruption: Insights From an EEG Study of Buddhist Jhāna Meditation

in Frontiers in Human Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Brain Connectivity Based Prediction of Alzheimer’s Disease in Patients With Mild Cognitive Impairment Based on Multi-Modal Images

Structural and metabolic connectivity are advanced features that facilitate the diagnosis of patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Connectivity from a single imaging modality, however, did not show evident discriminative value in predicting MCI-to-AD conversion, possibly because the inter-modal information was not considered when quantifying the relationship between brain regions. Here we introduce a novel approach that extracts connectivity based on both structural and metabolic information to improve AD early diagnosis. Principal component analysis was performed on each imaging modality to extract the key discriminative patterns of each brain region in an independent auxiliary domain composed of AD and normal control (NC) subjects, which were then used to project the two subtypes of MCI to the low-dimensional space. The connectivity between each target brain region and all other regions was quantified via a multi-task regression model using the projected data. The prediction performance was evaluated in 75 stable MCI (sMCI) patients and 51 progressive MCI (pMCI) patients who converted to AD within 3 years. We achieved 79.37% accuracy, with 74.51% sensitivity and 82.67% specificity, in predicting MCI-to-AD progression, superior to other existing algorithms using either structural and metabolic connectivities alone or a combination thereof. Our results demonstrate the effectiveness of multi-modal connectivity, serving as robust biomarker for early AD diagnosis.

in Frontiers in Human Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Differential Striatal Axonal Arborizations of the Intratelencephalic and Pyramidal-Tract Neurons: Analysis of the Data in the MouseLight Database

There exist two major types of striatum-targeting neocortical neurons, specifically, intratelencephalic (IT) neurons and pyramidal-tract (PT) neurons. Regarding their striatal projections, it was once suggested that IT axons are extended whereas PT axons are primarily focal. However, subsequent study with an increased number of well-stained extended axons concluded that such an apparent distinction was spurious due to limited sample size. Recent work using genetically labeled neurons reintroduced the differential spatial extent of the striatal projections of IT and PT neurons through population-level analyses, complemented by observations of single axons. However, quantitative IT vs. PT comparison of a large number of axons remained to be conducted. We analyzed the data of axonal end-points of 161 IT neurons and 33 PT neurons in the MouseLight database (http://ml-neuronbrowser.janelia.org/). The number of axonal end-points in the ipsilateral striatum exhibits roughly monotonically decreasing distributions in both neuron types. Excluding neurons with no ipsilateral end-point, the distributions of the logarithm of the number of ipsilateral end-points are considerably overlapped between IT and PT neurons, although the proportion of neurons having more than 50 ipsilateral end-points is somewhat larger in IT neurons than in PT neurons. Looking at more details, among IT subpopulations in the secondary motor area (MOs), layer 5 neurons and bilateral striatum-targeting layer 2/3 neurons, but not contralateral striatum-non-targeting layer 2/3 neurons, have a larger number of ipsilateral end-points than MOs PT neurons. We also found that IT ipsilateral striatal axonal end-points are on average more widely distributed than PT end-points, especially in the medial-lateral direction. These results indicate that IT and PT striatal axons differ in the frequencies and spatial extent of end-points while there are wide varieties within each neuron type.

in Frontiers in Neural Circuits | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Identification of KCC2 Mutations in Human Epilepsy Suggests Strategies for Therapeutic Transporter Modulation

Epilepsy is a common neurological disorder characterized by recurrent and unprovoked seizures thought to arise from impaired balance between neuronal excitation and inhibition. Our understanding of the neurophysiological mechanisms that render the brain epileptogenic remains incomplete, reflected by the lack of satisfactory treatments that can effectively prevent epileptic seizures without significant drug-related adverse effects. Type 2 K+-Cl cotransporter (KCC2), encoded by SLC12A5, is important for chloride homeostasis and neuronal excitability. KCC2 dysfunction attenuates Cl extrusion and impairs GABAergic inhibition, and can lead to neuronal hyperexcitability. Converging lines of evidence from human genetics have secured the link between KCC2 dysfunction and the development of epilepsy. Here, we review KCC2 mutations in human epilepsy and discuss potential therapeutic strategies based on the functional impact of these mutations. We suggest that a strategy of augmenting KCC2 activity by antagonizing its critical inhibitory phosphorylation sites may be a particularly efficacious method of facilitating Cl extrusion and restoring GABA inhibition to treat medication-refractory epilepsy and other seizure disorders.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### The Effect of Balance and Coordination Exercises on Quality of Life in Older Adults: A Mini-Review

The ability to control balance during activities of daily living (ADL) is impaired in older adults as a result of deterioration in the sensory systems (i.e., vestibular, visual, somatosensory), the cognitive system (central nervous system), and the musculoskeletal system. Consequently, many older adults face a risk of falling during their ADL. In most cases, falls and related injuries impair the quality of life and result in physical limitations, anxiety, loss of confidence, and fear of falling. Among a variety of fall prevention interventions, adapted physical activity programs have been suggested for improving balance control during ADL. These programs challenge the sensory, cognitive, and musculoskeletal systems while addressing balance constraints such as orientation in space, changes in direction, and the speed or height of the center of mass during static and dynamic situations resembling ADL. The above-mentioned elements can be dealt with through a combination of balance and coordination exercises that challenge the postural control systems in multiple dimensions—including vertical and horizontal changes of the center of mass, standing on unstable surfaces with a reduced base of support, and changing body directions. Consequently, such exercises require environmental information-processing. The combination of dual-task, function-oriented challenges while controlling balance stimulates the sensory and neuromuscular control mechanisms. Among older adults, these programs have been found to improve static and dynamic stability, as well as a number of aspects in the quality of life. Recently, they have also been found to improve cognitive functions such as memory and spatial cognition.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Dreaming of a New World Where Alzheimer’s Is a Treatable Disorder

Alzheimer’s disease (AD) is the most common form of dementia. It’s a chronic and untreatable neurodegenerative disease with irreversible progression and has important social and economic implications in terms of direct medical and social care costs. Despite prolonged and expensive efforts employed by the scientific community over the last few decades, no effective treatments are still available for patients, and the development of disease-modifying drugs is now a really urgent need. The recent failure of clinical trials based on the immunotherapeutic approach against amyloid-β(Aβ) protein questioned the validity of the “amyloid cascade hypothesis” as the molecular machinery causing the disease. Indeed, most attempts to design effective treatments for AD have been based until now on molecular targets suggested to be implicated in AD pathogenesis by the amyloid cascade hypothesis. However, mounting evidence from scientific literature supports the view of AD as a multifactorial disease that results from the concomitant action of multiple molecular players. This view, together with the lack of success of the disease-modifying single-target approaches, strongly suggests that AD drug design needs to be shifted towards multi-targeted compounds or drug combinations acting synergistically on the main core features of disease pathogenesis. The discovery of drug candidates targeting multiple factors involved in AD would greatly improve drug development. So, it is reasonable that upcoming strategies for the design of preventive and/or therapeutic agents for AD point to a multi-pronged approach including more than one druggable target to definitely defeat the disease.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Catalpol Exerts a Neuroprotective Effect in the MPTP Mouse Model of Parkinson’s Disease

The degeneration of dopaminergic (DA) neurons in Parkinson’s disease (PD) is related to inflammation and oxidative stress. Anti-inflammatory agents could reduce the risk or slow the progression of PD. Catalpol, an iridoid glycoside extracted from the roots of Rehmannia radix, has been reported to reduce the release of inflammatory factors and exert neuroprotective effects. 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated mice were used as the PD model and the roles of catalpol on DA neurons and its potential mechanism were investigated in this study. We found that catalpol administration mitigated the loss of DA neurons induced by MPTP and increased exploratory behavior along with tyrosine hydroxylase (TH) expression, which was accompanied by astrocyte and microglia activation. Importantly, catalpol administration significantly inhibited MPTP-triggered oxidative stress, restored growth-associated protein 43 (GAP43) and vascular endothelial growth factor (VEGF) levels. Further, we found that catalpol suppressed the activation of MKK4/JNK/c-Jun signaling, and reduced the pro-inflammatory factors and inflammasome in the mouse model of PD. Our results suggest that catalpol relieves MPTP-triggered oxidative stress, which may benefit to avoid the occurrence of chronic inflammatory reaction. Catalpol alleviates MPTP-triggered oxidative stress and thereby prevents neurodegenerative diseases-related inflammatory reaction, highlighting its therapeutic potential for the management of PD symptoms.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Sex and Gender Driven Modifiers of Alzheimer’s: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks

Research indicates that after advanced age, the major risk factor for late-onset Alzheimer’s disease (AD) is female sex. Out of every three AD patients, two are females with postmenopausal women contributing to over 60% of all those affected. Sex- and gender-related differences in AD have been widely researched and several emerging lines of evidence point to different vulnerabilities that contribute to dementia risk. Among those being considered, it is becoming widely accepted that gonadal steroids contribute to the gender disparity in AD, as evidenced by the “estrogen hypothesis.” This posits that sex hormones, 17β-estradiol in particular, exert a neuroprotective effect by shielding females’ brains from disease development. This theory is further supported by recent findings that the onset of menopause is associated with the emergence of AD-related brain changes in women in contrast to men of the same age. In this review, we discuss genetic, medical, societal, and lifestyle risk factors known to increase AD risk differently between the genders, with a focus on the role of hormonal changes, particularly declines in 17β-estradiol during the menopause transition (MT) as key underlying mechanisms.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### The Immune System Drives Synapse Loss During Lipopolysaccharide-Induced Learning and Memory Impairment in Mice

Although lipopolysaccharides (LPS) have been used to establish animal models of memory loss akin to what is observed in Alzheimer’s disease (AD), the exact mechanisms involved have not been substantiated. In this study, we established an animal model of learning and memory impairment induced by LPS and explored the biological processes and pathways involved. Mice were continuously intraperitoneally injected with LPS for 7 days. Learning- and memory-related behavioral performance and the pathological processes involved were assessed using the Morris water maze test and immunostaining, respectively. We detected comprehensive expression of C1q, C3, microglia, and their regulatory cytokines in the hippocampus. After 7 days of LPS administration, we were able to observe LPS-induced learning and memory impairment in the mice, which was attributed to neural impairment and synapse loss in the hippocampus. We elucidated that the immune system was activated, with the classical complement pathway and microglial phagocytosis being involved in the synapse loss. This study demonstrates that an LPS-injected mouse can serve as an early memory impairment model for studies on anti-AD drugs.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 15, 2019 12:00 AM.

• #### Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist

Immune regulation is a finely balanced process of positive and negative signals. PD-L1 and its receptor PD-1 are critical regulators of autoimmune, anti-viral and anti-tumoural T cell responses. Although the function of its predominant membrane-bound form is well-established, the source and biological activity of soluble PD-L1 (sPD-L1) remain incompletely understood. Here, we show that sPD-L1 in human healthy tissues and tumours is produced by exaptation of an intronic LINE-2A (L2A) endogenous retroelement in the CD274 gene, encoding PD-L1, which causes omission of the transmembrane domain and the regulatory sequence in the canonical 3' untranslated region. The alternatively spliced CD274-L2A transcript forms the major source of sPD-L1 and is highly conserved in hominids, but lost in mice and a few related species. Importantly, CD274-L2A-encoded sPD-L1 lacks measurable T cell inhibitory activity. Instead, it functions as a receptor antagonist, blocking the inhibitory activity of PD-L1 bound on cellular or exosomal membranes.

in eLife: latest articles on November 15, 2019 12:00 AM.

• #### Risk factors for asthma among schoolchildren who participated in a case-control study in urban Uganda

Data on asthma aetiology in Africa are scarce. We investigated the risk factors for asthma among schoolchildren (5-17years) in urban Uganda. We conducted a case-control study, among 555 cases and 1,115 controls. Asthma was diagnosed by study clinicians. The main risk factors for asthma were tertiary education for fathers [adjusted OR (95% CI); 2.32 (1.71-3.16)] and mothers [1.85 (1.38-2.48)]; area of residence at birth, with children born in a small town or in the city having an increased asthma risk compared to schoolchildren born in rural areas [2.16 (1.60-2.92)] and [2.79 (1.79-4.35)], respectively; father's and mother's history of asthma; children's own allergic conditions; atopy; and cooking on gas/electricity. In conclusion, asthma was associated with a strong rural-town-city risk gradient, higher parental socio-economic status and urbanicity. This work provides the basis for future studies to identify specific environmental/lifestyle factors responsible for increasing asthma risk among children in urban areas in LMICs.

in eLife: latest articles on November 15, 2019 12:00 AM.

• #### Functional diversity among sensory neurons from efficient coding principles

by Julijana Gjorgjieva, Markus Meister, Haim Sompolinsky

In many sensory systems the neural signal is coded by the coordinated response of heterogeneous populations of neurons. What computational benefit does this diversity confer on information processing? We derive an efficient coding framework assuming that neurons have evolved to communicate signals optimally given natural stimulus statistics and metabolic constraints. Incorporating nonlinearities and realistic noise, we study optimal population coding of the same sensory variable using two measures: maximizing the mutual information between stimuli and responses, and minimizing the error incurred by the optimal linear decoder of responses. Our theory is applied to a commonly observed splitting of sensory neurons into ON and OFF that signal stimulus increases or decreases, and to populations of monotonically increasing responses of the same type, ON. Depending on the optimality measure, we make different predictions about how to optimally split a population into ON and OFF, and how to allocate the firing thresholds of individual neurons given realistic stimulus distributions and noise, which accord with certain biases observed experimentally.

in PLOS Computational Biology: New Articles on November 14, 2019 10:00 PM.

• #### No substantial change in the balance between model-free and model-based control via training on the two-step task

by Elmar D. Grosskurth, Dominik R. Bach, Marcos Economides, Quentin J. M. Huys, Lisa Holper

Human decisions can be habitual or goal-directed, also known as model-free (MF) or model-based (MB) control. Previous work suggests that the balance between the two decision systems is impaired in psychiatric disorders such as compulsion and addiction, via overreliance on MF control. However, little is known whether the balance can be altered through task training. Here, 20 healthy participants performed a well-established two-step task that differentiates MB from MF control, across five training sessions. We used computational modelling and functional near-infrared spectroscopy to assess changes in decision-making and brain hemodynamic over time. Mixed-effects modelling revealed overall no substantial changes in MF and MB behavior across training. Although our behavioral and brain findings show task-induced changes in learning rates, these parameters have no direct relation to either MF or MB control or the balance between the two systems, and thus do not support the assumption of training effects on MF or MB strategies. Our findings indicate that training on the two-step paradigm in its current form does not support a shift in the balance between MF and MB control. We discuss these results with respect to implications for restoring the balance between MF and MB control in psychiatric conditions.

in PLOS Computational Biology: New Articles on November 14, 2019 10:00 PM.

• #### A model of how depth facilitates scene-relative object motion perception

by Oliver W. Layton, D. C. Niehorster

Many everyday interactions with moving objects benefit from an accurate perception of their movement. Self-motion, however, complicates object motion perception because it generates a global pattern of motion on the observer’s retina and radically influences an object’s retinal motion. There is strong evidence that the brain compensates by suppressing the retinal motion due to self-motion, however, this requires estimates of depth relative to the object—otherwise the appropriate self-motion component to remove cannot be determined. The underlying neural mechanisms are unknown, but neurons in brain areas MT and MST may contribute given their sensitivity to motion parallax and depth through joint direction, speed, and disparity tuning. We developed a neural model to investigate whether cells in areas MT and MST with well-established neurophysiological properties can account for human object motion judgments during self-motion. We tested the model by comparing simulated object motion signals to human object motion judgments in environments with monocular, binocular, and ambiguous depth. Our simulations show how precise depth information, such as that from binocular disparity, may improve estimates of the retinal motion pattern due the self-motion through increased selectivity among units that respond to the global self-motion pattern. The enhanced self-motion estimates emerged from recurrent feedback connections in MST and allowed the model to better suppress the appropriate direction, speed, and disparity signals from the object’s retinal motion, improving the accuracy of the object’s movement direction represented by motion signals.

in PLOS Computational Biology: New Articles on November 14, 2019 10:00 PM.

• #### Non-equilibrium critical dynamics of bursts in <i>θ</i> and <i>δ</i> rhythms as fundamental characteristic of sleep and wake micro-architecture

by Jilin W. J. L. Wang, Fabrizio Lombardi, Xiyun Zhang, Christelle Anaclet, Plamen Ch. Ivanov

Origin and functions of intermittent transitions among sleep stages, including short awakenings and arousals, constitute a challenge to the current homeostatic framework for sleep regulation, focusing on factors modulating sleep over large time scales. Here we propose that the complex micro-architecture characterizing the sleep-wake cycle results from an underlying non-equilibrium critical dynamics, bridging collective behaviors across spatio-temporal scales. We investigate θ and δ wave dynamics in control rats and in rats with lesions of sleep-promoting neurons in the parafacial zone. We demonstrate that intermittent bursts in θ and δ rhythms exhibit a complex temporal organization, with long-range power-law correlations and a robust duality of power law (θ-bursts, active phase) and exponential-like (δ-bursts, quiescent phase) duration distributions, typical features of non-equilibrium systems self-organizing at criticality. Crucially, such temporal organization relates to anti-correlated coupling between θ- and δ-bursts, and is independent of the dominant physiologic state and lesions, a solid indication of a basic principle in sleep dynamics.

in PLOS Computational Biology: New Articles on November 14, 2019 10:00 PM.

## Objectives

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. No disease modifying therapy exists for the treatment of patients with HD. The purpose of this study was therefore to investigate early disease mechanisms which potentially could be used as a target therapeutically.

## Methods

Lymphocyte activity in cerebrospinal fluid (CSF) from four cohorts of HTT gene expansion carriers (n = 121 in total) and controls were analyzed by flow cytometry and ELISA based techniques.

## Results

The data of this study provides evidence of immune abnormalities before motor onset of disease. In CSF of HTT gene expansion carriers we found increased levels of proinflammatory cytokines, including IL‐17, and increased consumption of the lymphocyte growth factor IL‐7 before motor onset of HD. In concordance, we observed an increased prevalence of IL‐17 producing Th17.1 cells in the CSF of HTT gene expansion carriers, predominantly in pre‐motor manifest individuals. The frequency of intrathecal Th17.1 cells correlated negatively with progression of HD and the level of neurodegeneration, suggesting a role of Th17.1 cells in the early disease stage. We also observed a skewing in the balance between proinflammatory and regulatory T cells potentially favoring a proinflammatory intrathecal environment in HTT gene expansion carriers.

## Interpretation

These data suggest that Th17.1 cells are implicated in the earliest pathogenic phases of HD and suggest that treatment to dampen T cell‐driven inflammation before motor onset might be of benefit in HTT gene expansion carriers.

## Objective

To compare response to rituximab (RTX) between adult patients positive for myelin oligodendrocyte glycoprotein (MOG) and aquaporin‐4 (AQP4) antibodies.

## Methods

We prospectively studied adult patients with MOG or AQP4 antibodies who received RTX under an individualized dosing schedule adapted to the biological effect of RTX monitored by memory B‐cell measurement. Memory B cells were counted monthly and when relapse occurred. The biological effect of RTX was considered significant with < 0.05% memory B cells in peripheral blood lymphocytes.

## Results

In 16 patients with MOG antibodies and 29 with AQP4 antibodies, mean follow‐up was 19 (range 9–38) and 38 (13–79) months. Under RTX, 10 relapses occurred in 6/16 (37.5%) patients with MOG antibodies and 13 occurred in 7/29 (24%) with AQP4 antibodies. The median time of relapse after the most recent infusion was 2.6 (0.6–5.8) and 7 (0.8–13) months, respectively (p<0.001). Memory B cells had reemerged in 2 of 10 (20%) relapses in patients with MOG antibodies and 12 of 13 (92.5%) with AQP4 antibodies (p<0.001).

## Interpretation

In AQP4 antibody‐associated disorder, relapse mostly occurs when the biological effect of RTX decreases, which argues for treatment efficacy. In MOG antibody‐associated disorder, the efficacy of RTX is not constant because one third of patients showed relapse despite an effective biological effect of RTX. In this subpopulation, memory B‐cell depletion was unable to prevent relapse, which was probably caused by different immunological mechanisms. These findings should be taken into account to improve treatment strategies for MOG antibody‐associated disorder.

## Abstract

It is generally thought that muscle excitability is almost exclusively controlled by currents responsible for generation of action potentials. We propose that smaller ion channel currents that contribute to setting the resting potential and to subthreshold fluctuations in membrane potential can also modulate excitability in important ways. These channels open at voltages more negative than action potential threshold and are thus termed subthreshold currents. As subthreshold currents are orders of magnitude smaller than the currents responsible for the action potential, they are hard to identify and easily overlooked. Discovery of their importance in regulation of excitability opens new avenues for improved therapy for muscle channelopathies and diseases of the neuromuscular junction.

• #### A coupled autoencoder approach for multi-modal analysis of cell types. (arXiv:1911.05663v1 [q-bio.NC])

Recent developments in high throughput profiling of individual neurons have spurred data driven exploration of the idea that there exist natural groupings of neurons referred to as cell types. The promise of this idea is that the immense complexity of brain circuits can be reduced, and effectively studied by means of interactions between cell types. While clustering of neuron populations based on a particular data modality can be used to define cell types, such definitions are often inconsistent across different characterization modalities. We pose this issue of cross-modal alignment as an optimization problem and develop an approach based on coupled training of autoencoders as a framework for such analyses. We apply this framework to a Patch-seq dataset consisting of transcriptomic and electrophysiological profiles for the same set of neurons to study consistency of representations across modalities, and evaluate cross-modal data prediction ability. We explore the problem where only a subset of neurons is characterized with more than one modality, and demonstrate that representations learned by coupled autoencoders can be used to identify types sampled only by a single modality.

in q-bio.NC updates on arXiv.org on November 14, 2019 01:30 AM.

• #### Decoding Neural Responses in Mouse Visual Cortex through a Deep Neural Network. (arXiv:1911.05479v1 [q-bio.NC])

Finding a code to unravel the population of neural responses that leads to a distinct animal behavior has been a long-standing question in the field of neuroscience. With the recent advances in machine learning, it is shown that the hierarchically Deep Neural Networks (DNNs) perform optimally in decoding unique features out of complex datasets. In this study, we utilize the power of a DNN to explore the computational principles in the mammalian brain by exploiting the Neuropixel data from Allen Brain Institute. We decode the neural responses from mouse visual cortex to predict the presented stimuli to the animal for natural (bear, trees, cheetah, etc.) and artificial (drifted gratings, orientated bars, etc.) classes. Our results indicate that neurons in mouse visual cortex encode the features of natural and artificial objects in a distinct manner, and such neural code is consistent across animals. We investigate this by applying transfer learning to train a DNN on the neural responses of a single animal and test its generalized performance across multiple animals. Within a single animal, DNN is able to decode the neural responses with as much as 100% classification accuracy. Across animals, this accuracy is reduced to 91%. This study demonstrates the potential of utilizing the DNN models as a computational framework to understand the neural coding principles in the mammalian brain.

in q-bio.NC updates on arXiv.org on November 14, 2019 01:30 AM.

• #### Self-organized bistability: is it relevant for brain dynamics?. (arXiv:1911.05382v1 [cond-mat.stat-mech])

Self-organized bistability is the counterpart of "self-organized criticality" (SOC), for systems tuning themselves to the edge of bistability of a discontinuous/first-order phase transition, rather than to the critical point of a continuous/second order one. The equations defining the theory of SOB turn out to be very similar to a mesoscopic (Landau-Ginzburg) theory recently proposed to describe the dynamics in the cerebral cortex. This theory describes the bistable/oscillating neuronal activity of coupled mesoscopic patches of cortex, homeostatically regulated by short-term synaptic plasticity. However, the theory for cortex dynamics entails significant differences with respect to SOB, including the lack of a (bulk) conservation law, the absence of a perfect separation of timescales between driving and dissipation and, the fact that in the former there is a parameter that controls the overall system state (in blatant contrast with the very idea of self-organization). Here, we scrutinize --by employing a combination of analytical and computational tools-- the analogies and differences between both theories and explore whether in some limit SOB could play an important role to explain the emergence of scale-invariant neuronal avalanches observed empirically in the cortex. We conclude that actually, in the limit of infinitely slow synaptic-dynamics, the two theories behave identically, but the separation of timescales required for the self-organization mechanism to be effective does not seem to be biologically plausible. We discuss the key differences between self-organization mechanisms with or without conservation and separated timescales, and in particular, we scrutinize the implications of our findings in neuroscience, hopefully shedding new light into the problem of scale invariance in cortical dynamics.

in q-bio.NC updates on arXiv.org on November 14, 2019 01:30 AM.

• #### Learning From Brains How to Regularize Machines. (arXiv:1911.05072v1 [cs.LG])

Despite impressive performance on numerous visual tasks, Convolutional Neural Networks (CNNs) --- unlike brains --- are often highly sensitive to small perturbations of their input, e.g. adversarial noise leading to erroneous decisions. We propose to regularize CNNs using large-scale neuroscience data to learn more robust neural features in terms of representational similarity. We presented natural images to mice and measured the responses of thousands of neurons from cortical visual areas. Next, we denoised the notoriously variable neural activity using strong predictive models trained on this large corpus of responses from the mouse visual system, and calculated the representational similarity for millions of pairs of images from the model's predictions. We then used the neural representation similarity to regularize CNNs trained on image classification by penalizing intermediate representations that deviated from neural ones. This preserved performance of baseline models when classifying images under standard benchmarks, while maintaining substantially higher performance compared to baseline or control models when classifying noisy images. Moreover, the models regularized with cortical representations also improved model robustness in terms of adversarial attacks. This demonstrates that regularizing with neural data can be an effective tool to create an inductive bias towards more robust inference.

in q-bio.NC updates on arXiv.org on November 14, 2019 01:30 AM.

• #### Activation of Brainstem Neurons During Mesencephalic Locomotor Region-Evoked Locomotion in the Cat

The distribution of locomotor-activated neurons in the brainstem of the cat was studied by c-Fos immunohistochemistry in combination with antibody-based cellular phenotyping following electrical stimulation of the mesencephalic locomotor region (MLR) – the anatomical constituents of which remain debated today, primarily between the cuneiform (CnF) and the pedunculopontine tegmental nuclei (PPT). Effective MLR sites were co-extensive with the CnF nucleus. Animals subject to the locomotor task showed abundant Fos labeling in the CnF, parabrachial nuclei of the subcuneiform region, periaqueductal gray, locus ceruleus (LC)/subceruleus (SubC), Kölliker–Fuse, magnocellular and lateral tegmental fields, raphe, and the parapyramidal region. Labeled neurons were more abundant on the side of stimulation. In some animals, Fos-labeled cells were also observed in the ventral tegmental area, medial and intermediate vestibular nuclei, dorsal motor nucleus of the vagus, n. tractus solitarii, and retrofacial nucleus in the ventrolateral medulla. Many neurons in the reticular formation were innervated by serotonergic fibers. Numerous locomotor-activated neurons in the parabrachial nuclei and LC/SubC/Kölliker–Fuse were noradrenergic. Few cholinergic neurons within the PPT stained for Fos. In the medulla, serotonergic neurons within the parapyramidal region and the nucleus raphe magnus were positive for Fos. Control animals, not subject to locomotion, showed few Fos-labeled neurons in these areas. The current study provides positive evidence for a role for the CnF in the initiation of locomotion while providing little evidence for the participation of the PPT. The results also show that MLR-evoked locomotion involves the parallel activation of reticular and monoaminergic neurons in the pons/medulla, and provides the anatomical and functional basis for spinal monoamine release during evoked locomotion. Lastly, the results indicate that vestibular, cardiovascular, and respiratory centers are centrally activated during MLR-evoked locomotion. Altogether, the results show a complex pattern of neuromodulatory influences of brainstem neurons by electrical activation of the MLR.

in Frontiers in Systems Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Modeling Brain Somatic Mosaicism With Cerebral Organoids, Including a Note on Mutant Microglia

The brain is a genomic mosaic. Cell-to-cell genomic differences, which are the result of somatic mutations during development and aging, contribute to cellular diversity in the nervous system. This genomic diversity has important implications for nervous system development, function, and disease. Brain somatic mosaicism might contribute to individualized behavioral phenotypes and has been associated with several neuropsychiatric and neurodegenerative disorders. Therefore, understanding the causes and consequences of somatic mosaicism in neural circuits is of great interest. Recent advances in 3D cell culture technology have provided new means to study human organ development and various human pathologies in vitro. Cerebral organoids (“mini-brains”) are pluripotent stem cell-derived 3D culture systems that recapitulate, to some extent, the developmental processes and organization of the developing human brain. Here, I discuss the application of these neural organoids for modeling brain somatic mosaicism in a lab dish. Special emphasis is given to the potential role of microglial mutations in the pathogenesis of neurodegenerative diseases.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Mild Mechanic Stimulate on Acupoints Regulation of CGRP-Positive Cells and Microglia Morphology in Spinal Cord of Sciatic Nerve Injured Rats

Objective

The objective of this study is to observe the effects of mild mechanical stimulation on acupuncture points of spinal motor neurons and active substances of sciatic nerve injury in rats, and to explore the morphological basis for the recovery of motor function in rats with sciatic nerve injury, using mild acupuncture. Acupuncture in the local area of injury may cause further damage to the peripheral nerve injury. We believe that mild mechanical stimulation on the surface, using some specific acupuncture points can also have a positive effect on nerve repair. This method, called Chinese tuina, has existed for more than 2,000 years in China.

Methods

This study establishes a rat model using sciatic nerve crush injury. Rats received Chinese tuina in accordance with the principle of the three methods and three points, once a day, for 20 days. The rats’ status of hindlimb recovery was detected by a sciatic functional index. The labeled neuronal cell body was used to evaluate the fiber recovery after the rats’ sciatic nerve injury, using a neural tracing technique. Our team studied motor neuronal cell bodies, CGRP-positive cells, and the microglia of damaged sciatic nerves which were stained with fluorescent triple staining, adopting a confocal multi-layer scanning technique, and then the changes in neuronal activity distribution and expression, and changes of time and treatment were described, using the method of morphological description.

Results

Sciatic nerve injury decreased the survival rate of motor neurons, affected CGRP-positive cells, and activated microglia in the ventral horn of the spinal cord. Compared with the model group, the survival of spinal ventral horn motor neurons was increased through tuina intervention. The swelling of CGRP-positive cells was alleviated, and the degree of microglia activation was less than that of the model group.

Conclusion

This study used visual morphological findings to assess changes in neurons and active substances with time after injury of the peripheral nerve, and demonstrated that peripheral mild acupuncture intervention improved the capacity of neurofibrillary axoplasmic transport, regulated microglia activation, and significantly promoted the recovery of sciatic nerve injury.

in Frontiers in Integrative Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Bilingualism for Dementia: Neurological Mechanisms Associated With Functional and Structural Changes in the Brain

As the number of older adults increases, the prevalence of dementias, such as Alzheimer’s dementia (AD), vascular dementia, dementia with Lewy bodies, and frontotemporal dementias, also increases. Despite research into pharmacological approaches for treating diverse diseases, there is still no cure. Recently, novel non-pharmacological interventions are attracting attention. Non-pharmacological approaches include cognitive stimulation, alterations in diet, physical activity, and social engagement. Cognitive stimulating activities protect against the negative effects of cognitive decline caused by age-related neurogenerative diseases. Bilingualism is one form of cognitive stimulation that requires multiple aspects of brain activity and has been shown to delay the onset of dementia symptoms in patients by approximately 4–5 years as compared with monolingual patients through cognitive reserve. The purpose of this review was to bilingualism protects against cognitive decline associated with AD and other dementias. We discuss potential underlying neurological mechanisms, including: (1) stimulating adult neurogenesis, (2) enhancing synaptogenesis, (3) strengthening functional connectivity that bilingualism may delay clinical AD symptoms, (4) protecting white matter integrity, and (5) preserving gray matter density.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Unfolding the Effects of Acute Cardiovascular Exercise on Neural Correlates of Motor Learning Using Convolutional Neural Networks

Cardiovascular exercise is known to promote the consolidation of newly acquired motor skills. Previous studies seeking to understand the neural correlates underlying motor memory consolidation that is modulated by exercise, have relied so far on using traditional statistical approaches for a priori selected features from neuroimaging data, including EEG. With recent advances in machine learning, data-driven techniques such as deep learning have shown great potential for EEG data decoding for brain-computer interfaces, but have not been explored in the context of exercise. Here, we present a novel Convolutional Neural Network (CNN)-based pipeline for analysis of EEG data to study the brain areas and spectral EEG measures modulated by exercise. To the best of our knowledge, this work is the first one to demonstrate the ability of CNNs to be trained in a limited sample size setting. Our approach revealed discriminative spectral features within a refined frequency band (27–29 Hz) as compared to the wider beta bandwidth (15–30 Hz), which is commonly used in data analyses, as well as corresponding brain regions that were modulated by exercise. These results indicate the presence of finer EEG spectral features that could have been overlooked using conventional hypothesis-driven statistical approaches. Our study thus demonstrates the feasibility of using deep network architectures for neuroimaging analysis, even in small-scale studies, to identify robust brain biomarkers and investigate neuroscience-based questions.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Effect of Theta Transcranial Alternating Current Stimulation and Phase-Locked Transcranial Pulsed Current Stimulation on Learning and Cognitive Control

Non-invasive brain stimulation (NIBS) is emerging as a robust treatment alternative for major depressive disorder, with a potential for achieving higher remission rates by providing targeted stimulation to underlying brain networks, such as the salience network (SN). Growing evidence suggests that these therapeutic effects are dependent on the frequency and phase synchrony between SN oscillations and stimulation as well as the task-specific state of the SN during stimulation. However, the development of phase-synchronized non-invasive stimulation has proved challenging until recently. Here, we use a phase-locked pulsed brain stimulation approach to study the effects of two NIBS methods: transcranial alternating current stimulation (tACS) versus phase-locked transcranial pulsed current stimulation (tPCS), on the SN during an SN activating task. 20 healthy volunteers participated in the study. Each volunteer partook in four sessions, receiving one stimulation type at random (theta-tACS, peak tPCS, trough tPCS or sham) while undergoing a learning game, followed by an unstimulated test based on learned material. Each session lasted approximately 1.5 h, with an interval of at least 2 days to allow for washout and to avoid cross-over effects. Our results showed no statistically significant effect of stimulation on the event related potential (ERP) recordings, resting electroencephalogram (EEG), and the performance of the volunteers. While stimulation effects were not apparent in this study, the nominal performance of the phase-locking algorithm offers a technical foundation for further research in determining effective stimulation paradigms and conditions. Specifically, future work should investigate stronger stimulation and true task-specific stimulation of SN nodes responsible for the task as well as their recording. If refined, NIBS could offer an effective, homebased treatment option.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Neural Processes of Proactive and Reactive Controls Modulated by Motor-Skill Experiences

This study investigated the experience of open and closed motor skills on modulating proactive and reactive control processes in task switching. Fifty-four participants who were open-skilled (n = 18) or closed-skilled athletes (n = 18) or non-athletic adults (n = 18) completed a cued task-switching paradigm task. This task tapped into proactive or reactive controls of executive functions under different validity conditions. Electroencephalograms of the participants were captured during the task. In the 100% validity condition, the open-skilled participants showed significantly lower switch cost of response time than the closed-skilled and control participants. Results showed that the open-skilled participants had less positive-going parietal cue-locked P3 in the switch than repeat trials. Participants in the control group showed more positive-going cue-locked P3 in the switch than repeat trials, whereas the closed-skilled participants had no significant differences between the two types of trials. In the 50% validity condition, the open- and closed-skilled participants had less switch cost of response time than the control participants. Participants in the open- and closed-skilled groups showed less positive-going parietal stimulus-locked P3 in the switch than repeat trials, which was not the case for those in the control group. Our findings confirm the dissociation between proactive and reactive controls in relation to their modulations by the different motor-skill experiences. Both proactive and reactive controls of executive functions could be strengthened by exposing individuals to anticipatory or non-anticipatory enriched environments, suggesting proactive and reactive controls involved in motor-skill development seem to be transferable to domain-general executive functions.

in Frontiers in Human Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Estimating Cognitive Workload in an Interactive Virtual Reality Environment Using EEG

With the recent surge of affordable, high-performance virtual reality (VR) headsets, there is unlimited potential for applications ranging from education, to training, to entertainment, to fitness and beyond. As these interfaces continue to evolve, passive user-state monitoring can play a key role in expanding the immersive VR experience, and tracking activity for user well-being. By recording physiological signals such as the electroencephalogram (EEG) during use of a VR device, the user's interactions in the virtual environment could be adapted in real-time based on the user's cognitive state. Current VR headsets provide a logical, convenient, and unobtrusive framework for mounting EEG sensors. The present study evaluates the feasibility of passively monitoring cognitive workload via EEG while performing a classical n-back task in an interactive VR environment. Data were collected from 15 participants and the spatio-spectral EEG features were analyzed with respect to task performance. The results indicate that scalp measurements of electrical activity can effectively discriminate three workload levels, even after suppression of a co-varying high-frequency activity.

in Frontiers in Human Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Distinguishing Old From New Referents During Discourse Comprehension: Evidence From ERPs and Oscillations

In this EEG study, we used pre-registered and exploratory ERP and time-frequency analyses to investigate the resolution of anaphoric and non-anaphoric noun phrases during discourse comprehension. Participants listened to story contexts that described two antecedents, and subsequently read a target sentence with a critical noun phrase that lexically matched one antecedent (‘old’), matched two antecedents (‘ambiguous’), partially matched one antecedent in terms of semantic features (‘partial-match’), or introduced another referent (non-anaphoric, ‘new’). After each target sentence, participants judged whether the noun referred back to an antecedent (i.e., an ‘old/new’ judgment), which was easiest for ambiguous nouns and hardest for partially matching nouns. The noun-elicited N400 ERP component demonstrated initial sensitivity to repetition and semantic overlap, corresponding to repetition and semantic priming effects, respectively. New and partially matching nouns both elicited a subsequent frontal positivity, which suggested that partially matching anaphors may have been processed as new nouns temporarily. ERPs in an even later time window and ERPs time-locked to sentence-final words suggested that new and partially matching nouns had different effects on comprehension, with partially matching nouns incurring additional processing costs up to the end of the sentence. In contrast to the ERP results, the time-frequency results primarily demonstrated sensitivity to noun repetition, and did not differentiate partially matching anaphors from new nouns. In sum, our results show the ERP and time-frequency effects of referent repetition during discourse comprehension, and demonstrate the potentially demanding nature of establishing the anaphoric meaning of a novel noun.

in Frontiers in Human Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Prediction and Mismatch Negativity Responses Reflect Impairments in Action Semantic Processing in Adults With Autism Spectrum Disorders

The neurophysiological mechanisms underlying motor and language difficulties in autism spectrum disorders (ASD) are still largely unclear. The present work investigates biological indicators of sound processing, (action-) semantic understanding and predictive coding and their correlation with clinical symptoms of ASD. Twenty-two adults with high-functioning ASD and 25 typically developed (TD) participants engaged in an auditory, passive listening, Mismatch Negativity (MMN) task while high-density electroencephalography (EEG) was recorded. Action and non-action words were presented in the context of sounds, which were either semantically congruent with regard to the body part they relate to or semantically incongruent or unrelated. The anticipatory activity before sound onset, the Prediction Potential (PP), was significantly reduced in the ASD group specifically for action, but not for non-action sounds. The early-MMN-like responses to words (latency: 120 ms) were differentially modulated across groups: controls showed larger amplitudes for words in action-sound compared to non-action contexts, whereas ASD participants demonstrated enlarged early-MMN-like responses only in a pure tone context, with no other modulation dependent on action sound context. Late-MMN-like responses around 560 ms post-stimulus onset revealed body-part-congruent action-semantic priming for words in control participants, but not in the ASD group. Importantly, neurophysiological indices of semantic priming in ASD participants correlated with the extent of autistic traits as revealed by the Autism Spectrum Quotient (AQ). The data suggest that high-functioning adults with ASD show a specific deficit in semantic processing and predictive coding of sounds and words related to action, which is absent for neutral, non-action, sounds.

in Frontiers in Human Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Children With Reading Difficulty Rely on Unimodal Neural Processing for Phonemic Awareness

Phonological awareness skills in children with reading difficulty (RD) may reflect impaired automatic integration of orthographic and phonological representations. However, little is known about the underlying neural mechanisms involved in phonological awareness for children with RD. Eighteen children with RD, ages 9–13, participated in a functional magnetic resonance imaging (fMRI) study designed to assess the relationship of two constructs of phonological awareness, phoneme synthesis, and phoneme analysis, with crossmodal rhyme judgment. Participants completed a rhyme judgment task presented in two modality conditions; unimodal auditory only and crossmodal audiovisual. Measures of phonological awareness were correlated with unimodal, but not crossmodal, lexical processing. Moreover, these relationships were found only in unisensory brain regions, and not in multisensory brain areas. The results of this study suggest that children with RD rely on unimodal representations and unisensory brain areas, and provide insight into the role of phonemic awareness in mapping between auditory and visual modalities during literacy acquisition.

in Frontiers in Human Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### EEG-Based Brain Functional Connectivity in First-Episode Schizophrenia Patients, Ultra-High-Risk Individuals, and Healthy Controls During P50 Suppression

Dysfunctional processing of auditory sensory gating has generally been found in schizophrenic patients and ultra-high-risk (UHR) individuals. The aim of the study was to investigate the differences of functional interaction between brain regions and performance during the P50 sensory gating in UHR group compared with those in first-episode schizophrenia patients (FESZ) and healthy controls (HC) groups. The study included 128-channel scalp Electroencephalogram (EEG) recordings during the P50 auditory paradigm for 35 unmedicated FESZ, 30 drug-free UHR, and 40 HC. Cortical sources of scalp electrical activity were recomputed using exact low-resolution electromagnetic tomography (eLORETA), and functional brain networks were built at the source level and compared between the groups (FESZ, UHR, HC). A classifier using decision tree was designed for differentiating the three groups, which uses demographic characteristics, MATRICS Consensus Cognitive Battery parameters, behavioral features in P50 paradigm, and the measures of functional brain networks based on graph theory during P50 sensory gating. The results showed that very few brain connectivities were significantly different between FESZ and UHR groups during P50 sensory gating, and that a large number of brain connectivities were significantly different between FESZ and HC groups and between UHR and HC groups. Furthermore, the FESZ group had a stronger connection in the right superior frontal gyrus and right insula than the HC group. And the UHR group had an enhanced connection in the paracentral lobule and the middle temporal gyrus compared with the HC group. Moreover, comparison of classification analysis results showed that brain network metrics during P50 sensory gating can improve the accuracy of the classification for FESZ, UHR and HC groups. Our findings provide insight into the mechanisms of P50 suppression in schizophrenia and could potentially improve the performance of early identification and diagnosis of schizophrenia for the earliest intervention.

in Frontiers in Human Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Endoplasmic Reticulum Stress-Mediated Basolateral Amygdala GABAergic Neuron Injury Is Associated With Stress-Induced Mental Disorders in Rats

The amygdala is an important center of fear learning and memory and plays a critical role in regulating stress disorders. Previous studies have shown that changes in the amygdala caused by stress are an important cause of mental disorders including anxiety, but the specific mechanism remains unclear. Therefore, the purpose of this study was to investigate whether mental disorders induced by stress are related to γ-aminobutyric acid (GABA)ergic neuron damage in the basolateral amygdala (BLA) and whether endoplasmic reticulum stress (ERS) is involved in the injury process. Rat models of different durations of stress were established by restraint and forced ice-water swimming. Behavioral tests and high-performance liquid chromatography (HPLC) were used to detect anxiety in rats and changes in neurotransmitter levels in the BLA. Morphological approaches and microscopy-based multicolor tissue cytometry (MMTC) were used to detect the damage-induced changes in GABAergic neurons in the BLA. Immunofluorescence double labeling was used to detect the expression of ERS-related proteins before and after the inhibition of protein kinase R-like endoplasmic reticulum kinase (PERK) pathway. Stress resulted in damage to GABAergic neurons in the BLA, decreased GABA and increased glutamic acid (GLU) levels, perturbation of the excitation/inhibition (E/I) ratio in the BLA, and obvious anxiety disorders in rats. Moreover, ERS-mediated GABAergic neuron injury was an important cause of neurotransmitter level changes in the BLA. These results suggested that ERS-mediated GABAergic neuron injury in the BLA may be an important cause of stress-induced mental disorders.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### Differences of Microglia in the Brain and the Spinal Cord

Microglia were previously regarded as a homogenous myeloid cell lineage in the mammalian central nervous system (CNS). However, accumulating evidences show that microglia in the brain and SC are quite different in development, cellular phenotypes and biological functions. Although this is a very interesting phenomenon, the underlying mechanisms and its significance for neurological diseases in association with behavioral and cognitive changes are still unclear. How microglia differ between these two regions and whether such diversity may contribute to CNS development and functions as well as neurological diseases will be discussed in this Perspective.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### NMDAR and JNK Activation in the Spinal Trigeminal Nucleus Caudalis Contributes to Masseter Hyperalgesia Induced by Stress

It is commonly accepted that psychological stress is closely associated with the occurrence and development of chronic orofacial pain. However, the pathogenesis underlying this process has not been fully elucidated. In the present study, we explored the role of N-methyl-D-aspartate receptors (NMDARs) and Jun N-terminal kinase (JNK) mediated intercellular communication between neurons and astrocytes in the spinal trigeminal nucleus caudalis (Vc) in the induction of masseter hyperalgesia by psychological stress in rats. We found that subjecting rats to 14 days of restraint stress (8 h/d) caused a significant decrease in body weight gain, behavioral changes and marked masseter hyperalgesia in the rats. We also found that exposure to restraint stress for 14 days caused the expression of pJNK in astrocytes in the Vc to significantly increase, and intrathecally infusing a JNK inhibitor significantly prevented restraint stress-induced masseter hyperalgesia in the rats. In addition, after exposure to restraint stress for 14 days, the stressed group exhibited a noticeably increased expression level of pNR2B in neurons in the Vc. Then, we intrathecally injected MK-801 (an NMDAR inhibitor) and ifenprodil (a selective NR2B subunit antagonist) and observed that the two types of inhibitors not only alleviated masseter hyperalgesia but also significantly inhibited the phosphorylation of JNK in the Vc after restraint stress; this indicates that the effect of NMDAR antagonists may influence the activation of astrocytic JNK. Furthermore, inhibitors of neuronal nitric oxide synthase (nNOS) activation and guanylate cyclase (GC) inhibitor could not only inhibit the expression of pJNK in the Vc, but also effectively alleviate masseter hyperalgesia induced by restraint stress. Taken together, our results suggest that NMDAR activation could increase JNK phosphorylation in astrocytes after restraint stress, which may depend on the nNOS-GC pathway. The intercellular communication between neurons and astrocytes in the Vc may play a key role in the induction of masseter muscle hyperalgesia by psychological stress in rats.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 14, 2019 12:00 AM.

• #### How contraction has shaped evolution

Two unicellular relatives of animals reveal that coordinated contractions of groups of cells using actomyosin predated animal multicellularity during evolution.

in eLife: latest articles on November 14, 2019 12:00 AM.

• #### The cerebellum shows its stripes

New studies examine how the different sub-structures in the cerebellum are organized to receive information during complex behavioral tasks

in eLife: latest articles on November 14, 2019 12:00 AM.

• #### Movement of accessible plasma membrane cholesterol by GRAMD1 lipid transfer protein complex

Cholesterol is a major structural component of the plasma membrane (PM). The majority of PM cholesterol forms complexes with other PM lipids, making it inaccessible for intracellular transport. Transition of PM cholesterol between accessible and inaccessible pools maintains cellular homeostasis, but how cells monitor PM cholesterol accessibility remains unclear. We show that endoplasmic reticulum (ER)-anchored lipid transfer proteins, the GRAMD1s, sense and transport accessible PM cholesterol to the ER. GRAMD1s bind one another and populate at ER-PM contacts by sensing a transient expansion of the accessible pool of PM cholesterol via GRAM domains and facilitate its transport via StART-like domains. Cells lacking all three GRAMD1s exhibit striking expansion of the accessible pool of PM cholesterol due to less efficient PM to ER transport of accessible cholesterol. Thus, GRAMD1s facilitate movement of accessible PM cholesterol to the ER in order to counteract acute increase of PM cholesterol, activating non-vesicular cholesterol transport.

in eLife: latest articles on November 14, 2019 12:00 AM.

• #### The ion selectivity filter is not an activation gate in TRPV1-3 channels

Activation of TRPV1 channels in sensory neurons results in opening of a cation permeation pathway that triggers the sensation of pain. Opening of TRPV1 has been proposed to involve two gates that appear to prevent ion permeation in the absence of activators: the ion selectivity filter on the external side of the pore and the S6 helices that line the cytosolic half of the pore. Here we measured the access of thiol-reactive ions and compounds across the selectivity filters in rodent TRPV1-3 channels. Although our results are consistent with structural evidence that the selectivity filters in these channels are dynamic, they demonstrate that cations can permeate the ion selectivity filters even when channels are closed. Our results suggest that the selectivity filters in TRPV1-3 channels do not function as activation gates but might contribute to coupling structural rearrangements in the external pore to those in the cytosolic S6 gate.

in eLife: latest articles on November 14, 2019 12:00 AM.

• #### Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel

Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, a mutation that decreases ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.

in eLife: latest articles on November 14, 2019 12:00 AM.

We studied an accelerated longitudinal cohort of adolescents and young adults (n = 234, two time points) to investigate dynamic reconfigurations in myeloarchitecture. Intracortical profiles were generated using magnetization transfer (MT) data, a myelin-sensitive magnetic resonance imaging contrast. Mixed-effect models of depth specific intracortical profiles demonstrated two separate processes i) overall increases in MT, and ii) flattening of the MT profile related to enhanced signal in mid-to-deeper layers, especially in heteromodal and unimodal association cortices. This development was independent of morphological changes. Enhanced MT in mid-to-deeper layers was found to spatially co-localise specifically with gene expression markers of oligodendrocytes. Interregional covariance analysis revealed that these intracortical changes contributed to a gradual differentiation of higher-order from lower-order systems. Depth-dependent trajectories of intracortical myeloarchitectural development contribute to the maturation of structural hierarchies in the human neocortex, providing a model for adolescent development that bridges microstructural and macroscopic scales of brain organisation.

in eLife: latest articles on November 14, 2019 12:00 AM.

• #### Formation of a β-barrel membrane protein is catalyzed by the interior surface of the assembly machine protein BamA

The β-barrel assembly machine (Bam) complex in Gram-negative bacteria and its counterparts in mitochondria and chloroplasts fold and insert outer membrane β-barrel proteins. BamA, an essential component of the complex, is itself a β-barrel and is proposed to play a central role in assembling other barrel substrates. Here, we map the path of substrate insertion by the Bam complex using site-specific crosslinking to understand the molecular mechanisms that control β-barrel folding and release. We find that the C-terminal strand of the substrate is stably held by BamA and that the N-terminal strands of the substrate are assembled inside the BamA β-barrel. Importantly, we identify contacts between the assembling β-sheet and the BamA interior surface that determine the rate of substrate folding. Our results support a model in which the interior wall of BamA acts as a chaperone to catalyze β-barrel assembly.

in eLife: latest articles on November 14, 2019 12:00 AM.

• #### Stimulating the hippocampal posterior-medial network enhances task-dependent connectivity and memory

Successful episodic memory involves dynamic increases in activity across distributed hippocampal networks, including the posterior-medial (PMN) and the anterior-temporal (ATN) networks. We tested whether this up-regulation of functional connectivity during memory processing can be enhanced within hippocampal networks by noninvasive stimulation, and whether such task-dependent connectivity enhancement predicts memory improvement. Participants received stimulation targeting the PMN or an out-of-network control location. We compared the effects of stimulation on fMRI connectivity during an autobiographical retrieval task versus during rest within the PMN and the ATN. PMN-targeted stimulation significantly increased connectivity during autobiographical retrieval versus rest within the PMN. This effect was not observed in the ATN, or in either network following control stimulation. Task-dependent increases in connectivity within the medial temporal lobe predicted improved performance of a separate episodic memory test. It is therefore possible to enhance the task-dependent regulation of hippocampal network connectivity that supports memory processing using noninvasive stimulation.

in eLife: latest articles on November 14, 2019 12:00 AM.

• #### 28th Annual Computational Neuroscience Meeting: CNS*2019

in Most Recent Articles: BMC Neuroscience on November 14, 2019 12:00 AM.

• #### Quantifying pluripotency landscape of cell differentiation from scRNA-seq data by continuous birth-death process

by Jifan Shi, Tiejun Li, Luonan Chen, Kazuyuki Aihara

Modeling cell differentiation from omics data is an essential problem in systems biology research. Although many algorithms have been established to analyze scRNA-seq data, approaches to infer the pseudo-time of cells or quantify their potency have not yet been satisfactorily solved. Here, we propose the Landscape of Differentiation Dynamics (LDD) method, which calculates cell potentials and constructs their differentiation landscape by a continuous birth-death process from scRNA-seq data. From the viewpoint of stochastic dynamics, we exploited the features of the differentiation process and quantified the differentiation landscape based on the source-sink diffusion process. In comparison with other scRNA-seq methods in seven benchmark datasets, we found that LDD could accurately and efficiently build the evolution tree of cells with pseudo-time, in particular quantifying their differentiation landscape in terms of potency. This study provides not only a computational tool to quantify cell potency or the Waddington potential landscape based on scRNA-seq data, but also novel insights to understand the cell differentiation process from a dynamic perspective.

in PLOS Computational Biology: New Articles on November 13, 2019 10:00 PM.

• #### Impairment of Sharp-Wave Ripples in a Murine Model of Dravet Syndrome

Dravet syndrome (DS) is a severe early-onset epilepsy associated with heterozygous loss-of-function mutations in SCN1A. Animal models of DS with global Scn1a haploinsufficiency recapitulate the DS phenotype, including seizures, premature death, and impaired spatial memory performance. Spatial memory requires hippocampal sharp-wave ripples (SPW-Rs), which consist of high-frequency field potential oscillations (ripples, 100–260 Hz) superimposed on a slower SPW. Published in vitro electrophysiologic recordings in DS mice demonstrate reduced firing of GABAergic inhibitory neurons, which are essential for the formation of SPW-R complexes. Here, in vivo electrophysiologic recordings of hippocampal local field potential in both male and female mice demonstrate that Scn1a haploinsufficiency slows intrinsic ripple frequency and reduces the rate of SPW-R occurrence. In DS mice, peak ripple-band power is shifted to lower frequencies, average intertrough intervals of individually detected ripples are slower, and the rate of SPW-R generation is reduced, while SPW amplitude remains unaffected. These alterations in SPW-R properties, in combination with published reductions in interneuron function in DS, suggest a direct link between reduced inhibitory neuron excitability and impaired SPW-R function. A simple interconnected, conductance-based in silico interneuron network model was used to determine whether reduced sodium conductance is sufficient to slow ripple frequency, and stimulation with a modeled SPW demonstrates that reduced sodium conductance alone is sufficient to slow oscillatory frequencies. These findings forge a potential mechanistic link between impaired SPW-R generation and Scn1a mutation in DS mice, expanding the set of disorders in which SPW-R dysfunction contributes to impaired memory.

SIGNIFICANCE STATEMENT Disruption of sharp-wave ripples, a characteristic hippocampal rhythm coordinated by the precise timing of GABAergic interneurons, impairs spatial learning and memory. Prior in vitro patch-clamp recordings in brain slices from genetic mouse models of Dravet syndrome (DS) reveal reduced sodium current and excitability in GABAergic interneurons but not excitatory cells, suggesting a causal role for impaired interneuron activity in seizures and cognitive impairment. Here, heterozygous Scn1a mutation in DS mice reduces hippocampal sharp-wave ripple occurrence and slows internal ripple frequency in vivo and a simple in silico model demonstrates reduction in interneuron function alone is sufficient to slow model oscillations. Together, these findings provide a plausible pathophysiologic mechanism for Scn1a gene mutation to impair spatial memory.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Minimizing Precision-Weighted Sensory Prediction Errors via Memory Formation and Switching in Motor Adaptation

Humans predict the sensory consequences of motor commands by learning internal models of the body and of environment perturbations. When facing a sensory prediction error, should we attribute this error to a change in our body, and update the body internal model, or to a change in the environment? In the latter case, should we update an existing perturbation model or create a new model? Here, we propose that a decision-making process compares the models' prediction errors, weighted by their precisions, to select and update either the body model or an existing perturbation model. When no model can predict a perturbation, a new perturbation model is created and selected. When a model is selected, both the prediction's mean estimate and uncertainty are updated to minimize future prediction errors and to increase the precision of the predictions. Results from computer simulations, which we verified in an arm visuomotor adaptation experiment with subjects of both sexes, account for short aftereffects and large savings after adaptation to large, but not small, perturbations. Results also clarify previous data in the absence of errors (error-clamp): motor memories show an initial lack of decay after a large perturbation, but gradual decay after a small perturbation. Finally, qualitative individual differences in adaptation were explained by subjects selecting and updating either the body model or a perturbation model. Our results suggest that motor adaptation belongs to a general class of learning according to which memories are created when no existing memories can predict sensory data accurately and precisely.

SIGNIFICANCE STATEMENT When movements are followed by unexpected outcomes, such as following the introduction of a visuomotor or a force field perturbation, or the sudden removal of such perturbations, it is unclear whether the CNS updates existing memories or creates new memories. Here, we propose a novel model of adaptation, and investigate, via computer simulations and behavioral experiments, how the amplitude and schedule of the perturbation, as well as the characteristics of the learner, lead to the selection and update of existing memories or the creation of new memories. Our results provide insights into a number of puzzling and contradictory motor adaptation data, as well as into qualitative individual differences in adaptation.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Hemispheric Asymmetry of Globus Pallidus Relates to Alpha Modulation in Reward-Related Attentional Tasks

Whereas subcortical structures such as the basal ganglia have been widely explored in relation to motor control, recent evidence suggests that their mechanisms extend to the domain of attentional switching. We here investigated the subcortical involvement in reward related top-down control of visual alpha-band oscillations (8–13 Hz), which have been consistently linked to mechanisms supporting the allocation of visuospatial attention. Given that items associated with contextual saliency (e.g., monetary reward or loss) attract attention, it is not surprising that the acquired salience of visual items further modulates. The executive networks controlling such reward-dependent modulations of oscillatory brain activity have yet to be fully elucidated. Although such networks have been explored in terms of corticocortical interactions, subcortical regions are likely to be involved. To uncover this, we combined MRI and MEG data from 17 male and 11 female participants, investigating whether derived measures of subcortical structural asymmetries predict interhemispheric modulation of alpha power during a spatial attention task. We show that volumetric hemispheric lateralization of globus pallidus (GP) and thalamus (Th) explains individual hemispheric biases in the ability to modulate posterior alpha power. Importantly, for the GP, this effect became stronger when the value saliency parings in the task increased. Our findings suggest that the GP and Th in humans are part of a subcortical executive control network, differentially involved in modulating posterior alpha activity in the presence of saliency. Further investigation aimed at uncovering the interaction between subcortical and neocortical attentional networks would provide useful insight in future studies.

SIGNIFICANCE STATEMENT Whereas the involvement of subcortical regions into higher level cognitive processing, such as attention and reward attribution, has been already indicated in previous studies, little is known about its relationship with the functional oscillatory underpinnings of said processes. In particular, interhemispheric modulation of alpha band (8–13 Hz) oscillations, as recorded with magnetoencephalography, has been previously shown to vary as a function of salience (i.e., monetary reward/loss) in a spatial attention task. We here provide novel insights into the link between subcortical and cortical control of visual attention. Using the same reward-related spatial attention paradigm, we show that the volumetric lateralization of subcortical structures (specifically globus pallidus and thalamus) explains individual biases in the modulation of visual alpha activity.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### The Abused Inhalant Toluene Impairs Medial Prefrontal Cortex Activity and Risk/Reward Decision-Making during a Probabilistic Discounting Task

Inhalant (e.g., toluene) misuse is linked to behavioral and cognitive deficits in humans, yet preclinical studies of the effect of inhalants on higher-order cognition are limited. We addressed this gap in the literature by examining the effect of toluene vapor exposure on risk/reward decision-making in male and female Sprague-Dawley rats using a probabilistic discounting task. In this task, rodents chose a risky/large reward or a safe/small reward, with the odds of risky reinforcement descending or ascending throughout the test session. We observed a dose-dependent, sex-independent deficit in behavioral flexibility during probabilistic discounting caused by acute toluene exposure. Rats exposed to toluene vapor during adolescence and tested as adults performed comparably to air-treated controls and were susceptible to the effects of an acute toluene challenge. These behavioral flexibility deficits observed suggests dysfunctional medial prefrontal cortex (mPFC) activity. To address this hypothesis, we virally expressed the genetically encoded calcium sensor GCaMP6f in glutamatergic mPFC neurons and monitored calcium transients in real-time using in vivo fiber photometry. mPFC activity peaked before either lever press during free-choice trials in toluene- and air-treated animals. During forced-choice trials, GCaMP6f transients shifted from pre-risky to pre-safe choice, an effect mitigated by acute toluene exposure. mPFC activity decreased during rewarded trials, with larger decreases following risky/large wins compared with safe/small wins. Toluene-treated animals also had decreased mPFC activity during rewarded trials, but there was no distinction between risky/large wins and safe/small wins. These results provide physiological evidence for mPFC-dependent behavioral deficits caused by toluene.

SIGNIFICANCE STATEMENT Inhalants (e.g., toluene) are an understudied class of drugs of abuse that cause devastating behavioral and cognitive deficits in humans. Understanding the neurobiological interactions of toluene vapor using animal models is important for developing effective treatment strategies for inhalant addicts. Here we find that toluene vapor reduces behavioral flexibility in rodents making risk/reward-based decisions. The medial prefrontal cortex (mPFC) drives behavioral flexibility during this type of decision-making and we show that toluene reduces the ability of mPFC neurons to track optimal choices as reward probabilities change. Toluene also reduces these neurons' ability to distinguish between small and large rewards. A combination of these factors likely leads to the impaired performance in probabilistic discounting following acute toluene exposure.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Functional Localization of the Frontal Eye Fields in the Common Marmoset Using Microstimulation

The frontal eye field (FEF) is a critical region for the deployment of overt and covert spatial attention. Although investigations in the macaque continue to provide insight into the neural underpinnings of the FEF, due to its location within a sulcus, the macaque FEF is virtually inaccessible to electrophysiological techniques such as high-density and laminar recordings. With a largely lissencephalic cortex, the common marmoset (Callithrix jacchus) is a promising alternative primate model for studying FEF microcircuitry. Putative homologies have been established with the macaque FEF on the basis of cytoarchitecture and connectivity; however, physiological investigation in awake, behaving marmosets is necessary to physiologically locate this area. Here, we addressed this gap using intracortical microstimulation in a broad range of frontal cortical areas in three adult marmosets (two males, one female). We implanted marmosets with 96-channel Utah arrays and applied microstimulation trains while they freely viewed video clips. We evoked short-latency fixed vector saccades at low currents (<50 μA) in areas 45, 8aV, 8C, and 6DR. We observed a topography of saccade direction and amplitude consistent with findings in macaques and humans: small saccades in ventrolateral FEF and large saccades combined with contralateral neck and shoulder movements encoded in dorsomedial FEF. Our data provide compelling evidence supporting homology between marmoset and macaque FEF and suggest that the marmoset is a useful primate model for investigating FEF microcircuitry and its contributions to oculomotor and cognitive functions.

SIGNIFICANCE STATEMENT The frontal eye field (FEF) is a critical cortical region for overt and covert spatial attention. The microcircuitry of this area remains poorly understood because in the macaque, the most commonly used model, it is embedded within a sulcus and is inaccessible to modern electrophysiological and imaging techniques. The common marmoset is a promising alternative primate model due to its lissencephalic cortex and potential for genetic manipulation. However, evidence for homologous cortical areas in this model remains limited and unclear. Here, we applied microstimulation in frontal cortical areas in marmosets to physiologically identify FEF. Our results provide compelling evidence for an FEF in the marmoset and suggest that the marmoset is a useful model for investigating FEF microcircuitry.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Fine-Grained Mapping of Cortical Somatotopies in Chronic Complex Regional Pain Syndrome

It has long been thought that severe chronic pain conditions, such as complex regional pain syndrome (CRPS), are not only associated with, but even maintained by a reorganization of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations in CRPS patients, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used fMRI to characterize the S1 representation of the affected and unaffected hand in humans (of either sex) with unilateral CRPS. The cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable with those of both the unaffected hand and healthy controls. We found no differential relation between affected versus unaffected hand map measures and clinical measures (pain severity, upper limb disability, disease duration). Thus, if any map reorganization occurs, it does not appear to be directly related to pain and disease severity. These findings compel us to reconsider the cortical mechanisms underlying CRPS and the rationale for interventions that aim to "restore" somatotopic representations to treat pain.

SIGNIFICANCE STATEMENT This study shows that the spatial map of the fingers in somatosensory cortex is largely preserved in chronic complex regional pain syndrome (CRPS). These findings challenge the treatment rationale for restoring somatotopic representations in complex regional pain syndrome patients.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Dendritic Spikes Expand the Range of Well Tolerated Population Noise Structures

The brain operates surprisingly well despite the noisy nature of individual neurons. The central mechanism for noise mitigation in the nervous system is thought to involve averaging over multiple noise-corrupted inputs. Subsequently, there has been considerable interest in identifying noise structures that can be integrated linearly in a way that preserves reliable signal encoding. By analyzing realistic synaptic integration in biophysically accurate neuronal models, I report a complementary denoising approach that is mediated by focal dendritic spikes. Dendritic spikes might seem to be unlikely candidates for noise reduction due to their miniscule integration compartments and poor averaging abilities. Nonetheless, the extra thresholding step introduced by dendritic spike generation increases neuronal tolerance for a broad category of noise structures, some of which cannot be resolved well with averaging. This property of active dendrites compensates for compartment size constraints and expands the repertoire of conditions that can be processed by neuronal populations.

SIGNIFICANCE STATEMENT Noise, or random variability, is a prominent feature of the neuronal code and poses a fundamental challenge for information processing. To reconcile the surprisingly accurate output of the brain with the inherent noisiness of biological systems, previous work examined signal integration in idealized neurons. The notion that emerged from this body of work is that accurate signal representation relies largely on input averaging in neuronal dendrites. In contrast to the prevailing view, I show that denoising in simulated neurons with realistic morphology and biophysical properties follows a different strategy: dendritic spikes act as classifiers that assist in extracting information from a variety of noise structures that have been considered before to be particularly disruptive for reliable brain function.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Aversive Training Induces Both Presynaptic and Postsynaptic Suppression in Drosophila

The α'β' subtype of Drosophila mushroom body neurons (MBn) is required for memory acquisition, consolidation and early memory retrieval after aversive olfactory conditioning. However, in vivo functional imaging studies have failed to detect an early forming memory trace in these neurons as reflected by an enhanced G-CaMP signal in response to presentation of the learned odor. Moreover, whether cellular memory traces form early after conditioning in the mushroom body output neurons (MBOn) downstream of the α'β' MBn remains unknown. Here, we show that aversive olfactory conditioning suppresses the calcium responses to the learned odor in both α'3 and α'2 axon segments of α'β' MBn and in the dendrites of α'3 MBOn immediately after conditioning using female flies. Notably, the cellular memory traces in both α'3 MBn and α'3 MBOn are short-lived and persist for <30 min. The suppressed response in α'3 MBn is accompanied by a reduction of acetylcholine (ACh) release, suggesting that the memory trace in postsynaptic α'3 MBOn may simply reflect the suppression in presynaptic α'3 MBn. Furthermore, we show that the α'3 MBn memory trace does not occur from the inhibition of GABAergic neurons via GABAA receptor activation. Because activation of the α'3 MBOn drives approach behavior of adult flies, our results demonstrate that aversive conditioning promotes avoidance behavior through suppression of the α'3 MBn–MBOn circuit.

SIGNIFICANCE STATEMENT Drosophila learn to avoid an odor if that odor is repeatedly paired with electric shock. Mushroom body neurons (MBns) are known to be major cell types that mediate this form of aversive conditioning. Here we show that aversive conditioning causes a reduced response to the conditioned odor in an axon branch of one subtype of the MBn for no more than 30 min after conditioning, and in the dendrites of postsynaptic, MB output neurons (MBOns). Because experimenter-induced activation of the MBOn induces approach behavior by the fly, our data support a model that aversive learning promotes avoidance by suppressing the MBn–MBOn synapses that normally promote attraction.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Diversity of Ocular Dominance Patterns in Visual Cortex Originates from Variations in Local Cortical Retinotopy

The primary visual cortex contains a detailed map of retinal stimulus position (retinotopic map) and eye input (ocular dominance map) that results from the precise arrangement of thalamic afferents during cortical development. For reasons that remain unclear, the patterns of ocular dominance are very diverse across species and can take the shape of highly organized stripes, convoluted beads, or no pattern at all. Here, we use a new image-processing algorithm to measure ocular dominance patterns more accurately than in the past. We use these measurements to demonstrate that ocular dominance maps follow a common organizing principle that makes the cortical axis with the slowest retinotopic gradient orthogonal to the ocular dominance stripes. We demonstrate this relation in multiple regions of the primary visual cortex from individual animals, and different species. Moreover, consistent with the increase in the retinotopic gradient with visual eccentricity, we demonstrate a strong correlation between eccentricity and ocular dominance stripe width. We also show that an eye/polarity grid emerges within the visual cortical map when the representation of light and dark stimuli segregates along an axis orthogonal to the ocular dominance stripes, as recently demonstrated in cats. Based on these results, we propose a developmental model of visual cortical topography that sorts thalamic afferents by eye input and stimulus polarity, and then maximizes the binocular retinotopic match needed for depth perception and the light-dark retinotopic mismatch needed to process stimulus orientation. In this model, the different ocular dominance patterns simply emerge from differences in local retinotopic cortical topography.

SIGNIFICANCE STATEMENT Thalamocortical afferents segregate in primary visual cortex by eye input and light-dark polarity. This afferent segregation forms cortical patterns that vary greatly across species for reasons that remain unknown. Here we show that the formation of ocular dominance patterns follows a common organizing principle across species that aligns the cortical axis of ocular dominance segregation with the axis of slowest retinotopic gradient. Based on our results, we propose a model of visual cortical topography that sorts thalamic afferents by eye input and stimulus polarity along orthogonal axes with the slowest and fastest retinotopic gradients, respectively. This organization maximizes the binocular retinotopic match needed for depth perception and the light-dark retinotopic mismatch needed to process stimulus orientation in carnivores and primates.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Activation of the Intrinsic Pain Inhibitory Circuit from the Midcingulate Cg2 to Zona Incerta Alleviates Neuropathic Pain

Neuropathic pain is one of the most common and notorious neurological diseases. The changes in cerebral structures after nerve injury and the corresponding contributions to neuropathic pain are not well understood. Here we found that the majority of glutamatergic neurons in the area 2 of midcingulate cortex (MCC Cg2Glu) were inhibited by painful stimulation in male mice. Optogenetic manipulation revealed that these neurons were tonically involved in the inhibitory modulation of multimodal nociception. We further identified the projections to GABAergic neurons in the zona incerta (ZIGABA) mediated the pain inhibitory role. However, MCC Cg2Glu became hypoactive after nerve injury. Although a brief activation of the MCC Cg2Glu to ZIGABA circuit was able to relieve the aversiveness associated with spontaneous ongoing pain, consecutive activation of the circuit was required to alleviate neuropathic allodynia. In contrast, glutamatergic neurons in the area 1 of MCC played opposite roles in pain modulation. They became hyperactive after nerve injury and only consecutive inhibition of their activity relieved allodynia. These results demonstrate that MCC Cg2Glu constitute a component of intrinsic pain inhibitory circuitry and their hypoactivity underlies neuropathic pain. We propose that selective and persistent activation of the MCC Cg2Glu to ZIGABA circuit may serve as a potential therapeutic strategy for this disease.

SIGNIFICANCE STATEMENT Glutamatergic neurons in the area 2 of midcingulate cortex (MCC Cg2Glu) are tonically involved in the intrinsic pain inhibition via projecting to GABAergic neurons in the zona incerta. They are hypoactive after nerve injury. Selective activation of the circuit compensates the reduction of its analgesic strength and relieves neuropathic pain. Therefore, MCC Cg2Glu and the related analgesic circuit may serve as therapeutic targets for neuropathic pain. In contrast, MCC Cg1Glu have an opposite role in pain modulation and become hyperactive after nerve injury. The present study provides novel evidence for the concept that neuropathic pain is associated with the dysfunction of endogenous pain modulatory system and new perspective on the treatment of neuropathic pain.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### The p75NTR Influences Cerebellar Circuit Development and Adult Behavior via Regulation of Cell Cycle Duration of Granule Cell Progenitors

Development of brain circuitry requires precise regulation and timing of proliferation and differentiation of neural progenitor cells. The p75 neurotrophin receptor (p75NTR) is highly expressed in the proliferating granule cell precursors (GCPs) during development of the cerebellum. In a previous paper, we showed that proNT3 promoted GCP cell cycle exit via p75NTR. Here we used genetically modified rats and mice of both sexes to show that p75NTR regulates the duration of the GCP cell cycle, requiring activation of RhoA. Rats and mice lacking p75NTR have dysregulated GCP proliferation, with deleterious effects on cerebellar circuit development and behavioral consequences persisting into adulthood. In the absence of p75NTR, the GCP cell cycle is accelerated, leading to delayed cell cycle exit, prolonged GCP proliferation, increased glutamatergic input to Purkinje cells, and a deficit in delay eyeblink conditioning, a cerebellum-dependent form of learning. These results demonstrate the necessity of appropriate developmental timing of the cell cycle for establishment of proper connectivity and associated behavior.

SIGNIFICANCE STATEMENT The cerebellum has been shown to be involved in numerous behaviors in addition to its classic association with motor function. Cerebellar function is disrupted in a variety of psychiatric disorders, including those on the autism spectrum. Here we show that the p75 neurotrophin receptor, which is abundantly expressed in the proliferating cerebellar granule cell progenitors, regulates the cell cycle of these progenitors. In the absence of this receptor, the cell cycle is dysregulated, leading to excessive progenitor proliferation, which alters the balance of inputs to Purkinje cells, disrupting the circuitry and leading to functional deficits that persist into adulthood.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Telomerase Reverse Transcriptase and p53 Regulate Mammalian Peripheral Nervous System and CNS Axon Regeneration Downstream of c-Myc

Although several genes have been identified to promote axon regeneration in the CNS, our understanding of the molecular mechanisms by which mammalian axon regeneration is regulated is still limited and fragmented. Here by using female mouse sensory axon and optic nerve regeneration as model systems, we reveal an unexpected role of telomerase reverse transcriptase (TERT) in regulation of axon regeneration. We also provide evidence that TERT and p53 act downstream of c-Myc to control sensory axon regeneration. More importantly, overexpression of p53 in sensory neurons and retinal ganglion cells is sufficient to promote sensory axon and optic never regeneration, respectively. The study reveals a novel c-Myc-TERT-p53 signaling pathway, expanding horizons for novel approaches promoting CNS axon regeneration.

SIGNIFICANCE STATEMENT Despite significant progress during the past decade, our understanding of the molecular mechanisms by which mammalian CNS axon regeneration is regulated is still fragmented. By using sensory axon and optic nerve regeneration as model systems, the study revealed an unexpected role of telomerase reverse transcriptase (TERT) in regulation of axon regeneration. The results also delineated a c-Myc-TERT-p53 pathway in controlling axon growth. Last, our results demonstrated that p53 alone was sufficient to promote sensory axon and optic nerve regeneration in vivo. Collectively, the study not only revealed a new mechanisms underlying mammalian axon regeneration, but also expanded the pool of potential targets that can be manipulated to enhance CNS axon regeneration.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Hair Bundle Stimulation Mode Modifies Manifestations of Mechanotransduction Adaptation

Sound detection in auditory sensory hair cells depends on the deflection of the stereocilia hair bundle which opens mechano-electric transduction (MET) channels. Adaptation is hypothesized to be a critical property of MET that contributes to the auditory system's wide dynamic range and sharp frequency selectivity. Our recent work using a stiff probe to displace hair bundles showed that the fastest adaptation mechanism (fast adaptation) does not require calcium entry. Using fluid-jet stimuli, others obtained data showing only a calcium-dependent fast adaptation response. Because cochlear stereocilia do not move coherently and the hair cell response depends critically on the magnitude and time course of the hair bundle deflection, we developed a high-speed imaging technique to quantify this deflection in rat cochlear hair cells. The fluid jet delivers a force stimulus, and force steps lead to a complex time course of hair bundle displacement (mechanical creep), which affects the hair cell's macroscopic MET current response by masking the time course of the fast adaptation response. Modifying the fluid-jet stimulus to generate a hair bundle displacement step produced rapidly adapting currents that did not depend on membrane potential, confirming that fast adaptation does not depend on calcium entry. MET current responses differ with stimulus modality and will shape receptor potentials of different hair cell types based on their in vivo stimulus mode. These transformations will directly affect how stimuli are encoded.

SIGNIFICANCE STATEMENT Mechanotransduction by sensory hair cells represents a key first step for the sound sensing ability in vertebrates. The sharp frequency tuning and wide dynamic range of sound sensation are hypothesized to require a mechanotransduction adaptation mechanism. Recent work indicated that the apparent calcium dependence of the fastest adaptation differs with the method of cochlear hair cell stimulation. Here, we reconcile existing data and show that calcium entry does not drive the fastest adaptation process, independent of the stimulation method. With force stimulation of the hair bundle, adaptation manifests differently than with displacement stimulation, indicating that the stimulation mode of the hair bundle will affect the hair cell receptor current and stimulus coding.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Tumor Necrosis Factor-{alpha}-Mediated Metaplastic Inhibition of LTP Is Constitutively Engaged in an Alzheimer's Disease Model

LTP, a fundamental mechanism of learning and memory, is a highly regulated process. One form of regulation is metaplasticity (i.e., the activity-dependent and long-lasting changes in neuronal state that orchestrate the direction, magnitude, and persistence of future synaptic plasticity). We have previously described a heterodendritic metaplasticity effect, whereby strong high-frequency priming stimulation in stratum oriens inhibits subsequent LTP in the stratum radiatum of hippocampal area CA1, potentially by engagement of the enmeshed astrocytic network. This effect may occur due to neuron-glia interactions in response to priming stimulation that leads to the release of gliotransmitters. Here we found in male rats that TNFα and associated signal transduction enzymes, but not interleukin-1β (IL-1β), were responsible for mediating the metaplasticity effect. Replacing priming stimulation with TNFα incubation reproduced these effects. As TNFα levels are elevated in Alzheimer's disease, we examined whether heterodendritic metaplasticity is dysregulated in a transgenic mouse model of the disease, either before or after amyloid plaque formation. We showed that TNFα and IL-1β levels were significantly increased in aged but not young transgenic mice. Although control LTP was impaired in the young transgenic mice, it was not TNFα-dependent. In the older transgenic mice, however, LTP was impaired in a way that occluded further reduction by heterosynaptic metaplasticity, whereas LTP was entirely rescued by incubation with a TNFα antibody, but not an IL-1β antibody. Thus, TNFα mediates a heterodendritic metaplasticity in healthy rodents that becomes constitutively and selectively engaged in a mouse model of Alzheimer's disease.

SIGNIFICANCE STATEMENT The proinflammatory cytokine TNFα is known to be capable of inhibiting LTP and is upregulated several-fold in brain tissue, serum, and CSF of Alzheimer's disease (AD) patients. However, the mechanistic roles played by TNFα in plasticity and AD remain poorly understood. Here we show that TNFα and its downstream signaling molecules p38 MAPK, ERK, and JNK contribute fundamentally to a long-range metaplastic inhibition of LTP in rats. Moreover, the impaired LTP in aged APP/PS1 mice is rescued by incubation with a TNFα antibody. Thus, there is an endogenous engagement of the metaplasticity mechanism in this mouse model of AD, supporting the idea that blocking TNFα might be of therapeutic benefit in the disease.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Modeling a Neurexin-3{alpha} Human Mutation in Mouse Neurons Identifies a Novel Role in the Regulation of Transsynaptic Signaling and Neurotransmitter Release at Excitatory Synapses

Presynaptic α-neurexins are highly expressed and more frequently linked to neuropsychiatric and neurodevelopmental disorders than β-neurexins. However, how extracellular sequences specific to α-neurexins enable synaptic transmission is poorly understood. We identified a mutation in an extracellular region of neurexin-3α (A687T), located in a region conserved among α-neurexins and throughout vertebrate evolution, in a patient diagnosed with profound intellectual disability and epilepsy. We systematically interrogated this mutation using a knockdown-replacement approach, and discovered that the A687T mutation enhanced presynaptic morphology and increased two critical presynaptic parameters: (1) presynaptic release probability, and (2) the size of the readily releasable pool exclusively at excitatory synapses in mixed sex primary mouse hippocampal cultures. Introduction of the mutation in vivo and subsequent analysis in ex vivo brain slices made from male and female mice revealed a significant increase in excitatory presynaptic neurotransmission that occluded presynaptic but not postsynaptic LTP. Mechanistically, neurexin-3αA687T enhanced binding to LRRTM2 without altering binding to postsynaptic neuroligin-1. Thus, neurexin-3αA687T unexpectedly produced the first neurexin presynaptic gain-of-function phenotype and revealed unanticipated novel insights into how α-neurexin extracellular sequences govern both transsynaptic adhesion and presynaptic neurotransmitter release.

SIGNIFICANCE STATEMENT Despite decades of scientific scrutiny, how precise α-neurexin extracellular sequences control synapse function remains enigmatic. One largely unpursued avenue to identify the role of precise extracellular sequences is the interrogation of naturally occurring missense mutations. Here, we identified a neurexin-3α missense mutation in a compound heterozygous patient diagnosed with profound intellectual disability and epilepsy and systematically interrogated this mutation. Using in vitro and in vivo molecular replacement, electrophysiology, electron microscopy, and structure–function analyses, we reveal a novel role for neurexin-3α, unanticipated based on α-neurexin knock-out models, in controlling presynaptic morphology and neurotransmitter release at excitatory synapses. Our findings represent the first neurexin gain-of-function phenotype and provide new fundamentally important insight into the synaptic biology of α-neurexins.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Female-Specific Effects of CGRP Suggest Limited Efficacy of New Migraine Treatments in Males

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Synthesis of Hemispheric ITD Tuning from the Readout of a Neural Map: Commonalities of Proposed Coding Schemes in Birds and Mammals

A major cue to infer sound direction is the difference in arrival time of the sound at the left and right ears, called interaural time difference (ITD). The neural coding of ITD and its similarity across species have been strongly debated. In the barn owl, an auditory specialist relying on sound localization to capture prey, ITDs within the physiological range determined by the head width are topographically represented at each frequency. The topographic representation suggests that sound direction may be inferred from the location of maximal neural activity within the map. Such topographical representation of ITD, however, is not evident in mammals. Instead, the preferred ITD of neurons in the mammalian brainstem often lies outside the physiological range and depends on the neuron's best frequency. Because of these disparities, it has been assumed that how spatial hearing is achieved in birds and mammals is fundamentally different. However, recent studies reveal ITD responses in the owl's forebrain and midbrain premotor area that are consistent with coding schemes proposed in mammals. Particularly, sound location in owls could be decoded from the relative firing rates of two broadly and inversely ITD-tuned channels. This evidence suggests that, at downstream stages, the code for ITD may not be qualitatively different across species. Thus, while experimental evidence continues to support the notion of differences in ITD representation across species and brain regions, the latest results indicate notable commonalities, suggesting that codes driving orienting behavior in mammals and birds may be comparable.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### Wide. Fast. Deep: Recent Advances in Multiphoton Microscopy of In Vivo Neuronal Activity

Multiphoton microscopy (MPM) has emerged as one of the most powerful and widespread technologies to monitor the activity of neuronal networks in awake, behaving animals over long periods of time. MPM development spanned across decades and crucially depended on the concurrent improvement of calcium indicators that report neuronal activity as well as surgical protocols, head fixation approaches, and innovations in optics and microscopy technology. Here we review the last decade of MPM development and highlight how in vivo imaging has matured and diversified, making it now possible to concurrently monitor thousands of neurons across connected brain areas or, alternatively, small local networks with sampling rates in the kilohertz range. This review includes different laser scanning approaches, such as multibeam technologies as well as recent developments to image deeper into neuronal tissues using new, long-wavelength laser sources. As future development will critically depend on our ability to resolve and discriminate individual neuronal spikes, we will also describe a simple framework that allows performing quantitative comparisons between the reviewed MPM instruments. Finally, we provide our own opinion on how the most recent MPM developments can be leveraged at scale to enable the next generation of discoveries in brain function.

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

• #### This Week in The Journal

in Journal of Neuroscience current issue on November 13, 2019 05:30 PM.

## Objective

Otaplimastat is a neuroprotectant that inhibits matrix metalloproteases pathway, and reduces edema and intracerebral hemorrhage (ICH) induced by recombinant tissue plasminogen activator (rtPA) in animal stroke models. We aimed to assess the safety and efficacy of otaplimastat in patients receiving rtPA.

## Methods

This was a phase 2, two‐part, multicenter trial in stroke patients (19–80 years) receiving rtPA. Intravenous otaplimastat was administered <30 min after rtPA. Stage 1 was a single‐arm, open‐label safety study in 11 patients. Otaplimastat 80 mg was administered twice daily for 3 days. Stage 2 was a randomized, double‐blind, placebo‐controlled study involving 69 patients, assigned (1:1:1) to otaplimastat 40 mg, 80 mg or a placebo. The primary endpoint was the occurrence of parenchymal hematoma (PH) on day 1. Secondary endpoints included serious adverse events (SAE), mortality, and modified Rankin scale (mRS) distribution at 90 days (clinicaltrials.gov Identifier: NCT02787278).

## Results

No safety issues were encountered in stage 1. The incidence of PH during stage 2 was comparable: 0/22 with the placebo, 0/22 with otaplimastat 40 mg, and 1/21 with the 80 mg dose. No differences in the SAE (13%, 17%, 14%) or death (8.3%, 4.2%, 4.8%) were observed among the three groups. Three adverse events (chills, muscle rigidity, hepatotoxicity) were judged to be related to otaplimastat.

## Interpretation

Intravenous otaplimastat adjunctive therapy in patients receiving rtPA is feasible and generally safe. The functional efficacy of otaplimastat needs to be investigated with further large trials.

• #### Analgesic Effects of Compression at Trigger Points Are Associated With Reduction of Frontal Polar Cortical Activity as Well as Functional Connectivity Between the Frontal Polar Area and Insula in Patients With Chronic Low Back Pain: A Randomized Trial

Background

Compression of myofascial trigger points (MTrPs) in muscles is reported to reduce chronic musculoskeletal pain. Although the prefrontal cortex (PFC) is implicated in development of chronic pain, the mechanisms of how MTrP compression at low back regions affects PFC activity remain under debate. In this study, we investigated effects of MTrP compression on brain hemodynamics and EEG oscillation in subjects with chronic low back pain.

Methods

The study was a prospective, randomized, parallel-group trial and an observer and subject-blinded clinical trial. Thirty-two subjects with chronic low back pain were divided into two groups: subjects with compression at MTrPs (n = 16) or those with non-MTrPs (n = 16). Compression at MTrP or non-MTrP for 30 s was applied five times, and hemodynamic activity (near-infrared spectroscopy; NIRS) and EEGs were simultaneously recorded during the experiment.

Results

The results indicated that compression at MTrPs significantly (1) reduced subjective pain (P < 0.05) and increased the pressure pain threshold (P < 0.05), (2) decreased the NIRS hemodynamic activity in the frontal polar area (pPFC) (P < 0.05), and (3) increased the current source density (CSD) of EEG theta oscillation in the anterior part of the PFC (P < 0.05). CSD of EEG theta oscillation was negatively correlated with NIRS hemodynamic activity in the pPFC (P < 0.05). Furthermore, functional connectivity in theta bands between the medial pPFC and insula cortex was significantly decreased in the MTrP group (P < 0.05). The functional connectivity between those regions was positively correlated with subjective low back pain (P < 0.05).

Discussion

The results suggest that MTrP compression at the lumbar muscle modulates pPFC activity and functional connectivity between the pPFC and insula, which may relieve chronic musculoskeletal pain.

Trial registration

This trial was registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000033913) on 27 August 2018, at https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000038660.

in Frontiers in Systems Neuroscience | New and Recent Articles on November 13, 2019 12:00 AM.

• #### COALIA: A Computational Model of Human EEG for Consciousness Research

Understanding the origin of the main physiological processes involved in consciousness is a major challenge of contemporary neuroscience, with crucial implications for the study of Disorders of Consciousness (DOC). The difficulties in achieving this task include the considerable quantity of experimental data in this field, along with the non-intuitive, nonlinear nature of neuronal dynamics. One possibility of integrating the main results from the experimental literature into a cohesive framework, while accounting for nonlinear brain dynamics, is the use of physiologically-inspired computational models. In this study, we present a physiologically-grounded computational model, attempting to account for the main micro-circuits identified in the human cortex, while including the specificities of each neuronal type. More specifically, the model accounts for thalamo-cortical (vertical) regulation of cortico-cortical (horizontal) connectivity, which is a central mechanism for brain information integration and processing. The distinct neuronal assemblies communicate through feedforward and feedback excitatory and inhibitory synaptic connections implemented in a template brain accounting for long-range connectome. The EEG generated by this physiologically-based simulated brain is validated through comparison with brain rhythms recorded in humans in two states of consciousness (wakefulness, sleep). Using the model, it is possible to reproduce the local disynaptic disinhibition of basket cells (fast GABAergic inhibition) and glutamatergic pyramidal neurons through long-range activation of vasoactive intestinal-peptide (VIP) interneurons that induced inhibition of somatostatin positive (SST) interneurons. The model (COALIA) predicts that the strength and dynamics of the thalamic output on the cortex control the local and long-range cortical processing of information. Furthermore, the model reproduces and explains clinical results regarding the complexity of transcranial magnetic stimulation TMS-evoked EEG responses in DOC patients and healthy volunteers, through a modulation of thalamo-cortical connectivity that governs the level of cortico-cortical communication. This new model provides a quantitative framework to accelerate the study of the physiological mechanisms involved in the emergence, maintenance and disruption (sleep, anesthesia, DOC) of consciousness.

in Frontiers in Systems Neuroscience | New and Recent Articles on November 13, 2019 12:00 AM.

• #### Contactless Assessment of Cerebral Autoregulation by Photoplethysmographic Imaging at Green Illumination

Accurate and practical assessment of the brain circulation is needed to adequately estimate the viability of cerebral blood flow regulatory mechanisms in various physiological conditions. The objective of our study was to examine feasibility of the contactless green-light imaging photoplethysmography (PPG) for assessing cerebral autoregulation by revealing the dynamic relationships between cortical microcirculation assessed by PPG and changes in systemic blood pressure caused by visceral and somatic peripheral stimuli. In anesthetized male Wistar rats, the PPG video images of the open parietal cortex (either with unimpaired or dissected dura mater), electrocardiogram, and systemic arterial blood pressure (ABP) in the femoral artery were continuously recorded before, during and after visceral (colorectal distension) or somatic (tail squeezing) stimulation. In the vast majority of experiments with intact and removed dura mater, both spontaneous and peripheral stimulation-evoked changes in ABP negatively correlated with the accompanying alterations in the amplitude of pulsatile PPG component (APC), i.e., an increase of ABP resulted in a decrease of APC and vice versa. The most pronounced ABP and APC alterations were induced by noxious stimuli. Visceral painful stimulation in all cases caused short-term hypotension with simultaneous increase in cortical APC, whereas somatic noxious stimuli in 8 of 21 trials produced hypertensive effect with decreased APC. Animals with pressure 50-70 mmHg possessed higher negative cerebrovascular response rate of ABP-APC gradients than rats with either lower or higher pressure. Severe hypotension reversed the negative ratio to positive one, which was especially evident under visceral pain stimulation. Amplitude of the pulsatile PPG component probably reflects the regulation of vascular tone of cerebral cortex in response to systemic blood pressure fluctuations. When combined with different kinds of peripheral stimuli, the technique is capable for evaluation of normal and elucidation of impaired cerebrovascular system reactivity to particular physiological events, for example pain. The reported contactless PPG monitoring of cortical circulatory dynamics during neurosurgical interventions in combination with recordings of changes in other physiological parameters, such as systemic blood pressure and ECG, has the appealing potential to monitor viability of the cortex vessels and determine the state of patient’s cerebrovascular autoregulation.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 13, 2019 12:00 AM.

• #### White Matter Hyperintensities Relate to Basal Ganglia Functional Connectivity and Memory Performance in aMCI and SVMCI

Cerebral small vessel diseases play a crucial role in both vascular and non-vascular dementias. The location of white matter hyperintensities (WMHs), a neuroimaging marker of cerebral small vessel disease, has been found to vary between different types of dementias, and those in the basal ganglia (BG) have been particularly associated with vascular cognitive impairment (VCI). However, anatomical variation of WMHs across BG nuclei and its effect on brain network dysconnectivity has not been clearly elucidated. The study sample consisted of 40 patients with amnestic mild cognitive impairment (aMCI), 40 with subcortical vascular MCI (SVMCI), and 40 healthy control subjects. We examined the volume of WMH using T2-weighted magnetic resonance imaging. We also assessed the disturbances in BG-cortical communication by measuring resting-state functional connectivity (rsFC) from the functional magnetic resonance imaging signal. WMHs were more pronounced in the SVMCI group particularly in the caudate regions. In SVMCI patients, while higher WMHs in the dorsal caudate correlated with weaker FC with executive control regions and worse immediate recall performance, WMHs in the ventral caudate were associated with weaker FC with anterior default mode regions and worse delayed recall performance. In contrast, in aMCI patients, BG WMHs were not correlated with their changes in functional connectivity changes, which showed weaker connectivity with almost all BG structures, rather than restricting to specific BG subdivisions as observed in the SVMCI group. Our findings demonstrate that heterogeneously distributed BG WMHs are associated with changes in functional network interactions and verbal episodic memory performance only in SVMCI patients, which establishes a link between cerebrovascular-related structural abnormality, functional integrity of BG circuits, and episodic memory impairments in SVMCI, and may reflect a differential role of the cerebrovascular pathology in disrupting network-level communications and cognition between Alzheimer’s and subcortical vascular dementia.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 13, 2019 12:00 AM.

• #### EphA4 Negatively Regulates Myelination by Inhibiting Schwann Cell Differentiation in the Peripheral Nervous System

Myelin plays a crucial role in axon function recovery following nerve damage, and the interaction between Schwann cells (SCs) and regenerating axons profoundly affects myelin formation. Eph receptor A4 (EphA4), a member of the Eph tyrosine kinase receptor family, regulates cell-cell interactions via its ligand ephrins. However, our current knowledge on how EphA4 regulates the formation of myelin sheaths remains limited. In order to explore the roles of EphA4 in myelination in the peripheral nervous system, we used a combination of (1) a co-culture model of dorsal root ganglion (DRG) explants and SCs, (2) a SC differentiation model induced by db-cAMP, and (3) a regeneration model of crushed sciatic nerves in rats. Our results demonstrated that EphA4 inhibited myelination by inhibiting SC differentiation and facilitating SC proliferation in vitro. The in vivo experiments revealed that EphA4 expression in SCs is upregulated following nerve crush injury and then downregulated during remyelination. Moreover, silencing of EphA4 by siRNA or overexpression of EphA4 by genetic manipulation can accelerate or slow down nerve remyelination in crushed sciatic nerves. Taken together, our results suggest that EphA4 may negatively regulate myelination by abrogating SC differentiation.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 13, 2019 12:00 AM.

• #### Moderate-Intensity Aerobic Exercise Restores Appetite and Prefrontal Brain Activity to Images of Food Among Persons Dependent on Methamphetamine: A Functional Near-Infrared Spectroscopy Study

The brain prefrontal control system is critical to successful recovery from substance use disorders, and the prefrontal cortex (PFC) regulates striatal reward-related processes. Substance-dependent individuals exhibit an increased response to drug rewards and decreased response to natural, nondrug rewards. Short-term aerobic exercise can ameliorate craving and inhibitory deficits in methamphetamine users, but the effect of exercise on food reward is unknown. This study used functional near-infrared spectroscopy (fNIRS) to measure the effects of moderate- and high-intensity short-term aerobic exercise on prefrontal activity related to food images and recorded the subjective feelings of appetite in methamphetamine-dependent users. In total, 56 men who met the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for methamphetamine dependence, with a mean (SD) body mass index of 24.7 (3.5) kg/m2 and age of 30.2 (5.1) years, were randomly assigned to one of two exercise groups: moderate intensity (n = 28; 65%–75% of maximum heart rate) and high intensity (n = 28; 76%–85% of heart rate maximum). Each group also performed a resting control session for 35 min 1 week before or after the exercise, in a counterbalanced order. Mean oxygenated hemoglobin concentration changes in the PFC when viewing visual food cues were assessed by fNIRS, and subjective feelings of appetite were self-rated using visual analog scales after moderate- or high-intensity aerobic exercise and after the resting control session. A continuous-wave NIRS device was used to obtain functional data: eight sources and seven detectors were placed on the scalp covering the PFC, resulting in 20 channels per participant. We found that moderate-intensity aerobic exercise significantly increased both, the activation of the left orbitofrontal cortex (OFC) to images of high-calorie food (P = 0.02) and subjective sensations of hunger (F(1,54) = 7.16, P = 0.01). To our knowledge, this study provides the first evidence that moderate-intensity aerobic exercise increases OFC activity associated with high-calorie food images and stimulates appetite in methamphetamine-dependent individuals. These changes suggest that exercise may reestablish the food reward pathway hijacked by drugs and restore sensitivity to natural rewards. This evidence may contribute to the development of specific exercise programs for populations with methamphetamine dependence.

in Frontiers in Human Neuroscience | New and Recent Articles on November 13, 2019 12:00 AM.

• #### Bridging the Gap Between Second Language Acquisition Research and Memory Science: The Case of Foreign Language Attrition

The field of second language acquisition (SLA) is by nature of its subject a highly interdisciplinary area of research. Learning a (foreign) language, for example, involves encoding new words, consolidating and committing them to long-term memory, and later retrieving them. All of these processes have direct parallels in the domain of human memory and have been thoroughly studied by researchers in that field. Yet, despite these clear links, the two fields have largely developed in parallel and in isolation from one another. The present article aims to promote more cross-talk between SLA and memory science. We focus on foreign language (FL) attrition as an example of a research topic in SLA where the parallels with memory science are especially apparent. We discuss evidence that suggests that competition between languages is one of the mechanisms of FL attrition, paralleling the interference process thought to underlie forgetting in other domains of human memory. Backed up by concrete suggestions, we advocate the use of paradigms from the memory literature to study these interference effects in the language domain. In doing so, we hope to facilitate future cross-talk between the two fields and to further our understanding of FL attrition as a memory phenomenon.

in Frontiers in Human Neuroscience | New and Recent Articles on November 13, 2019 12:00 AM.

• #### Optimal Stimulation Protocol in a Bistable Synaptic Consolidation Model

Synaptic changes induced by neural activity need to be consolidated to maintain memory over a timescale of hours. In experiments, synaptic consolidation can be induced by repeating a stimulation protocol several times and the effectiveness of consolidation depends crucially on the repetition frequency of the stimulations. We address the question: is there an understandable reason why induction protocols with repetitions at some frequency work better than sustained protocols—even though the accumulated stimulation strength might be exactly the same in both cases? In real synapses, plasticity occurs on multiple time scales from seconds (induction), to several minutes (early phase of long-term potentiation) to hours and days (late phase of synaptic consolidation). We use a simplified mathematical model of just two times scales to elucidate the above question in a purified setting. Our mathematical results show that, even in such a simple model, the repetition frequency of stimulation plays an important role for the successful induction, and stabilization, of potentiation.

in Frontiers in Computational Neuroscience | New and Recent Articles on November 13, 2019 12:00 AM.

• #### Distinct Functional Connectivity Patterns Are Associated With Social and Cognitive Lifestyle Factors: Pathways to Cognitive Reserve

The importance of diverse lifestyle factors in sustaining cognition during aging and delaying the onset of decline in Alzheimer’s disease and related dementias cannot be overstated. We explored the influence of cognitive, social, and physical lifestyle factors on resting-state lagged linear connectivity (LLC) in high-density electroencephalography (EEG) in adults, ages 35–75 years. Diverse lifestyle factors build cognitive reserve (CR), protecting cognition in the presence of physical brain decline. Differences in LLC were examined between high- and low-CR groups formed using cognitive, social, and exercise lifestyle factors. LLC is a measure of lagged coherence that excludes zero phase contributions and limits the effects of volume conduction on connectivity estimates. Significant differences in LLC were identified for cognitive and social factors, but not exercise. Participants high in social CR possessed greater local and long-range connectivity in theta and low alpha for eyes-open and eyes-closed recording conditions. In contrast, participants high in cognitive CR exhibited greater eyes-closed long-range connectivity between the occipital lobe and other cortical regions in low alpha. Greater eyes-closed local LLC in delta was also present in men high in cognitive CR. Cognitive factor scores correlated with sustained attention, whereas social factors scores correlated with spatial working memory. Gender was a significant covariate in our analyses, with women displaying higher local and long-range LLC in low beta. Our findings support distinct relationships between CR and LLC, as well as CR and cognitive function for cognitive and social subcomponents. These patterns reflect the importance of diverse lifestyle factors in building CR.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 13, 2019 12:00 AM.

• #### Distinct Disruptive Patterns of Default Mode Subnetwork Connectivity Across the Spectrum of Preclinical Alzheimer’s Disease

Background: The early progression continuum of Alzheimer’s disease (AD) has been considered to advance through subjective cognitive decline (SCD), non-amnestic mild cognitive impairment (naMCI), and amnestic mild cognitive impairment (aMCI). Altered functional connectivity (FC) in the default mode network (DMN) is regarded as a hallmark of AD. Furthermore, the DMN can be divided into two subnetworks, the anterior and posterior subnetworks. However, little is known about distinct disruptive patterns in the subsystems of the DMN across the preclinical AD spectrum. This study investigated the connectivity patterns of anterior DMN (aDMN) and posterior DMN (pDMN) across the preclinical AD spectrum.

Methods: Resting-state functional magnetic resonance imaging (rs-fMRI) was used to investigate the FC in the DMN subnetworks in 20 healthy controls (HC), eight SCD, 11 naMCI, and 28 aMCI patients. Moreover, a correlation analysis was used to examine associations between the altered connectivity of the DMN subnetworks and the neurocognitive performance.

Results: Compared to the HC, SCD patients showed increased FC in the bilateral superior frontal gyrus (SFG), naMCI patients showed increased FC in the left inferior parietal lobule (IPL), and aMCI patients showed increased FC in the bilateral IPL in the aDMN; while SCD patients showed decreased FC in the precuneus, naMCI patients showed increased FC in the left middle temporal gyrus (MTG), and aMCI patients also showed increased FC in the right middle frontal gyrus (MFG) in the pDMN. Notably, the FC between the ventromedial prefrontal cortex (vmPFC) and the left MFG and the IPL in the aDMN was associated with episodic memory in the SCD and aMCI groups. Interestingly, the FC between the posterior cingulated cortex (PCC) and several regions in the pDMN was associated with other cognitive functions in the SCD and naMCI groups.

Conclusions: This study demonstrates that the three preclinical stages of AD exhibit distinct FC alternations in the DMN subnetworks. Furthermore, the patient group data showed that the altered FC involves cognitive function. These findings can provide novel insights for tailored clinical intervention across the preclinical AD spectrum.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 13, 2019 12:00 AM.

## Objective

To analyze why numerous acute stroke treatments were successful in the laboratory but failed in large clinical trials.

## Methods

We searched all phase III trials of medical treatments for acute ischemic stroke and corresponding early clinical and experimental studies. We compared the overall efficacy and assessed the impact of publication bias and study design on the efficacy. Furthermore, we estimated power and true report probability of experimental studies.

## Results

We identified 50 phase III trials with 46,008 subjects, 75 early clinical trials with 12,391 subjects, and 209 experimental studies with >7,141 subjects. Three (6%) phase III, 24 (32%) early clinical, and 143 (69.08%) experimental studies were positive. The mean treatment effect was 0.76 (0.70‐0.83) in experimental studies, 0.87 (0.71‐1.06) in early and 1.00 (0.95‐1.06) in phase III trials. Funnel plot asymmetry and trim‐and‐fill revealed a clear publication bias in experimental studies and early clinical trials. Study design and adherence to quality criteria had a considerable impact on estimated effect sizes. The mean power of experimental studies was 17%. Assuming a bias of 30% and pre‐study odds of 0.5‐0.7, this leads to a true report probability of less than 50%.

## Interpretation

Pivotal study design differences between experimental studies and clinical trials, including different primary endpoints and time‐to‐treatment, publication bias, neglected quality criteria and low power contribute to the stepwise efficacy decline of stroke treatments from experimental studies to phase III clinical trials. Even under conservative estimates, less than half of published positive experimental stroke studies are truly positive.

## Objective

To examine whether genetic variation affecting the expression or function of lipid‐lowering drug targets is associated with Alzheimer's disease (AD) risk, to evaluate the potential impact of long‐term exposure to corresponding therapeutics.

## Methods

We conducted Mendelian randomization analyses using variants in genes that encode the protein targets of several approved lipid‐lowering drug classes: HMGCR (encoding the target for statins); PCSK9 (encoding the target for PCSK9 inhibitors e.g. evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe); APOB (encoding the target of mipomersen). Variants were weighted by associations with low‐density lipoprotein cholesterol (LDL‐C) using data from lipid genetics consortia (N up to 295 826). We meta‐analysed MR estimates for regional variants weighted by LDL‐C on AD risk from two large samples (total N = 24718 cases, 56685 controls).

## Results

Models for HMGCR, APOB and NPC1L1 did not suggest that the use of related lipid‐lowering drug classes would affect AD risk. In contrast, exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL‐C inducible by the drug target = 1.45; 95% confidence interval: 1.23, 1.69). This risk increase was opposite to, though more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition.

## Interpretation

We did not identify genetic support for the repurposing of statins, ezetimibe or mipomersen for AD prevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9 inhibitors may be warranted.

## Objective

To investigate if midlife atherosclerosis is associated with different dementia subtypes and related underlying pathologies.

## Methods

Participants comprised the cardiovascular cohort of the Swedish prospective population‐based Malmö Diet and Cancer Study (n=6103). Carotid plaques and intima media thickness (IMT) were measured at baseline (1991‐1994). Dementia incidence until 2014 was obtained from national registers. Diagnoses were reviewed and validated in medical records.

In a cognitively unimpaired subcohort (n=330), β‐amyloid42 and tau were quantified in CSF and white matter hyperintensity volume, lacunar infarcts, and cerebral microbleeds were estimated on MRI (2009‐2015).

## Results

During 20 years of follow‐up, 462 individuals developed dementia (mean age at baseline 57.5±5.9 years, 58% women). Higher IMT in midlife was associated with an increased hazard ratio (HR) of all‐cause dementia (adjusted HR 1.14 [95% CI 1.03‐1.26]) and vascular dementia (adjusted HR 1.32 [1.10‐1.57]), but not Alzheimer's dementia (AD) (adjusted HR 0.95 [0.77‐1.17]). Carotid plaques were associated with vascular dementia when assessed as a three graded score (adjusted HR 1.90 [1.07‐3.38]).

In the cognitively unimpaired subcohort (53.8±4.6 years at baseline, 60% women) higher IMT in midlife was associated with development of small vessel disease (adjusted OR 1.47 [1.05‐2.06]) but not significantly with abnormal CSF AD biomarkers (adjusted OR 1.28 [0.87‐1.90] and 1.35 [0.86‐2.13]). Carotid plaques revealed no significant association with any of the underlying brain pathologies.

## Interpretation

Our findings support an association between midlife atherosclerosis and development of vascular dementia and cerebral small vessel disease, but not between atherosclerosis and subsequent AD or AD pathology.

• #### Does Prenatal Exposure to Maternal Inflammation Causes Sex Differences in Schizophrenia-Related Behavioral Outcomes in Adult Rats?

in eNeuro current issue on November 12, 2019 05:30 PM.

• #### Correction for Kreiner et al., Multiple modes of convergent adaptation in the spread of glyphosate-resistant Amaranthus tuberculatus [Corrections]

EVOLUTION Correction for “Multiple modes of convergent adaptation in the spread of glyphosate-resistant Amaranthus tuberculatus,” by Julia M. Kreiner, Darci Ann Giacomini, Felix Bemm, Bridgit Waithaka, Julian Regalado, Christa Lanz, Julia Hildebrandt, Peter H. Sikkema, Patrick J. Tranel, Detlef Weigel, John R. Stinchcombe, and Stephen I. Wright, which was first...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Multiple health and environmental impacts of foods [Sustainability Science]

Food choices are shifting globally in ways that are negatively affecting both human health and the environment. Here we consider how consuming an additional serving per day of each of 15 foods is associated with 5 health outcomes in adults and 5 aspects of agriculturally driven environmental degradation. We find...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### A MYC2/MYC3/MYC4-dependent transcription factor network regulates water spray-responsive gene expression and jasmonate levels [Plant Biology]

Mechanical stimuli, such as wind, rain, and touch affect plant development, growth, pest resistance, and ultimately reproductive success. Using water spray to simulate rain, we demonstrate that jasmonic acid (JA) signaling plays a key role in early gene-expression changes, well before it leads to developmental changes in flowering and plant...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Distinct mechanisms of Drosophila CRYPTOCHROME-mediated light-evoked membrane depolarization and in vivo clock resetting [Physiology]

Drosophila CRYPTOCHROME (dCRY) mediates electrophysiological depolarization and circadian clock resetting in response to blue or ultraviolet (UV) light. These light-evoked biological responses operate at different timescales and possibly through different mechanisms. Whether electron transfer down a conserved chain of tryptophan residues underlies biological responses following dCRY light activation has been...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### A small molecule protects mitochondrial integrity by inhibiting mTOR activity [Pharmacology]

Apoptosis activation by cytochrome c release from mitochondria to cytosol is a normal cellular response to mitochondrial damage. Using cellular apoptosis assay, we have found small-molecule apoptosis inhibitors that protect cells from mitochondrial damage. Previously, we reported the discovery of a small molecule, Compound A, which blocks dopaminergic neuron death...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Retinotopic specializations of cortical and thalamic inputs to area MT [Neuroscience]

Retinotopic specializations in the ventral visual stream, especially foveal adaptations, provide primates with high-acuity vision in the central visual field. However, visual field specializations have not been studied in the dorsal visual stream, dedicated to processing visual motion and visually guided behaviors. To investigate this, we injected retrograde neuronal tracers...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Relation between gamma oscillations and neuronal plasticity in the visual cortex [Neuroscience]

Use-dependent long-term changes of neuronal response properties must be gated to prevent irrelevant activity from inducing inappropriate modifications. Here we test the hypothesis that local network dynamics contribute to such gating. As synaptic modifications depend on temporal contiguity between presynaptic and postsynaptic activity, we examined the effect of synchronized gamma...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Cooperation and spatial self-organization determine rate and efficiency of particulate organic matter degradation in marine bacteria [Microbiology]

The recycling of particulate organic matter (POM) by microbes is a key part of the global carbon cycle. This process is mediated by the extracellular hydrolysis of polysaccharides, which can trigger social behaviors in bacteria resulting from the production of public goods. Despite the potential importance of public good-mediated interactions,...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Microbial communities in the tropical air ecosystem follow a precise diel cycle [Microbiology]

The atmosphere is vastly underexplored as a habitable ecosystem for microbial organisms. In this study, we investigated 795 time-resolved metagenomes from tropical air, generating 2.27 terabases of data. Despite only 9 to 17% of the generated sequence data currently being assignable to taxa, the air harbored a microbial diversity that...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### An onboard checking mechanism ensures effector delivery of the type VI secretion system in Vibrio cholerae [Microbiology]

The type VI secretion system (T6SS) is a lethal yet energetically costly weapon in gram-negative bacteria. Through contraction of a long sheath, the T6SS ejects a few copies of effectors accompanied by hundreds of structural carrier proteins per delivery. The few ejected effectors, however, dictate T6SS functions. It remains elusive...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa [Medical Sciences]

Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant Mycobacterium tuberculosis (Mtb) strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells [Medical Sciences]

Reduced serum testosterone (T), or hypogonadism, affects millions of men and is associated with many pathologies, including infertility, cardiovascular diseases, metabolic syndrome, and decreased libido and sexual function. Administering T-replacement therapy (TRT) reverses many of the symptoms associated with low T levels. However, TRT is linked to side effects such...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma [Medical Sciences]

Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### HMGB1-C1q complexes regulate macrophage function by switching between leukotriene and specialized proresolving mediator biosynthesis [Immunology and Inflammation]

Macrophage polarization is critical to inflammation and resolution of inflammation. We previously showed that high-mobility group box 1 (HMGB1) can engage receptor for advanced glycation end product (RAGE) to direct monocytes to a proinflammatory phenotype characterized by production of type 1 IFN and proinflammatory cytokines. In contrast, HMGB1 plus C1q...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Human-specific tandem repeat expansion and differential gene expression during primate evolution [Genetics]

Short tandem repeats (STRs) and variable number tandem repeats (VNTRs) are important sources of natural and disease-causing variation, yet they have been problematic to resolve in reference genomes and genotype with short-read technology. We created a framework to model the evolution and instability of STRs and VNTRs in apes. We...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Natural human genetic variation determines basal and inducible expression of PM20D1, an obesity-associated gene [Genetics]

PM20D1 is a candidate thermogenic enzyme in mouse fat, with its expression cold-induced and enriched in brown versus white adipocytes. Thiazolidinedione (TZD) antidiabetic drugs, which activate the peroxisome proliferator-activated receptor-γ (PPARγ) nuclear receptor, are potent stimuli for adipocyte browning yet fail to induce Pm20d1 expression in mouse adipocytes. In contrast,...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Evolution of sexual cooperation from sexual conflict [Evolution]

In many species that form pair bonds, males display to their mate after pair formation. These displays elevate the female’s investment into the brood. This is a form of cooperation because without the display, female investment is reduced to levels that are suboptimal for both sexes. The presence of such...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

Adaptive radiations are prominent components of the world’s biodiversity. They comprise many species derived from one or a small number of ancestral species in a geologically short time that have diversified into a variety of ecological niches. Several authors have proposed that introgressive hybridization has been important in the generation...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### A global-level assessment of the effectiveness of protected areas at resisting anthropogenic pressures [Environmental Sciences]

One-sixth of the global terrestrial surface now falls within protected areas (PAs), making it essential to understand how far they mitigate the increasing pressures on nature which characterize the Anthropocene. In by far the largest analysis of this question to date and not restricted to forested PAs, we compiled data...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

• #### Linking global drivers of agricultural trade to on-the-ground impacts on biodiversity [Sustainability Science]

Consumption of globally traded agricultural commodities like soy and palm oil is one of the primary causes of deforestation and biodiversity loss in some of the world’s most species-rich ecosystems. However, the complexity of global supply chains has confounded efforts to reduce impacts. Companies and governments with sustainability commitments struggle...

in Proceedings of the National Academy of Sciences Recent Issues on November 12, 2019 05:01 PM.

## Objective

Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is widely established for older generation AEDs, whereas there is limited evidence about newer AEDs. Our aim is to assess the benefit of newer generation AEDs TDM in epilepsy.

## Methods

We performed a randomised, controlled trial comparing systematic with rescue TDM of lamotrigine, levetiracetam, oxcarbazepine, topiramate, brivaracetam, zonisamide, or pregabalin. Participants were adults with epilepsy, in whom treatment with newer generation AEDs was initiated or needed adjustment. In the systematic TDM arm, AED plasma levels were available at each appointment, whereas in the rescue TDM arm, levels were known only if a study endpoint was reached (inefficacy or adverse events). The primary outcome was the proportion of participants followed over one year without reaching one of the predefined endpoint.

## Results

151 participants were enrolled; global retention in the study was similar in both arms (56% overall, 58% in the systematic and 53% in rescue TDM arm, p=0.6 Cox regression). There was no difference in term of outcome regarding treatment efficacy or tolerability. Partial adherence of clinicians to TDM (adjusting or not AED dosage based on blood levels) did not explain this lack of benefit.

## Interpretation

This study provides Class A evidence that systematic drug level monitoring of newer generation AEDs does not bring tangible benefits in the management of patients with epilepsy. Poor correlation between clinical effects and drug levels likely accounts for this finding. However, TDM is useful in several situations, such as pregnancy, as well as compliance issues.

• #### Emerging intersections between neuroscience and glioma biology

Nature Neuroscience, Published online: 12 November 2019; doi:10.1038/s41593-019-0540-y

Emerging intersections between neuroscience and glioma biology

in Nature Neuroscience - Issue - nature.com science feeds on November 12, 2019 12:00 AM.

• #### A ventral CA1 to nucleus accumbens core engram circuit mediates conditioned place preference for cocaine

Nature Neuroscience, Published online: 12 November 2019; doi:10.1038/s41593-019-0524-y

Zhou et al. show that the reward and context information of cocaine-associated memory is stored in selectively strengthened inter-engram connections from the ventral CA1 to the nucleus accumbens core, forming an ‘engram circuit’ that mediates memory recall.

in Nature Neuroscience - Issue - nature.com science feeds on November 12, 2019 12:00 AM.

• #### Acetylcholine Mediates Dynamic Switching Between Information Coding Schemes in Neuronal Networks

Rate coding and phase coding are the two major coding modes seen in the brain. For these two modes, network dynamics must either have a wide distribution of frequencies for rate coding, or a narrow one to achieve stability in phase dynamics for phase coding. Acetylcholine (ACh) is a potent regulator of neural excitability. Acting through the muscarinic receptor, ACh reduces the magnitude of the potassium M-current, a hyperpolarizing current that builds up as neurons fire. The M-current contributes to several excitability features of neurons, becoming a major player in facilitating the transition between Type 1 (integrator) and Type 2 (resonator) excitability. In this paper we argue that this transition enables a dynamic switch between rate coding and phase coding as levels of ACh release change. When a network is in a high ACh state variations in synaptic inputs will lead to a wider distribution of firing rates across the network and this distribution will reflect the network structure or pattern of external input to the network. When ACh is low, network frequencies become narrowly distributed and the structure of a network or pattern of external inputs will be represented through phase relationships between firing neurons. This work provides insights into how modulation of neuronal features influences network dynamics and information processing across brain states.

in Frontiers in Systems Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Internalized GPCRs as Potential Therapeutic Targets for the Management of Pain

Peripheral and central neurons in the pain pathway are well equipped to detect and respond to extracellular stimuli such as pro-inflammatory mediators and neurotransmitters through the cell surface expression of receptors that can mediate rapid intracellular signaling. Following injury or infection, activation of cell surface G protein-coupled receptors (GPCRs) initiates cell signaling processes that lead to the generation of action potentials in neurons or inflammatory responses such as cytokine secretion by immune cells. However, it is now appreciated that cell surface events alone may not be sufficient for all receptors to generate their complete signaling repertoire. Following an initial wave of signaling at the cell surface, active GPCRs can engage with endocytic proteins such as the adaptor protein β-arrestin (βArr) to promote clathrin-mediated internalization. Classically, βArr-mediated internalization of GPCRs was hypothesized to terminate signaling, yet for multiple GPCRs known to contribute to pain, it has been demonstrated that endocytosis can also promote a unique “second wave” of signaling from intracellular membranes, including those of endosomes and the Golgi, that is spatiotemporally distinct from initial cell-surface events. In the context of pain, understanding the cellular and molecular mechanisms that drive spatiotemporal signaling of GPCRs is invaluable for understanding how pain occurs and persists, and how current analgesics achieve efficacy or promote side-effects. This review article discusses the importance of receptor localization for signaling outcomes of pro- and anti-nociceptive GPCRs, and new analgesic opportunities emerging through the development of “location-biased” ligands that favor binding with intracellular GPCR populations.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Prionoid Proteins in the Pathogenesis of Neurodegenerative Diseases

There is a growing body of evidence that prionoid protein behaviors are a core element of neurodegenerative diseases (NDs) that afflict humans. Common elements in pathogenesis, pathological effects and protein-level behaviors exist between Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). These extend beyond the affected neurons to glial cells and processes. This results in a complicated system of disease progression, which often takes advantage of protective processes to promote the propagation of pathological protein aggregates. This review article provides a current snapshot of knowledge on these proteins and their intrinsic role in the pathogenesis and disease progression seen across NDs.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Re-innervation of the Denervated Dentate Gyrus by Sprouting Associational and Commissural Mossy Cell Axons in Organotypic Tissue Cultures of Entorhinal Cortex and Hippocampus

Collateral sprouting of surviving axons contributes to the synaptic reorganization after brain injury. To study this clinically relevant phenomenon, we used complex organotypic tissue cultures of mouse entorhinal cortex (EC) and hippocampus (H). Single EC-H cultures were generated to analyze associational sprouting, and double EC-H cultures were used to evaluate commissural sprouting of mossy cells in the dentate gyrus (DG) following entorhinal denervation. Entorhinal denervation (transection of the perforant path) was performed at 14 days in vitro (DIV) and associational/commissural sprouting was assessed at 28 DIV. First, associational sprouting was studied in genetically hybrid EC-H cultures of beta-actin-GFPtg and wild-type mice. Using calretinin as a marker, associational axons were found to re-innervate almost the entire entorhinal target zone. Denervation experiments performed with EC-H cultures of Thy1-YFPtg mice, in which mossy cells are YFP-positive, confirmed that the overwhelming majority of sprouting associational calretinin-positive axons are mossy cell axons. Second, we analyzed associational/commissural sprouting by combining wild-type EC-H cultures with calretinin-deficient EC-H cultures. In these cultures, only wild-type mossy cells contain calretinin, and associational and commissural mossy cell collaterals can be distinguished using calretinin as a marker. Nearly the entire DG entorhinal target zone was re-innervated by sprouting of associational and commissural mossy cell axons. Finally, viral labeling of newly formed associational/commissural axons revealed a rapid post-lesional sprouting response. These findings demonstrate extensive and rapid re-innervation of the denervated DG outer molecular layer by associational and commissural mossy cell axons, similar to what has been reported to occur in juvenile rodent DG in vivo.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Effectiveness of Noise-Attenuating Headphones on Physiological Responses for Children With Autism Spectrum Disorders

Objective: The purpose of this study was to evaluate the proof of concept of an intervention to decrease sympathetic activation as measured by skin conductivity (electrodermal activity, EDA) in children with an autism spectrum disorder (ASD) and auditory hypersensitivity (hyperacusis). In addition, researchers examined if the intervention provided protection against the negative effects of decibel level of environmental noises on electrodermal measures between interventions. The feasibility of implementation and outcome measures within natural environments were evaluated.

Method: A single-subject multi-treatment design was used with six children, aged 8–16 years, with a form of Autism (i.e., Autism, PDD-NOS). Participants used in-ear (IE) and over-ear (OE) headphones for two randomly sequenced treatment phases. Each child completed four phases: (1) a week of baseline data collection; (2) a week of an intervention; (3) a week of no intervention; and (4) a week of the other intervention. Empatica E4 wristbands collected EDA data. Data was collected on 16–20 occasions per participant, with five measurements per phase.

Results: Separated tests for paired study phases suggested that regardless of intervention type, noise attenuating headphones led to a significance difference in both skin conductance levels (SCL) and frequency of non-specific conductance responses (NS-SCRs) between the baseline measurement and subsequent phases. Overall, SCL and NS-SCR frequency significantly decreased between baseline and the first intervention phase. A protective effect of the intervention was tested by collapsing intervention results into three phases. Slope correlation suggested constant SCL and NS-SCR frequency after initial use of the headphones regardless of the increase in environmental noises. A subsequent analysis of the quality of EDA data identified that later phases of data collection were associated with better data quality.

Conclusion: Many children with ASD have hypersensitivities to sound resulting in high levels of sympathetic nervous system reactivity, which is associated with problematic behaviors and distress. The findings of this study suggest that the use of noise attenuating headphones for individuals with ASD and hyperacusis may reduce sympathetic activation. Additionally, results suggest that the use of wearable sensors to collect physiological data in natural environments is feasible with established protocols and training procedures.

in Frontiers in Integrative Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Aged Opossums Show Alterations in Spatial Learning Behavior and Reduced Neurogenesis in the Dentate Gyrus

In many mammalian species including opossums, adult neurogenesis, the function of which is not completely understood, declines with aging. Aging also causes impairment of cognition. To understand whether new neurons contribute to learning and memory, we performed experiments on young and aged laboratory opossums, Monodelphis domestica, and examined the association between spatial memory using the Morris water maze test and the rate of adult neurogenesis in the dentate gyrus (DG). Modification of this test allowed us to assess how both young and aged opossums learn and remember the location of the platform in the water maze. We found that both young and aged opossums were motivated to perform this task. However, aged opossums needed more time to achieve the test than young opossums. Classical parameters measuring spatial learning in a water maze during a probe test showed that young opossums spent more time in the platform zone crossing it more often than aged opossums. Additionally, hippocampal neurogenesis was lower in the aged opossums than in the young animals but new neurons were still generated in the DG of aged opossums. Our data revealed individual differences in the levels of doublecortin in relation to memory performance across aged opossums. These differences were correlated with distinct behaviors, particularly, aged opossums with high levels of DCX achieved high performance levels in the water maze task. We, therefore suggest that new neurons in the DG of Monodelphis opossums contribute to learning and memory.

in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Enhancing Attention by Synchronizing Respiration and Fingertip Pressure: A Pilot Study Using Functional Near-Infrared Spectroscopy

Sustained attention is a fundamental ability ensuring effective cognitive processing and can be enhanced by meditation practice. However, keeping a focused meditative state is challenging for novices because involuntary mind-wandering frequently occurs during their practice. Inspired by the potential of force-control tasks in invoking internal somatic attention, we proposed a haptics-assisted meditation (HAM) to help reduce mind-wandering and enhance attention. During HAM, participants were instructed to maintain awareness on the respiration and meanwhile adjust bimanual fingertip pressures to keep synchronized with the respiration. This paradigm required somatosensory attention as a physiological foundation, aiming to help novices meditate starting with the body and gradually gain essential meditation skills. A cross-sectional study on 12 novices indicated that the participants reported less mind-wandering during HAM compared with the classic breath-counting meditation (BCM). In a further longitudinal study, the experimental group with 10 novices showed significantly improved performance in several attentional tests after 5 days’ practice of HAM. They tended to show more significant improvements in a few tests than did the control group performing the 5-day BCM practice. To investigate the brain activities related to HAM, we applied functional near-infrared spectroscopy (fNIRS) to record cerebral hemodynamic responses from the prefrontal and sensorimotor cortices when performing HAM, and we assessed the changes in cerebral activation and functional connectivity (FC) after the 5-day HAM practice. The prefrontal and sensorimotor regions demonstrated a uniform activation when performing HAM, and there was a significant increase in the right prefrontal activation after the practice. We also observed significant changes in the FC between the brain regions related to the attention networks. These behavioral and neural findings together provided preliminary evidence for the effectiveness of HAM on attention enhancement in the early stage of meditation learning.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Brain–Immune Interactions and Neuroinflammation After Traumatic Brain Injury

Traumatic brain injury (TBI) is the principal cause of death and disability in children and young adults. Clinical and preclinical research efforts have been carried out to understand the acute, life-threatening pathophysiological events happening after TBI. In the past few years, however, it was recognized that TBI causes significant morbidity weeks, months, or years after the initial injury, thereby contributing substantially to the overall burden of TBI and the decrease of life expectancy in these patients. Long-lasting sequels of TBI include cognitive decline/dementia, sensory-motor dysfunction, and psychiatric disorders, and most important for patients is the need for socio-economic rehabilitation affecting their quality of life. Cerebrovascular alterations have been described during the first week after TBI for direct consequence development of neuroinflammatory process in relation to brain edema. Within the brain–immune interactions, the complement system, which is a family of blood and cell surface proteins, participates in the pathophysiology process. In fact, the complement system is part of the primary defense and clearance component of innate and adaptive immune response. In this review, the complement activation after TBI will be described in relation to the activation of the microglia and astrocytes as well as the blood–brain barrier dysfunction during the first week after the injury. Considering the neuroinflammatory activity as a causal element of neurological handicaps, some major parallel lines of complement activity in multiple sclerosis and Alzheimer pathologies with regard to cognitive impairment will be discussed for chronic TBI. A better understanding of the role of complement activation could facilitate the development of new therapeutic approaches for TBI.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Propriospinal Neurons: Essential Elements of Locomotor Control in the Intact and Possibly the Injured Spinal Cord

Propriospinal interneurons (INs) communicate information over short and long distances within the spinal cord. They act to coordinate different parts of the body by linking motor circuits that control muscles across the forelimbs, trunk, and hindlimbs. Their role in coordinating locomotor circuits near and far may be invaluable to the recovery of locomotor function lost due to injury to the spinal cord where the flow of motor commands from the brain and brainstem to spinal motor circuits is disrupted. The formation and activation of circuits established by spared propriospinal INs may promote the re-emergence of locomotion. In light of progress made in animal models of spinal cord injury (SCI) and in human patients, we discuss the role of propriospinal INs in the intact spinal cord and describe recent studies investigating the assembly and/or activation of propriospinal circuits to promote recovery of locomotion following SCI.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### High-Fat Diet Induces Neuroinflammation and Mitochondrial Impairment in Mice Cerebral Cortex and Synaptic Fraction

Brain mitochondrial dysfunction is involved in the development of neurological and neurodegenerative diseases. Mitochondria specifically located at synapses play a key role in providing energy to support synaptic functions and plasticity, thus their defects may lead to synaptic failure, which is a common hallmark of neurodegenerative diseases. High-Fat Diet (HFD) consumption increases brain oxidative stress and impairs brain mitochondrial functions, although the underlying mechanisms are not completely understood. The aim of our study is to analyze neuroinflammation and mitochondrial dysfunctions in brain cortex and synaptosomal fraction isolated from a mouse model of diet-induced obesity. Male C57Bl/6 mice were divided into two groups fed a standard diet or HFD for 18 weeks. At the end of the treatment, inflammation (detected by ELISA), antioxidant state (measured by enzymatic activity), mitochondrial functions and efficiency (detected by oxidative capacity and Seahorse analysis), and brain-derived neurotrophic factor (BDNF) pathway (analyzed by western blot) were determined in brain cortex and synaptosomal fraction. In HFD animals, we observed an increase in inflammatory parameters and oxidative stress and a decrease in mitochondrial oxidative capacity both in the brain cortex and synaptosomal fraction. These alterations parallel with modulation of BDNF, a brain key signaling molecule that is linking synaptic plasticity and energy metabolism. Neuroinflammation HFD-dependent negatively affects BDNF pathway and mitochondrial activity in the brain cortex. The effect is even more pronounced in the synaptic region, where the impaired energy supply may have a negative impact on neuronal plasticity.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Synergy of Glutamatergic and Cholinergic Modulation Induces Plateau Potentials in Hippocampal OLM Interneurons

Oriens-lacunosum moleculare (OLM) cells are hippocampal inhibitory interneurons that are implicated in the regulation of information flow in the CA1 circuit, inhibiting cortical inputs to distal pyramidal cell dendrites, whilst disinhibiting CA3 inputs to pyramidal cells. OLM cells express metabotropic cholinergic (mAChR) and glutamatergic (mGluR) receptors, so modulation of these cells via these receptors may contribute to switching between functional modes of the hippocampus. Using a transgenic mouse line to identify OLM cells, we found that both mAChR and mGluR activation caused the cells to exhibit long-lasting depolarizing plateau potentials following evoked spike trains. Both mAChR- and mGluR-induced plateau potentials were eliminated by blocking transient receptor potential (TRP) channels, and were dependent on intracellular calcium concentration and calcium entry. Pharmacological tests indicated that Group I mGluRs are responsible for the glutamatergic induction of plateaus. There was also a pronounced synergy between the cholinergic and glutamatergic modulation, plateau potentials being generated by agonists applied together at concentrations too low to elicit any change when applied individually. This synergy could enable OLM cells to function as coincidence detectors of different neuromodulatory systems, leading to their enhanced and prolonged activation and a functional change in information flow within the hippocampus.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Activation of α7 Nicotinic Acetylcholine Receptor Protects Against 1-Methyl-4-Phenylpyridinium-Induced Astroglial Apoptosis

Astrocytes, as the largest population of glial subtype, play crucial roles in normal brain function and pathological conditions, such as Parkinson’s disease (PD). Restoring the functions of astrocyte is a promising new therapeutic target for PD. Astrocytes can express multiple types of neurotransmitter receptors, including functional α7 nicotinic acetylcholine receptor (α7nAChR). Previously, we found that a non-selective α7nAChR agonist nicotine exerted a protective effect against H2O2-induced astrocyte apoptosis via an α7nAChR-dependent pathway. However, the molecular mechanism of the antiapoptotic response of astroglial α7nAChR has not been studied. In the present study, using pharmacological inhibition and genetic knockout of α7nAChR, we assessed the antiapoptotic effects of an α7nAChR agonist PNU-282987 in primary cultured astrocytes treated with 1-methyl-4-phenylpyridinium (MPP+). PNU-282987 promoted the viability of astrocytes, alleviated MPP+ induced apoptosis, and decreased the number of GFAP+/TUNEL+ cells. Meanwhile, PNU-282987 upregulated the expression of the antiapoptotic protein Bcl-2 and downregulated the expression of the apoptotic protein Bax and cleaved-caspase-3. Moreover, the suppression of the JNK-p53-caspase-3 signaling may underlie the neuroprotective property of PNU-282987. Therefore, PNU-282987 ameliorates astroglial apoptosis induced by MPP+ through α7nAChR-JNK-p53 signaling. Our findings suggest that PNU-282987 may be a potential drug for restoring astroglial functions in the treatment of PD.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Astrocyte Changes in the Prefrontal Cortex From Aged Non-suicidal Depressed Patients

Glia alterations in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) have been postulated to play an important role in the pathophysiology of psychiatric disorders. Astroglia is the most abundant type of glial cells in the central nervous system. The expression levels of astrocyte markers (glial fibrillary acidic protein (GFAP), synemin-α, synemin-β, vimentin, nestin) in isolated gray matter from postmortem ACC and DLPFC were determined to investigate the possible involvement of astrocytes in depression. Donors were aged non-suicidal subjects with bipolar disorder (BPD) or major depressive disorder (MDD), and matched controls. GFAP mRNA levels were significantly increased in the ACC of BPD patients. However, GFAP immunohistochemistry showed that the area fraction of GFAP immunoreactive astrocytes was decreased in the ACC of BPD patients, while there were no changes in the cell density and integrated optical density (IOD), indicating that there might be a reduction of GFAP-positive astrocyte processes and remodeling of the astrocyte network in BPD. Furthermore, in controls, DLPFC GFAP mRNA levels were significantly lower with a time of death at daytime (08:01–20:00 h) compared to nighttime (20:01–08:00 h). In depression, such a diurnal pattern was not present. These findings in BPD and MDD subjects warrant further studies given the crucial roles of astrocytes in the central nervous system.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Biosensors Show the Pharmacokinetics of S-Ketamine in the Endoplasmic Reticulum

The target for the “rapid” (<24 h) antidepressant effects of S-ketamine is unknown, vitiating programs to rationally develop more effective rapid antidepressants. To describe a drug’s target, one must first understand the compartments entered by the drug, at all levels—the organ, the cell, and the organelle. We have, therefore, developed molecular tools to measure the subcellular, organellar pharmacokinetics of S-ketamine. The tools are genetically encoded intensity-based S-ketamine-sensing fluorescent reporters, iSKetSnFR1 and iSKetSnFR2. In solution, these biosensors respond to S-ketamine with a sensitivity, S-slope = delta(F/F0)/(delta[S-ketamine]) of 0.23 and 1.9/μM, respectively. The iSKetSnFR2 construct allows measurements at <0.3 μM S-ketamine. The iSKetSnFR1 and iSKetSnFR2 biosensors display >100-fold selectivity over other ligands tested, including R-ketamine. We targeted each of the sensors to either the plasma membrane (PM) or the endoplasmic reticulum (ER). Measurements on these biosensors expressed in Neuro2a cells and in human dopaminergic neurons differentiated from induced pluripotent stem cells (iPSCs) show that S-ketamine enters the ER within a few seconds after appearing in the external solution near the PM, then leaves as rapidly after S-ketamine is removed from the extracellular solution. In cells, S-slopes for the ER and PM-targeted sensors differ by <2-fold, indicating that the ER [S-ketamine] is less than 2-fold different from the extracellular [S-ketamine]. Organelles represent potential compartments for the engagement of S-ketamine with its antidepressant target, and potential S-ketamine targets include organellar ion channels, receptors, and transporters.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Generation and Characterization of Specific Monoclonal Antibodies and Nanobodies Directed Against the ATP-Gated Channel P2X4

The P2X4 channel is involved in different physiological and pathological conditions and functions in the nervous system. Despite the existence of several mouse models for which the expression of the gene was manipulated, there is still little information on the expression of the protein at the cellular level. In particular, supposedly specific available antibodies have often proved to recognize unrelated proteins in P2X4-deficient mice. Here, we used an in vivo DNA vaccine approach to generate a series of monoclonal antibodies and nanobodies specific for human, mouse, and rat P2X4 channels. We further characterized these antibodies and show that they solely recognize the native form of the proteins both in biochemical and cytometric applications. Some of these antibodies prove to specifically recognize P2X4 channels by immunostaining in brain or sensory ganglia slices, as well as at the cellular and subcellular levels. Due to their clonality, these different antibodies should represent versatile tools for further characterizing the cellular functions of P2X4 in the nervous system as well as at the periphery.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Single Synapse LTP: A Matter of Context?

The most commonly studied form of synaptic plasticity is long-term potentiation (LTP). Over the last 15 years, it has been possible to induce structural and functional LTP in dendritic spines using two-photon glutamate uncaging, allowing for studying the signaling mechanisms of LTP with single synapse resolution. In this review, we compare different stimulation methods to induce single synapse LTP and discuss how LTP is expressed. We summarize the underlying signaling mechanisms that have been studied with high spatiotemporal resolution. Finally, we discuss how LTP in a single synapse can be affected by excitatory and inhibitory synapses nearby. We argue that single synapse LTP is highly dependent on context: the choice of induction method, the history of the dendritic spine and the dendritic vicinity crucially affect signaling pathways and expression of single synapse LTP.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### SIRT3 Regulation of Mitochondrial Quality Control in Neurodegenerative Diseases

Neurodegenerative diseases are disorders that are characterized by a progressive decline of motor and/or cognitive functions caused by the selective degeneration and loss of neurons within the central nervous system. The most common neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Neurons have high energy demands, and dysregulation of mitochondrial quality and function is an important cause of neuronal degeneration. Mitochondrial quality control plays an important role in maintaining mitochondrial integrity and ensuring normal mitochondrial function; thus, defects in mitochondrial quality control are also significant causes of neurodegenerative diseases. The mitochondrial deacetylase SIRT3 has been found to have a large effect on mitochondrial function. Recent studies have also shown that SIRT3 has a role in mitochondrial quality control, including in the refolding or degradation of misfolded/unfolded proteins, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis, all of which are affected in neurodegenerative diseases.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Tau Phosphorylation in a Mouse Model of Temporal Lobe Epilepsy

Hyperphosphorylation of the microtubule-associated protein tau and its resultant aggregation into neurofibrillary tangles (NFT) is a pathological characteristic of neurodegenerative disorders known as tauopathies. Tau is a neuronal protein involved in the stabilization of microtubule structures of the axon and the aberrant phosphorylation of tau is associated with several neurotoxic effects. The discovery of tau pathology and aggregates in the cortex of Temporal lobe epilepsy (TLE) patients has focused interest on hyperphosphorylation of tau as a potential mechanism contributing to increased states of hyperexcitability and cognitive decline. Previous studies using animal models of status epilepticus and tissue from patients with TLE have shown increased tau phosphorylation in the brain following acute seizures and during epilepsy, with tau phosphorylation correlating with cognitive deficits in patients. Suggesting a functional role of tau during epilepsy, studies in tau-deficient and tau-overexpressing mice have demonstrated a causal role of tau during seizure generation. Previous studies, analyzing the impact of seizures on tau hyperphosphorylation, have mainly used animal models of acute seizures. These models, however, do not replicate all aspects of chronic epilepsy. In this study, we investigated the effects of acute seizures (status epilepticus) and chronic epilepsy upon the expression and phosphorylation of tau using the intra-amygdala kainic acid (KA)-induced status epilepticus mouse model. Status epilepticus resulted in an immediate increase in total tau levels in the hippocampus, in particular, the dentate gyrus, and phosphorylation of the AT8 epitope (Ser202, Thr205), with phosphorylated tau mainly localizing to the mossy fibers of the dentate gyrus. During epilepsy, abnormal phosphorylation of tau was detected again at the AT8 epitope with lower total tau levels in the CA3 and CA1 subfields of the hippocampus. Chronic epilepsy in mice also resulted in a strong localization of AT8 phospho-tau to microglia, indicating a distinct pattern of tau hyperphosphorylation during chronic epilepsy compared to status epilepticus. Our results reaffirm previous observations of tau phosphorylation post-status epilepticus, but also elaborate on tau alterations in epileptic mice which more faithfully mimic TLE. Our results confirm seizures affect tau hyperphosphorylation, however, suggest epitope-specific phosphorylation of tau and differences in cell-specific localization according to disease progression.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Differences in Semantic Memory Encoding Strategies in Young, Healthy Old and MCI Patients

Associative processes, such as the encoding of associations between words in a list, can enhance episodic memory performance and are thought to deteriorate with age. Here, we examine the nature of age-related deficits in the encoding of associations, by using a free recall paradigm with visual arrays of objects. Fifty-five participants (26 young students; 20 cognitive healthy older adults; nine patients with Mild Cognitive Impairment, MCI) were shown multiple slides (experimental trials), each containing an array of nine common objects for recall. Most of the arrays contained three objects from three semantic categories, each. In the remaining arrays, the nine objects were unrelated. Eye fixations were also monitored during the viewing of the arrays, in a subset of the participants. While for young participants the immediate recall was higher for the semantically related arrays, this effect was diminished in healthy elderly and totally absent in MCI patients. Furthermore, only in the young group did the sequence of eye fixations show a semantic scanning pattern during encoding, even when the related objects were non- adjacent in the array. Healthy elderly and MCI patients were not influenced by the semantic relatedness of items during the array encoding, to the same extent as young subjects, as observed by a lack of (or reduced) semantic scanning. The results support a version of the encoding of the association aging-deficit hypothesis.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 12, 2019 12:00 AM.

• #### Uncovering the subtype-specific temporal order of cancer pathway dysregulation

by Sahand Khakabimamaghani, Dujian Ding, Oliver Snow, Martin Ester

Cancer is driven by genetic mutations that dysregulate pathways important for proper cell function. Therefore, discovering these cancer pathways and their dysregulation order is key to understanding and treating cancer. However, the heterogeneity of mutations between different individuals makes this challenging and requires that cancer progression is studied in a subtype-specific way. To address this challenge, we provide a mathematical model, called Subtype-specific Pathway Linear Progression Model (SPM), that simultaneously captures cancer subtypes and pathways and order of dysregulation of the pathways within each subtype. Experiments with synthetic data indicate the robustness of SPM to problem specifics including noise compared to an existing method. Moreover, experimental results on glioblastoma multiforme and colorectal adenocarcinoma show the consistency of SPM’s results with the existing knowledge and its superiority to an existing method in certain cases. The implementation of our method is available at https://github.com/Dalton386/SPM.

in PLOS Computational Biology: New Articles on November 11, 2019 10:00 PM.

• #### Adaptation in structured populations and fuzzy boundaries between hard and soft sweeps

by Yichen Zheng, Thomas Wiehe

Selective sweeps, the genetic footprint of positive selection, have been extensively studied in the past decades, with dozens of methods developed to identify swept regions. However, these methods suffer from both false positive and false negative reports, and the candidates identified with different methods are often inconsistent with each other. We propose that a biological cause of this problem can be population subdivision, and a technical cause can be incomplete, or inaccurate, modeling of the dynamic process associated with sweeps. Here we used simulations to show how these effects interact and potentially cause bias. In particular, we show that sweeps maybe misclassified as either hard or soft, when the true time stage of a sweep and that implied, or pre-supposed, by the model do not match. We call this “temporal misclassification”. Similarly, “spatial misclassification (softening)” can occur when hard sweeps, which are imported by migration into a new subpopulation, are falsely identified as soft. This can easily happen in case of local adaptation, i.e. when the sweeping allele is not under positive selection in the new subpopulation, and the underlying model assumes panmixis instead of substructure. The claim that most sweeps in the evolutionary history of humans were soft, may have to be reconsidered in the light of these findings.

in PLOS Computational Biology: New Articles on November 11, 2019 10:00 PM.

• #### A population of bang-bang switches of defective interfering particles makes within-host dynamics of dengue virus controllable

by Tarunendu Mapder, Sam Clifford, John Aaskov, Kevin Burrage

The titre of virus in a dengue patient and the duration of this viraemia has a profound effect on whether or not a mosquito will become infected when it feeds on the patient and this, in turn, is a key driver of the magnitude of a dengue outbreak. The assessment of the heterogeneity of viral dynamics in dengue-infected patients and its precise treatment are still uncertain. Infection onset, patient physiology and immune response are thought to play major roles in the development of the viral load. Research has explored the interference and spontaneous generation of defective virus particles, but have not examined both the antibody and defective particles during natural infection. We explore the intrinsic variability in the within-host dynamics of viraemias for a population of patients using the method of population of models (POMs). A dataset from 208 patients is used to initially calibrate 20,000 models for the infection kinetics for each of the four dengue virus serotypes. The calibrated POMs suggests that naturally generated defective particles may interfere with the viraemia, but the generated defective virus particles are not adequate to reduce high fever and viraemia duration. The effect of adding excess defective dengue virus interfering particles to patients as a therapeutic is evaluated using the calibrated POMs in a bang-bang (on-off or two-step) optimal control setting. Bang-bang control is a class of binary feedback control that turns either ‘ON’ or ‘OFF’ at different time points, determined by the system feedback. Here, the bang-bang control estimates the mathematically optimal dose and duration of the intervention for each model in the POM set.

in PLOS Computational Biology: New Articles on November 11, 2019 10:00 PM.

• #### Developmental nicotine exposure alters synaptic input to hypoglossal motoneurons, and is associated with altered function of upper airway muscles

Abstract

Nicotine exposure during the fetal and neonatal periods (Developmental nicotine exposure, DNE) is associated with ineffective upper airway protective reflexes in infants. This could be explained by desensitized chemoreceptors and/or mechanoreceptors, diminished neuromuscular transmission or altered synaptic transmission among central neurons, as each of these systems depend in part on cholinergic signaling through nicotinic acetylcholine receptors (nAChRs). Here we showed that DNE blunts the response of the genioglossus muscle to nasal airway occlusion in lightly anesthetized rat pups. The genioglossus muscle helps keep the upper airway open and is innervated by hypoglossal motoneurons (XIIMNs). Experiments using the phrenic nerve-diaphragm preparation showed that DNE does not alter transmission across the neuromuscular junction. Accordingly, we used whole cell recordings from XIIMNs in brainstem slices to examine the influence of DNE on glutamatergic synaptic transmission under baseline conditions and in response to an acute nicotine challenge. DNE did not alter excitatory transmission under baseline conditions. Analysis of cumulative probability distributions revealed that acute nicotine challenge of P1-P2 preparations resulted in an increase in the frequency of nicotine-induced glutamatergic inputs to XIIMNs in both control and DNE. By contrast, P3-P5 DNE pups showed a decrease, rather than an increase in frequency. We suggest that this, together with previous studies showing that DNE is associated with a compensatory increase in inhibitory synaptic input to XIIMNs, leads to an excitatory-inhibitory imbalance. This imbalance may contribute to the blunting of airway protective reflexes observed in nicotine exposed animals and human infants.

Significance statement The number one risk factor for sudden infant death (SIDS) is maternal smoking. While the use of nicotine delivery devices such as e-cigarettes is increasing among women of childbearing age, reflecting the belief that the use of nicotine alone is safer than tobacco, SIDS deaths are not decreasing, suggesting that nicotine is the link between maternal smoking and SIDS. Here we show that perinatal nicotine exposure alters a major motor pathway responsible for upper airway patency during sleep. We also introduce an animal model that is well suited to probing the mechanisms underlying the link between maternal nicotine consumption and SIDS, and a phenotype that nicely models key aspects of the events believed to give rise to SIDS.

in RSS PAP on November 11, 2019 05:30 PM.

• #### Dynamic remodeling of a basolateral-to-central amygdala glutamatergic circuit across fear states

Nature Neuroscience, Published online: 11 November 2019; doi:10.1038/s41593-019-0528-7

Hartley et al. report the bidirectional remodeling of a basolateral amygdala-to-central amygdala neural circuit, where input onto corticotropin-releasing factor (CRF)-expressing and CRF-negative neurons is shaped by the acquisition and extinction of fear memory.

in Nature Neuroscience - Issue - nature.com science feeds on November 11, 2019 12:00 AM.

• #### Memory retrieval modulates spatial tuning of single neurons in the human entorhinal cortex

Nature Neuroscience, Published online: 11 November 2019; doi:10.1038/s41593-019-0523-z

Qasim et al. describe neurons in the human entorhinal cortex that activate near the locations in space that a person is cued to recall during a memory task. These results show one way in which the cognitive map shifts according to memory demands.

in Nature Neuroscience - Issue - nature.com science feeds on November 11, 2019 12:00 AM.

• #### An integrative framework for perceptual disturbances in psychosis

Nature Reviews Neuroscience, Published online: 11 November 2019; doi:10.1038/s41583-019-0234-1

Emerging data suggest a key role for dopamine in the perceptual disturbances that occur in psychotic disorders. In this Review, Horga and Abi-Dargham discuss a framework focused on perceptual inference, emphasizing the role of dopamine and the relevant associative cortico–striatal circuits.

in Nature Reviews Neuroscience - Issue - nature.com science feeds on November 11, 2019 12:00 AM.

• #### B cells in autoimmune and neurodegenerative central nervous system diseases

Nature Reviews Neuroscience, Published online: 11 November 2019; doi:10.1038/s41583-019-0233-2

In individuals with inflammation of the central nervous system, B cells enter and accumulate in the cerebrospinal fluid, brain parenchyma and perivascular spaces. Here, Joseph Sabatino and colleagues review the contributions of B cells — both in the periphery and sequestered within the central nervous system — to the pathogenesis of several autoimmune and neurodegenerative diseases.

in Nature Reviews Neuroscience - Issue - nature.com science feeds on November 11, 2019 12:00 AM.

• #### The generation of a protocadherin cell-surface recognition code for neural circuit assembly

Publication date: December 2019

Source: Current Opinion in Neurobiology, Volume 59

Author(s): Daniele Canzio, Tom Maniatis

The assembly of functional neural circuits in vertebrate organisms requires complex mechanisms of self-recognition and self-avoidance. Neurites (axons and dendrites) from the same neuron recognize and avoid self, but engage in synaptic interactions with other neurons. Vertebrate neural self-avoidance requires the expression of distinct repertoires of clustered Protocadherin (Pcdh) cell-surface protein isoforms, which act as cell-surface molecular barcodes that mediate highly specific homophilic self-recognition, followed by repulsion. The generation of sufficiently diverse cell-surface barcodes is achieved by the stochastic and combinatorial activation of a subset of clustered Pcdh promoters in individual neurons. This remarkable mechanism leads to the generation of enormous molecular diversity at the cell surface. Here we review recent studies showing that stochastic expression of individual Pcdhα isoforms is accomplished through an extraordinary mechanism involving the activation of ‘antisense strand’ promoter within Pcdhα ‘variable’ exons, antisense transcription of a long non-coding RNA through the upstream ‘sense strand’ promoter, demethylation of this promoter, binding of the CTCF/cohesin complex and DNA looping to a distant enhancer through a mechanism of chromatin ‘extrusion’.

in ScienceDirect Publication: Current Opinion in Neurobiology on November 09, 2019 07:00 PM.

• #### Tonic exploration governs both flexibility and lapses

by R. Becket Ebitz, Brianna J. Sleezer, Hank P. Jedema, Charles W. Bradberry, Benjamin Y. Hayden

In many cognitive tasks, lapses (spontaneous errors) are tacitly dismissed as the result of nuisance processes like sensorimotor noise, fatigue, or disengagement. However, some lapses could also be caused by exploratory noise: randomness in behavior that facilitates learning in changing environments. If so, then strategic processes would need only up-regulate (rather than generate) exploration to adapt to a changing environment. This view predicts that more frequent lapses should be associated with greater flexibility because these behaviors share a common cause. Here, we report that when rhesus macaques performed a set-shifting task, lapse rates were negatively correlated with perseverative error frequency across sessions, consistent with a common basis in exploration. The results could not be explained by local failures to learn. Furthermore, chronic exposure to cocaine, which is known to impair cognitive flexibility, did increase perseverative errors, but, surprisingly, also improved overall set-shifting task performance by reducing lapse rates. We reconcile these results with a state-switching model in which cocaine decreases exploration by deepening attractor basins corresponding to rule states. These results support the idea that exploratory noise contributes to lapses, affecting rule-based decision-making even when it has no strategic value, and suggest that one key mechanism for regulating exploration may be the depth of rule states.

in PLOS Computational Biology: New Articles on November 08, 2019 10:00 PM.

• #### Loss of Tiparp results in aberrant layering of the cerebral cortex

Abstract

TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an enzyme that adds a single ADP-ribose moiety to itself or other proteins. Tiparp is highly expressed in the brain; however, its function in this organ is unknown. Here we used Tiparp-/- mice to determine Tiparp’s role in the development of the prefrontal cortex. Loss of Tiparp resulted in an aberrant organization of the mouse cortex, where the upper layers presented increased cell density in the knockout mice compared with wildtype. Tiparp loss predominantly affected the correct distribution and number of GABAergic neurons. Furthermore, neural progenitor cell proliferation was significantly reduced. Neural stem cells derived from Tiparp-/- mice showed a slower rate of migration. Cytoskeletal components, such as α-tubulin are key regulators of neuronal differentiation and cortical development. α-tubulin mono-ADP-ribosylation levels were reduced in Tiparp-/- cells, suggesting the Tiparp plays a role in the mono-ADP-ribosylation of α-tubulin. Despite the mild phenotype presented by Tiparp-/- mice, our findings reveal an important function for Tiparp and mono-ADP-ribosylation in the correct development of the cortex. Unravelling Tiparp’s role in the cortex, could pave the way to a better understanding of a wide spectrum of neurological diseases which are known to have increased expression of the TIPARP gene.

Significance Statement TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an enzyme which adds a single ADP-ribose moiety to itself or other proteins and is highly expressed in the brain. However, its function in this organ remains unknown. Here we show that Tiparp affects neural progenitor cell proliferation and migration, and its loss leads to aberrant organization of the mouse cortex, predominantly by disrupting the correct distribution and number of GABAergic neurons. Cytoskeletal components, such as α-tubulin, are key regulators of neuronal differentiation and cortical development, here we show that Tiparp is part of a complex that interacts with α-tubulin and plays a role in its mono-ADP-ribosylation. Despite the mild phenotype presented by the Tiparp knockout mouse our findings reveal an important function of mono-ADP-ribosylation by this enzyme in the correct development of the cortex.

in RSS PAP on November 08, 2019 05:30 PM.

• #### Can Grid Cell Ensembles Represent Multiple Spaces?

Neural Computation, Volume 31, Issue 12, Page 2324-2347, December 2019.

• #### Replicating Neuroscience Observations on ML/MF and AM Face Patches by Deep Generative Model

Neural Computation, Volume 31, Issue 12, Page 2348-2367, December 2019.

• #### On the Effect of the Activation Function on the Distribution of Hidden Nodes in a Deep Network

Neural Computation, Volume 31, Issue 12, Page 2562-2580, December 2019.

• #### Every Local Minimum Value Is the Global Minimum Value of Induced Model in Nonconvex Machine Learning

Neural Computation, Volume 31, Issue 12, Page 2293-2323, December 2019.

• #### Spike-Based Winner-Take-All Computation: Fundamental Limits and Order-Optimal Circuits

Neural Computation, Volume 31, Issue 12, Page 2523-2561, December 2019.

• #### The Effect of Signaling Latencies and Node Refractory States on the Dynamics of Networks

Neural Computation, Volume 31, Issue 12, Page 2492-2522, December 2019.

• #### Safe Triplet Screening for Distance Metric Learning

Neural Computation, Volume 31, Issue 12, Page 2432-2491, December 2019.

• #### Bayesian Filtering with Multiple Internal Models: Toward a Theory of Social Intelligence

Neural Computation, Volume 31, Issue 12, Page 2390-2431, December 2019.

• #### Reinforcement Learning in Spiking Neural Networks with Stochastic and Deterministic Synapses

Neural Computation, Volume 31, Issue 12, Page 2368-2389, December 2019.

• #### Optical voltage imaging in neurons: moving from technology development to practical tool

Nature Reviews Neuroscience, Published online: 08 November 2019; doi:10.1038/s41583-019-0231-4

Genetically encoded voltage indicators (GEVIs) are emerging tools to elucidate the inner workings of the brain. In this Review, Knopfel and Song outline the potentials of GEVI imaging based on recent neurotechnological and conceptual advances in the brain sciences.

in Nature Reviews Neuroscience - Issue - nature.com science feeds on November 08, 2019 12:00 AM.

• #### Short-Term Attractive Tilt Aftereffects Predicted by a Recurrent Network Model of Primary Visual Cortex

Adaptation is a multi-faceted phenomenon that is of interest in terms of both its function and its potential to reveal underlying neural processing. Many behavioral studies have shown that after exposure to an oriented adapter the perceived orientation of a subsequent test is repulsed away from the orientation of the adapter. This is the well-known Tilt Aftereffect (TAE). Recently, we showed that the dynamics of recurrently connected networks may contribute substantially to the neural changes induced by adaptation, especially on short time scales. Here we extended the network model and made the novel behavioral prediction that the TAE should be attractive, not repulsive, on a time scale of a few 100 ms. Our experiments, using a novel adaptation protocol that specifically targeted adaptation on a short time scale, confirmed this prediction. These results support our hypothesis that recurrent network dynamics may contribute to short-term adaptation. More broadly, they show that understanding the neural processing of visual inputs that change on the time scale of a typical fixation requires a detailed analysis of not only the intrinsic properties of neurons, but also the slow and complex dynamics that emerge from their recurrent connectivity. We argue that this is but one example of how even simple recurrent networks can underlie surprisingly complex information processing, and are involved in rudimentary forms of memory, spatio-temporal integration, and signal amplification.

in Frontiers in Systems Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Modeling the Ongoing Dynamics of Short and Long-Range Temporal Correlations in Broadband EEG During Movement

Electroencephalogram (EEG) undergoes complex temporal and spectral changes during voluntary movement intention. Characterization of such changes has focused mostly on narrowband spectral processes such as Event-Related Desynchronization (ERD) in the sensorimotor rhythms because EEG is mostly considered as emerging from oscillations of the neuronal populations. However, the changes in the temporal dynamics, especially in the broadband arrhythmic EEG have not been investigated for movement intention detection. The Long-Range Temporal Correlations (LRTC) are ubiquitously present in several neuronal processes, typically requiring longer timescales to detect. In this paper, we study the ongoing changes in the dynamics of long- as well as short-range temporal dependencies in the single trial broadband EEG during movement intention. We obtained LRTC in 2 s windows of broadband EEG and modeled it using the Autoregressive Fractionally Integrated Moving Average (ARFIMA) model which allowed simultaneous modeling of short- and long-range temporal correlations. There were significant (p < 0.05) changes in both broadband long- and short-range temporal correlations during movement intention and execution. We discovered that the broadband LRTC and narrowband ERD are complementary processes providing distinct information about movement because eliminating LRTC from the signal did not affect the ERD and conversely, eliminating ERD from the signal did not affect LRTC. Exploring the possibility of applications in Brain Computer Interfaces (BCI), we used hybrid features with combinations of LRTC, ARFIMA, and ERD to detect movement intention. A significantly higher (p < 0.05) classification accuracy of 88.3 ± 4.2% was obtained using the combination of ARFIMA and ERD features together, which also predicted the earliest movement at 1 s before its onset. The ongoing changes in the long- and short-range temporal correlations in broadband EEG contribute to effectively capturing the motor command generation and can be used to detect movement successfully. These temporal dependencies provide different and additional information about the movement.

in Frontiers in Systems Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Differential Properties of the Synaptogenic Activities of the Neurexin Ligands Neuroligin1 and LRRTM2

Synaptic cell adhesion molecules are well established to exhibit synaptogenic activity when overexpressed in target cells, indicating that they are involved in formation and functional maturation of synapses. The postsynaptic adhesion proteins Neuroligin1 and LRRTM2 both induce synaptic vesicle clusters in presynaptic axons in vitro by transsynaptically interacting with neurexins. In neurons, this is accompanied by the induction of glutamatergic, but not GABAergic synapses. Although the synaptogenic activity of Neuroligin1 has been well characterized, the properties of the synaptogenic activities of other synaptic adhesion molecules are largely unknown. In this paper, we now compared characteristics of the synaptogenic activities of Neuroligin1 and LRRTM2 upon overexpression in cultured mouse cortical neurons. Individual cortical neurons were transfected with Neuroligin1 and LRRTM2 expression plasmids, respectively, and synaptic vesicle clustering in contacting axons was examined by immunostaining for the vesicle membrane protein VAMP2. In immature neurons at 6–7 days in vitro (DIV) both Neuroligin1 and LRRTM2 exhibited strong synaptogenic activity. However, upon further neuronal differentiation only LRRTM2 retained significant synaptogenic activity at 12–13 DIV. A similar differential developmental maturation of the synaptogenic activities of Neuroligin1 and LRRTM2 was observed for the induction of glutamatergic synapses, which were detected by co-immunostaining for VGLUT1 and Homer1. Most interestingly, the synaptogenic activity of Neuroligin1 was strongly dependent on the expression and function of the synaptic adhesion molecule N-cadherin in immature neurons. In contrast, the synaptogenic activity of LRRTM2 was independent of N-cadherin expression and function in both immature (6–7 DIV) and more mature neurons (14–15 DIV). Taken together, our results with overexpression in cultured cortical neurons revealed striking differences in the properties of the synaptogenic activities of Neuroligin1 and LRRTM2, although both transsynaptically interact with presynaptic neurexins.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Different Amyloid-β Self-Assemblies Have Distinct Effects on Intracellular Tau Aggregation

Alzheimer’s disease (AD) pathology is characterized by the aggregation of beta-amyloid (Aβ) and tau in the form of amyloid plaques and neurofibrillary tangles in the brain. It has been found that a synergistic relationship between these two proteins may contribute to their roles in disease progression. However, how Aβ and tau interact has not been fully characterized. Here, we analyze how tau seeding or aggregation is influenced by different Aβ self-assemblies (fibrils and oligomers). Our cellular assays utilizing tau biosensor cells show that transduction of Aβ oligomers into the cells greatly enhances seeded tau aggregation in a concentration-dependent manner. In contrast, transduced Aβ fibrils slightly reduce tau seeding while untransduced Aβ fibrils promote it. We also observe that the transduction of α-synuclein fibrils, another amyloid protein, has no effect on tau seeding. The enhancement of tau seeding by Aβ oligomers was confirmed using tau fibril seeds derived from both recombinant tau and PS19 mouse brain extracts containing human tau. Our findings highlight the importance of considering the specific form and cellular location of Aβ self-assembly when studying the relationship between Aβ and tau in future AD therapeutic development.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### The Calmodulin Binding Region of the Synaptic Vesicle Protein Mover Is Required for Homomeric Interaction and Presynaptic Targeting

Neurotransmitter release is mediated by an evolutionarily conserved machinery. The synaptic vesicle (SV) associated protein Mover/TPRGL/SVAP30 does not occur in all species and all synapses. Little is known about its molecular properties and how it may interact with the conserved components of the presynaptic machinery. Here, we show by deletion analysis that regions required for homomeric interaction of Mover are distributed across the entire molecule, including N-terminal, central and C-terminal regions. The same regions are also required for the accumulation of Mover in presynaptic terminals of cultured neurons. Mutating two phosphorylation sites in N-terminal regions did not affect these properties. In contrast, a point mutation in the predicted Calmodulin (CaM) binding sequence of Mover abolished both homomeric interaction and presynaptic targeting. We show that this sequence indeed binds Calmodulin, and that recombinant Mover increases Calmodulin signaling upon heterologous expression. Our data suggest that presynaptic accumulation of Mover requires homomeric interaction mediated by regions distributed across large areas of the protein, and corroborate the hypothesis that Mover functionally interacts with Calmodulin signaling.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Performance Evaluation of Visual Noise Imposed Stochastic Resonance Effect on Brain-Computer Interface Application: A Comparison Between Motion-Reversing Simple Ring and Complex Checkerboard Patterns

Adding noise to a weak input signal can enhance the response of a non-linear system, a phenomenon known as stochastic resonance (SR). SR has been demonstrated in a variety of diverse sensory systems including the visual system, where visual noise enhances human motion perception and detection performance. The SR effect has not been extensively studied in brain-computer interface (BCI) applications. This study compares the performance of BCIs based on SR-influenced steady-state motion visual evoked potentials. Stimulation paradigms were used between a periodically monochromatic motion-reversing simple ring and complex alternating checkerboard stimuli. To induce the SR effect, dynamic visual noise was masked on both the periodic simple and complex stimuli. Offline results showed that the recognition accuracy of different stimulation targets followed an inverted U-shaped function of noise level, which is a hallmark of SR. With the optimal visual noise level, the proposed visual noise masked checkerboard BCI paradigm achieved faster and more stable detection performance due to the noise-enhanced brain responses. This work demonstrates that the SR effect can be employed in BCI applications and can achieve considerable performance improvements.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Spastin MIT Domain Disease-Associated Mutations Disrupt Lysosomal Function

The hereditary spastic paraplegias (HSPs) are genetic motor neuron diseases characterized by progressive degeneration of corticospinal tract axons. Mutations in SPAST, encoding the microtubule-severing ATPase spastin, are the most common causes of HSP. The broad SPAST mutational spectrum indicates a haploinsufficiency pathogenic mechanism in most cases. Most missense mutations cluster in the ATPase domain, where they disrupt the protein's ability to sever microtubules. However, several putative missense mutations in the protein's microtubule interacting and trafficking (MIT) domain have also been described, but the pathogenicity of these mutations has not been verified with functional studies. Spastin promotes endosomal tubule fission, and defects in this lead to lysosomal enzyme mistrafficking and downstream lysosomal abnormalities. We investigated the function of three disease-associated spastin MIT mutants and found that none was able to promote normal endosomal tubule fission, lysosomal enzyme receptor trafficking, or lysosomal morphology. One of the mutations affected recruitment of spastin to endosomes, a property that requires the canonical function of the MIT domain in binding endosomal sorting complex required for transport (ESCRT)-III proteins. However, the other mutants did not affect spastin's endosomal recruitment, raising the possibility of pathologically important non-canonical roles for the MIT domain. In conclusion, we demonstrate that spastin MIT mutants cause functional abnormalities related to the pathogenesis of HSP. These mutations do not directly affect spastin's microtubule-severing capacity, and so we identify a new molecular pathological mechanism by which spastin mutations may cause disease.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

Diabetic retinopathy (DR) is a common complication of diabetes and constitutes a major cause of vision impairment and blindness in the world. DR has long been described exclusively as a microvascular disease of the eye. However, in recent years, a growing interest has been focused on the contribution of neuroretinal degeneration to the pathogenesis of the disease, and there are observations suggesting that neuronal death in the early phases of DR may favor the development of microvascular abnormalities, followed by the full manifestation of the disease. However, the mediators that are involved in the crosslink between neurodegeneration and vascular changes have not yet been identified. According to our hypothesis, vascular endothelial growth factor (VEGF) could probably be the most important connecting link between the death of retinal neurons and the occurrence of microvascular lesions. Indeed, VEGF is known to play important neuroprotective actions; therefore, in the early phases of DR, it may be released in response to neuronal suffering, and it would act as a double-edged weapon inducing both neuroprotective and vasoactive effects. If this hypothesis is correct, then any retinal stress causing neuronal damage should be accompanied by VEGF upregulation and by vascular changes. Similarly, any compound with neuroprotective properties should also induce VEGF downregulation and amelioration of the vascular lesions. In this review, we searched for a correlation between neurodegeneration and vasculopathy in animal models of retinal diseases, examining the effects of different neuroprotective substances, ranging from nutraceuticals to antioxidants to neuropeptides and others and showing that reducing neuronal suffering also prevents overexpression of VEGF and vascular complications. Taken together, the reviewed evidence highlights the crucial role played by mediators such as VEGF in the relationship between retinal neuronal damage and vascular alterations and suggests that the use of neuroprotective substances could be an efficient strategy to prevent the onset or to retard the development of DR.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Editorial: Mitochondria and Endoplasmic Reticulum Dysfunction in Parkinson’s Disease

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Visuospatial Attention and Saccadic Inhibitory Control in Children With Cerebral Palsy

in Frontiers in Human Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Dual-Task Interference on Early and Late Stages of Facial Emotion Detection Is Revealed by Human Electrophysiology

Rapid and accurate processing of potential social threats is paramount to social thriving, and provides a clear evolutionary advantage. Though automatic processing of facial expressions has been assumed for some time, some researchers now question the extent to which this is the case. Here, we provide electrophysiological data from a psychological refractory period (PRP) dual-task paradigm in which participants had to decide whether a target face exhibited a neutral or fearful expression, as overlap with a concurrent auditory tone categorization task was experimentally manipulated. Specifically, we focused on four event-related potentials (ERP) linked to emotional face processing, covering distinct processing stages and topography: the early posterior negativity (EPN), early frontal positivity (EFP), late positive potential (LPP), and also the face-sensitive N170. As expected, there was an emotion modulation of each ERP. Most importantly, there was a significant attenuation of this emotional response proportional to the degree of task overlap for each component, except the N170. In fact, when the central overlap was greatest, this emotion-specific amplitude was statistically null for the EFP and LPP, and only marginally different from zero for the EPN. N170 emotion modulation was, on the other hand, unaffected by central overlap. Thus, our results show that emotion-specific ERPs for three out of four processing stages—i.e., perceptual encoding (EPN), emotion detection (EFP), or content evaluation (LPP)—are attenuated and even eliminated by central resource scarcity. Models assuming automatic processing should be revised to account for these results.

in Frontiers in Human Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### The Dynamics of Attention Shifts Among Concurrent Speech in a Naturalistic Multi-speaker Virtual Environment

Focusing attention on one speaker on the background of other irrelevant speech can be a challenging feat. A longstanding question in attention research is whether and how frequently individuals shift their attention towards task-irrelevant speech, arguably leading to occasional detection of words in a so-called unattended message. However, this has been difficult to gauge empirically, particularly when participants attend to continuous natural speech, due to the lack of appropriate metrics for detecting shifts in internal attention. Here we introduce a new experimental platform for studying the dynamic deployment of attention among concurrent speakers, utilizing a unique combination of Virtual Reality (VR) and Eye-Tracking technology. We created a Virtual Café in which participants sit across from and attend to the narrative of a target speaker. We manipulated the number and location of distractor speakers by placing additional characters throughout the Virtual Café. By monitoring participant’s eye-gaze dynamics, we studied the patterns of overt attention-shifts among concurrent speakers as well as the consequences of these shifts on speech comprehension. Our results reveal important individual differences in the gaze-pattern displayed during selective attention to speech. While some participants stayed fixated on a target speaker throughout the entire experiment, approximately 30% of participants frequently shifted their gaze toward distractor speakers or other locations in the environment, regardless of the severity of audiovisual distraction. Critically, preforming frequent gaze-shifts negatively impacted the comprehension of target speech, and participants made more mistakes when looking away from the target speaker. We also found that gaze-shifts occurred primarily during gaps in the acoustic input, suggesting that momentary reductions in acoustic masking prompt attention-shifts between competing speakers, in line with “glimpsing” theories of processing speech in noise. These results open a new window into understanding the dynamics of attention as they wax and wane over time, and the different listening patterns employed for dealing with the influx of sensory input in multisensory environments. Moreover, the novel approach developed here for tracking the locus of momentary attention in a naturalistic virtual-reality environment holds high promise for extending the study of human behavior and cognition and bridging the gap between the laboratory and real-life.

in Frontiers in Human Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Robustness of Radiomics for Survival Prediction of Brain Tumor Patients Depending on Resection Status

Prediction of overall survival based on multimodal MRI of brain tumor patients is a difficult problem. Although survival also depends on factors that cannot be assessed via preoperative MRI such as surgical outcome, encouraging results for MRI-based survival analysis have been published for different datasets. We assess if and how established radiomic approaches as well as novel methods can predict overall survival of brain tumor patients on the BraTS challenge dataset. This dataset consists of multimodal preoperative images of 211 glioblastoma patients from several institutions with reported resection status and known survival. In the official challenge setting, only patients with a reported gross total resection (GTR) are taken into account. We therefore evaluated previously published methods as well as different machine learning approaches on the BraTS dataset. For different types of resection status, these approaches are compared to a baseline, a linear regression on patient age only. This naive approach won the 3rd place out of 26 participants in the BraTS survival prediction challenge 2018. Previously published radiomic signatures show significant correlations and predictiveness to patient survival for patients with a reported subtotal resection. However, for patients with reported GTR, none of the evaluated approaches was able to outperform the age-only baseline in a cross-validation setting, explaining the poor performance of approaches based on radiomics in the BraTS challenge 2018.

in Frontiers in Computational Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Intraspinal Plasticity Associated With the Development of Autonomic Dysreflexia After Complete Spinal Cord Injury

Traumatic spinal cord injury (SCI) leads to disruption of sensory, motor and autonomic function, and triggers structural, physiological and biochemical changes that cause reorganization of existing circuits that affect functional recovery. Propriospinal neurons (PN) appear to be very plastic within the inhibitory microenvironment of the injured spinal cord by forming compensatory circuits that aid in relaying information across the lesion site and, thus, are being investigated for their potential to promote locomotor recovery after experimental SCI. Yet the role of PN plasticity in autonomic dysfunction is not well characterized, notably, the disruption of supraspinal modulatory signals to spinal sympathetic neurons after SCI at the sixth thoracic spinal segment or above resulting in autonomic dysreflexia (AD). This condition is characterized by unmodulated sympathetic reflexes triggering sporadic hypertension associated with baroreflex mediated bradycardia in response to noxious yet unperceived stimuli below the injury to reduce blood pressure. AD is frequently triggered by pelvic visceral distension (bowel and bladder), and there are documented structural relationships between injury-induced sprouting of pelvic visceral afferent C-fibers. Their excitation of lumbosacral PN, in turn, sprout and relay noxious visceral sensory stimuli to rostral disinhibited thoracic sympathetic preganglionic neurons (SPN) that manifest hypertension. Herein, we review evidence for maladaptive plasticity of PN in neural circuits mediating heightened sympathetic reflexes after complete high thoracic SCI that manifest cardiovascular dysfunction, as well as contemporary research methodologies being employed to unveil the precise contribution of PN plasticity to the pathophysiology underlying AD development.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Commentary: The Role of the Anion in Salt (NaCl) Detection by Mouse Taste Buds

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Coincident Activation of Glutamate Receptors Enhances GABAA Receptor-Induced Ionic Plasticity of the Intracellular Cl−-Concentration in Dissociated Neuronal Cultures

Massive activation of γ-amino butyric acid A (GABAA) receptors during pathophysiological activity induces an increase in the intracellular Cl-concentration ([Cl]i), which is sufficient to render GABAergic responses excitatory. However, to what extent physiological levels of GABAergic activity can influence [Cl]i is not known. Aim of the present study is to reveal whether moderate activation of GABAA receptors mediates functionally relevant [Cl]i changes and whether these changes can be augmented by coincident glutamatergic activity. To address these questions, we used whole-cell patch-clamp recordings from cultured cortical neurons [at days in vitro (DIV) 6–22] to determine changes in the GABA reversal potential (EGABA) induced by short bursts of GABAergic and/or synchronized glutamatergic stimulation. These experiments revealed that pressure-application of 10 short muscimol pulses at 10 Hz induced voltage-dependent [Cl]i changes. Under current-clamp conditions this muscimol burst induced a [Cl]i increase of 3.1 ± 0.4 mM (n = 27), which was significantly enhanced to 4.6 ± 0.5 mM (n = 27) when glutamate was applied synchronously with the muscimol pulses. The muscimol-induced [Cl]i increase significantly attenuated the inhibitory effect of GABA, as determined by the GABAergic rheobase shift. The synchronous coapplication of glutamate pulses had no additional effect on the attenuation of GABAergic inhibition, despite the larger [Cl]i transients under these conditions. In summary, these results indicate that moderate GABAergic activity can induce functionally relevant [Cl]i transients, which were enhanced by coincident glutamate pulses. This ionic plasticity of [Cl]i may contribute to short-term plasticity of the GABAergic system.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### P2Y6 and P2X7 Receptor Antagonism Exerts Neuroprotective/ Neuroregenerative Effects in an Animal Model of Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by decreased dopamine bioavailability in the substantia nigra and the striatum. Taking into account that adenosine-5’-triphosphate (ATP) and its metabolites are intensely released in the 6-hydroxydopamine (6-OHDA) animal model of PD, screening of purinergic receptor gene expression was performed. Effects of pharmacological P2Y6 or P2X7 receptor antagonism were studied in preventing or reversing hemiparkinsonian behavior and dopaminergic deficits in this animal model. P2X7 receptor antagonism with Brilliant Blue G (BBG) at a dose of 75 mg/kg re-established the dopaminergic nigrostriatal pathway in rats injured with 6-OHDA. Selective P2Y6 receptor antagonism by MRS2578 prevented dopaminergic neuron death in SH-SY5Y cells in vitro and in vivo in the substantia nigra of rats injured with 6-OHDA. Moreover, in vivo analysis showed that both treatments were accompanied by a reduction of microglial activation in the substantia nigra. Altogether, these data provide evidence that antagonism of P2X7 or P2Y6 receptors results in neuroregenerative or neuroprotective effects, respectively, possibly through modulation of neuroinflammatory responses.

in Frontiers in Cellular Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Association Between Atrial Fibrillation and Dementia: A Meta-Analysis

Background: A potential evidence from previous epidemiological studies remains conflicting findings regarding the association between atrial fibrillation (AF) and dementia risk. We, therefore, carried out a meta-analysis of relevant studies to investigate the magnitude of the association between AF and dementia risk.

Methods: We performed a systematic literature search of PubMed, EMBASE, and Google Scholar for potential studies between January 1, 1990, and December 31, 2018, with no restriction on the publication language. All potential studies were independently assessed by two reviewers. We only included observational studies that calculated the odds ratio (OR)/hazards ratio (HR) for dementia associated with atrial fibrillation. We first assessed the heterogeneity among study-specific HRs using the Q statistic and I2 statistic. We then used the random-effects model to obtain the overall HR and its 95% CI for all studies. We also tested and corrected for publication bias by funnel plot–based methods. The quality of each study was assessed with the Newcastle Ottawa Scale.

Results: A total of 16 studies with 2,415,356 individuals, and approximately 200,653 cases of incidence dementia were included in this study. Patients with AF had a greater risk of incidence dementia than those without AF (random-effect hazard ratio HR: 1.36, 95% CI: 1.23–1.51, p < 0.0001; I2 = 83.58). Funnel plot and Egger test did not reveal significant publication bias. However, limitations of the study included high heterogeneity and varying degrees of confounder adjustment across individual studies.

Conclusion: This study serves as added evidence supporting the hypothesis that AF is associated with an increased risk of dementia. More studies are needed to establish whether optimal treatment of AF can reduce or mitigate the risk of dementia.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Parkinson’s Disease–Mild Cognitive Impairment (PD-MCI): A Useful Summary of Update Knowledge

Mild cognitive impairment (MCI) is a common feature in Parkinson’s Disease (PD), even at the time of diagnosis. Some levels of heterogeneity in nature and severity of cognitive impairment and risk of conversion to Parkinson’s Disease Dementia (PDD) exist. This brief overview summarized the current understanding of MCI in PD, by considering the following major points: historical development of the clinical entity, evaluation, epidemiology, predictors and outcomes, neuroimaging findings, pathophysiology, treatment, and pharmacological and non-pharmacological intervention. MCI in PD represents a concept in evolution and plays a pivotal role in advancing our understanding of the disease mechanisms, with the ultimate goal of building effective strategies to prevent conversion into PDD. Challenges for future research are also discussed.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Diabetes, a Contemporary Risk for Parkinson’s Disease: Epidemiological and Cellular Evidences

Diabetes mellitus (DM), a group of diseases characterized by defective glucose metabolism, is the most widespread metabolic disorder affecting over 400 million adults worldwide. This pathological condition has been implicated in the pathogenesis of a number of central encephalopathies and peripheral neuropathies. In further support of this notion, recent epidemiological evidence suggests a link between DM and Parkinson’s disease (PD), with hyperglycemia emerging as one of the culprits in neurodegeneration involving the nigrostriatal pathway, the neuroanatomical substrate of the motor symptoms affecting parkinsonian patients. Indeed, dopaminergic neurons located in the mesencephalic substantia nigra appear to be particularly vulnerable to oxidative stress and degeneration, likely because of their intrinsic susceptibility to mitochondrial dysfunction, which may represent a direct consequence of hyperglycemia and hyperglycemia-induced oxidative stress. Other pathological pathways induced by increased intracellular glucose levels, including the polyol and the hexosamine pathway as well as the formation of advanced glycation end-products, may all play a pivotal role in mediating the detrimental effects of hyperglycemia on nigral dopaminergic neurons. In this review article, we will examine the epidemiological as well as the molecular and cellular clues supporting the potential susceptibility of nigrostriatal dopaminergic neurons to hyperglycemia.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Aging Impairs Cerebrovascular Reactivity at Preserved Resting Cerebral Arteriolar Tone and Vascular Density in the Laboratory Rat

The age-related (mal)adaptive modifications of the cerebral microvascular system have been implicated in cognitive impairment and worse outcomes after ischemic stroke. The magnitude of the hyperemic response to spreading depolarization (SD), a recognized principle of ischemic lesion development has also been found to be reduced by aging. Here, we set out to investigate whether the SD-coupled reactivity of the pial arterioles is subject to aging, and whether concomitant vascular rarefaction may contribute to the age-related insufficiency of the cerebral blood flow (CBF) response. CBF was assessed with laser-speckle contrast analysis (LASCA), and the tone adjustment of pial arterioles was followed with intrinsic optical signal (IOS) imaging at green light illumination through a closed cranial window created over the parietal cortex of isoflurane-anesthetized young (2 months old) and old (18 months old) male Sprague–Dawley rats. Global forebrain ischemia and later reperfusion were induced by the bilateral occlusion and later release of both common carotid arteries. SDs were elicited repeatedly with topical 1M KCl. Pial vascular density was measured in green IOS images of the brain surface, while the density and resting diameter of the cortical penetrating vasculature was estimated with micro-computed tomography of paraformaldehyde-fixed cortical samples. Whilst pial arteriolar dilation in response to SD or ischemia induction were found reduced in the old rat brain, the density and resting diameter of pial cortical vessels, and the degree of SD-related oligemia emerged as variables unaffected by age in our experiments. Spatial flow distribution analysis identified an age-related shift to a greater representation of higher flow ranges in the reperfused cortex. According to our data, impairment of functional arteriolar dilation, at preserved vascular density and resting vascular tone, may be implicated in the age-related deficit of the CBF response to SD, and possibly in the reduced efficacy of neurovascular coupling in the aging brain. SD has been recognized as a potent pathophysiological contributor to ischemic lesion expansion, in part because of the insufficiency of the associated CBF response. Therefore, the age-related impairment of cerebral vasoreactivity as shown here is suggested to contribute to the age-related acceleration of ischemic lesion development.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### Corrigendum: Age-Dependent Relationship Between Plasma Aβ40 and Aβ42 and Total Tau Levels in Cognitively Normal Subjects

in Frontiers in Aging Neuroscience | New and Recent Articles on November 08, 2019 12:00 AM.

• #### "Females Are Not Just 'Protected Males": Sex-Specific Vulnerabilities in Placenta and Brain after Prenatal Immune Disruption

Abstract

Current perceptions of genetic and environmental vulnerabilities in the developing fetus are biased toward male outcomes. An argument is made that males are more vulnerable to gestational complications and neurodevelopmental disorders, the implication being that an understanding of disrupted development in males is sufficient to understand causal mechanisms that are assumed to be similar but attenuated in females. Here we examine this assumption in the context of immune-driven alterations in fetal brain development and related outcomes in female and male mice. Pregnant C57BL/6 mice were treated with low-dose lipopolysaccharide at embryonic day 12.5. Placental pathology, acute fetal brain inflammation and hypoxia, long-term changes in adult cortex cytoarchitecture, altered densities and ratio of excitatory (Satb2+) to inhibitory (parvalbumin+) neuronal subtypes, postnatal growth, and behavior outcomes were compared between male and female offspring. We find that while males experience more pronounced placental pathology, fetal brain hypoxia, depleted PV and Satb2+ densities, and social and learning-related behavioral abnormalities, females exhibit unique acute inflammatory signaling in fetal brain, postnatal growth delay, opposite alterations in cortical PV densities, changes in juvenile behavior, delayed postnatal body growth, and elevated anxiety-related behavior as adults. While males are more severely impacted by prenatal immune disruption by several measures, females exposed to the same insult exhibit a unique set of vulnerabilities and developmental consequences that is not present in males. Our results clearly outline disparate sex-specific features of prenatal vulnerability to inflammatory insults and warn against the casual extrapolation of male disease mechanisms to females.

in eNeuro current issue on November 07, 2019 05:30 PM.

• #### Cognitive Flexibility Improves Memory for Delayed Intentions

Abstract

The ability to delay the execution of a goal until the appropriate time, prospective memory (PM), can be supported by the following two different cognitive control strategies: proactive control involving working memory maintenance of the goal and active monitoring of the environment; or reactive control relying on timely retrieval of goal information from episodic memory. Certain situations tend to favor each strategy, but the manner in which individuals adjust their strategy in response to changes in the environment is unknown. Across two experiments, human participants performed a delayed-recognition PM task embedded in an ongoing visual search task that fluctuated in difficulty. A control strategy was identified from moment to moment using reaction time costs and fMRI measures of goal maintenance. We found that people fluidly modified control strategies in accordance with changes in task demands (e.g., shifting toward proactive control when task difficulty decreased). This cognitive flexibility proved adaptive as it was associated with improved PM performance.

in eNeuro current issue on November 07, 2019 05:30 PM.

• #### Optogenetically-Induced Population Discharge Threshold as a Sensitive Measure of Network Excitability

Abstract

Network excitability is governed by synaptic efficacy, intrinsic excitability, and the circuitry in which these factors are expressed. The complex interplay between these factors determines how circuits function and, at the extreme, their susceptibility to seizure. We have developed a sensitive, quantitative estimate of network excitability in freely behaving mice using a novel optogenetic intensity-response procedure. Synchronous activation of deep sublayer CA1 pyramidal cells produces abnormal network-wide epileptiform population discharges (PDs) that are nearly indistinguishable from spontaneously-occurring interictal spikes (IISs). By systematically varying light intensity, and therefore the magnitude of the optogenetically-mediated current, we generated intensity-response curves using the probability of PD as the dependent variable. Manipulations known to increase excitability, such as sub-convulsive doses (20 mg/kg) of the chemoconvulsant pentylenetetrazol (PTZ), produced a leftward shift in the curve compared to baseline. The anti-epileptic drug levetiracetam (LEV; 40 mk/kg), in combination with PTZ, produced a rightward shift. Optogenetically-induced PD threshold (oPDT) baselines were stable over time, suggesting the metric is appropriate for within-subject experimental designs with multiple pharmacological manipulations.

in eNeuro current issue on November 07, 2019 05:30 PM.

• #### Excitation of Diverse Classes of Cholecystokinin Interneurons in the Basal Amygdala Facilitates Fear Extinction

Abstract

There is growing evidence that interneurons (INs) orchestrate neural activity and plasticity in corticoamygdala circuits to regulate fear behaviors. However, defining the precise role of cholecystokinin-expressing INs (CCK INs) remains elusive due to the technical challenge of parsing this population from CCK-expressing principal neurons (CCK PNs). Here, we used an intersectional genetic strategy in CCK-Cre;Dlx5/6-Flpe double-transgenic mice to study the anatomical, molecular and electrophysiological properties of CCK INs in the basal amygdala (BA) and optogenetically manipulate these cells during fear extinction. Electrophysiological recordings confirmed that this strategy targeted GABAergic cells and that a significant proportion expressed functional cannabinoid CB1 receptors; a defining characteristic of CCK-expressing basket cells. However, immunostaining showed that subsets of the genetically-targeted cells expressed either neuropeptide Y (NPY; 29%) or parvalbumin (PV; 17%), but not somatostatin (SOM) or Ca2+/calmodulin-dependent protein kinase II (CaMKII)-α. Further morphological and electrophysiological analyses showed that four IN types could be identified among the EYFP-expressing cells: CCK/cannabinoid receptor type 1 (CB1R)-expressing basket cells, neurogliaform cells, PV+ basket cells, and PV+ axo-axonic cells. At the behavioral level, in vivo optogenetic photostimulation of the targeted population during extinction acquisition led to reduced freezing on a light-free extinction retrieval test, indicating extinction memory facilitation; whereas photosilencing was without effect. Conversely, non-selective (i.e., inclusive of INs and PNs) photostimulation or photosilencing of CCK-targeted cells, using CCK-Cre single-transgenic mice, impaired extinction. These data reveal an unexpectedly high degree of phenotypic complexity in a unique population of extinction-modulating BA INs.

in eNeuro current issue on November 07, 2019 05:30 PM.

• #### Reward devaluation attenuates cue-evoked sucrose seeking and is associated with the elimination of excitability differences between ensemble and non-ensemble neurons in the nucleus accumbens

Abstract

Animals must learn relationships between foods and the environmental cues that predict their availability for survival. Such cue-food associations are encoded in sparse sets of neurons or ‘neuronal ensembles’ in the nucleus accumbens (NAc). For these ensemble-encoded, cue-controlled appetitive responses to remain adaptive, they must allow for their dynamic updating depending on acute changes in internal states such as physiological hunger or the perceived desirability of food. However, how these neuronal ensembles are recruited and physiologically modified following the update of such learned associations is unclear. To investigate this, we examined the effects of devaluation on ensemble plasticity at the levels of recruitment, intrinsic excitability, and synaptic physiology in sucrose conditioned Fos-GFP mice that express green fluorescent protein (GFP) in recently activated neurons. Neuronal ensemble activation patterns and their physiology were examined using immunohistochemistry and slice electrophysiology, respectively. Reward-specific devaluation following four days of ad lib sucrose consumption, but not general caloric devaluation, attenuated cue-evoked sucrose seeking. This suggests that changes in the hedonic and/or incentive value of sucrose, and not caloric need drove this behavior. Moreover, devaluation attenuated the size of the neuronal ensemble recruited by the cue in the NAc shell. Finally, it eliminated the relative enhanced excitability of ensemble (GFP+) neurons against non-ensemble (GFP–) neurons observed under Non-devalued conditions, and did not induce any ensemble-specific changes in excitatory synaptic physiology. Our findings provide new insights into neuronal ensemble mechanisms that underlie the changes in the incentive and/or hedonic impact of cues that support adaptive food seeking.

Significance statement Learned associations between food and the cues that predict their availability are encoded in neuronal ensembles in reward-relevant brain areas, such as the nucleus accumbens. Such learning is often accompanied by synaptic and intrinsic plasticity within these ensemble neurons. However, it is unclear how these plasticity changes manifest specifically in cue-activated neurons in response to decreases in reward value, e.g. following reward-specific or general (caloric) devaluation. We reveal that shifts in excitability, but not excitatory synaptic physiology between ensemble and non-ensemble neurons in the nucleus accumbens shell coincide with reward-specific devaluation. Our findings provide new insights into how changes in the perceived properties of food reward update cue-food associations by potentially fine-tuning neuronal excitability.

in RSS PAP on November 07, 2019 05:30 PM.

• #### Reply to ‘Only negligible deviations from electroneutrality are expected in dendritic spines’

Nature Reviews Neuroscience, Published online: 07 November 2019; doi:10.1038/s41583-019-0239-9

Reply to ‘Only negligible deviations from electroneutrality are expected in dendritic spines’

in Nature Reviews Neuroscience - Issue - nature.com science feeds on November 07, 2019 12:00 AM.

• #### Only negligible deviations from electroneutrality are expected in dendritic spines

Nature Reviews Neuroscience, Published online: 07 November 2019; doi:10.1038/s41583-019-0238-x

Only negligible deviations from electroneutrality are expected in dendritic spines

in Nature Reviews Neuroscience - Issue - nature.com science feeds on November 07, 2019 12:00 AM.

• #### Diverse Neuron Properties and Complex Network Dynamics in the Cerebellar Cortical Inhibitory Circuit

Neuronal inhibition can be defined as a spatiotemporal restriction or suppression of local microcircuit activity. The importance of inhibition relies in its fundamental role in shaping signal processing in single neurons and neuronal circuits. In this context, the activity of inhibitory interneurons proved the key to endow networks with complex computational and dynamic properties. In the last 50 years, the prevailing view on the functional role of cerebellar cortical inhibitory circuits was that excitatory and inhibitory inputs sum spatially and temporally in order to determine the motor output through Purkinje cells (PCs). Consequently, cerebellar inhibition has traditionally been conceived in terms of restricting or blocking excitation. This assumption has been challenged, in particular in the cerebellar cortex where all neurons except granule cells (and unipolar brush cells in specific lobules) are inhibitory and fire spontaneously at high rates. Recently, a combination of electrophysiological recordings in vitro and in vivo, imaging, optogenetics and computational modeling, has revealed that inhibitory interneurons play a much more complex role in regulating cerebellar microcircuit functions: inhibition shapes neuronal response dynamics in the whole circuit and eventually regulate the PC output. This review elaborates current knowledge on cerebellar inhibitory interneurons [Golgi cells, Lugaro cells (LCs), basket cells (BCs) and stellate cells (SCs)], starting from their ontogenesis and moving up to their morphological, physiological and plastic properties, and integrates this knowledge with that on the more renown granule cells and PCs. We will focus on the circuit loops in which these interneurons are involved and on the way they generate feed-forward, feedback and lateral inhibition along with complex spatio-temporal response dynamics. In this perspective, inhibitory interneurons emerge as the real controllers of cerebellar functioning.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 07, 2019 12:00 AM.

• #### Pou2f2 Regulates the Distribution of Dorsal Interneurons in the Mouse Developing Spinal Cord

Spinal dorsal interneurons, which are generated during embryonic development, relay and process sensory inputs from the periphery to the central nervous system. Proper integration of these cells into neuronal circuitry depends on their correct positioning within the spinal parenchyma. Molecular cues that control neuronal migration have been extensively characterized but the genetic programs that regulate their production remain poorly investigated. Onecut (OC) transcription factors have been shown to control the migration of the dorsal interneurons (dINs) during spinal cord development. Here, we report that the OC factors moderate the expression of Pou2f2, a transcription factor essential for B-cell differentiation, in spinal dINs. Overexpression or inactivation of Pou2f2 leads to alterations in the differentiation of dI2, dI3 and Phox2a-positive dI5 populations and to defects in the distribution of dI2-dI6 interneurons. Thus, an OC-Pou2f2 genetic cascade regulates adequate diversification and distribution of dINs during embryonic development.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 07, 2019 12:00 AM.

• #### Region-Specific Reduction of BDNF Protein and Transcripts in the Hippocampus of Juvenile Rats Prenatally Treated With Sodium Valproate

Autism is a neurodevelopmental disorder characterized by a deep deficit in language and social interaction, accompanied by restricted, stereotyped and repetitive behaviors. The use of genetic autism animal models has revealed that the alteration of the mechanisms controlling the formation and maturation of neural circuits are points of convergence for the physiopathological pathways in several types of autism. Brain Derived Neurotrophic Factor (BDNF), a key multifunctional regulator of brain development, has been related to autism in several ways. However, its precise role is still elusive, in part, due to its extremely complex posttranscriptional regulation. In order to contribute to this topic, we treated prenatal rats with Valproate, a well-validated model of autism, to analyze BDNF levels in the hippocampus of juvenile rats. Valproate-treated rats exhibited an autism-like behavioral profile, characterized by a deficit in social interaction, anxiety-like behavior and repetitive behavior. In situ hybridization (ISH) experiments revealed that Valproate reduced BDNF mRNA, especially long-3′UTR-containing transcripts, in specific areas of the dentate gyrus (DG) and CA3 regions. At the same time, Valproate reduced BDNF immunoreactivity in the suprapyramidal and lucidum layers of CA3, but improved hippocampus-dependent spatial learning. The molecular changes reported here may help to explain the cognitive and behavioral signs of autism and reinforce BDNF as a potential molecular target for this neurodevelopmental disorder.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 07, 2019 12:00 AM.

• #### Multimodal Integration of Brain Images for MRI-Based Diagnosis in Schizophrenia

Magnetic resonance imaging (MRI) has been proposed as a source of information for automatic prediction of individual diagnosis in schizophrenia. Optimal integration of data from different MRI modalities is an active area of research aimed at increasing diagnostic accuracy. Based on a sample of 96 patients with schizophrenia and a matched sample of 115 healthy controls that had undergone a single multimodal MRI session, we generated individual brain maps of gray matter vbm, 1back, and 2back levels of activation (nback fMRI), maps of amplitude of low-frequency fluctuations (resting-state fMRI), and maps of weighted global brain connectivity (resting-state fMRI). Four unimodal classifiers (Ridge, Lasso, Random Forests, and Gradient boosting) were applied to these maps to evaluate their classification accuracies. Based on the assignments made by the algorithms on test individuals, we quantified the amount of predictive information shared between maps (what we call redundancy analysis). Finally, we explored the added accuracy provided by a set of multimodal strategies that included post-classification integration based on probabilities, two-step sequential integration, and voxel-level multimodal integration through one-dimensional-convolutional neural networks (1D-CNNs). All four unimodal classifiers showed the highest test accuracies with the 2back maps (80% on average) achieving a maximum of 84% with the Lasso. Redundancy levels between brain maps were generally low (overall mean redundancy score of 0.14 in a 0–1 range), indicating that each brain map contained differential predictive information. The highest multimodal accuracy was delivered by the two-step Ridge classifier (87%) followed by the Ridge maximum and mean probability classifiers (both with 85% accuracy) and by the 1D-CNN, which achieved the same accuracy as the best unimodal classifier (84%). From these results, we conclude that from all MRI modalities evaluated task-based fMRI may be the best unimodal diagnostic option in schizophrenia. Low redundancy values point to ample potential for accuracy improvements through multimodal integration, with the two-step Ridge emerging as a suitable strategy.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 07, 2019 12:00 AM.

• #### Neurons Expressing Pathological Tau Protein Trigger Dramatic Changes in Microglial Morphology and Dynamics

Microglial cells, the resident macrophages of the brain, are important players in the pathological process of numerous neurodegenerative disorders, including tauopathies, a heterogeneous class of diseases characterized by intraneuronal Tau aggregates. However, microglia response in Tau pathologies remains poorly understood. Here, we exploit a genetic zebrafish model of tauopathy, combined with live microglia imaging, to investigate the behavior of microglia in vivo in the disease context. Results show that while microglia were almost immobile and displayed long and highly dynamic branches in a wild-type context, in presence of diseased neurons, cells became highly mobile and displayed morphological changes, with highly mobile cell bodies together with fewer and shorter processes. We also imaged, for the first time to our knowledge, the phagocytosis of apoptotic tauopathic neurons by microglia in vivo and observed that microglia engulfed about as twice materials as in controls. Finally, genetic ablation of microglia in zebrafish tauopathy model significantly increased Tau hyperphosphorylation, suggesting that microglia provide neuroprotection to diseased neurons. Our findings demonstrate for the first time the dynamics of microglia in contact with tauopathic neurons in vivo and open perspectives for the real-time study of microglia in many neuronal diseases.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 07, 2019 12:00 AM.

• #### A Custom Microcontrolled and Wireless-Operated Chamber for Auditory Fear Conditioning

Animal behavioral paradigms, such as classical conditioning and operant conditioning, are an important tool to study the neural basis of cognition and behavior. These paradigms involve manipulating sensory stimuli in a way that learning processes are induced under controlled experimental conditions. However, the majority of the commercially available equipment did not offer flexibility to manipulate stimuli. Therefore, the development of most versatile devices would allow the study of more complex cognitive functions. The purpose of this work is to present a low-cost, customized and wireless-operated chamber for animal behavior conditioning, based on the joint operation of two microcontroller modules: Arduino Due and ESP8266-12E. Our results showed that the auditory stimulation system allows setting the carrier frequency in the range of 1 Hz up to more than 100 kHz and the sound stimulus can be modulated in amplitude, also over a wide range of frequencies. Likewise, foot-shock could be precisely manipulated regarding its amplitude (from ∼200 μA to ∼1500 μA) and frequency (up to 20 pulses per second). Finally, adult rats exposed to a protocol of cued fear conditioning in our device showed consistent behavioral response and electrophysiological evoked responses in the midbrain auditory pathway. Furthermore, the device developed in the current study represents an open source alternative to develop customized protocols to study fear memory under conditions of varied sensory stimuli.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on November 07, 2019 12:00 AM.

• #### Opposite Effects of Neuroprotective Cannabinoids, Palmitoylethanolamide, and 2-Arachidonoylglycerol on Function and Morphology of Microglia

Various studies performed in cultured cells and in in vivo models of neuronal damage showed that cannabinoids exert a neuroprotective effect. The increase in cannabinoids and cannabinoid like substances after stroke has been postulated to limit the content of neuronal injury. As well-accepted, inflammation, and neuronal damage are coupled processes and microglial cells as the main intrinsic immunological effector within the brain play a central role in their regulation. Treatment with the endocannabinoid, 2-arachidonoylglycerol (2-AG) or the endocannabinoid-like substance, palmitoylethanolamide (PEA) affected microglial cells and led to a decrease in the number of damaged neurons after excitotoxical lesion in organotypic hippocampal slice cultures (OHSC). 2-AG activated abnormal cannabidiol (abn-CBD) receptor, PEA was shown to mediate neuroprotection via peroxisome proliferator-activated receptor (PPAR)α. Despite the known neuroprotective and anti-inflammatory properties, the potential synergistic effect, namely possible entourage effect after treatment with the combination of these two protective cannabinoids has not been examined yet. After excitotoxical lesion OHSC were treated with PEA, 2-AG or a combination of both and the number of damaged neurons was evaluated. To investigate the role of microglial cells in PEA and 2-AG mediated protection, primary microglial cell cultures were treated with lipopolysaccharide (LPS) and 2-AG, PEA or a combination of those. Thereafter, we measured NO production, ramification index, proliferation and PPARα distribution in microglial cells. While PEA or 2-AG alone were neuroprotective, their co-application vanished the protective effect. This behavior was independent of microglial cells. Furthermore, PEA and 2-AG had contrary effects on ramification index and on NO production. No significant changes were observed in the proliferation rate of microglial cells after treatment. The expression of PPARα was not changed upon stimulation with PEA or 2-AG, but the distribution was significantly altered. 2-AG and PEA mediated neuroprotection was abolished when co-applied. Both cannabinoids exert contrary effects on morphology and function of microglial cells. Co-application of both cannabinoids with different targets did not lead to a positive additive effect as expected, presumably due to the contrary polarization of microglial cells.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 07, 2019 12:00 AM.

• #### Bioscaffold-Induced Brain Tissue Regeneration

Brain tissue lost after a stroke is not regenerated, although a repair response associated with neurogenesis does occur. A failure to regenerate functional brain tissue is not caused by the lack of available neural cells, but rather the absence of structural support to permit a repopulation of the lesion cavity. Inductive bioscaffolds can provide this support and promote the invasion of host cells into the tissue void. The putative mechanisms of bioscaffold degradation and its pivotal role to permit invasion of neural cells are reviewed and discussed in comparison to peripheral wound healing. Key differences between regenerating and non-regenerating tissues are contrasted in an evolutionary context, with a special focus on the neurogenic response as a conditio sine qua non for brain regeneration. The pivotal role of the immune system in biodegradation and the formation of a neovasculature are contextualized with regeneration of peripheral soft tissues. The application of rehabilitation to integrate newly forming brain tissue is suggested as necessary to develop functional tissue that can alleviate behavioral impairments. Pertinent aspects of brain tissue development are considered to provide guidance to produce a metabolically and functionally integrated de novo tissue. Although little is currently known about mechanisms involved in brain tissue regeneration, this review outlines the various components and their interplay to provide a framework for ongoing and future studies. It is envisaged that a better understanding of the mechanisms involved in brain tissue regeneration will improve the design of biomaterials and the methods used for implantation, as well as rehabilitation strategies that support the restoration of behavioral functions.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 07, 2019 12:00 AM.

• #### The Beta Amyloid Dysfunction (BAD) Hypothesis for Alzheimer’s Disease

Beta amyloid, Aβ 1–42, originally named as Amyloid A4 protein, is one of the most investigated peptides in neuroscience and has attracted substantial interest since its discovery as the main insoluble fibril-type protein in cerebrovascular amyloid angiopathy (Glenner and Wong, 1984; Masters et al., 1985) of Alzheimer’s disease (AD). From the very beginning, Aβ was regarded per se as a “bad molecule,” triggering the so-called “beta amyloid cascade hypothesis” (Hardy and Higgins, 1992). This hypothesis ignored any physiological function for in situ generated Aβ monomer with normal production and turnover rate (Bateman et al., 2006). Accordingly, pan-Aβ-related therapeutic approaches were designed to eliminate or lower the three structural isoforms in parallel: (1) the pre-amyloid monomer, (2) the misfolded oligomer, and (3) the final fibril. While we already knew about poor correlations between plaques and cognitive decline quite early (Terry et al., 1991), data for an essential benign physiological role for Aβ monomer at low concentrations were also not considered to be relevant. Here, a different Beta Amyloid hypothesis is described, the so-called “Beta Amyloid Dysfunction hypothesis,” which, in contrast to the “Beta Amyloid Cascade hypothesis,” builds on the homeostasis of essential Aβ monomer in the synaptic vesicle cycle (SVC). Disease-relevant early pathology emerges through disturbance of the Aβ homeostasis by so far unknown factors leading to the formation of misfolded Aβ oligomers. These early species interfere with the synaptic physiological Aβ monomer regulation and exert their neurotoxicity via various receptors for sticky oligomer-type Aβ aggregates. The Beta Amyloid Dysfunction (BAD) hypothesis is introduced and shown to explain negative clinical results of Gamma-secretase and Beta-secretase (BACE) inhibitors as well as pan-Aβ isotype unselective immunotherapies. This hypothesis gives guidance to what needs to be done therapeutically to revive successful clinical testing in AD for this highly validated target. The BAD hypothesis will need further refinement in particular through more detailed exploration for the role of physiological Aβ monomer.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 07, 2019 12:00 AM.

• #### Do Walking Muscle Synergies Influence Propensity of Severe Slipping?

Slipping is frequently responsible for falling injuries. Preventing slips, and more importantly severe slips, is of importance in fall prevention. Our previous study characterized mild slipping and severe slipping by the analysis of muscle synergies. Significant discrepancies in motor control of slipping have been observed between mild and severe slippers. We are further interested in whether differences exist in baseline motor control patterns between persons who experience mild and severe slips when exposed to a slippery contaminant. This study investigated walking with a muscle synergy approach to detect if walking muscle synergies differ between groups experiencing different slip severities. Twenty healthy young adults (eight mild slippers and 12 severe slippers) participated in this study and their muscle synergies of walking were extracted. Muscle synergy analysis showed that mild slippers had a higher contribution of hamstring and quadriceps during walking while severe slippers had increased contribution of the tibialis group. This study provides novel information that may contribute to identifying diagnostic techniques for identifying persons or populations with a high risk of fall based on their walking patterns.

in Frontiers in Human Neuroscience | New and Recent Articles on November 07, 2019 12:00 AM.

• #### Neural Network Model for Detection of Edges Defined by Image Dynamics

Insects can detect the presence of discrete objects in their visual fields based on a range of differences in spatiotemporal characteristics between the images of object and background. This includes but is not limited to relative motion. Evidence suggests that edge detection is an integral part of this capability, and this study examines the ability of a bio-inspired processing model to detect the presence of boundaries between two regions of a one-dimensional visual field, based on general differences in image dynamics. The model consists of two parts. The first is an early vision module inspired by insect visual processing, which implements adaptive photoreception, ON and OFF channels with transient and sustained characteristics, and delayed and undelayed signal paths. This is replicated for a number of photoreceptors in a small linear array. It is followed by an artificial neural network trained to discriminate the presence vs. absence of an edge based on the array output signals. Input data are derived from natural imagery and feature both static and moving edges between regions with moving texture, flickering texture, and static patterns in all possible combinations. The model can discriminate the presence of edges, stationary or moving, at rates far higher than chance. The resources required (numbers of neurons and visual signals) are realistic relative to those available in the insect second optic ganglion, where the bulk of such processing would be likely to take place.

in Frontiers in Computational Neuroscience | New and Recent Articles on November 07, 2019 12:00 AM.

• #### Longitudinal Changes in Functional Connectivity of the Caudate Is Associated With Recovery From Bell’s Palsy

Several studies have demonstrated through resting-state functional magnetic resonance imaging (fMRI) that functional connectivity changes are important in the recovery from Bell’s palsy (BP); however, these studies have only focused on the cortico-cortical connectivity. It is unclear how corticostriatal connectivity relates to the recovery process of patients with BP. In the present study, we evaluated the relationship between longitudinal changes of caudate-based functional connectivity and longitudinal changes of facial performance in patients with intractable BP. Twenty-one patients with intractable BP underwent resting-state fMRI as well as facial behavioral assessments prior to treatment (PT) and at the middle stage of treatment (MT); and 21 age- and sex-matched healthy controls (HC) were recruited and received the same protocol. The caudate was divided into dorsal and ventral sub-regions and separate functional connectivity was calculated. Compared with HC, patients with intractable BP at the PT stage showed decreased functional connectivity of both the dorsal and ventral caudate mainly distributed in the somatosensory network, including the bilateral precentral gyrus (MI), left postcentral gyrus, media frontal gyrus, and superior temporal gyrus (STG). Alternatively, patients in the MT stage showed decreased functional connectivity primarily distributed in the executive network and somatosensory network, including the bilateral cingulate cortex (CC), left anterior cingulate cortex (LACC), inferior prefrontal gyrus (IFG), MI, STG, and paracentral lobe. The longitudinal changes in functional connectivity of both the dorsal and ventral caudate were mainly observed in the executive network, including the right ACC, left CC, and IFG. Functional connectivity changes in the right ACC and left IFG were significantly correlated with changes in facial behavioral performance. These findings indicated that corticostriatal connectivity changes are associated with recovery from BP.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 07, 2019 12:00 AM.

• #### Prediction of PD-L1 inhibition effects for HIV-infected individuals

by Valerya Zheltkova, Jordi Argilaguet, Cristina Peligero, Gennady Bocharov, Andreas Meyerhans

The novel therapies with immune checkpoint inhibitors hold great promises for patients with chronic virus infections and cancers. This is based mainly on the partial reversal of the exhausted phenotype of antigen-specific cytotoxic CD8 T cells (CTL). Recently, we have shown that the restoration of HIV-specific T cell function depends on the HIV infection stage of an infected individual. Here we aimed to answer two fundamental questions: (i) Can one estimate growth parameters for the HIV-specific proliferative responsiveness upon PD-L1 blockade ex vivo? (ii) Can one use these parameter estimates to predict clinical benefit for HIV-infected individuals displaying diverse infection phenotypes? To answer these questions, we first analyzed HIV-1 Gag-specific CD8 T cell proliferation by time-resolved CFSE assays and estimated the effect of PD-L1 blockade on division and death rates, and specific precursor frequencies. These values were then incorporated into a model for CTL-mediated HIV control and the effects on CTL frequencies, viral loads and CD4 T cell counts were predicted for different infection phenotypes. The biggest absolute increase in CD4 T cell counts was in the group of slow progressors while the strongest reduction in virus loads was observed in progressor patients. These results suggest a significant clinical benefit only for a subgroup of HIV-infected individuals. However, as PD1 is a marker of lymphocyte activation and expressed on several lymphocyte subsets including also CD4 T cells and B cells, we subsequently examined the multiple effects of anti-PD-L1 blockade beyond those on CD8 T cells. This extended model then predicts that the net effect on HIV load and CD4 T cell number depends on the interplay between positive and negative effects of lymphocyte subset activation. For a physiologically relevant range of affected model parameters, PD-L1 blockade is likely to be overall beneficial for HIV-infected individuals.

in PLOS Computational Biology: New Articles on November 06, 2019 10:00 PM.

## Objective

Symptomatic head trauma associated with American‐style football (ASF) has been linked to brain pathology, along with physical and mental distress in later life. Still, the longer‐term effects of such trauma on objective metrics of cognitive‐motor function remain poorly understood. We hypothesized that ASF‐related symptomatic head trauma would predict worse gait performance, particularly during dual task conditions (i.e., walking while performing an additional cognitive task), in later life.

## Methods

Sixty‐six retired professional ASF players aged 29‐75 years completed a health and wellness questionnaire. They also completed a validated smartphone‐based assessment in their own homes, during which gait was monitored while walking normally and while performing a verbalized serial‐subtraction cognitive task.

## Results

Participants who reported more symptomatic head trauma, defined as the total number of impacts to the head or neck followed by concussion‐related symptoms, exhibited greater dual task cost (i.e., percent increase) to stride time variability (i.e., the coefficient of variation of mean stride time). Those who reported ≥1 hit followed by loss of consciousness, compared to those who did not, also exhibited greater dual task costs to this metric. Relationships between reported trauma and dual task costs were independent of age, BMI, NFL career duration, and history of musculoskeletal surgery. Symptomatic head trauma was not correlated with average stride times in either walking condition.

## Interpretation

Remote, smartphone‐based assessments of dual task walking may be utilized to capture meaningful data sensitive to the long‐term impact of symptomatic head trauma in former professional ASF players and other contact sport athletes.

## Objective

Clinical outcomes in multiple sclerosis (MS) are highly variable. We aim to determine the long‐term clinical outcomes in MS, and to identify early prognostic features of these outcomes.

## Methods

132 people presenting with a clinically isolated syndrome (CIS) were prospectively recruited between 1984‐87, and followed up clinically and radiologically 1, 5, 10, 14, 20 and now 30 years later. All available notes and magnetic resonance imaging (MRI) scans were reviewed, and MS was defined according to the 2010 McDonald criteria.

## Results

Clinical outcome data was obtained in 120 participants at 30 years. Eighty were known to have developed MS by 30 years. Expanded disability status scale (EDSS) scores were available in 107 participants, of whom 77 had MS: thirty‐two (42%) remained fully ambulatory (EDSS ≤3.5) all of whom had relapsing‐remitting MS (RRMS), three (4%) had RRMS and EDSS >3.5, 26 (34%) had secondary progressive MS (all had EDSS >3.5), and MS contributed to death in 16 (20%). Of those with MS, 11 have been treated with a DMT. The strongest early predictors (within 5 years of presentation) of secondary progressive MS (SPMS) at 30 years were presence of baseline infratentorial lesions and deep white matter lesions at one year.

## Interpretation

Thirty years after onset, in a largely untreated cohort, there was a divergence of MS outcomes; some people accrued substantial disability early on, while others ran a more favourable long‐term course. These outcomes could, in part, be predicted by radiological findings from within a year of first presentation.

• #### PiRNA-DQ541777 Contributes to Neuropathic Pain via Targeting Cdk5rap1

Piwi-Interacting RNA (piRNA) is the largest class of small noncoding RNA and is involved in various physiological and pathological processes. However, whether it has a role in pain modulation remains unknown. In the present study, we found that spinal piRNA-DQ541777 (piR-DQ541777) was significantly increased in the male mouse model of sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain. Knockdown of spinal piR-DQ541777 alleviated CCI-induced thermal hyperalgesia and mechanical allodynia and spinal neuronal sensitization. However, the overexpression of spinal piR-DQ541777 in naive mice produced pain behaviors and increased spinal neuron sensitization. Furthermore, we found that piR-DQ541777 regulates pain behaviors by targeting CDK5 regulatory subunit-associated protein 1 (Cdk5rap1). CCI increased the methylation level of CpG islands in the cdk5rap1 promoter and consequently reduced the expression of Cdk5rap1, which was reversed by the knockdown of piR-DQ541777 and mimicked by the overexpression of piR-DQ541777 in naive mice. Finally, piR-DQ541777 increased the methylation level of CpG islands by recruiting DNA methyltransferase 3A (DNMT3a) to cdk5rap1 promoter. In conclusion, this study represents a novel role of piR-DQ541777 in the regulation of neuropathic pain through the methylation of cdk5rap1.

SIGNIFICANCE STATEMENT Chronic pain affects ~20% of the population of the world and is a major global public health problem. Although we have studied the neurobiological mechanism of neuropathic pain for decades, there is still no ideal drug available to treat it. This work indicates that a novel role of Piwi-interacting RNA (piRNA) DQ541777 in the regulation of neuropathic pain through the methylation of cdk5rap1. Our findings provide the first evidence of the regulatory effect of piRNAs on neuropathic pain, which may improve our understanding of pain mechanisms and lead to the discovery of novel drug targets for the prevention and treatment of neuropathic pain.

in Journal of Neuroscience current issue on November 06, 2019 05:30 PM.

• #### Awake microglia are less alert

Nature Reviews Neuroscience, Published online: 06 November 2019; doi:10.1038/s41583-019-0243-0

Two studies show that, compared with microglia in anaesthetized mice, microglia in awake mice show reduced surveillance owing to an increase in noradrenaline signalling.

in Nature Reviews Neuroscience - Issue - nature.com science feeds on November 06, 2019 12:00 AM.

• #### Seizure Susceptibility Corrupts Inferior Colliculus Acoustic Integration

Evidence suggests that the pathophysiology associated with epileptic susceptibility may disturb the functional connectivity of neural circuits and compromise the brain functions, even when seizures are absent. Although memory impairment is a common comorbidity found in patients with epilepsy, it is still unclear whether more caudal structures may play a role in cognitive deficits, particularly in those cases where there is no evidence of hippocampal sclerosis. This work used a genetically selected rat strain for seizure susceptibility (Wistar audiogenic rat, WAR) and distinct behavioral (motor and memory-related tasks) and electrophysiological (inferior colliculus, IC) approaches to access acoustic primary integrative network properties. The IC neural assemblies’ response was evaluated by auditory transient (focusing on bottom-up processing) and steady-state evoked response (ASSR, centering on feedforward and feedback forces over neural circuitry). The results show that WAR displayed no disturbance in motor performance or hippocampus-dependent memory tasks. Nonetheless, WAR animals exhibited significative impairment for auditory fear conditioning (AFC) along with no indicative of IC plastic changes between the pre-conditioning and test phases (ASSR coherence analysis). Furthermore, WAR’s IC response to transient stimuli presented shorter latency and higher amplitude compared with Wistar; and the ASSR analysis showed similar results for WAR and Wistar animals under subthreshold dose of pentylenetetrazol (pro-convulsive drug) for seizure-induction. Our work demonstrated alterations at WAR IC neural network processing, which may explain the associated disturbance on AFC memory.

in Frontiers in Systems Neuroscience | New and Recent Articles on November 06, 2019 12:00 AM.

• #### Pre-treatment With Fasudil Prevents Neomycin-Induced Hair Cell Damage by Reducing the Accumulation of Reactive Oxygen Species

Ototoxic drug-induced hair cell (HC) damage is one of the main causes of sensorineural hearing loss, which is one of the most common sensory disorders in humans. Aminoglycoside antibiotics are common ototoxic drugs, and these can cause the accumulation of intracellular oxygen free radicals and lead to apoptosis in HCs. Fasudil is a Rho kinase inhibitor and vasodilator that has been widely used in the clinic and has been shown to have neuroprotective effects. However, the possible application of fasudil in protecting against aminoglycoside-induced HC loss and hearing loss has not been investigated. In this study, we investigated the ability of fasudil to protect against neomycin-induced HC loss both in vitro and in vivo. We found that fasudil significantly reduced the HC loss in cochlear whole-organ explant cultures and reduced the cell death of auditory HEI-OC1 cells after neomycin exposure in vitro. Moreover, we found that fasudil significantly prevented the HC loss and hearing loss of mice in the in vivo neomycin damage model. Furthermore, we found that fasudil could significantly inhibit the Rho signaling pathway in the auditory HEI-OC1 cells after neomycin exposure, thus further reducing the neomycin-induced accumulation of reactive oxygen species and subsequent apoptosis in HEI-OC1 cells. This study suggests that fasudil might contribute to the increased viability of HCs after neomycin exposure by inhibition of the Rho signaling pathway and suggests a new therapeutic target for the prevention of aminoglycoside-induced HC loss and hearing loss.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 06, 2019 12:00 AM.

• #### Selectively Enhanced Development of Working Memory in Musically Trained Children and Adolescents

In the current longitudinal study, we investigated the development of working memory in musically trained and nontrained children and adolescents, aged 9–20. We measured working memory with the Digit Span (DS) forwards and backwards tests (N = 106) and the Trail-Making A and B (TMT-A and B; N = 104) tests three times, in 2011, 2013, and 2016. We expected that musically trained participants would outperform peers with no musical training. Indeed, we found that the younger musically trained participants, in particular, outperformed their nontrained peers in the TMT-A, TMT-B and DS forwards tests. These tests all primarily require active maintenance of a rule in memory or immediate recall. In contrast, we found no group differences in the backwards test that requires manipulation and updating of information in working memory. These results suggest that musical training is more strongly associated with heightened working memory capacity and maintenance than enhanced working memory updating, especially in late childhood and early adolescence.

in Frontiers in Integrative Neuroscience | New and Recent Articles on November 06, 2019 12:00 AM.

• #### Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila

Mutations in patatin-like phospholipase domain-containing protein 6 (PNPLA6) have been linked with a number of inherited diseases with clinical symptoms that include spastic paraplegia, ataxia, and chorioretinal dystrophy. PNPLA6 is an evolutionary conserved protein whose ortholog in Drosophila is Swiss-Cheese (SWS). Both proteins are phospholipases hydrolyzing lysophosphatidylcholine (LPC) and phosphatidylcholine (PC). Consequently, loss of SWS/PNPLA6 in flies and mice increases both lipids and leads to locomotion deficits and neurodegeneration. PNPLA6 knock-out mice are embryonic lethal, and a mutation creating an early stop codon in human PNPLA6 has only been identified in compound heterozygote patients. In contrast, disease-causing point mutations are found in homozygous patients, with some localized in the phospholipase domain while others are in a region that contains several cNMP binding sites. To investigate how different mutations affect the function of PNPLA6 in an in vivo model, we expressed them in the Drosophila sws1 null mutant. Expressing wild-type PNPLA6 suppressed the locomotion and degenerative phenotypes in sws1 and restored lipid levels, confirming that the human protein can replace fly SWS. In contrast, none of the mutant proteins restored lipid levels, although they suppressed the behavioral and degenerative phenotypes, at least in early stages. These results show that these mutant forms of PNPLA6 retain some biological function, indicating that disruption of lipid homeostasis is only part of the pathogenic mechanism. Furthermore, our finding that mutations in the cNMP binding sites prevented the restoration of normal lipid levels supports previous evidence that cNMP regulates the phospholipase activity of PNPLA6.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 06, 2019 12:00 AM.

• #### More Reliable EEG Electrode Digitizing Methods Can Reduce Source Estimation Uncertainty, but Current Methods Already Accurately Identify Brodmann Areas

Electroencephalography (EEG) and source estimation can be used to identify brain areas activated during a task, which could offer greater insight on cortical dynamics. Source estimation requires knowledge of the locations of the EEG electrodes. This could be provided with a template or obtained by digitizing the EEG electrode locations. Operator skill and inherent uncertainties of a digitizing system likely produce a range of digitization reliabilities, which could affect source estimation and the interpretation of the estimated source locations. Here, we compared the reliabilities of five digitizing methods (ultrasound, structured-light 3D scan, infrared 3D scan, motion capture probe, and motion capture) and determined the relationship between digitization reliability and source estimation uncertainty, assuming other contributors to source estimation uncertainty were constant. We digitized a mannequin head using each method five times and quantified the reliability and validity of each method. We created five hundred sets of electrode locations based on our reliability results and applied a dipole fitting algorithm (DIPFIT) to perform source estimation. The motion capture method, which recorded the locations of markers placed directly on the electrodes had the best reliability with an average electrode variability of 0.001 cm. Then, in order of decreasing reliability were the method using a digitizing probe in the motion capture system, an infrared 3D scanner, a structured-light 3D scanner, and an ultrasound digitization system. Unsurprisingly, uncertainty of the estimated source locations increased with greater variability of EEG electrode locations and less reliable digitizing systems. If EEG electrode location variability was ∽1 cm, a single source could shift by as much as 2 cm. To help translate these distances into practical terms, we quantified Brodmann area accuracy for each digitizing method and found that the average Brodmann area accuracy for all digitizing methods was >80%. Using a template of electrode locations reduced the Brodmann area accuracy to ∽50%. Overall, more reliable digitizing methods can reduce source estimation uncertainty, but the significance of the source estimation uncertainty depends on the desired spatial resolution. For accurate Brodmann area identification, any of the digitizing methods tested can be used confidently.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 06, 2019 12:00 AM.

• #### Toward a Hybrid Passive BCI for the Modulation of Sustained Attention Using EEG and fNIRS

in Frontiers in Human Neuroscience | New and Recent Articles on November 06, 2019 12:00 AM.

• #### Effects of Expressive Writing on Neural Processing During Learning

in Frontiers in Human Neuroscience | New and Recent Articles on November 06, 2019 12:00 AM.

• #### Altered Cerebro-Cerebellar Limbic Network in AD Spectrum: A Resting-State fMRI Study

Recent evidence suggests that the cerebellum is related to motor and non-motor cognitive functions, and that several coupled cerebro-cerebellar networks exist, including links with the limbic network. Since several limbic structures are affected by Alzheimer pathology, even in the preclinical stages of Alzheimer’s disease (AD), we aimed to investigate the cerebral limbic network activity from the perspective of the cerebellum. Twenty patients with mild cognitive impairment (MCI), 18 patients with AD, and 26 healthy controls (HC) were recruited to acquire Resting-state functional MRI (rs-fMRI). We used seed-based approach to construct the cerebro-cerebellar limbic network. Two-sample t-tests were carried out to explore the differences of the cerebellar limbic network connectivity. The first result, a sub-scale network including the bilateral posterior part of the orbitofrontal cortex (POFC) extending to the anterior insular cortex (AIC) and left inferior parietal lobule (L-IPL), showed greater functional connectivity in MCI than in HC and less functional connectivity in AD than in MCI. The location of this sub-scale network was in accordance with components of the ventral attention network. Second, there was decreased functional connectivity to the right mid-cingulate cortex (MCC) in the AD and MCI patient groups relative to the HC group. As the cerebellum is not compromised by Alzheimer pathology in the prodromal stage of AD, this pattern indicates that the sub-scale ventral attention network may play a pivotal role in functional compensation through the coupled cerebro-cerebellar limbic network in MCI, and the cerebellum may be a key node in the modulation of social cognition.

in Frontiers in Neural Circuits | New and Recent Articles on November 06, 2019 12:00 AM.

• #### Nicotine Bound to Its Receptors: New Structures for a Vexing Pathopharmacological Problem

In this issue of Neuron, Gharpure et al. (2019) nearly complete atomic-level descriptions for binding, permeation, and subunit interactions at the two major heteropentameric nicotinic receptors—those governing nicotine’s rewarding and aversive effects. Can we finally design highly selective and useful nicotinic drugs?

in Neuron on November 06, 2019 12:00 AM.

• #### Retinal Circuits for Seeing in the Dark

How can we relate processing in the retina to an animal’s behavior? In this issue of Neuron, Smeds et al. (2019) report that when “every photon counts,” mice trade sensitivity for reliability to master visual tasks.

in Neuron on November 06, 2019 12:00 AM.

• #### Electrodiffusion Theory to Map the Voltage Distribution in Dendritic Spines at a Nanometer Scale

Electrodiffusion—that is, the interaction between electric fields and ionic diffusion—is applicable when analyzing the electrical properties of electrolytes in femto-liter compartments such as dendritic spines. In a classical electrical engineering approach, electricity in conductors is studied by linear combinations of terms like resistance and capacitance, which are the building blocks of classical electrical circuits. However, electrophysiological media are electrolyte based and thus are better modeled by electrodiffusion.

in Neuron on November 06, 2019 12:00 AM.

• #### No Extraction of Spine Neck Resistance from Underdetermined Equations

From voltage-dye measurements of dendritic spine responses to uncaging of glutamate, Cartailler et al. (2018) reported extracting a value of spine neck resistance by optimization of an electrodiffusion model. This comment focuses on flaws in the modeling and optimization. It is based on a more exhaustive blog post (Barbour, 2018) and the authors’ response (Cartailler and Holcman, 2018).

in Neuron on November 06, 2019 12:00 AM.

• #### “One Must Imagine Sisyphus Happy”: Unveiling the Intimate Secrets of a Tenacious Fruitfly

Perseverance in foraging is a high-risk/high-gain strategy. In this issue of Neuron, Sayin et al. (2019) decipher the neuronal circuit that arbitrates this choice in Drosophila. The fly’s remarkable tenacity illuminates the interaction between working memory and decision making.

in Neuron on November 06, 2019 12:00 AM.

• #### Solving the Mysteries of Dementia: FTD Mutant Tau Impairs Structural Axon Initial Segment Plasticity

Accumulation of abnormal Tau is a characteristic feature of a number of neurodegenerative disorders, called tauopathies. What is the reason for Tau toxicity in neuronal cells? In this issue of Neuron, Sohn et al. (2019) found that FTD mutant Tau-V337M blocks axon initial segment (AIS) plasticity, causing neuronal hyperexcitability.

in Neuron on November 06, 2019 12:00 AM.

• #### Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology

Like other cancers, brain tumors (gliomas) are composed of many different cell types, including non-neoplastic monocytic cells (macrophages and microglia). In this Review, Gutmann and Kettenmann discuss the importance of these cells to glioma development, maintenance, and treatment response.

in Neuron on November 06, 2019 12:00 AM.

• #### Inhibitory Synapse Formation at the Axon Initial Segment

The axon initial segment (AIS) is the site of action potential (AP) initiation in most neurons and is thus a critical site in the regulation of neuronal excitability. Normal function within the discrete AIS compartment requires intricate molecular machinery to ensure the proper concentration and organization of voltage-gated and ligand-gated ion channels; in humans, dysfunction at the AIS due to channel mutations is commonly associated with epileptic disorders. In this review, we will examine the molecular mechanisms underlying the formation of the only synapses found at the AIS: synapses containing γ-aminobutyric type A receptors (GABAARs). GABAARs are heteropentamers assembled from 19 possible subunits and are the primary mediators of fast synaptic inhibition in the brain. Although the total GABAAR population is incredibly heterogeneous, only one specific GABAAR subtype—the α2-containing receptor—is enriched at the AIS. These AIS synapses are innervated by GABAergic chandelier cells, and this inhibitory signaling is thought to contribute to the tight control of AP firing. Here, we will summarize the progress made in understanding the regulation of GABAAR synapse formation, concentrating on post-translational modifications of subunits and on interactions with intracellular proteins. We will then discuss subtype-specific synapse formation, with a focus on synapses found at the AIS, and how these synapses influence neuronal excitation.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 05, 2019 12:00 AM.

• #### Arousal Contributions to Resting-State fMRI Connectivity and Dynamics

Resting-state functional magnetic resonance imaging (rsfMRI) is being widely used for charting brain connectivity and dynamics in healthy and diseased brains. However, the resting state paradigm allows an unconstrained fluctuation of brain arousal, which may have profound effects on resting-state fMRI signals and associated connectivity/dynamic metrics. Here, we review current understandings of the relationship between resting-state fMRI and brain arousal, in particular the effect of a recently discovered event of arousal modulation on resting-state fMRI. We further discuss potential implications of arousal-related fMRI modulation with a focus on its potential role in mediating spurious correlations between resting-state connectivity/dynamics with physiology and behavior. Multiple hypotheses are formulated based on existing evidence and remain to be tested by future studies.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 05, 2019 12:00 AM.

• #### Brain–Blood Partition Coefficient and Cerebral Blood Flow in Canines Using Calibrated Short TR Recovery (CaSTRR) Correction Method

The brain–blood partition coefficient (BBPC) is necessary for quantifying cerebral blood flow (CBF) when using tracer based techniques like arterial spin labeling (ASL). A recent improvement to traditional MRI measurements of BBPC, called calibrated short TR recovery (CaSTRR), has demonstrated a significant reduction in acquisition time for BBPC maps in mice. In this study CaSTRR is applied to a cohort of healthy canines (n = 17, age = 5.0 – 8.0 years) using a protocol suited for application in humans at 3T. The imaging protocol included CaSTRR for BBPC maps, pseudo-continuous ASL for CBF maps, and high resolution anatomical images. The standard CaSTRR method of normalizing BBPC to gadolinium-doped deuterium oxide phantoms was also compared to normalization using hematocrit (Hct) as a proxy value for blood water content. The results show that CaSTRR is able to produce high quality BBPC maps with a 4 min acquisition time. The BBPC maps demonstrate significantly higher BBPC in gray matter (0.83 ± 0.05 mL/g) than in white matter (0.78 ± 0.04 mL/g, p = 0.006). Maps of CBF acquired with pCASL demonstrate a negative correlation between gray matter perfusion and age (p = 0.003). Voxel-wise correction for BBPC is also shown to improve contrast to noise ratio between gray and white matter in CBF maps. A novel aspect of the study was to show that that BBPC measurements can be calculated based on the known Hct of the blood sample placed in scanner. We found a strong correlation (R2 = 0.81 in gray matter, R2 = 0.59 in white matter) established between BBPC maps normalized to the doped phantoms and BBPC maps normalized using Hct. This obviates the need for doped water phantoms which simplifies both the acquisition protocol and the post-processing methods. Together this suggests that CaSTRR represents a feasible, rapid method to account for BBPC variability when quantifying CBF. As canines have been used widely for aging and Alzheimer’s disease studies, the CaSTRR method established in the animals may further improve CBF measurements and advance our understanding of cerebrovascular changes in aging and neurodegeneration.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 05, 2019 12:00 AM.

• #### Divide and Conquer: Stratifying Training Data by Tumor Grade Improves Deep Learning-Based Brain Tumor Segmentation

It is a general assumption in deep learning that more training data leads to better performance, and that models will learn to generalize well across heterogeneous input data as long as that variety is represented in the training set. Segmentation of brain tumors is a well-investigated topic in medical image computing, owing primarily to the availability of a large publicly-available dataset arising from the long-running yearly Multimodal Brain Tumor Segmentation (BraTS) challenge. Research efforts and publications addressing this dataset focus predominantly on technical improvements of model architectures and less on properties of the underlying data. Using the dataset and the method ranked third in the BraTS 2018 challenge, we performed experiments to examine the impact of tumor type on segmentation performance. We propose to stratify the training dataset into high-grade glioma (HGG) and low-grade glioma (LGG) subjects and train two separate models. Although we observed only minor gains in overall mean dice scores by this stratification, examining case-wise rankings of individual subjects revealed statistically significant improvements. Compared to a baseline model trained on both HGG and LGG cases, two separately trained models led to better performance in 64.9% of cases (p < 0.0001) for the tumor core. An analysis of subjects which did not profit from stratified training revealed that cases were missegmented which had poor image quality, or which presented clinically particularly challenging cases (e.g., underrepresented subtypes such as IDH1-mutant tumors), underlining the importance of such latent variables in the context of tumor segmentation. In summary, we found that segmentation models trained on the BraTS 2018 dataset, stratified according to tumor type, lead to a significant increase in segmentation performance. Furthermore, we demonstrated that this gain in segmentation performance is evident in the case-wise ranking of individual subjects but not in summary statistics. We conclude that it may be useful to consider the segmentation of brain tumors of different types or grades as separate tasks, rather than developing one tool to segment them all. Consequently, making this information available for the test data should be considered, potentially leading to a more clinically relevant BraTS competition.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 05, 2019 12:00 AM.

• #### Comparison of Multi-Compartment Cable Models of Human Auditory Nerve Fibers

Background: Multi-compartment cable models of auditory nerve fibers have been developed to assist in the improvement of cochlear implants. With the advancement of computational technology and the results obtained from in vivo and in vitro experiments, these models have evolved to incorporate a considerable degree of morphological and physiological details. They have also been combined with three-dimensional volume conduction models of the cochlea to simulate neural responses to electrical stimulation. However, no specific rules have been provided on choosing the appropriate cable model, and most models adopted in recent studies were chosen without a specific reason or by inheritance.

Methods: Three of the most cited biophysical multi-compartment cable models of the human auditory nerve, i.e., Rattay et al. (2001b), Briaire and Frijns (2005), and Smit et al. (2010), were implemented in this study. Several properties of single fibers were compared among the three models, including threshold, conduction velocity, action potential shape, latency, refractory properties, as well as stochastic and temporal behaviors. Experimental results regarding these properties were also included as a reference for comparison.

Results: For monophasic single-pulse stimulation, the ratio of anodic vs. cathodic thresholds in all models was within the experimental range despite a much larger ratio in the model by Briaire and Frijns. For biphasic pulse-train stimulation, thresholds as a function of both pulse rate and pulse duration differed between the models, but none matched the experimental observations even coarsely. Similarly, for all other properties including the conduction velocity, action potential shape, and latency, the models presented different outcomes and not all of them fell within the range observed in experiments.

Conclusions: While all three models presented similar values in certain single fiber properties to those obtained in experiments, none matched all experimental observations satisfactorily. In particular, the adaptation and temporal integration behaviors were completely missing in all models. Further extensions and analyses are required to explain and simulate realistic auditory nerve fiber responses to electrical stimulation.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on November 05, 2019 12:00 AM.

• #### Aftereffect and Reproducibility of Three Excitatory Repetitive TMS Protocols for a Response Inhibition Task

A number of repetitive transcranial magnetic stimulation (rTMS) protocols have been developed for modulating brain function non-invasively. To identify the most powerful one, these protocols have been compared in the context of the motor system. However, to what extent the conclusions could be generalized to high-level functions is largely unknown. In this study, we compared the modulatory effect of three excitatory rTMS protocols on high-level cognition represented by response inhibition ability. Our first experiment revealed that intermittent theta-burst stimulation (iTBS) could significantly improve reaction time in a stop signal task, while 5-Hz and 25-Hz stimuli were ineffective. This iTBS effect was significantly higher than that for the sham simulation and only occurred in the second session of the stop signal task after iTBS in the first experiment. However, this aftereffect of iTBS was not reproduced in the second experiment, indicating high variability across subjects. Thus, on the one hand, our findings indicate that iTBS on the pre-SMA could improve inhibitory control, but on the other hand, the reliability and reproducibility of this effect needs further investigation.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on November 05, 2019 12:00 AM.

• #### Beta-Band Resonance and Intrinsic Oscillations in a Biophysically Detailed Model of the Subthalamic Nucleus-Globus Pallidus Network

Increased beta-band oscillatory activity in the basal ganglia network is associated with Parkinsonian motor symptoms and is suppressed with medication and deep brain stimulation (DBS). The origins of the beta-band oscillations, however, remains unclear with both intrinsic oscillations arising within the subthalamic nucleus (STN)—external globus pallidus (GPe) network and exogenous beta-activity, originating outside the network, proposed as potential sources of the pathological activity. The aim of this study was to explore the relative contribution of autonomous oscillations and exogenous oscillatory inputs in the generation of pathological oscillatory activity in a biophysically detailed model of the parkinsonian STN-GPe network. The network model accounts for the integration of synaptic currents and their interaction with intrinsic membrane currents in dendritic structures within the STN and GPe. The model was used to investigate the development of beta-band synchrony and bursting within the STN-GPe network by changing the balance of excitation and inhibition in both nuclei, and by adding exogenous oscillatory inputs with varying phase relationships through the hyperdirect cortico-subthalamic and indirect striato-pallidal pathways. The model showed an intrinsic susceptibility to beta-band oscillations that was manifest in weak autonomously generated oscillations within the STN-GPe network and in selective amplification of exogenous beta-band synaptic inputs near the network's endogenous oscillation frequency. The frequency at which this resonance peak occurred was determined by the net level of excitatory drive to the network. Intrinsic or endogenously generated oscillations were too weak to support a pacemaker role for the STN-GPe network, however, they were considerably amplified by sparse cortical beta inputs and were further amplified by striatal beta inputs that promoted anti-phase firing of the cortex and GPe, resulting in maximum transient inhibition of STN neurons. The model elucidates a mechanism of cortical patterning of the STN-GPe network through feedback inhibition whereby intrinsic susceptibility to beta-band oscillations can lead to phase locked spiking under parkinsonian conditions. These results point to resonance of endogenous oscillations with exogenous patterning of the STN-GPe network as a mechanism of pathological synchronization, and a role for the pallido-striatal feedback loop in amplifying beta oscillations.

in Frontiers in Computational Neuroscience | New and Recent Articles on November 05, 2019 12:00 AM.

• #### Age and Sex Influence the Neuro-inflammatory Response to a Peripheral Acute LPS Challenge

Aging is associated with an exaggerated response to peripheral inflammatory challenges together with behavioral and cognitive deficits. Studies considering both age and sex remain limited, despite sex dimorphism of astrocytes and microglial cells is largely recognized. To fill this knowledge gap, we investigated the effect of a single intraperitoneal lipopolysaccharide (LPS) administration in adult and aged mice. We assessed the expression of different inflammatory mediators, and the microglial response through binding of [18F]-VC701 tracer to translocator protein (TSPO) receptors in the male and female brain. Aged female brain showed a higher pro-inflammatory response to LPS compared to adult female and to aged male, as revealed by ex vivo binding to TSPO receptors and pro-inflammatory mediator transcript levels. The highest astroglial reaction was observed in the brain of aged females. Differently to the other groups of animals, in aged males LPS challenge did not affect transcription of triggering receptor expressed on myeloid cells 2 (TREM2). In conclusion, our study shows that in the mouse’s brain the neuro-inflammatory response to an acute peripheral insult is sex- and age-dependent. Moreover, our results might set the basis for further studies aimed at identifying sex-related targets involved in the modulation of the aberrant neuro-inflammatory response that characterizes aging. This knowledge could be relevant for the treatment of conditions such as delirium and dementia.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 05, 2019 12:00 AM.

• #### The Ventricular System Enlarges Abnormally in the Seventies, Earlier in Men, and First in the Frontal Horn: A Study Based on More Than 3,000 Scans

Objectives: To detect on computed tomography (CT) brain scans the trajectories of normal and abnormal ventricular enlargement during aging.

Methods: For each 1-year age cohort, we assessed in 3,193 axial CT scans the Evans’ index (EI) in the anterior frontal horns and the parieto-occipital (POR) and temporal ratio (TR) in the posterior and inferior horns. Cut-off values for abnormal enlargement were based on previous clinical studies.

Results: The mean age associated with normal linear measures was 71 years. Values for all three measures increased with age, showing a linear relationship below—but not above—each cut-off value. The mean age of participants with abnormal enlargement on CT progressed from 79 years for EI to 83 years for POR to 87 years for TR. These results suggested that ventricular dilatation progresses in an age–location relationship. First comes enlargement of the frontal horns (13.8% of scans), followed by the parieto-occipital horns (15.1% of scans) and then temporal horn enlargement (6.8% of scans). Scans from men displayed abnormal values earlier than scans from women (on average 6 years). Risk increased 5.1% annually for abnormal EI, 9.0% for abnormal POR, and 11% for abnormal TR (all p < 0.001). The most frequent agreement between categories (normal–abnormal) for values of neuroimaging measures was identified for POR–TR.

Conclusion: The results of this large radiological study suggest that the ventricular system enlarges progressively during aging, and in a subset of patients follows an abnormal consecutive geometric dilatation, influenced by age and sex.

in Frontiers in Aging Neuroscience | New and Recent Articles on November 05, 2019 12:00 AM.

• #### Network-based analysis of prostate cancer cell lines reveals novel marker gene candidates associated with radioresistance and patient relapse

by Michael Seifert, Claudia Peitzsch, Ielizaveta Gorodetska, Caroline Börner, Barbara Klink, Anna Dubrovska

in PLOS Computational Biology: New Articles on November 04, 2019 10:00 PM.

• #### Neural field models for latent state inference: Application to large-scale neuronal recordings

by Michael E. Rule, David Schnoerr, Matthias H. Hennig, Guido Sanguinetti

Large-scale neural recording methods now allow us to observe large populations of identified single neurons simultaneously, opening a window into neural population dynamics in living organisms. However, distilling such large-scale recordings to build theories of emergent collective dynamics remains a fundamental statistical challenge. The neural field models of Wilson, Cowan, and colleagues remain the mainstay of mathematical population modeling owing to their interpretable, mechanistic parameters and amenability to mathematical analysis. Inspired by recent advances in biochemical modeling, we develop a method based on moment closure to interpret neural field models as latent state-space point-process models, making them amenable to statistical inference. With this approach we can infer the intrinsic states of neurons, such as active and refractory, solely from spiking activity in large populations. After validating this approach with synthetic data, we apply it to high-density recordings of spiking activity in the developing mouse retina. This confirms the essential role of a long lasting refractory state in shaping spatiotemporal properties of neonatal retinal waves. This conceptual and methodological advance opens up new theoretical connections between mathematical theory and point-process state-space models in neural data analysis.

in PLOS Computational Biology: New Articles on November 04, 2019 10:00 PM.

• #### Differential regulatory network-based quantification and prioritization of key genes underlying cancer drug resistance based on time-course RNA-seq data

by Jiajun Zhang, Wenbo Zhu, Qianliang Wang, Jiayu Gu, L. Frank Huang, Xiaoqiang Sun

Drug resistance is a major cause for the failure of cancer chemotherapy or targeted therapy. However, the molecular regulatory mechanisms controlling the dynamic evolvement of drug resistance remain poorly understood. Thus, it is important to develop methods for identifying key gene regulatory mechanisms of the resistance to specific drugs. In this study, we developed a data-driven computational framework, DryNetMC, using a differential regulatory network-based modeling and characterization strategy to quantify and prioritize key genes underlying cancer drug resistance. The DryNetMC does not only infer gene regulatory networks (GRNs) via an integrated approach, but also characterizes and quantifies dynamical network properties for measuring node importance. We used time-course RNA-seq data from glioma cells treated with dbcAMP (a cAMP activator) as a realistic case to reconstruct the GRNs for sensitive and resistant cells. Based on a novel node importance index that comprehensively quantifies network topology, network entropy and expression dynamics, the top ranked genes were verified to be predictive of the drug sensitivities of different glioma cell lines, in comparison with other existing methods. The proposed method provides a quantitative approach to gain insights into the dynamic adaptation and regulatory mechanisms of cancer drug resistance and sheds light on the design of novel biomarkers or targets for predicting or overcoming drug resistance.

in PLOS Computational Biology: New Articles on November 04, 2019 10:00 PM.

• #### Bayesian inference of metabolic kinetics from genome-scale multiomics data

by Peter C. St. John, Jonathan Strutz, Linda J. Broadbelt, Keith E. J. Tyo, Yannick J. Bomble

Modern biological tools generate a wealth of data on metabolite and protein concentrations that can be used to help inform new strain designs. However, learning from these data to predict how a cell will respond to genetic changes, a key need for engineering, remains challenging. A promising technique for leveraging omics measurements in metabolic modeling involves the construction of kinetic descriptions of the enzymatic reactions that occur within a cell. Parameterizing these models from biological data can be computationally difficult, since methods must also quantify the uncertainty in model parameters resulting from the observed data. While the field of Bayesian inference offers a wide range of methods for efficiently estimating distributions in parameter uncertainty, such techniques are poorly suited to traditional kinetic models due to their complex rate laws and resulting nonlinear dynamics. In this paper, we employ linear-logarithmic kinetics to simplify the calculation of steady-state flux distributions and enable efficient sampling and inference methods. We demonstrate that detailed information on the posterior distribution of parameters can be obtained efficiently at a variety of problem scales, including nearly genome-scale kinetic models trained on multiomics datasets. These results allow modern Bayesian machine learning tools to be leveraged in understanding biological data and in developing new, efficient strain designs.

in PLOS Computational Biology: New Articles on November 04, 2019 10:00 PM.

• #### Novel comparison of evaluation metrics for gene ontology classifiers reveals drastic performance differences

by Ilya Plyusnin, Liisa Holm, Petri Törönen

Automated protein annotation using the Gene Ontology (GO) plays an important role in the biosciences. Evaluation has always been considered central to developing novel annotation methods, but little attention has been paid to the evaluation metrics themselves. Evaluation metrics define how well an annotation method performs and allows for them to be ranked against one another. Unfortunately, most of these metrics were adopted from the machine learning literature without establishing whether they were appropriate for GO annotations. We propose a novel approach for comparing GO evaluation metrics called Artificial Dilution Series (ADS). Our approach uses existing annotation data to generate a series of annotation sets with different levels of correctness (referred to as their signal level). We calculate the evaluation metric being tested for each annotation set in the series, allowing us to identify whether it can separate different signal levels. Finally, we contrast these results with several false positive annotation sets, which are designed to expose systematic weaknesses in GO assessment. We compared 37 evaluation metrics for GO annotation using ADS and identified drastic differences between metrics. We show that some metrics struggle to differentiate between different signal levels, while others give erroneously high scores to the false positive data sets. Based on our findings, we provide guidelines on which evaluation metrics perform well with the Gene Ontology and propose improvements to several well-known evaluation metrics. In general, we argue that evaluation metrics should be tested for their performance and we provide software for this purpose (https://bitbucket.org/plyusnin/ads/). ADS is applicable to other areas of science where the evaluation of prediction results is non-trivial.

in PLOS Computational Biology: New Articles on November 04, 2019 10:00 PM.

• #### Feasibility of functional magnetic resonance imaging of ocular dominance and orientation preference in primary visual cortex

by Marilia Menezes de Oliveira, James C. Pang, Peter A. Robinson, Xiaochen Liu, Mark M. Schira

A recent hemodynamic model is extended and applied to simulate and explore the feasibility of detecting ocular dominance (OD) and orientation preference (OP) columns in primary visual cortex by means of functional magnetic resonance imaging (fMRI). The stimulation entails a short oriented bar stimulus being presented to one eye and mapped to cortical neurons with corresponding OD and OP selectivity. Activated neurons project via patchy connectivity to excite other neurons with similar OP in nearby visual fields located preferentially along the direction of stimulus orientation. The resulting blood oxygen level dependent (BOLD) response is estimated numerically via the model’s spatiotemporal hemodynamic response function. The results are then used to explore the feasibility of detecting spatial OD-OP modulation, either directly measuring BOLD or by using Wiener deconvolution to filter the image and estimate the underlying neural activity. The effect of noise is also considered and it is estimated that direct detection can be robust for fMRI resolution of around 0.5 mm, whereas detection with Wiener deconvolution is possible at a broader range from 0.125 mm to 1 mm resolution. The detection of OD-OP features is strongly dependent on hemodynamic parameters, such as low velocity and high damping reduce response spreads and result in less blurring. The short-bar stimulus that gives the most detectable response is found to occur when neural projections are at 45 relative to the edge of local OD boundaries, which provides a constraint on the OD-OP architecture even when it is not fully resolved.

in PLOS Computational Biology: New Articles on November 04, 2019 10:00 PM.

## Objective

Autism spectrum disorder (ASD) affects 1 in 59 children, yet except for rare genetic causes, the etiology in most ASD remains unknown. In the ASD brain, inflammatory cytokine and transcript profiling shows increased expression of genes encoding mediators of the innate immune response. We evaluated postmortem brain tissue for adaptive immune cells and immune cell–mediated cytotoxic damage that could drive this innate immune response in the ASD brain.

## Methods

Standard neuropathology diagnostic methods including histology and immunohistochemistry were extended with automated image segmentation to quantify identified pathologic features in the postmortem brains.

## Results

We report multifocal perivascular lymphocytic cuffs contain increased numbers of lymphocytes in ~65% of ASD compared to control brains in males and females, across all ages, in most brain regions, and in white and gray matter, and leptomeninges. CD3+ T lymphocytes predominate over CD20+ B lymphocytes and CD8+ over CD4+ T lymphocytes in ASD brains. Importantly, the perivascular cuff lymphocyte numbers correlate to the quantity of astrocyte‐derived round membranous blebs. Membranous blebs form as a cytotoxic reaction to lymphocyte attack. Consistent with multifocal immune cell–mediated injury at perivascular cerebrospinal fluid (CSF)–brain barriers, a subset of white matter vessels have increased perivascular space (with jagged contours) and collagen in ASD compared to control brains. CSF–brain barrier pathology is also evident at cerebral cortex pial and ventricular ependymal surfaces in ASD.

## Interpretation

The findings suggest dysregulated cellular immunity damages astrocytes at foci along the CSF–brain barrier in ASD. ANN NEUROL 2019

• #### Inception loops discover what excites neurons most using deep predictive models

Nature Neuroscience, Published online: 04 November 2019; doi:10.1038/s41593-019-0517-x

The authors develop a deep learning approach that enables an efficient search of the input space to find the best stimuli for modeled neurons. When tested, these stimuli are most effective at driving their matching cells in the brain.

in Nature Neuroscience - Issue - nature.com science feeds on November 04, 2019 12:00 AM.

• #### Identity domains capture individual differences from across the behavioral repertoire

Nature Neuroscience, Published online: 04 November 2019; doi:10.1038/s41593-019-0516-y

Forkosh, Karamihalev and colleagues present a framework for inferring stable traits from a broad range of behavioral readouts and apply it to capture biologically relevant individual differences in mice.

in Nature Neuroscience - Issue - nature.com science feeds on November 04, 2019 12:00 AM.

• #### Author Correction: Inhibitory connectivity defines the realm of excitatory plasticity

Nature Neuroscience, Published online: 01 November 2019; doi:10.1038/s41593-019-0546-5

Author Correction: Inhibitory connectivity defines the realm of excitatory plasticity

in Nature Neuroscience - Issue - nature.com science feeds on November 01, 2019 12:00 AM.

• #### Sensory and Motor Conduction Velocity in Spontaneously Hypertensive Rats: Sex and Aging Investigation

The literature is extensive on how hypertension affects the morphology and function of the central nervous system (CNS) and is being focused on multiple organ damage involving the kidneys, heart, endothelium and retina. Hypertension damage to the peripheral nervous system is less explored in the literature. We have previously shown morphometric alterations in large and small caliber myelinated fibers of nerves in the adult spontaneously hypertensive rat (SHR). However, the functional correlation of these findings has not been explored. We performed an electrophysiological investigation of hind limb nerves in SHR of both genders in different ages. Normotensive Wistar-Kyoto (WKY) rats were used as controls. Electrophysiological recordings and determination of motor (MCV) and sensory (SCV) nerve conduction velocity were performed in the same animals at four different ages: 5, 8, 20 and 40 weeks after birth. Comparisons were made between ages, genders and animal strain. We showed a continuous body weight increase in adult life in all animals studied. MCV got stable at 20-week old hypertensive animals and continued to increase in normotensive ones. The SCV was constant between the ages of 20 and 40 weeks old in female SHR and decreased in male SHR while it continued to increase in WKY animals. The electrophysiological investigation of the nerves in WKY and SHR from both genders and different ages, associated with morphological and morphometric data from the literature suggest that hypertension affects the nerve function and might corroborate the development of a peripheral neuropathy.

in Frontiers in Systems Neuroscience | New and Recent Articles on November 01, 2019 12:00 AM.

• #### Multiple Functions of KBP in Neural Development Underlie Brain Anomalies in Goldberg-Shprintzen Syndrome

Kinesin-binding protein (KBP; KIF1BP; KIAA1279) functions as a regulator for a subset of kinesins, many of which play important roles in neural development. Previous studies have shown that KBP is expressed in nearly all tissue with cytoplasmic localization. Autosomal recessive mutations in KIAA1279 cause a rare neurological disorder, Goldberg-Shprintzen syndrome (GOSHS), characterized by microcephaly, polymicrogyria, intellectual disability, axonal neuropathy, thin corpus callosum and peripheral neuropathy. Most KIAA1279 mutations found in GOSHS patients are homozygous nonsense mutations that result in KBP loss-of-function. However, it is not fully understood how KBP dysfunction causes these defects. Here, we used in utero electroporation (IUE) to express KBP short hairpin RNA (shRNA) with green fluorescent protein (GFP) in neural progenitor cells of embryonic day (E) 14 mice, and collected brain slices at different developmental stages. By immunostaining of neuronal lineage markers, we found that KBP knockdown does not affect the neural differentiation process. However, at 4 days post IUE, many cells were located in the intermediate zone (IZ). Moreover, at postnatal day (P) 6, about one third of the cells, which have become mature neurons, remained ectopically in the white matter (WM), while cells that have reached Layer II/III of the cortex showed impaired dendritic outgrowth and axonal projection. We also found that KBP knockdown induces apoptosis during the postnatal period. Our findings indicate that loss of KBP function leads to defects in neuronal migration, morphogenesis, maturation, and survival, which may be responsible for brain phenotypes observed in GOSHS.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 01, 2019 12:00 AM.

• #### Prion-Like Propagation of Protein Misfolding and Aggregation in Amyotrophic Lateral Sclerosis

The discovery that prion protein can misfold into a pathological conformation that encodes structural information capable of both propagation and inducing severe neuropathology has revolutionized our understanding of neurodegenerative disease. Many neurodegenerative diseases with a protein misfolding component are now classified as “prion-like” owing to the propagation of both symptoms and protein aggregation pathology in affected individuals. The neuromuscular disorder amyotrophic lateral sclerosis (ALS) is characterized by protein inclusions formed by either TAR DNA-binding protein of 43 kDa (TDP-43), Cu/Zn superoxide dismutase (SOD1), or fused in sarcoma (FUS), in both upper and lower motor neurons. Evidence from in vitro, cell culture, and in vivo studies has provided strong evidence to support the involvement of a prion-like mechanism in ALS. In this article, we review the evidence suggesting that prion-like propagation of protein aggregation is a primary pathomechanism in ALS, focusing on the key proteins and genes involved in disease (TDP-43, SOD1, FUS, and C9orf72). In each case, we discuss the evidence ranging from biophysical studies to in vivo examinations of prion-like spreading. We suggest that the idiopathic nature of ALS may stem from its prion-like nature and that elucidation of the specific propagating protein assemblies is paramount to developing effective therapies.

in Frontiers in Molecular Neuroscience | New and Recent Articles on November 01, 2019 12:00 AM.

• #### Reductions in COQ2 Expression Relate to Reduced ATP Levels in Multiple System Atrophy Brain

Multiple system atrophy (MSA) is a progressive neurodegenerative disease clinically characterized by parkinsonism and cerebellar ataxia, and pathologically by oligodendrocyte α-synuclein inclusions. Genetic variants of COQ2 are associated with an increased risk for MSA in certain populations. Also, deficits in the level of coenzyme Q10 and its biosynthetic enzymes are associated with MSA. Here, we measured ATP levels and expression of biosynthetic enzymes for coenzyme Q10, including COQ2, in multiple regions of MSA and control brains. We found a reduction in ATP levels in disease-affected regions of MSA brain that associated with reduced expression of COQ2 and COQ7, supporting the concept that abnormalities in the biosynthesis of coenzyme Q10 play an important role in the pathogenesis of MSA.

in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on November 01, 2019 12:00 AM.

• #### Diminished Frontal Theta Activity During Gaming in Young Adults With Internet Gaming Disorder

Cognitive control is essential for flexible, top-down, goal-directed behavior. Individuals with Internet gaming disorder (IGD) are characterized by impaired prefrontal cortex function and cognitive control. This results in an increase in stimulus-driven habitual behavior, particularly related to pathological gaming. In the present study, we investigated the electroencephalographic (EEG) activity in individuals with IGD. Twenty-four individuals with IGD and 35 healthy control (HC) subjects were recruited. We analyzed their EEG activity while the subjects played their favorite game (30–40 min duration). We compared the band power between the two groups. During gaming, the left frontal theta, alpha, and beta band activities were lower in subjects with IGD than in HCs. Moreover, the left frontal theta power negatively correlated with IGD severity. These results indicate that left frontal theta power could be used as a neurophysiological biomarker for the detection of diminished cognitive control patterns in individuals with IGD.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on November 01, 2019 12:00 AM.

• #### Characteristics of Kinematic Parameters in Decoding Intended Reaching Movements Using Electroencephalography (EEG)

The utility of premovement electroencephalography (EEG) for decoding movement intention during a reaching task has been demonstrated. However, the kind of information the brain represents regarding the intended target during movement preparation remains unknown. In the present study, we investigated which movement parameters (i.e., direction, distance, and positions for reaching) can be decoded in premovement EEG decoding. Eight participants performed 30 types of reaching movements that consisted of 1 of 24 movement directions, 7 movement distances, 5 horizontal target positions, and 5 vertical target positions. Event-related spectral perturbations were extracted using independent components, some of which were selected via an analysis of variance for further binary classification analysis using a support vector machine. When each parameter was used for class labeling, all possible binary classifications were performed. Classification accuracies for direction and distance were significantly higher than chance level, although no significant differences were observed for position. For the classification in which each movement was considered as a different class, the parameters comprising two vectors representing each movement were analyzed. In this case, classification accuracies were high when differences in distance were high, the sum of distances was high, angular differences were large, and differences in the target positions were high. The findings further revealed that direction and distance may provide the largest contributions to movement. In addition, regardless of the parameter, useful features for classification are easily found over the parietal and occipital areas.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on November 01, 2019 12:00 AM.

• #### Activation of Corticothalamic Layer 6 Cells Decreases Angular Tuning in Mouse Barrel Cortex

In the mouse whisker system, the contribution of L6 corticothalamic cells (L6 CT) to cortical and thalamic processing of the whisker deflection direction was investigated. A genetically defined population of L6 CT cells project to infragranular GABAergic interneurons that hyperpolarize neurons in somatosensory barrel cortex (BC). Optogenetic activation of these neurons switched BC to an adapted mode in which excitatory cells lost their angular tuning. In contrast, however, this was not the case with a general activation of inhibitory interneurons via optogenetic activation of Gad2-expressing cells. The decrease in angular tuning, when L6 CT cells were activated, was due to changes in cortical inhibition, and not inherited from changes in the thalamic output. Furthermore, L6 CT driven cortical inhibition, but not the general activation of GABAergic interneurons, abolished adaptation to whisker responses. In the present study, evidence is presented that a subpopulation of L6 CT activates a specific circuit of GABAergic interneurons that will predispose neocortex toward processing of tactile information requiring multiple whisker touches, such as in a texture discrimination task.

in Frontiers in Neural Circuits | New and Recent Articles on November 01, 2019 12:00 AM.

• #### Subscription and Copyright Information

in Trends in Neurosciences on November 01, 2019 12:00 AM.

• #### Editorial Board and Contents

in Trends in Neurosciences on November 01, 2019 12:00 AM.

• #### Bespoke genomic regulation

Nature Reviews Neuroscience, Published online: 31 October 2019; doi:10.1038/s41583-019-0241-2

Dendritic activation and action potentials lead to the expression of distinct heterodimers of the inducible transcription factor NPAS4, which show distinct DNA binding patterns; these patterns were recapitulated on exposure of mice to a novel environment.

in Nature Reviews Neuroscience - Issue - nature.com science feeds on October 31, 2019 12:00 AM.

• #### SK Channel Modulates Synaptic Plasticity by Tuning CaMKIIα/β Dynamics

N-Methyl-D-Aspartate Receptor 1 (NMDAR)-linked Ca++ current represents a significant percentage of post-synaptic transient that modulates synaptic strength and is pertinent to dendritic spine plasticity. In the hippocampus, Ca++ transient produced by glutamatergic ionotropic neurotransmission facilitates Ca++-Calmodulin-dependent kinase 2 (CaMKII) Thr286 phosphorylation and promote long-term potentiation (LTP) expression. At CA1 post-synaptic densities, Ca++ transients equally activate small conductance (SK2) channel which regulates excitability by suppressing Ca++ movement. Here, we demonstrate that upstream attenuation of GluN1 function in the hippocampus led to a decrease in Thr286 CaMKIIα phosphorylation, and increased SK2 expression. Consistent with the loss of GluN1 function, potentiation of SK channel in wild type hippocampus reduced CaMKIIα expression and abrogate synaptic localization of T286 pCaMKIIα. Our results demonstrate that positive modulation of SK channel at hippocampal synapses likely refine GluN1-linked plasticity by tuning dendritic localization of CaMKIIα.

in Frontiers in Synaptic Neuroscience | New and Recent Articles on October 31, 2019 12:00 AM.

• #### Generalization of Object Localization From Whiskers to Other Body Parts in Freely Moving Rats

Rats can be trained to associate relative spatial locations of objects with the spatial location of rewards. Here we ask whether rats can localize static silent objects with other body parts in the dark, and if so with what resolution. We addressed these questions in trained rats, whose interactions with the objects were tracked at high-resolution before and after whisker trimming. We found that rats can use other body parts, such as trunk and ears, to localize objects. Localization resolution with non-whisking body parts (henceforth, ‘body’) was poorer than that obtained with whiskers, even when left with a single whisker at each side. Part of the superiority of whiskers was obtained via the use of multiple contacts. Transfer from whisker to body localization occurred within one session, provided that body contacts with the objects occurred before whisker trimming, or in the next session otherwise. This transfer occurred whether temporal cues were used for discrimination or when discrimination was based on spatial cues alone. Rats’ decision in each trial was based on the sensory cues acquired in that trial and on decisions and reward locations in previous trials. When sensory cues were acquired by body contacts, rat decisions relied more on the reward location in previous trials. Overall, the results suggest that rats can generalize the idea of relative object location across different body parts, while preferring to rely on whiskers-based localization, which occurs earlier and conveys higher resolution.

in Frontiers in Integrative Neuroscience | New and Recent Articles on October 31, 2019 12:00 AM.

• #### ShuTu: Open-Source Software for Efficient and Accurate Reconstruction of Dendritic Morphology

Neurons perform computations by integrating inputs from thousands of synapses—mostly in the dendritic tree—to drive action potential firing in the axon. One fruitful approach to studying this process is to record from neurons using patch-clamp electrodes, fill the recorded neurons with a substance that allows subsequent staining, reconstruct the three-dimensional architectures of the dendrites, and use the resulting functional and structural data to develop computer models of dendritic integration. Accurately producing quantitative reconstructions of dendrites is typically a tedious process taking many hours of manual inspection and measurement. Here we present ShuTu, a new software package that facilitates accurate and efficient reconstruction of dendrites imaged using bright-field microscopy. The program operates in two steps: (1) automated identification of dendritic processes, and (2) manual correction of errors in the automated reconstruction. This approach allows neurons with complex dendritic morphologies to be reconstructed rapidly and efficiently, thus facilitating the use of computer models to study dendritic structure-function relationships and the computations performed by single neurons.

in Frontiers in Neuroinformatics | New and Recent Articles on October 31, 2019 12:00 AM.

• #### Extracting Reproducible Time-Resolved Resting State Networks Using Dynamic Mode Decomposition

Resting state networks (RSNs) extracted from functional magnetic resonance imaging (fMRI) scans are believed to reflect the intrinsic organization and network structure of brain regions. Most traditional methods for computing RSNs typically assume these functional networks are static throughout the duration of a scan lasting 5–15 min. However, they are known to vary on timescales ranging from seconds to years; in addition, the dynamic properties of RSNs are affected in a wide variety of neurological disorders. Recently, there has been a proliferation of methods for characterizing RSN dynamics, yet it remains a challenge to extract reproducible time-resolved networks. In this paper, we develop a novel method based on dynamic mode decomposition (DMD) to extract networks from short windows of noisy, high-dimensional fMRI data, allowing RSNs from single scans to be resolved robustly at a temporal resolution of seconds. After validating the method on a synthetic dataset, we analyze data from 120 individuals from the Human Connectome Project and show that unsupervised clustering of DMD modes discovers RSNs at both the group (gDMD) and the single subject (sDMD) levels. The gDMD modes closely resemble canonical RSNs. Compared to established methods, sDMD modes capture individualized RSN structure that both better resembles the population RSN and better captures subject-level variation. We further leverage this time-resolved sDMD analysis to infer occupancy and transitions among RSNs with high reproducibility. This automated DMD-based method is a powerful tool to characterize spatial and temporal structures of RSNs in individual subjects.

in Frontiers in Computational Neuroscience | New and Recent Articles on October 31, 2019 12:00 AM.

• #### Noise correlations and perceptual inference

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Mihály Bányai, Gergő Orbán

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Decoding and encoding (de)mixed population responses

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Sander W Keemink, Christian K Machens

A central tenet of neuroscience is that the brain works through large populations of interacting neurons. With recent advances in recording techniques, the inner working of these populations has come into full view. Analyzing the resulting large-scale data sets is challenging because of the often complex and ‘mixed’ dependency of neural activities on experimental parameters, such as stimuli, decisions, or motor responses. Here we review recent insights gained from analyzing these data with dimensionality reduction methods that ‘demix’ these dependencies. We demonstrate that the mappings from (carefully chosen) experimental parameters to population activities appear to be typical and stable across tasks, brain areas, and animals, and are often identifiable by linear methods. By considering when and why dimensionality reduction and demixing work well, we argue for a view of population coding in which populations represent (demixed) latent signals, corresponding to stimuli, decisions, motor responses, and so on. These latent signals are encoded into neural population activity via non-linear mappings and decoded via linear readouts. We explain how such a scheme can facilitate the propagation of information across cortical areas, and we review neural network architectures that can reproduce the encoding and decoding of latent signals in population activities. These architectures promise a link from the biophysics of single neurons to the activities of neural populations.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Visual novelty, curiosity, and intrinsic reward in machine learning and the brain

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Andrew Jaegle, Vahid Mehrpour, Nicole Rust

A strong preference for novelty emerges in infancy and is prevalent across the animal kingdom. When incorporated into reinforcement-based machine learning algorithms, visual novelty can act as an intrinsic reward signal that vastly increases the efficiency of exploration and expedites learning, particularly in situations where external rewards are difficult to obtain. Here we review parallels between recent developments in novelty-driven machine learning algorithms and our understanding of how visual novelty is computed and signaled in the primate brain. We propose that in the visual system, novelty representations are not configured with the principal goal of detecting novel objects, but rather with the broader goal of flexibly generalizing novelty information across different states in the service of driving novelty-based learning.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### A common probabilistic framework for perceptual and statistical learning

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): József Fiser, Gábor Lengyel

System-level learning of sensory information is traditionally divided into two domains: perceptual learning that focuses on acquiring knowledge suitable for fine discrimination between similar sensory inputs, and statistical learning that explores the mechanisms that develop complex representations of unfamiliar sensory experiences. The two domains have been typically treated in complete separation both in terms of the underlying computational mechanisms and the brain areas and processes implementing those computations. However, a number of recent findings in both domains call in question this strict separation. We interpret classical and more recent results in the general framework of probabilistic computation, provide a unifying view of how various aspects of the two domains are interlinked, and suggest how the probabilistic approach can also alleviate the problem of dealing with widely different types of neural correlates of learning. Finally, we outline several directions along which our proposed approach fosters new types of experiments that can promote investigations of natural learning in humans and other species.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Learning predictive structure without a teacher: decision strategies and brain routes

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Zoe Kourtzi, Andrew E Welchman

Extracting the structure of complex environments is at the core of our ability to interpret the present and predict the future. This skill is important for a range of behaviours from navigating a new city to learning music and language. Classical approaches that investigate our ability to extract the principles of organisation that govern complex environments focus on reward-based learning. Yet, the human brain is shown to be expert at learning generative structure based on mere exposure and without explicit reward. Individuals are shown to adapt to–unbeknownst to them–changes in the environment’s temporal statistics and predict future events. Further, we present evidence for a common brain architecture for unsupervised structure learning and reward-based learning, suggesting that the brain is built on the premise that ‘learning is its own reward’ to support adaptive behaviour.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### The distinct methylation landscape of maturing neurons and its role in Rett syndrome pathogenesis

Publication date: December 2019

Source: Current Opinion in Neurobiology, Volume 59

Author(s): Laura A Lavery, Huda Y Zoghbi

Rett syndrome (RTT) is one of the most common causes of intellectual and developmental disabilities in girls, and is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). Here we will review our current understanding of RTT, the landscape of pathogenic mutations and function of MeCP2, and culminate with recent advances elucidating the distinct DNA methylation landscape in the brain that may explain why disease symptoms are delayed and selective to the nervous system.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Neuroscience out of control: control-theoretic perspectives on neural circuit dynamics

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Ta-Chu Kao, Guillaume Hennequin

A major challenge in systems neuroscience is to understand how the dynamics of neural circuits give rise to behaviour. Analysis of complex dynamical systems is also at the heart of control engineering, where it is central to the design of robust control strategies. Although a rich engineering literature has grown over decades to facilitate the analysis of such systems, little of it has percolated into neuroscience so far. Here, we give a brief introduction to a number of core control-theoretic concepts that provide useful perspectives on neural circuit dynamics. We introduce important mathematical tools related to these concepts, and establish connections to neural circuit analysis, focusing on a number of themes that have arisen from the modern ‘state-space’ view on neural population dynamics.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Functional flexibility in cortical circuits

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Jessica A Cardin

Cortical networks receive a highly variable stream of inputs from internal and external influences, and must flexibly adapt their operations on a short timescale. Recent work has highlighted this state-dependent functional flexibility of cortical circuits and provided initial insights into underlying circuit-level mechanisms. Transitions from quiescent to aroused or task-engaged behavioral states are associated with common motifs of network activity, including changes in correlations and enhanced sensory encoding. Evidence points to a key role for selective activation of specific GABAergic interneuron populations in mediating mode-switching in cortical networks. Finally, inhibitory interneurons may function as a critical target for convergent state-dependent neuromodulatory sculpting of cortical circuits.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### V1 microcircuits underlying mouse visual behavior

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Steffen Katzner, Gregory Born, Laura Busse

Visual behavior is based on the concerted activity of neurons in visual areas, where sensory signals are integrated with top-down information. In the past decade, the advent of new tools, such as functional imaging of populations of identified single neurons, high-density electrophysiology, virus-assisted circuit mapping, and precisely timed, cell-type specific manipulations, has advanced our understanding of the neuronal microcircuits underlying visual behavior. Studies in head-fixed mice, where such tools can routinely be applied, begin to provide new insights into the neural code of primary visual cortex (V1) underlying visual perception, and the micro-circuits of attention, predictive processing, and learning.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Causes and consequences of representational drift

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Michael E Rule, Timothy O’Leary, Christopher D Harvey

The nervous system learns new associations while maintaining memories over long periods, exhibiting a balance between flexibility and stability. Recent experiments reveal that neuronal representations of learned sensorimotor tasks continually change over days and weeks, even after animals have achieved expert behavioral performance. How is learned information stored to allow consistent behavior despite ongoing changes in neuronal activity? What functions could ongoing reconfiguration serve? We highlight recent experimental evidence for such representational drift in sensorimotor systems, and discuss how this fits into a framework of distributed population codes. We identify recent theoretical work that suggests computational roles for drift and argue that the recurrent and distributed nature of sensorimotor representations permits drift while limiting disruptive effects. We propose that representational drift may create error signals between interconnected brain regions that can be used to keep neural codes consistent in the presence of continual change. These concepts suggest experimental and theoretical approaches to studying both learning and maintenance of distributed and adaptive population codes.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### 25 years of criticality in neuroscience — established results, open controversies, novel concepts

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): J Wilting, V Priesemann

Twenty-five years ago, Dunkelmann and Radons (1994) showed that neural networks can self-organize to a critical state. In models, the critical state offers a number of computational advantages. Thus this hypothesis, and in particular the experimental work by Beggs and Plenz (2003), has triggered an avalanche of research, with thousands of studies referring to it. Nonetheless, experimental results are still contradictory. How is it possible, that a hypothesis has attracted active research for decades, but nonetheless remains controversial? We discuss the experimental and conceptual controversy, and then present a parsimonious solution that (i) unifies the contradictory experimental results, (ii) avoids disadvantages of a critical state, and (iii) enables rapid, adaptive tuning of network properties to task requirements.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Harnessing behavioral diversity to understand neural computations for cognition

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Simon Musall, Anne E Urai, David Sussillo, Anne K Churchland

With the increasing acquisition of large-scale neural recordings comes the challenge of inferring the computations they perform and understanding how these give rise to behavior. Here, we review emerging conceptual and technological advances that begin to address this challenge, garnering insights from both biological and artificial neural networks. We argue that neural data should be recorded during rich behavioral tasks, to model cognitive processes and estimate latent behavioral variables. Careful quantification of animal movements can also provide a more complete picture of how movements shape neural dynamics and reflect changes in brain state, such as arousal or stress. Artificial neural networks (ANNs) could serve as artificial model organisms to connect neural dynamics and rich behavioral data. ANNs have already begun to reveal how a wide range of different behaviors can be implemented, generating hypotheses about how observed neural activity might drive behavior and explaining diversity in behavioral strategies.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Autophagy and synaptic plasticity: epigenetic regulation

Publication date: December 2019

Source: Current Opinion in Neurobiology, Volume 59

Author(s): Jee-Yeon Hwang, Jingqi Yan, Ruth Suzanne Zukin

In neurons, autophagy is crucial to proper axon guidance, vesicular release, dendritic spine architecture, spine pruning and synaptic plasticity and, when dysregulated, is associated with brain disorders, including autism spectrum disorders, and neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Once thought to play a housekeeping function of removing misfolded proteins or compromised organelles, neuronal autophagy is now regarded as a finely tuned, real time surveillance and clearance system crucial to synaptic integrity and function. Here we review the role of autophagy in synaptic plasticity and its regulation by epigenetic mechanisms.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Transgenerational epigenetic inheritance: from phenomena to molecular mechanisms

Publication date: December 2019

Source: Current Opinion in Neurobiology, Volume 59

Author(s): Noa Liberman, Simon Yuan Wang, Eric Lieberman Greer

Inherited information not encoded in the DNA sequence can regulate a variety of complex phenotypes. However, how this epigenetic information escapes the typical epigenetic erasure that occurs upon fertilization and how it regulates behavior is still unclear. Here we review recent examples of brain related transgenerational epigenetic inheritance and delineate potential molecular mechanisms that could regulate how non-genetic information could be transmitted.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Object shape and surface properties are jointly encoded in mid-level ventral visual cortex

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Anitha Pasupathy, Taekjun Kim, Dina V Popovkina

Recognizing a myriad visual objects rapidly is a hallmark of the primate visual system. Traditional theories of object recognition have focused on how crucial form features, for example, the orientation of edges, may be extracted in early visual cortex and utilized to recognize objects. An alternative view argues that much of early and mid-level visual processing focuses on encoding surface characteristics, for example, texture. Neurophysiological evidence from primate area V4 supports a third alternative — the joint, but independent, encoding of form and texture — that would be advantageous for segmenting objects from the background in natural scenes and for object recognition that is independent of surface texture. Future studies that leverage deep convolutional network models, especially focusing on network failures to match biology and behavior, can advance our insights into how such a joint representation of form and surface properties might emerge in visual cortex.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### Choice (-history) correlations in sensory cortex: cause or consequence?

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Jakob H Macke, Hendrikje Nienborg

One challenge in neuroscience, as in other areas of science, is to make inferences about the underlying causal structure from correlational data. Here, we discuss this challenge in the context of choice correlations in sensory neurons, that is, trial-by-trial correlations, unexplained by the stimulus, between the activity of sensory neurons and an animal’s perceptual choice. Do these choice-correlations reflect feedforward, feedback signalling, both, or neither? We highlight recent results of correlational and causal examinations of choice and choice-history signals in sensory, and in part sensorimotor, cortex and address formal statistical frameworks to infer causal interactions from data.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### The role of adaptation in neural coding

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Alison I Weber, Adrienne L Fairhall

The concept of ‘neural coding’ supposes that neural firing patterns in some sense represent some external correlate, whether sensory, motor, or structural knowledge about the world. While the implied existence of a one-to-one mapping between external referents and neural firing has been useful, the prevalence of adaptation challenges this. Adaptation provides neural responses with dynamics on timescales that range from milliseconds up to many seconds. These timescales are highly relevant for sensory experience in the natural world, in which local statistical properties of inputs change continuously, and are additionally altered by active sensing. Adaptation has a number of consequences for coding: it creates short-term history dependence; it engenders complex feature selectivity that is time-varying; and it can serve to enhance information representation in dynamic environments. Considering how to best incorporate adaptation into neural models exposes a fundamental dichotomy in approaches to the description of neural systems: ones that take an explicitly ‘coding’ perspective versus ones that describe the system’s dynamics. Here we discuss the pros and cons of different approaches to the modeling of adaptive dynamics.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### New perspectives on dimensionality and variability from large-scale cortical dynamics

Publication date: October 2019

Source: Current Opinion in Neurobiology, Volume 58

Author(s): Tatiana A Engel, Nicholas A Steinmetz

The neocortex is a multi-scale network, with intricate local circuitry interwoven into a global mesh of long-range connections. Neural activity propagates within this network on a wide range of temporal and spatial scales. At the micro scale, neurophysiological recordings reveal coordinated dynamics in local neural populations, which support behaviorally relevant computations. At the macro scale, neuroimaging modalities measure global activity fluctuations organized into spatiotemporal patterns across the entire brain. Here we review recent advances linking the local and global scales of cortical dynamics and their relationship to behavior. We argue that diverse experimental observations on the dimensionality and variability of neural activity can be reconciled by considering how activity propagates in space and time on multiple spatial scales.

in ScienceDirect Publication: Current Opinion in Neurobiology on October 30, 2019 01:19 PM.

• #### The Cortico-Basal Ganglia-Cerebellar Network: Past, Present and Future Perspectives

Much of our present understanding of the function and operation of the basal ganglia rests on models of anatomical connectivity derived from tract-tracing approaches in rodents and primates. However, the last years have been characterized by promising step forwards in the in vivo investigation and comprehension of brain connectivity in humans. The aim of this review is to revise the current knowledge on basal ganglia circuits, highlighting similarities and differences across species, in order to widen the current perspective on the intricate model of the basal ganglia system. This will allow us to explore the implications of additional direct pathways running from cortex to basal ganglia and between basal ganglia and cerebellum recently described in animals and humans.

in Frontiers in Systems Neuroscience | New and Recent Articles on October 30, 2019 12:00 AM.

• #### MiR-137 Deficiency Causes Anxiety-Like Behaviors in Mice

Anxiety and depression are major public health concerns worldwide. Although genome-wide association studies have identified several genes robustly associated with susceptibility for these disorders, the molecular and cellular mechanisms associated with anxiety and depression is largely unknown. Reduction of microRNA-137 (miR-137) level has been implicated in the etiology of major depressive disorder. However, little is known about the in vivo impact of the loss of miR-137 on the biology of anxiety and depression. Here, we generated a forebrain-specific miR-137 knockout mouse line, and showed that miR-137 is critical for dendritic and synaptic growth in the forebrain. Mice with miR-137 loss-of-function exhibit anxiety-like behavior, and impaired spatial learning and memory. We then observe an elevated expression of EZH2 in the forebrain of miR-137 knockout mice, and provide direct evidence that knockdown of EZH2 can rescue anxious phenotypes associated with the loss of miR-137. Together our results suggest that loss of miR-137 contributes to the etiology of anxiety, and EZH2 might be a potential therapeutic target for anxiety and depressive phenotypes associated with the dysfunction of miR-137.

in Frontiers in Molecular Neuroscience | New and Recent Articles on October 30, 2019 12:00 AM.

• #### Biomarkers Obtained by Transcranial Magnetic Stimulation of the Motor Cortex in Epilepsy

Epilepsy is associated with numerous neurodevelopmental disorders. Transcranial magnetic stimulation (TMS) of the motor cortex coupled with electromyography (EMG) enables biomarkers that provide measures of cortical excitation and inhibition that are particularly relevant to epilepsy and related disorders. The motor threshold (MT), cortical silent period (CSP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long interval intracortical inhibition (LICI) are among TMS-derived metrics that are modulated by antiepileptic drugs. TMS may have a practical role in optimization of antiepileptic medication regimens, as studies demonstrate dose-dependent relationships between TMS metrics and acute medication administration. A close association between seizure freedom and normalization of cortical excitability with long-term antiepileptic drug use highlights a plausible utility of TMS in measures of anti-epileptic drug efficacy. Finally, TMS-derived biomarkers distinguish patients with various epilepsies from healthy controls and thus may enable development of disorder-specific biomarkers and therapies both within and outside of the epilepsy realm.

in Frontiers in Integrative Neuroscience | New and Recent Articles on October 30, 2019 12:00 AM.

• #### Accelerated Intermittent Theta-Burst Stimulation as a Treatment for Cocaine Use Disorder: A Proof-of-Concept Study

There are no effective treatments for cocaine use disorder (CUD), a chronic, relapsing brain disease characterized by dysregulated circuits related to cue reactivity, reward processing, response inhibition, and executive control. Transcranial magnetic stimulation (TMS) has the potential to modulate circuits and networks implicated in neuropsychiatric disorders, including addiction. Although acute applications of TMS have reduced craving in urine-negative cocaine users, the tolerability and safety of administering accelerated TMS to cocaine-positive individuals is unknown. As such, we performed a proof-of-concept study employing an intermittent theta-burst stimulation (iTBS) protocol in an actively cocaine-using sample. Although our main goal was to assess the tolerability and safety of administering three iTBS sessions daily, we also hypothesized that iTBS would reduce cocaine use in this non-treatment seeking cohort. We recruited 19 individuals with CUD to receive three open-label iTBS sessions per day, with approximately a 60-min interval between sessions, for 10 days over a 2-week period (30 total iTBS sessions). iTBS was delivered to left dorsolateral prefrontal cortex (dlPFC) with neuronavigation guidance. Compliance and safety were assessed throughout the trial. Cocaine use behavior was assessed before, during, and after the intervention and at 1- and 4-week follow-up visits. Of the 335 iTBS sessions applied, 73% were performed on participants with cocaine-positive urine tests. Nine of the 14 participants who initiated treatment received at least 26 of 30 iTBS sessions and returned for the 4-week follow-up visit. These individuals reduced their weekly cocaine consumption by 78% in amount of dollars spent and 70% in days of use relative to pre-iTBS cocaine use patterns. Similarly, individuals reduced their weekly consumption of nicotine, alcohol, and THC, suggesting iTBS modulated a common circuit across drugs of abuse. iTBS was well-tolerated, despite the expected occasional headaches. A single participant developed a transient neurological event of uncertain etiology on iTBS day 9 and cocaine-induced psychosis 2 weeks after discontinuation. It thus appears that accelerated iTBS to left dlPFC administered in active, chronic cocaine users is both feasible and tolerable in actively using cocaine participants with preliminary indications of efficacy in reducing both the amount and frequency of cocaine (and other off target drug) use. The neural underpinnings of these behavioral changes could help in the future development of effective treatment of CUD.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on October 30, 2019 12:00 AM.

• #### Two Neural Circuits to Point Towards Home Position After Passive Body Displacements

A challenge in motor control research is to understand the mechanisms underlying the transformation of sensory information into arm motor commands. Here, we investigated these transformation mechanisms for movements whose targets were defined by information issued from body rotations in the dark (i.e., idiothetic information). Immediately after being rotated, participants reproduced the amplitude of their perceived rotation using their arm (Experiment 1). The cortical activation during movement planning was analyzed using electroencephalography and source analyses. Task-related activities were found in regions of interest (ROIs) located in the prefrontal cortex (PFC), dorsal premotor cortex, dorsal region of the anterior cingulate cortex (ACC) and the sensorimotor cortex. Importantly, critical regions for the cognitive encoding of space did not show significant task-related activities. These results suggest that arm movements were planned using a sensorimotor-type of spatial representation. However, when a 8 s delay was introduced between body rotation and the arm movement (Experiment 2), we found that areas involved in the cognitive encoding of space [e.g., ventral premotor cortex (vPM), rostral ACC, inferior and superior posterior parietal cortex (PPC)] showed task-related activities. Overall, our results suggest that the use of a cognitive-type of representation for planning arm movement after body motion is necessary when relevant spatial information must be stored before triggering the movement.

in Frontiers in Neural Circuits | New and Recent Articles on October 30, 2019 12:00 AM.

• #### A Biologically-Inspired Model to Predict Perceived Visual Speed as a Function of the Stimulated Portion of the Visual Field

Spatial orientation relies on a representation of the position and orientation of the body relative to the surrounding environment. When navigating in the environment, this representation must be constantly updated taking into account the direction, speed, and amplitude of body motion. Visual information plays an important role in this updating process, notably via optical flow. Here, we systematically investigated how the size and the simulated portion of the field of view (FoV) affect perceived visual speed of human observers. We propose a computational model to account for the patterns of human data. This model is composed of hierarchical cells' layers that model the neural processing stages of the dorsal visual pathway. Specifically, we consider that the activity of the MT area is processed by populations of modeled MST cells that are sensitive to the differential components of the optical flow, thus producing selectivity for specific patterns of optical flow. Our results indicate that the proposed computational model is able to describe the experimental evidence and it could be used to predict expected biases of speed perception for conditions in which only some portions of the visual field are visible.

in Frontiers in Neural Circuits | New and Recent Articles on October 30, 2019 12:00 AM.

• #### Global vs. Network-Specific Regulations as the Source of Intrinsic Coactivations in Resting-State Networks

Spontaneous neural activities are endowed with specific patterning characterized by synchronizations within functionally relevant distant regions that are termed as resting-state networks (RSNs). Although the mechanisms that organize the large-scale neural systems are still largely unknown, recent studies have proposed a hypothesis that network-specific coactivations indeed emerge as the result of globally propagating neural activities with specific paths of transmission. However, the extent to which such a centralized global regulation, rather than network-specific control, contributes to the RSN synchronization remains unknown. In the present study, we investigated the contribution from each mechanism by directly identifying the global as well as local component of resting-state functional MRI (fMRI) data provided by human connectome project, using temporal independent component analysis (ICA). Based on the spatial distribution pattern, each ICA component was classified as global or local. Time lag mapping of each IC revealed several paths of global or semi-global propagations that are partially overlapping yet spatially distinct to each other. Consistent with previous studies, the time lag of global oscillation, although being less spatially homogenous than what was assumed to be, contributed to the RSN synchronization. However, an equivalent contribution was also shown on the part of the more locally confined activities that are independent to each other. While allowing the view that network-specific coactivation occurs as part of the sequences of global neural activities, these results further confirm an equally important role of the network-specific regulation for its coactivation, regardless of whether vascular artifacts contaminate the global component in fMRI measures.

in Frontiers in Systems Neuroscience | New and Recent Articles on October 29, 2019 12:00 AM.

• #### State-Dependent Entrainment of Prefrontal Cortex Local Field Potential Activity Following Patterned Stimulation of the Cerebellar Vermis

The cerebellum is involved in sensorimotor, cognitive, and emotional functions through cerebello-cerebral connectivity. Cerebellar neurostimulation thus likely affects cortical circuits, as has been shown in studies using cerebellar stimulation to treat neurological disorders through modulation of frontal EEG oscillations. Here we studied the effects of different frequencies of cerebellar stimulation on oscillations and coherence in the cerebellum and prefrontal cortex in the urethane-anesthetized rat. Local field potentials were recorded in the right lateral cerebellum (Crus I/II) and bilaterally in the prefrontal cortex (frontal association area, FrA) in adult male Sprague-Dawley rats. Stimulation was delivered to the cerebellar vermis (lobule VII) using single pulses (0.2 Hz for 60 s), or repeated pulses at 1 Hz (30 s), 5 Hz (10 s), 25 Hz (2 s), and 50 Hz (1 s). Effects of stimulation were influenced by the initial state of EEG activity which varies over time during urethane-anesthesia; 1 Hz stimulation was more effective when delivered during the slow-wave state (Stage 1), while stimulation with single-pulse, 25, and 50 Hz showed stronger effects during the activated state (Stage 2). Single-pulses resulted in increases in oscillatory power in the delta and theta bands for the cerebellum, and in frequencies up to 80 Hz in cortical sites. 1 Hz stimulation induced a decrease in 0–30 Hz activity and increased activity in the 30–200 Hz range, in the right FrA. 5 Hz stimulation reduced power in high frequencies in Stage 1 and induced mixed effects during Stage 2.25 Hz stimulation increased cortical power at low frequencies during Stage 2, and increased power in higher frequency bands during Stage 1. Stimulation at 50 Hz increased delta-band power in all recording sites, with the strongest and most rapid effects in the cerebellum. 25 and 50 Hz stimulation also induced state-dependent effects on cerebello-cortical and cortico-cortical coherence at high frequencies. Cerebellar stimulation can therefore entrain field potential activity in the FrA and drive synchronization of cerebello-cortical and cortico-cortical networks in a frequency-dependent manner. These effects highlight the role of the cerebellar vermis in modulating large-scale synchronization of neural networks in non-motor frontal cortex.

in Frontiers in Systems Neuroscience | New and Recent Articles on October 29, 2019 12:00 AM.

• #### Differential Effect of Visual and Proprioceptive Stimulation on Corticospinal Output for Reciprocal Muscles

This study investigated the corticospinal excitability of reciprocal muscles during tasks involving sensory difference between proprioceptive and visual inputs. Participants were instructed to relax their muscles and to observe a screen during vibratory stimulation. A video screen was placed on the board covering the right hand and forearm. Participants were randomly tested in four conditions: resting, control, static, and dynamic. The resting condition involved showing a black screen, the control condition, a mosaic patterned static videoclip; the static condition, a static videoclip of wrist flexion 0°; and the dynamic condition, a videoclip that corresponded to each participant’s closely-matched illusory wrist flexion angle and speed by vibration. Vibratory stimulation (frequency 80 Hz and duration 4 s) was applied to the distal tendon of the dominant right extensor carpi radialis (ECR) using a tendon vibrator in the control, static, and dynamic conditions. Four seconds after the vibratory stimulation (end of vibration), the primary motor cortex at the midpoint between the centers of gravity of the flexor carpi radialis (FCR) and ECR muscles was stimulated by transcranial magnetic stimulation (TMS). The ECR motor evoked potential (MEP) amplitudes significantly increased in the control condition compared to the resting condition, whereas the FCR MEP amplitudes did not change between the resting and control conditions. In addition, the ECR MEP amplitudes significantly increased in the static condition compared to the dynamic condition. However, the FCR MEP amplitudes significantly increased in the dynamic condition compared to the static condition. These results imply that the difference between visuo-proprioceptive information had an effect on corticospinal excitability for the muscle. In conclusion, we found that proprioceptive and visual information differentially altered the corticospinal excitability of reciprocal muscles.

in Frontiers in Integrative Neuroscience | New and Recent Articles on October 29, 2019 12:00 AM.

• #### BAF45D Downregulation in Spinal Cord Ependymal Cells Following Spinal Cord Injury in Adult Rats and Its Potential Role in the Development of Neuronal Lesions

The endogenous spinal cord ependymal cells (SCECs), which form the central canal (CC), are critically involved in proliferation, differentiation and migration after spinal cord injury (SCI) and represents a repair cell source in treating SCI. Previously, we reported that BAF45D is expressed in the SCECs and the spinal cord neurons in adult mice and knockdown of BAF45D fail to induce expression of PAX6, a neurogenic fate determinant, during early neural differentiation of human embryonic stem cells. However, the effects of SCI on expression of BAF45D have not been reported. The aim of this study is to explore the expression and potential role of BAF45D in rat SCI model. In this study, adult rats were randomly divided into intact, sham, and SCI groups. We first explored expression of BAF45D in the SCECs in intact adult rats. We then explored SCI-induced loss of motor neurons and lesion of neurites in the anterior horns induced by the SCI. We also investigated whether the SCI-induced lesions in SCECs are accompanied by the motor neuron lesions. Finally, we examined the effect of BAF45D knockdown on cell growth in neuro2a cells. Our data showed that BAF45D is expressed in SCECs, neurons, and oligodendrocytes but not astrocytes in the spinal cords of intact adult rats. After SCI, the structure of CC was disrupted and the BAF45D-positive SCEC-derivatives were decreased. During the early stages of SCI, when shape of CC was affected but there was no disruption in circular structure of the SCECs, it was evident that there was a significant reduction in the number of neurites and motor neurons in the anterior horns compared with those of intact rats. In comparison, a complete loss of SCECs accompanied by further loss of motor neurons but not neurites was observed at the later stage. BAF45D knockdown was also found to inhibit cell growth in neuro2a cells. These results highlight the decreased expression of BAF45D in SCI-injured SCECs and the potential role of BAF45D downregulation in development of neuronal lesion after SCI in adult rats.

in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on October 29, 2019 12:00 AM.

• #### Network Representations of Facial and Bodily Expressions: Evidence From Multivariate Connectivity Pattern Classification

Emotions can be perceived from both facial and bodily expressions. Our previous study has found the successful decoding of facial expressions based on the functional connectivity (FC) patterns. However, the role of the FC patterns in the recognition of bodily expressions remained unclear, and no neuroimaging studies have adequately addressed the question of whether emotions perceiving from facial and bodily expressions are processed rely upon common or different neural networks. To address this, the present study collected functional magnetic resonance imaging (fMRI) data from a block design experiment with facial and bodily expression videos as stimuli (three emotions: anger, fear, and joy), and conducted multivariate pattern classification analysis based on the estimated FC patterns. We found that in addition to the facial expressions, bodily expressions could also be successfully decoded based on the large-scale FC patterns. The emotion classification accuracies for the facial expressions were higher than that for the bodily expressions. Further contributive FC analysis showed that emotion-discriminative networks were widely distributed in both hemispheres, containing regions that ranged from primary visual areas to higher-level cognitive areas. Moreover, for a particular emotion, discriminative FCs for facial and bodily expressions were distinct. Together, our findings highlight the key role of the FC patterns in the emotion processing, indicating how large-scale FC patterns reconfigure in processing of facial and bodily expressions, and suggest the distributed neural representation for the emotion recognition. Furthermore, our results also suggest that the human brain employs separate network representations for facial and bodily expressions of the same emotions. This study provides new evidence for the network representations for emotion perception and may further our understanding of the potential mechanisms underlying body language emotion recognition.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on October 29, 2019 12:00 AM.

• #### Age-Related Differences in Functional and Structural Connectivity in the Spatial Navigation Brain Network

in Frontiers in Neural Circuits | New and Recent Articles on October 29, 2019 12:00 AM.

• #### Stem-cell-derived human microglia transplanted in mouse brain to study human disease

Nature Neuroscience, Published online: 28 October 2019; doi:10.1038/s41593-019-0525-x

Human stem cell-derived microglia integrate into mouse brain, displaying transcriptome signatures of microglia directly isolated from human brain and providing a chimeric model to study human-specific aspects of Alzheimer’s disease and other brain diseases.

in Nature Neuroscience - Issue - nature.com science feeds on October 28, 2019 12:00 AM.

• #### A deep learning framework for neuroscience

Nature Neuroscience, Published online: 28 October 2019; doi:10.1038/s41593-019-0520-2

A deep network is best understood in terms of components used to design it—objective functions, architecture and learning rules—rather than unit-by-unit computation. Richards et al. argue that this inspires fruitful approaches to systems neuroscience.

in Nature Neuroscience - Issue - nature.com science feeds on October 28, 2019 12:00 AM.

• #### Computational noise in reward-guided learning drives behavioral variability in volatile environments

Nature Neuroscience, Published online: 28 October 2019; doi:10.1038/s41593-019-0518-9

Findling, Skvortsova et al. find that a large fraction of non-greedy decisions that humans make in volatile environments do not stem from exploration but from the limited precision of learning, and further identify its neurophysiological correlates.

in Nature Neuroscience - Issue - nature.com science feeds on October 28, 2019 12:00 AM.

• #### A neural mechanism for deprivation state-specific expression of relevant memories in Drosophila

Nature Neuroscience, Published online: 28 October 2019; doi:10.1038/s41593-019-0515-z

The Drosophila neuropeptide leucokinin mediates hunger- and thirst-dependent expression of learned behaviors. State-relevant selection of appropriate memory emerges from competition between leucokinin and other modulators onto dopaminergic neurons.

in Nature Neuroscience - Issue - nature.com science feeds on October 28, 2019 12:00 AM.

• #### A Naturalistic Approach to the Hard Problem of Consciousness

Following a brief review of current efforts to identify the neuronal correlates of conscious processing (NCCP) an attempt is made to bridge the gap between the material neuronal processes and the immaterial dimensions of subjective experience. It is argued that this “hard problem” of consciousness research cannot be solved by only considering the neuronal underpinnings of cognition. The proposal is that the hard problem can be treated within a naturalistic framework if one considers not only the biological but also the socio-cultural dimensions of evolution. The argument is based on the following premises: perceptions are the result of a constructivist process that depends on priors. This applies both for perceptions of the outer world and the perception of oneself. Social interactions between agents endowed with the cognitive abilities of humans generated immaterial realities, addressed as social or cultural realities. This novel class of realities assumed the role of priors for the perception of oneself and the embedding world. A natural consequence of these extended perceptions is a dualist classification of observables into material and immaterial phenomena nurturing the concept of ontological substance dualism. It is argued that perceptions shaped by socio-cultural priors lead to the construction of a self-model that has both a material and an immaterial dimension. As priors are implicit and not amenable to conscious recollection the perceived immaterial dimension is experienced as veridical and not derivable from material processes—which is the hallmark of the hard problem. These considerations let the hard problem appear as the result of cognitive constructs that are amenable to naturalistic explanations in an evolutionary framework.

in Frontiers in Systems Neuroscience | New and Recent Articles on October 25, 2019 12:00 AM.

• #### Effects of Noisy Galvanic Vestibular Stimulation During a Bimanual Tracking Robotic Task

Background

Noisy galvanic vestibular stimulation (nGVS) has been shown to improve motor performance in people with and without disabilities. Previous investigations on the use of nGVS to improve upper-limb motor performance have focused on unimanual fine motor movements, nevertheless, bimanual gross movements are also essential for conducting activities of daily living and can be affected as a result of cerebral dysfunction. Consequently, in this study we investigated the effects of nGVS on bimanual gross motor performance.

Methods

Twelve healthy participants completed a visuomotor task in which they performed bimanual upper-limb movements using two robots. During the task, participants tracked a target that oscillated following a sinusoidal amplitude-modulated trajectory. In half of the trials, participants received subthreshold nGVS, in the other half, they received sham stimulation. Primary outcome measure: percent improvement in root mean square error (RMSE) between the target’s and cursors’ trajectories. Secondary outcome measures: percent improvement in lag between the cursors and target; and percent improvement in RMSE between the cursors’ trajectories. A post-test questionnaire was administered to evaluate the experience of participants.

Results

Tracking error was not affected by nGVS: left −2.6(5.5)%, p = 0.128; right −0.9(6.2)%, p = 0.639; nor was bimanual coordination −1.5(9.6)%, p = 0.590. When comparing if one hand was affected more than the other, we did not find a statistically significant difference (−1.7(3.3)%, p = 0.098). Similar results were found for the lag. Questionnaire results indicated that the robotic devices did not limit participants’ movements, did not make participants feel unsafe, nor were they difficult to control. Furthermore, participants did not feel unsafe with the nGVS device, nor did they report any discomfort due to nGVS.

Conclusion

Results suggest that nGVS applied to people without disabilities do not affect bimanual gross motor performance. However, as this was the first study to investigate such effects, stimulation parameters were based on previous unimanual fine motor studies. Future studies should investigate optimal stimulation parameters for improving upper-limb gross motor performance. Overall, participants felt safe using the robotic devices and receiving the noisy electrical stimulation. As such, a similar setup could potentially be employed for subsequent studies investigating the relation between upper-limb performance and nGVS.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on October 25, 2019 12:00 AM.

• #### The Relationship Between Local Field Potentials and the Blood-Oxygenation-Level Dependent MRI Signal Can Be Non-linear

Functional magnetic resonance imaging (fMRI) is currently one of the most important neuroimaging methods in neuroscience. The image contrast in fMRI relies on the blood-oxygenation-level dependent (BOLD) signal, which indirectly reflects neural activity through neurovascular coupling. Because the mechanism that links the BOLD signal to neural activities involves multiple complicated processes, where neural activity, regional metabolism, hemodynamics, and the BOLD signal are all inter-connected, understanding the quantitative relationship between the BOLD signal and the underlying neural activities is crucial for interpreting fMRI data. Simultaneous local field potential (LFP) and fMRI recordings provide a method to study neurovascular coupling. There were a few studies that have shown non-linearities in stimulus related responses, but whether there is any non-linearity in LFP—BOLD relationship at rest has not been specifically quantified. In this study, we analyzed the simultaneous LFP and resting state-fMRI data acquired from rodents, and found that the relationship between LFP and BOLD is non-linear under isoflurane (ISO) anesthesia, but linear under dexmedetomidine (DMED) anesthesia. Subsequent analysis suggests that such non-linearity may come from the non-Gaussian distribution of LFP power and switching from LFP power to LFP amplitude can alleviate the problem to a degree. We also confirmed that, despite the non-linearity in the mean LFP—BOLD curve, the Pearson correlation between the two signals is relatively unaffected.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on October 25, 2019 12:00 AM.

• #### The Impact of the Geometric Correction Scheme on MEG Functional Topology at Rest

Spontaneous activity is correlated across brain regions in large scale networks (RSN) closely resembling those recruited during several behavioral tasks and characterized by functional specialization and dynamic integration. Specifically, MEG studies revealed a set of central regions (dynamic core) possibly facilitating communication among differently specialized brain systems. However, source projected MEG signals, due to the fundamentally ill-posed inverse problem, are affected by spatial leakage, leading to the estimation of spurious, blurred connections that may affect the topological properties of brain networks and their integration. To reduce leakage effects, several correction schemes have been proposed including the Geometric Correction Scheme (GCS) whose theory, simulations and empirical results on topography of a few RSNs were already presented. However, its impact on the estimation of fundamental graph measures used to describe the architecture of interactions among brain regions has not been investigated yet. Here, we estimated dense, MEG band-limited power connectomes in theta, alpha, beta, and gamma bands from 13 healthy subjects (all young adults). We compared the connectivity and topology of MEG uncorrected and GCS-corrected connectomes. The use of GCS considerably reorganized the topology of connectivity, reducing the local, within-hemisphere interactions mainly in the beta and gamma bands and increasing across-hemisphere interactions mainly in the alpha and beta bands. Moreover, the number of hubs decreased in the alpha and beta bands, but the centrality of some fundamental regions such as the Posterior Cingulate Cortex (PCC), Supplementary Motor Area (SMA) and Middle Prefrontal Cortex (MPFC) remained strong in all bands, associated to an increase of the Global Efficiency and a decrease of Modularity. As a comparison, we applied orthogonalization on connectomes and ran the same topological analyses. The correlation values were considerably reduced, and orthogonalization mainly decreased local within-hemisphere interactions in all bands, similarly to GCS. Notably, the centrality of the PCC, SMA and MPFC was preserved in all bands, as for GCS, together with other hubs in the posterior parietal regions. Overall, leakage correction removes spurious local connections, but confirms the role of dynamic hub regions, specifically the anterior and posterior cingulate, in integrating information in the brain at rest.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on October 25, 2019 12:00 AM.

• #### Negatively Linking Connector Networks in Cognitive Control of Affective Pictures

Cognitive control of emotions depends on intermodular long-distance communications. However, negative connections between connector hubs are removed by traditional hard-thresholding approach in graph-theoretical research. Using soft-thresholding approach to reserve negative links, we explore time-varying features of connector hubs in intermodular communications during cognitive control of affective pictures. We develop a novel approach to sparse functional networks and construct negatively linking connector networks for positive, negative, and neutral pictures. We find that consisting of flexible hubs, the frontoparietal system dynamically top–down inhibits neural activities through negative connections from the salience subnetwork and visual processing area. Moreover, the shared connectors form functional backbones that dynamically reconfigure according to differently-valenced pictures in order to coordinate both stability and flexibility of cognitive connector networks. These results reveal the necessity of conserving negative links between intermodular communications in chronnectome research and deepen the understanding of how connector networks dynamically evolute during cognitive control of affective processing.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on October 25, 2019 12:00 AM.

• #### Deep Learning-Based Deep Brain Stimulation Targeting and Clinical Applications

Background

The purpose of the present study was to evaluate deep learning-based image-guided surgical planning for deep brain stimulation (DBS). We developed deep learning semantic segmentation-based DBS targeting and prospectively applied the method clinically.

Methods

T2 fast gradient-echo images from 102 patients were used for training and validation. Manually drawn ground truth information was prepared for the subthalamic and red nuclei with an axial cut ∼4 mm below the anterior–posterior commissure line. A fully convolutional neural network (FCN-VGG-16) was used to ensure margin identification by semantic segmentation. Image contrast augmentation was performed nine times. Up to 102 original images and 918 augmented images were used for training and validation. The accuracy of semantic segmentation was measured in terms of mean accuracy and mean intersection over the union. Targets were calculated based on their relative distance from these segmented anatomical structures considering the Bejjani target.

Results

Mean accuracies and mean intersection over the union values were high: 0.904 and 0.813, respectively, for the 62 training images, and 0.911 and 0.821, respectively, for the 558 augmented training images when 360 augmented validation images were used. The Dice coefficient converted from the intersection over the union was 0.902 when 720 training and 198 validation images were used. Semantic segmentation was adaptive to high anatomical variations in size, shape, and asymmetry. For clinical application, two patients were assessed: one with essential tremor and another with bradykinesia and gait disturbance due to Parkinson’s disease. Both improved without complications after surgery, and microelectrode recordings showed subthalamic nuclei signals in the latter patient.

Conclusion

The accuracy of deep learning-based semantic segmentation may surpass that of previous methods. DBS targeting and its clinical application were made possible using accurate deep learning-based semantic segmentation, which is adaptive to anatomical variations.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on October 24, 2019 12:00 AM.

• #### Fornix Stimulation Induces Metabolic Activity and Dopaminergic Response in the Nucleus Accumbens

The Papez circuit, including the fornix white matter bundle, is a well-known neural network that is involved in multiple limbic functions such as memory and emotional expression. We previously reported a large-animal study of deep brain stimulation (DBS) in the fornix that found stimulation-induced hemodynamic responses in both the medial limbic and corticolimbic circuits on functional resonance imaging (fMRI) and evoked dopamine responses in the nucleus accumbens (NAc), as measured by fast-scan cyclic voltammetry (FSCV). The effects of DBS on the fornix are challenging to analyze, given its structural complexity and connection to multiple neuronal networks. In this study, we extend our earlier work to a rodent model wherein we characterize regional brain activity changes resulting from fornix stimulation using fludeoxyglucose (18F-FDG) micro positron emission tomography (PET) and monitor neurochemical changes using FSCV with pharmacological confirmation. Both global functional changes and local changes were measured in a rodent model of fornix DBS. Functional brain activity was measured by micro-PET, and the neurochemical changes in local areas were monitored by FSCV. Micro-PET images revealed increased glucose metabolism within the medial limbic and corticolimbic circuits. Neurotransmitter efflux induced by fornix DBS was monitored at NAc by FSCV and identified by specific neurotransmitter reuptake inhibitors. We found a significant increase in the metabolic activity in several key regions of the medial limbic circuits and dopamine efflux in the NAc following fornix stimulation. These results suggest that electrical stimulation of the fornix modulates the activity of brain memory circuits, including the hippocampus and NAc within the dopaminergic pathway.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on October 24, 2019 12:00 AM.

• #### Functional MRI Readouts From BOLD and Diffusion Measurements Differentially Respond to Optogenetic Activation and Tissue Heating

Functional blood-oxygenation-level-dependent (BOLD) MRI provides a brain-wide readout that depends on the hemodynamic response to neuronal activity. Diffusion fMRI has been proposed as an alternative to BOLD fMRI and has been postulated to directly rely on neuronal activity. These complementary functional readouts are versatile tools to be combined with optogenetic stimulation to investigate networks of the brain. The cell-specificity and temporal precision of optogenetic manipulations promise to enable further investigation of the origin of fMRI signals. The signal characteristics of the diffusion fMRI readout vice versa may better resolve network effects of optogenetic stimulation. However, the light application needed for optogenetic stimulation is accompanied by heat deposition within the tissue. As both diffusion and BOLD are sensitive to temperature changes, light application can lead to apparent activations confounding the interpretation of fMRI data. The degree of tissue heating, the appearance of apparent activation in different fMRI sequences and the origin of these phenomena are not well understood. Here, we disentangled apparent activations in BOLD and diffusion measurements in rats from physiological activation upon sensory or optogenetic stimulation. Both, BOLD and diffusion fMRI revealed similar signal shapes upon sensory stimulation that differed clearly from those upon heating. Apparent activations induced by high-intensity light application were dominated by T2-effects and resulted in mainly negative signal changes. We estimated that even low-intensity light application used for optogenetic stimulation reduces the BOLD response close to the fiber by up to 0.4%. The diffusion fMRI signal contained T2, T2 and diffusion components. The apparent diffusion coefficient, which reflects the isolated diffusion component, showed negative changes upon both optogenetic and electric forepaw stimulation. In contrast, positive changes were detected upon high-intensity light application and thus ruled out heating as a major contributor to the diffusion fMRI signal.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on October 24, 2019 12:00 AM.

• #### Environmental Enrichment From Birth Impacts Parvalbumin Expressing Cells and Wisteria Floribunda Agglutinin Labelled Peri-Neuronal Nets Within the Developing Murine Striatum

Environmental enrichment can dramatically affect both the development and function of neural circuits. This is accomplished, at least in part, by the regulation of inhibitory cellular networks and related extracellular matrix glycoprotein structures known as perineuronal nets. The degree to which enhanced housing can influence brain areas involved in the planning and execution of actions is not well known. We examined the effect of enriching mice from birth on parvalbumin expression and perineuronal net formation in developing and adult striatum. This input nucleus of the basal ganglia consists of topographically discernible regions that serve different functions, providing a means of simultaneously examining the influence of environmental factors on discrete, but related networks. Greater densities of striatal parvalbumin positive cells and wisteria floribunda agglutinin labelled perineuronal nets were present in enriched pups during the second postnatal week, primarily within the lateral portion of the nucleus. Housing conditions continued to have an impact into adulthood, with enriched mice exhibiting higher parvalbumin positive cell densities in both medial and lateral striatum. Curiously, no differences due to housing conditions were detected in striatal perineuronal net densities of mature animals. The degree of overlap between striatal parvalbumin expression and perineuronal net formation was also increased, suggesting that heightened neural activity associated with enrichment may have contributed to greater engagement of networks affiliated with cells that express the calcium binding protein. Brain derived neurotrophic factor, an important regulator of inhibitory network maturation, is also subtly, but significantly affected within the striatum of enriched cohorts. Together, these findings suggest that environmental enrichment can exert cell specific effects within different divisions of an area vital for the regulation of action.

in Frontiers in Neuroanatomy | New and Recent Articles on October 24, 2019 12:00 AM.

• #### Evidence of Hyperacusis in Adult Rats Following Non-traumatic Sound Exposure

Manipulations that enhance neuroplasticity may inadvertently create opportunities for maladaptation. We have previously used passive exposures to non-traumatic white noise to open windows of plasticity in the adult rat auditory cortex and induce frequency-specific functional reorganizations of the tonotopic map. However, similar reorganizations in the central auditory pathway are thought to contribute to the generation of hearing disorders such as tinnitus and hyperacusis. Here, we investigate whether noise-induced reorganizations are accompanied by electrophysiological or behavioral evidence of tinnitus or hyperacusis in adult Long-Evans rats. We used a 2-week passive exposure to moderate-intensity (70 dB SPL) broadband white noise to reopen a critical period for spectral tuning such that a second 1-week exposure to 7 kHz tone pips produced an expansion of the 7 kHz frequency region in the primary auditory cortex (A1). We demonstrate for the first time that this expansion also takes place in the ventral auditory field (VAF). Sound exposure also led to spontaneous and sound-evoked hyperactivity in the anterior auditory field (AAF). Rats were assessed for behavioral evidence of tinnitus or hyperacusis using gap and tone prepulse inhibition of the acoustic startle response. We found that sound exposure did not affect gap-prepulse inhibition. However, sound exposure led to an improvement in prepulse inhibition when the prepulse was a 7 kHz tone, showing that exposed rats had enhanced sensorimotor gating for the exposure frequency. Together, our electrophysiological and behavioral results provide evidence of hyperacusis but not tinnitus in sound-exposed animals. Our findings demonstrate that periods of prolonged noise exposure may open windows of plasticity that can also be understood as windows of vulnerability, potentially increasing the likelihood for maladaptive plasticity to take place.

in Frontiers in Systems Neuroscience | New and Recent Articles on October 23, 2019 12:00 AM.

• #### MicroRNA-Based Separation of Cortico-Fugal Projection Neuron-Like Cells Derived From Embryonic Stem Cells

The purification of pluripotent stem cell-derived cortico-fugal projection neurons (PSC-CFuPNs) is useful for disease modeling and cell therapies related to the dysfunction of cortical motor neurons, such as amyotrophic lateral sclerosis (ALS) or stroke. However, no CFuPN-specific surface markers for the purification are known. Recently, microRNAs (miRNAs) have been reported as alternatives to surface markers. Here, we investigated this possibility by applying the miRNA switch, an mRNA technology, to enrich PSC-CFuPNs. An array study of miRNAs in mouse fetal brain tissue revealed that CFuPNs highly express miRNA-124-3p at E14.5 and E16.5. In response, we designed a miRNA switched that responds to miRNA-124-3p and applied it to mouse embryonic stem cell (ESC)-derived cortical neurons. Flow cytometry and quantitative polymerase chain reaction (qPCR) analyses showed the miRNA-124-3p switch enriched CFuPN-like cells from this population. Immunocytechemical analysis confirmed vGlut1/Emx1/Bcl11b triple positive CFuPN-like cells were increased from 6.5 to 42%. Thus, our miRNA-124-3p switch can uniquely enrich live CFuPN-like cells from mouse ESC-derived cortical neurons.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on October 23, 2019 12:00 AM.

• #### Origins of the Resting-State Functional MRI Signal: Potential Limitations of the “Neurocentric” Model

Resting-state functional connectivity (rsFC) is emerging as a research tool for systems and clinical neuroscience. The mechanism underlying resting-state functional MRI (rsfMRI) signal, however, remains incompletely understood. A widely held assumption is that the spontaneous fluctuations in blood oxygenation level-dependent (BOLD) signal reflect ongoing neuronal processes (herein called “neurocentric” model). In support of this model, evidence from human and animal studies collectively reveals that the spatial synchrony of spontaneously occurring electrophysiological signal recapitulates BOLD rsFC networks. Two recent experiments from independent labs designed to specifically examine neuronal origins of rsFC, however, suggest that spontaneously occurring neuronal events, as assessed by multiunit activity or local field potential (LFP), although statistically significant, explain only a small portion (∼10%) of variance in resting-state BOLD fluctuations. These two studies, although each with its own limitations, suggest that the spontaneous fluctuations in rsfMRI, may have complex cellular origins, and the “neurocentric” model may not apply to all brain regions.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on October 23, 2019 12:00 AM.

• #### Habituation of the Interlimb Reflex (ILR) Over the Biceps Brachii Muscle After Electrical Stimuli Over the Sural Nerve

Up to now relatively little is known about interlimb reflexes (ILR). Especially it is not well known whether ILR may habituate or not to subsequent stimuli. The main aim of the present investigation was to explore the short term habituation behavior of ILR. The electromyogram was recorded over the tonically active biceps brachii (BB) muscle in 11 healthy subjects contralateral and ipsilateral to supramaximum electrical stimuli (9–12 mA) that were delivered at 1.0 and 0.4 Hz over the left sural nerve. In addition, a selective averaging method was used to investigate the influence of preceding stimuli on the ILR. Thus, 30 blocks of 3 subsequent stimuli were used. All 1st ILR of each block were averaged together. Averages were also obtained for 2nd and 3rd ILR. While ILR amplitudes gained significantly both ipsilateral and contralateral to the stimulus (p < 0.05) after train stimuli as compared with single stimuli, ILR amplitudes showed a significant decrease at 1.0 Hz versus 0.4 Hz stimuli. ILR amplitudes decreased significantly after the 2nd and 3rd stimulus relative to the 1st (p < 0.05). ILR can be recorded bilaterally remote from the stimulus site. Furthermore, ILR show clear short term habituation behavior.

in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on October 23, 2019 12:00 AM.

• #### The Diagnostic Value of MRI-Based Texture Analysis in Discrimination of Tumors Located in Posterior Fossa: A Preliminary Study

Objectives

To investigate the diagnostic value of MRI-based texture analysis in discriminating common posterior fossa tumors, including medulloblastoma, brain metastatic tumor, and hemangioblastoma.

Methods

A total number of 185 patients were enrolled in the current study: 63 of them were diagnosed with medulloblastoma, 56 were diagnosed with brain metastatic tumor, and 66 were diagnosed with hemangioblastoma. Texture features were extracted from contrast-enhanced T1-weighted (T1C) images and fluid-attenuation inversion recovery (FLAIR) images within two matrixes. Mann–Whitney U test was conducted to identify whether texture features were significantly different among subtypes of tumors. Logistic regression analysis was performed to assess if they could be taken as independent predictors and to establish the integrated models. Receiver operating characteristic analysis was conducted to evaluate their performances in discrimination.

Results

There were texture features from both T1C images and FLAIR images found to be significantly different among the three types of tumors. The integrated model represented that the promising diagnostic performance of texture analysis depended on a series of features rather than a single feature. Moreover, the predictive model that combined texture features and clinical feature implied feasible performance in prediction with an accuracy of 0.80.

Conclusion

MRI-based texture analysis could potentially be served as a radiological method in discrimination of common tumors located in posterior fossa.

in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on October 23, 2019 12:00 AM.

• #### Dynamics of Neuronal Activity in the Cortical Column during Behavior: Both Neuron Type and Layers Matter

In this issue of Neuron, Yu et al. (2019) reveal the activity of excitatory cells and GABAergic inhibitory interneurons throughout the neocortical column during active sensation. The authors utilized a combination of spike waveform analysis and genetic tools to identify cell types, demonstrating their distinct patterns of recruitment during behavior.

in Neuron on October 23, 2019 12:00 AM.