Planet Neuroscience

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Demonstrating Brain-Level Interactions Between Visuospatial Attentional Demands and Working Memory Load While Driving Using Functional Near-Infrared Spectroscopy
Jakob Scheunemann, Anirudh Unni, Klas Ihme, Meike Jipp, Jochem W. Rieger
in Frontiers in Human Neuroscience | New and Recent Articles on January 23, 2019 06:00 AM.
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The “Instinct” of Imagination. A Neuro-Ethological Approach to the Evolution of the Reflective Mind and Its Application to Psychotherapy
Antonio Alcaro, Stefano Carta
in Frontiers in Human Neuroscience | New and Recent Articles on January 23, 2019 06:00 AM.
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Role for Chromatin Remodeling Factor Chd1 in Learning and Memory
Ines Schoberleitner, Anna Mutti, Anupam Sah, Alexandra Wille, Francisco Gimeno-Valiente, Paolo Piatti, Maria Kharitonova, Luis Torres, Gerardo López-Rodas, Jeffrey J. Liu, Nicolas Singewald, Christoph Schwarzer, Alexandra Lusser
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 23, 2019 06:00 AM.
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Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain
Roxana Aldea, Roy O. Weller, Donna M. Wilcock, Roxana O. Carare, Giles Richardson
in Frontiers in Aging Neuroscience | New and Recent Articles on January 23, 2019 06:00 AM.
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Motoric Cognitive Risk Syndrome: Could It Be Defined Through Increased Five-Times-Sit-to-Stand Test Time, Rather Than Slow Walking Speed?
Harmehr Sekhon, Cyrille P. Launay, Julia Chabot, Gilles Allali, Olivier Beauchet
in Frontiers in Aging Neuroscience | New and Recent Articles on January 23, 2019 06:00 AM.
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miRNA-7a-2-3p Inhibits Neuronal Apoptosis in Oxygen-Glucose Deprivation (OGD) Model
Zi-Bin Zhang, Ya-Xin Tan, Qiong Zhao, Liu-Lin Xiong, Jia Liu, Fei-Fei Xu, Yang Xu, Larisa Bobrovskaya, Xin-Fu Zhou, Ting-Hua Wang
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 23, 2019 06:00 AM.
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The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury
Maliheh Mohamadpour, Kristen Whitney, Peter J. Bergold
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 23, 2019 06:00 AM.
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Arbor -- a morphologically-detailed neural network simulation library for contemporary high-performance computing architectures. (arXiv:1901.07454v1 [q-bio.NC])

We introduce Arbor, a performance portable library for simulation of large networks of multi-compartment neurons on HPC systems. Arbor is open source software, developed under the auspices of the HBP. The performance portability is by virtue of back-end specific optimizations for x86 multicore, Intel KNL, and NVIDIA GPUs. When coupled with low memory overheads, these optimizations make Arbor an order of magnitude faster than the most widely-used comparable simulation software. The single-node performance can be scaled out to run very large models at extreme scale with efficient weak scaling.

HPC, GPU, neuroscience, neuron, software

in q-bio.NC updates on arXiv.org on January 23, 2019 01:30 AM.
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Online Estimation of Multiple Dynamic Graphs in Pattern Sequences. (arXiv:1901.07298v1 [stat.ML])

Many time-series data including text, movies, and biological signals can be represented as sequences of correlated binary patterns. These patterns may be described by weighted combinations of a few dominant structures that underpin specific interactions among the binary elements. To extract the dominant correlation structures and their contributions to generating data in a time-dependent manner, we model the dynamics of binary patterns using the state-space model of an Ising-type network that is composed of multiple undirected graphs. We provide a sequential Bayes algorithm to estimate the dynamics of weights on the graphs while gaining the graph structures online. This model can uncover overlapping graphs underlying the data better than a traditional orthogonal decomposition method, and outperforms an original time-dependent full Ising model. We assess the performance of the method by simulated data, and demonstrate that spontaneous activity of cultured hippocampal neurons is represented by dynamics of multiple graphs.

in q-bio.NC updates on arXiv.org on January 23, 2019 01:30 AM.
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Postoperative brain volumes are associated with one-year neurodevelopmental outcome in children with severe congenital heart disease. (arXiv:1901.07274v1 [q-bio.NC])

Children with congenital heart disease (CHD) remain at risk for neurodevelopmental impairment despite improved peri- and intraoperative care. Our prospective cohort study aimed to determine the relationship between perioperative brain volumes and neurodevelopmental outcome in neonates with severe CHD. Pre- and postoperative cerebral MRI was acquired in term born neonates with CHD undergoing neonatal cardiopulmonary bypass surgery. Brain volumes were measured using an atlas prior based automated method. One-year outcome was assessed with the Bayley-III. CHD infants (n=77) had lower pre- and postoper-ative total and regional brain volumes compared to controls (n=44, all p<0.01). CHD infants had poorer cognitive and motor outcome (p<=0.0001) and a trend towards lower language composite score compared to controls (p=0.06). The total and selected regional postoperative brain volumes predicted cognitive and language outcome (all p<0.04). This association was independent of length of intensive care unit stay for total, cortical, temporal, frontal and cerebellar volumes. In CHD neonates undergoing cardiopulmonary bypass surgery, pre- and postoperative brain volumes are reduced, and postoperative brain volumes predict cognitive and language outcome at one year. Reduced cerebral volumes in CHD patients could serve as a biomarker for im-paired outcome.

in q-bio.NC updates on arXiv.org on January 23, 2019 01:30 AM.
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Multiscale and multimodal network dynamics underpinning working memory. (arXiv:1901.06552v1 [q-bio.NC])

Working memory (WM) allows information to be stored and manipulated over short time scales. Performance on WM tasks is thought to be supported by the frontoparietal system (FPS), the default mode system (DMS), and interactions between them. Yet little is known about how these systems and their interactions relate to individual differences in WM performance. We address this gap in knowledge using functional MRI data acquired during the performance of a 2-back WM task, as well as diffusion tensor imaging data collected in the same individuals. We show that the strength of functional interactions between the FPS and DMS during task engagement is inversely correlated with WM performance, and that this strength is modulated by the activation of FPS regions but not DMS regions. Next, we use a clustering algorithm to identify two distinct subnetworks of the FPS, and find that these subnetworks display distinguishable patterns of gene expression. Activity in one subnetwork is positively associated with the strength of FPS-DMS functional interactions, while activity in the second subnetwork is negatively associated. Further, the pattern of structural linkages of these subnetworks explains their differential capacity to influence the strength of FPS-DMS functional interactions. To determine whether these observations could provide a mechanistic account of large-scale neural underpinnings of WM, we build a computational model of the system composed of coupled oscillators. Modulating the amplitude of the subnetworks in the model causes the expected change in the strength of FPS-DMS functional interactions, thereby offering support for a mechanism in which subnetwork activity tunes functional interactions. Broadly, our study presents a holistic account of how regional activity, functional interactions, and structural linkages together support individual differences in WM in humans.

in q-bio.NC updates on arXiv.org on January 23, 2019 01:30 AM.
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A Gestalt inference model for auditory scene segregation

by Debmalya Chakrabarty, Mounya Elhilali
Our current understanding of how the brain segregates auditory scenes into meaningful objects is in line with a Gestaltism framework. These Gestalt principles suggest a theory of how different attributes of the soundscape are extracted then bound together into separate groups that reflect different objects or streams present in the scene. These cues are thought to reflect the underlying statistical structure of natural sounds in a similar way that statistics of natural images are closely linked to the principles that guide figure-ground segregation and object segmentation in vision. In the present study, we leverage inference in stochastic neural networks to learn emergent grouping cues directly from natural soundscapes including speech, music and sounds in nature. The model learns a hierarchy of local and global spectro-temporal attributes reminiscent of simultaneous and sequential Gestalt cues that underlie the organization of auditory scenes. These mappings operate at multiple time scales to analyze an incoming complex scene and are then fused using a Hebbian network that binds together coherent features into perceptually-segregated auditory objects. The proposed architecture successfully emulates a wide range of well established auditory scene segregation phenomena and quantifies the complimentary role of segregation and binding cues in driving auditory scene segregation.
in PLOS Computational Biology: New Articles on January 22, 2019 10:00 PM.
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Generalizing clusters of similar species as a signature of coexistence under competition

by Rafael D’Andrea, Maria Riolo, Annette M. Ostling
Patterns of trait distribution among competing species can potentially reveal the processes that allow them to coexist. It has been recently proposed that competition may drive the spontaneous emergence of niches comprising clusters of similar species, in contrast with the dominant paradigm of greater-than-chance species differences. However, current clustering theory relies largely on heuristic rather than mechanistic models. Furthermore, studies of models incorporating demographic stochasticity and immigration, two key players in community assembly, did not observe clusters. Here we demonstrate clustering under partitioning of resources, partitioning of environmental gradients, and a competition-colonization tradeoff. We show that clusters are robust to demographic stochasticity, and can persist under immigration. While immigration may sustain clusters that are otherwise transient, too much dilutes the pattern. In order to detect and quantify clusters in nature, we introduce and validate metrics which have no free parameters nor require arbitrary trait binning, and weigh species by their abundances rather than relying on a presence-absence count. By generalizing beyond the circumstances where clusters have been observed, our study contributes to establishing them as an update to classical trait patterning theory.
in PLOS Computational Biology: New Articles on January 22, 2019 10:00 PM.
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Top-down inputs drive neuronal network rewiring and context-enhanced sensory processing in olfaction

by Wayne Adams, James N. Graham, Xuchen Han, Hermann Riecke
Much of the computational power of the mammalian brain arises from its extensive top-down projections. To enable neuron-specific information processing these projections have to be precisely targeted. How such a specific connectivity emerges and what functions it supports is still poorly understood. We addressed these questions in silico in the context of the profound structural plasticity of the olfactory system. At the core of this plasticity are the granule cells of the olfactory bulb, which integrate bottom-up sensory inputs and top-down inputs delivered by vast top-down projections from cortical and other brain areas. We developed a biophysically supported computational model for the rewiring of the top-down projections and the intra-bulbar network via adult neurogenesis. The model captures various previous physiological and behavioral observations and makes specific predictions for the cortico-bulbar network connectivity that is learned by odor exposure and environmental contexts. Specifically, it predicts that—after learning—the granule-cell receptive fields with respect to sensory and with respect to cortical inputs are highly correlated. This enables cortical cells that respond to a learned odor to enact disynaptic inhibitory control specifically of bulbar principal cells that respond to that odor. For this the reciprocal nature of the granule cell synapses with the principal cells is essential. Functionally, the model predicts context-enhanced stimulus discrimination in cluttered environments (‘olfactory cocktail parties’) and the ability of the system to adapt to its tasks by rapidly switching between different odor-processing modes. These predictions are experimentally testable. At the same time they provide guidance for future experiments aimed at unraveling the cortico-bulbar connectivity.
in PLOS Computational Biology: New Articles on January 22, 2019 10:00 PM.
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Differential mobility and local variation in infection attack rate

by David J. Haw, Derek A. T. Cummings, Justin Lessler, Henrik Salje, Jonathan M. Read, Steven Riley
Infectious disease transmission in animals is an inherently spatial process in which a host’s home location and their social mixing patterns are important, with the mixing of infectious individuals often different to that of susceptible individuals. Although incidence data for humans have traditionally been aggregated into low-resolution data sets, modern representative surveillance systems such as electronic hospital records generate high volume case data with precise home locations. Here, we use a gridded spatial transmission model of arbitrary resolution to investigate the theoretical relationship between population density, differential population movement and local variability in incidence. We show analytically that a uniform local attack rate is only possible for individual pixels in the grid if susceptible and infectious individuals move in the same way. Using a population in Guangdong, China, for which a robust quantitative description of movement is available (a movement kernel), and a natural history consistent with pandemic influenza; we show that local cumulative incidence is positively correlated with population density when susceptible individuals are more connected in space than infectious individuals. Conversely, under the less intuitively likely scenario, when infectious individuals are more connected, local cumulative incidence is negatively correlated with population density. The strength and direction of correlation changes sign for other kernel parameter values. We show that simulation models in which it is assumed implicitly that only infectious individuals move are assuming a slightly unusual specific correlation between population density and attack rate. However, we also show that this potential structural bias can be corrected by using the appropriate non-isotropic kernel that maps infectious-only code onto the isotropic dual-mobility kernel. These results describe a precise relationship between the spatio-social mixing of infectious and susceptible individuals and local variability in attack rates. More generally, these results suggest a genuine risk that mechanistic models of high-resolution attack rate data may reach spurious conclusions if the precise implications of spatial force-of-infection assumptions are not first fully characterized, prior to models being fit to data.
in PLOS Computational Biology: New Articles on January 22, 2019 10:00 PM.
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Correction for Liu et al., The genome landscape of ER{alpha}- and ER{beta}-binding DNA regions [Correction]
MEDICAL SCIENCES Correction for “The genome landscape of ERα- and ERβ-binding DNA regions,” by Yawen Liu, Hui Gao, Troels Torben Marstrand, Anders Ström, Eivind Valen, Albin Sandelin, Jan-Åke Gustafsson, and Karin Dahlman-Wright, which was first published February 19, 2008; 10.1073/pnas.0712085105 (Proc Natl Acad Sci USA 105:2604–2609). The authors wish to...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Correction for Kim and Goldberg, UBL domain of Usp14 and other proteins stimulates proteasome activities and protein degradation in cells [Correction]
BIOCHEMISTRY Correction for “UBL domain of Usp14 and other proteins stimulates proteasome activities and protein degradation in cells,” by Hyoung Tae Kim and Alfred L. Goldberg, which was first published November 28, 2018; 10.1073/pnas.1808731115 (Proc Natl Acad Sci USA 115:E11642–E11650). The authors note that the following statement should be added...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Correction for Lee et al., ZFAND5/ZNF216 is an activator of the 26S proteasome that stimulates overall protein degradation [Correction]
BIOCHEMISTRY Correction for “ZFAND5/ZNF216 is an activator of the 26S proteasome that stimulates overall protein degradation,” by Donghoon Lee, Shinichi Takayama, and Alfred L. Goldberg, which was first published September 25, 2018; 10.1073/pnas.1809934115 (Proc Natl Acad Sci USA 115:E9550–E9559). The authors note that the following statement should be added as...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Correction for Miloȷević et al., Changing demographics of scientific careers: The rise of the temporary workforce [Correction]
COLLOQUIUM Correction for “Changing demographics of scientific careers: The rise of the temporary workforce,” by Staša Milojević, Filippo Radicchi, and John P. Walsh, which was first published December 11, 2018; 10.1073/pnas.1800478115 (Proc Natl Acad Sci USA 115:12616–12623). The authors note that a reference was omitted from the article. The complete...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Clonal-level lineage commitment pathways of hematopoietic stem cells in vivo [Systems Biology]
While the aggregate differentiation of the hematopoietic stem cell (HSC) population has been extensively studied, little is known about the lineage commitment process of individual HSC clones. Here, we provide lineage commitment maps of HSC clones under homeostasis and after perturbations of the endogenous hematopoietic system. Under homeostasis, all donor-derived...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Human social motor solutions for human-machine interaction in dynamical task contexts [Psychological and Cognitive Sciences]
Multiagent activity is commonplace in everyday life and can improve the behavioral efficiency of task performance and learning. Thus, augmenting social contexts with the use of interactive virtual and robotic agents is of great interest across health, sport, and industry domains. However, the effectiveness of human–machine interaction (HMI) to effectively...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Global increase in DNA methylation during orange fruit development and ripening [Plant Biology]
DNA methylation is an important epigenetic mark involved in many biological processes. The genome of the climacteric tomato fruit undergoes a global loss of DNA methylation due to active DNA demethylation during the ripening process. It is unclear whether the ripening of other fruits is also associated with global DNA...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Ionic stress enhances ER-PM connectivity via phosphoinositide-associated SYT1 contact site expansion in Arabidopsis [Plant Biology]
The interorganelle communication mediated by membrane contact sites (MCSs) is an evolutionary hallmark of eukaryotic cells. MCS connections enable the nonvesicular exchange of information between organelles and allow them to coordinate responses to changing cellular environments. In plants, the importance of MCS components in the responses to environmental stress has...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis [Pharmacology]
Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Risk-taking bias in human decision-making is encoded via a right-left brain push-pull system [Neuroscience]
A person’s decisions vary even when options stay the same, like when a gambler changes bets despite constant odds of winning. Internal bias (e.g., emotion) contributes to this variability and is shaped by past outcomes, yet its neurobiology during decision-making is not well understood. To map neural circuits encoding bias,...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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The RNA degradosome promotes tRNA quality control through clearance of hypomodified tRNA [Microbiology]
The factors and mechanisms that govern tRNA stability in bacteria are not well understood. Here, we investigated the influence of posttranscriptional modification of bacterial tRNAs (tRNA modification) on tRNA stability. We focused on ThiI-generated 4-thiouridine (s4U), a modification found in bacterial and archaeal tRNAs. Comprehensive quantification of Vibrio cholerae tRNAs...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Type I interferon response impairs differentiation potential of pluripotent stem cells [Microbiology]
Upon virus infection, pluripotent stem cells neither induce nor respond to canonical type I interferons (IFN-I). To better understand this biology, we characterized induced pluripotent stem cells (iPSCs) as well as their differentiated parental or rederived counterparts. We confirmed that only iPSCs failed to respond to viral RNA, IFN-I, or...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Multidrug-resistant plasmids repress chromosomally encoded T6SS to enable their dissemination [Microbiology]
Acinetobacter baumannii (Ab) is a nosocomial pathogen with one of the highest rates of multidrug resistance (MDR). This is partially due to transmissible plasmids. Many Ab strains harbor a constitutively active type VI secretion system (T6SS) that is employed to kill nonkin bacteria. T6SS and plasmid conjugation both involve cell-to-cell...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody [Medical Sciences]
Breast cancers enduring treatment with chemotherapy may be enriched for cancer stem cells or tumor-initiating cells, which have an enhanced capacity for self-renewal, tumor initiation, and/or metastasis. Breast cancer cells that express the type I tyrosine kinaselike orphan receptor ROR1 also may have such features. Here we find that the...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Blocking IL-1{beta} reverses the immunosuppression in mouse breast cancer and synergizes with anti-PD-1 for tumor abrogation [Immunology and Inflammation]
Interleukin-1β (IL-1β) is abundant in the tumor microenvironment, where this cytokine can promote tumor growth, but also antitumor activities. We studied IL-1β during early tumor progression using a model of orthotopically introduced 4T1 breast cancer cells. Whereas there is tumor progression and spontaneous metastasis in wild-type (WT) mice, in IL-1β–deficient...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Disruption of RPGR protein interaction network is the common feature of RPGR missense variations that cause XLRP [Genetics]
Retinitis pigmentosa (RP) is an inherited retinal degenerative disease with severe vision impairment leading to blindness. About 10–15% of RP cases are caused by mutations in the RPGR gene, with RPGR mutations accounting for 70% of X-linked RP cases. The mechanism by which RPGR mutations cause photoreceptor cell dysfunction is...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss [Genetics]
We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Gorillas have been infected with the HERV-K (HML-2) endogenous retrovirus much more recently than humans and chimpanzees [Evolution]
Human endogenous retrovirus-K (HERV-K) human mouse mammary tumor virus-like 2 (HML-2) is the most recently active endogenous retrovirus group in humans, and the only group with human-specific proviruses. HML-2 expression is associated with cancer and other diseases, but extensive searches have failed to reveal any replication-competent proviruses in humans. However,...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Conserved transcriptomic profiles underpin monogamy across vertebrates [Evolution]
Social monogamy, typically characterized by the formation of a pair bond, increased territorial defense, and often biparental care, has independently evolved multiple times in animals. Despite the independent evolutionary origins of monogamous mating systems, several homologous brain regions and neuropeptides and their receptors have been shown to play a conserved...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Forage silica and water content control dental surface texture in guinea pigs and provide implications for dietary reconstruction [Ecology]
Recent studies have shown that phytoliths are softer than dental enamel but still act as abrasive agents. Thus, phytolith content should be reflected in dental wear. Because native phytoliths show lower indentation hardness than phytoliths extracted by dry ashing, we propose that the hydration state of plant tissue will also...
in Proceedings of the National Academy of Sciences Recent Issues on January 22, 2019 06:11 PM.
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Human verbal memory encoding is hierarchically distributed in a continuous processing stream: Human processing stream for verbal memory encoding
Abstract
Processing of memory is supported by coordinated activity in a network of sensory, association, and motor brain regions. It remains a major challenge to determine where memory is encoded for later retrieval. Here we used direct intracranial brain recordings from epilepsy patients performing free recall tasks to determine the temporal pattern and anatomical distribution of verbal memory encoding across the entire human cortex. High gamma frequency activity (65-115 Hz) showed consistent power responses during encoding of subsequently recalled and forgotten words on a subset of electrodes localized in 16 distinct cortical areas activated in the tasks. More of the high gamma power during word encoding, and less power before and after the word presentation, was characteristic of successful recall and observed across multiple brain regions. Latencies of the induced power changes and this subsequent memory effect between the recalled and forgotten words followed an anatomical sequence from visual to prefrontal cortical areas. Finally, the magnitude of the memory effect was unexpectedly found to be the largest in selected brain regions both at the top and at the bottom of the processing stream. These included the language processing areas of the prefrontal cortex and the downstream visual areas at the junction of the occipital and temporal lobes. Our results provide evidence for distributed encoding of verbal memory organized along a hierarchical posterior-to-anterior processing stream.
Significance Statement Verbal memory is a complex function supported by a network of brain regions specialized for perception, decision-making, and execution of action. Our results shed light on the temporal and anatomical organization of this network during encoding of memories for subsequent recall. By finding consistent differences in fast gamma activity recorded directly from the human brain during presentation of words that were later recalled or forgotten, we identified specific regions with the greatest memory effect. This subsequent memory effect was present across a feed-forward processing stream, providing evidence for hierarchical and distributed organization of verbal memory. The identified brain regions in the processing stream present new targets for brain modulation technologies to treat verbal and cognitive deficits in brain disorders.

in RSS PAP on January 22, 2019 05:31 PM.
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The Contribution of Iron to Protein Aggregation Disorders in the Central Nervous System
Karina Joppe, Anna-Elisa Roser, Fabian Maass, Paul Lingor
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 22, 2019 12:00 PM.
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Issue Information

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Annals of Neurology: Volume 85, Number 1, January 2019

A pair of PET images in the coronal plane showing 18F‐florbetapir uptake in a patient with type 1 narcopleps (NT1, left) and a healthy control (right) matched for age. NT1 patients had less deposition of beta‐amyloid than did control subjects. See Gabelle et al., pp. http://dx.doi.org/10.1002/ana.2537374–83, this issue.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Passages 2019

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Lyme Neuroborreliosis: Clinical Outcomes, Controversy, Pathogenesis, and Polymicrobial Infections

Lyme borreliosis is the object of numerous misconceptions. In this review, we revisit the fundamental manifestations of neuroborreliosis (meningitis, cranial neuritis, and radiculoneuritis), as these have withstood the test of time. We also discuss other manifestations that are less frequent. Stroke, as a manifestation of Lyme neuroborreliosis, is considered in the context of other infections. The summary of the literature regarding clinical outcomes of neuroborreliosis leads to its controversies. We also include new information on pathogenesis and on the polymicrobial nature of tick‐borne diseases. In this way, we update the review that we wrote in this journal in 1995. ANN NEUROL 2019;85:21–31.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Predicting Progression to Mild Cognitive Impairment

Despite much attention to the use of biomarkers for predicting Alzheimer disease, little information is available at the individual level. We used the population‐based Mayo Clinic Study of Aging to estimate absolute risk of cognitive impairment by biomarker group. Risk increased with age and any biomarker abnormality. For example, a 75‐year‐old with abnormal amyloid and cortical thinning biomarkers has about a 20% chance of cognitive impairment by age 80 years, whereas with normal biomarkers the chance is <10%. Persons with only one abnormal biomarker had similar intermediate risks. ANN NEUROL 2019;85:155–160.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Challenges of differential placebo effects in contemporary medicine: The example of brain stimulation

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Stroke Recovery in Rats after 24‐Hour–Delayed Intramuscular Neurotrophin‐3 Infusion

Objective

Neurotrophin‐3 (NT3) plays a key role in the development and function of locomotor circuits including descending serotonergic and corticospinal tract axons and afferents from muscle and skin. We have previously shown that gene therapy delivery of human NT3 into affected forelimb muscles improves sensorimotor recovery after stroke in adult and elderly rats. Here, to move toward the clinic, we tested the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after stroke.

Methods

Rats received unilateral ischemic stroke in sensorimotor cortex. To simulate a clinically feasible time to treatment, 24 hours later rats were randomized to receive NT3 or vehicle by infusion into affected triceps brachii for 4 weeks using implanted catheters and minipumps.

Results

Radiolabeled NT3 crossed from the bloodstream into the brain and spinal cord in rodents with or without strokes. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory impairment of the affected wrist. Functional magnetic resonance imaging during stimulation of the affected wrist showed spontaneous recovery of peri‐infarct blood oxygenation level–dependent signal that NT3 did not further enhance. Rather, NT3 induced neuroplasticity of the spared corticospinal and serotonergic pathways.

Interpretation

Our results show that delayed, peripheral infusion of NT3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke. ANN NEUROL 2019;85:32–46.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Serum Soluble Triggering Receptor Expressed on Myeloid Cells 2 as a Biomarker for Incident Dementia: The Hisayama Study

Objective

To investigate the association between serum soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a soluble type of an innate immune receptor expressed on the microglia, and the risk of dementia.

Methods

A total of 1,349 Japanese community residents aged 60 and older without dementia were followed prospectively for 10 years (2002–2012). Serum sTREM2 levels were quantified by using an enzyme‐linked immunosorbent assay and divided into quartiles. Cox proportional hazards model was used to estimate the hazard ratios (HRs) of serum sTREM2 levels on the risk of dementia.

Results

During the follow‐up, 300 subjects developed all‐cause dementia; 193 had Alzheimer's disease (AD), and 85 had vascular dementia (VaD). The age‐ and sex‐adjusted incidences of all‐cause dementia, AD, and VaD elevated significantly with higher serum sTREM2 levels (all p for trend < 0.012). These associations were not altered after adjustment for confounding factors, including high‐sensitive C‐reactive protein. Subjects with the highest quartile of serum sTREM2 levels had significantly higher multivariable‐adjusted risks of developing all‐cause dementia, AD, and VaD than those with the lowest quartile (HR = 2.03, 95% confidence interval [CI] = 1.39–2.97, p < 0.001 for all‐cause dementia; HR = 1.62, 95% CI = 1.02–2.55, p = 0.04 for AD; HR = 2.85, 95% CI = 1.35–6.02, p = 0.006 for VaD). No significant heterogeneity in the association of serum sTREM2 levels with the development of dementia was observed among the other risk factor subgroups (all p for heterogeneity > 0.11).

Interpretation

The present findings suggest a significant association between increased serum sTREM2 levels and the risk of developing all‐cause dementia, AD, and VaD in the general elderly Japanese population. ANN NEUROL 2019;85:47–58.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Six‐Month Assessment of a Hand Prosthesis with Intraneural Tactile Feedback

Objective

Hand amputation is a highly disabling event, which significantly affects quality of life. An effective hand replacement can be achieved if the user, in addition to motor functions, is provided with the sensations that are naturally perceived while grasping and moving. Intraneural peripheral electrodes have shown promising results toward the restoration of the sense of touch. However, the long‐term usability and clinical relevance of intraneural sensory feedback have not yet been clearly demonstrated.

Methods

To this aim, we performed a 6‐month clinical study with 3 transradial amputees who received implants of transverse intrafascicular multichannel electrodes (TIMEs) in their median and ulnar nerves. After calibration, electrical stimulation was delivered through the TIMEs connected to artificial sensors in the digits of a prosthesis to generate sensory feedback, which was then used by the subjects while performing different grasping tasks.

Results

All subjects, notwithstanding their important clinical differences, reported stimulation‐induced sensations from the phantom hand for the whole duration of the trial. They also successfully integrated the sensory feedback into their motor control strategies while performing experimental tests simulating tasks of real life (with and without the support of vision). Finally, they reported a decrement of their phantom limb pain and a general improvement in mood state.

Interpretation

The promising results achieved with all subjects show the feasibility of the use of intraneural stimulation in clinical settings. ANN NEUROL 2019;85:137–154.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Final Results of the RHAPSODY Trial: A Multi‐Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A‐APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke

Objective

Agonism of protease‐activated receptor (PAR) 1 by activated protein C (APC) provides neuro‐ and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A‐APC, reduces neurological injury and promotes vascular integrity; 3K3A‐APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A‐APC in ischemic stroke patients.

Methods

The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 μg/kg of 3K3A‐APC. After intravenous tissue plasminogen activator, intra‐arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates.

Results

Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest‐dose 3K3A‐APC tested, 540 μg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A‐APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066).

Interpretation

RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 μg/kg for the PAR1 active cytoprotectant, 3K3A‐APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation.

Clinical Trial Registration

Clinical Trial Registration‐URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125–136.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Attributable risk of Alzheimer's dementia attributed to age‐related neuropathologies

Objective

The degree to which Alzheimer's versus other neuropathologies contribute to the risk of Alzheimer's dementia is unknown. We examined the risk of Alzheimer's dementia attributable to pathologic AD and 8 other neuropathologies.

Methods

Participants (n = 1,161) came from 2 clinical‐pathological studies of aging. Multivariable logistic regression models examined associations of 8 neuropathological indices with Alzheimer's dementia and quantified the percentage of cases attributable to each. Furthermore, because some dementia cases are not driven by common neuropathologies, we re‐estimated the attributable risks after empirically adjusting for such cases.

Results

Of 1,161 persons, 512 (44.1%) had Alzheimer's dementia at time of death. With the exception of microinfarcts, all neuropathological indices were independently associated with greater odds of Alzheimer's dementia. Two hundred ten (41.0%) Alzheimer's dementia cases were attributable to pathological AD. Separately, 8.9% were attributable to macroscopic infarcts, 10.8% to Lewy bodies, 5.2% to hippocampal sclerosis, 11.7% to transactive response DNA‐binding protein 43, 8.1% to cerebral amyloid angiopathy, 6.0% to atherosclerosis, and 5.2% to arteriolosclerosis. A total of 83.3% of cases were attributable to all 8 indices combined. However, after further adjustment for cases driven by other factors, a total of 67.5% of cases were attributable to all 8 neuropathologic indices combined.

Interpretation

Pathological AD accounts for a considerable percentage of Alzheimer's dementia cases, but multiple other neuropathologies also contribute. In total, just over two‐thirds of Alzheimer's dementia cases are attributable to common age‐related neuropathologies, suggesting that other disease and resilience factors are important. ANN NEUROL 2019;85:114–124.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Clinical Outcomes Depending on Acute Blood Pressure After Cerebral Hemorrhage

Objective

To determine the association between clinical outcomes and acute systolic blood pressure (SBP) levels achieved after intracerebral hemorrhage (ICH).

Methods

Eligible patients who were randomized to the ATACH‐2 (Antihypertensive Treatment in Intracerebral Hemorrhage 2) trial (ClinicalTrials.gov: NCT01176565) were divided into 5 groups by 10‐mmHg strata of average hourly minimum SBP (<120, 120–130, 130–140, 140–150, and ≥ 150 mmHg) during 2 to 24 hours after randomization. Outcomes included: 90‐day modified Rankin Scale (mRS) 4 to 6; hematoma expansion, defined as an increase ≥6 ml from baseline to 24‐hour computed tomography; and cardiorenal adverse events within 7 days.

Results

Of the 1,000 subjects in ATACH‐2, 995 with available SBP data were included in the analyses. The proportion of mRS 4 to 6 was 37.5, 36.0, 42.8, 38.6, and 38.0%, respectively. For the “140 to 150” group relative to the “120 to 130,” the odds ratio (OR), adjusting for sex, race, age, onset‐to‐randomization time, baseline National Institutes of Health Stroke Scale score, hematoma volume, and hematoma location, was 1.62 (95% confidence interval [CI], 1.02–2.58). Hematoma expansion was identified in 16.9, 13.7, 21.4, 18.5, and 26.4%, respectively. The 140 to 150 (OR, 1.80; 95% CI, 1.05–3.09) and “≥150” (1.98; 1.12–3.51) showed a higher frequency of expansion than the 120 to 130 group. Cardiorenal events occurred in 13.6, 16.6, 11.5, 8.1, and 8.2%, respectively. The 140 to 150 (0.43; 0.19–0.88) and ≥ 150 (0.44; 0.18–0.96) showed a lower frequency of the events than the 120 to 130.

Interpretation

Beneficial effects of lowering and maintaining SBP at 120 to 130 mmHg during the first 24 hours on clinical outcomes by suppressing hematoma expansion was somewhat offset by cardiorenal complications. ANN NEUROL 2019;85:105–113.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Magnetic resonance T1w/T2w ratio: A parsimonious marker for Parkinson disease

Objective

Newer magnetic resonance imaging (MRI) techniques have shown promise in capturing early Parkinson disease (PD)‐related changes in the substantia nigra pars compacta (SNc), the key pathological loci. Their translational value, however, is hindered by technical complexity and inconsistent results.

Methods

A novel yet simple MRI contrast, the T1w/T2w ratio, was used to study 76 PD patients and 70 controls. The T1w/T2w ratio maps were analyzed using both voxel‐based and region‐of‐interest approaches in normalized space. The sensitivity and specificity of the SNc T1w/T2w ratio in discriminating between PD and controls also were assessed. In addition, its diagnostic performance was tested in a subgroup of PD patients with disease duration ≤2 years (PDE). A second independent cohort of 73 PD patients and 49 controls was used for validation.

Results

Compared to controls, PD patients showed a higher T1w/T2w ratio in both the right (cluster size = 164mm³, p < 0.0001) and left (cluster size = 213mm³, p < 0.0001) midbrain that was located ventrolateral to the red nucleus and corresponded to the SNc. The region‐of‐interest approach confirmed the group difference in the SNc T1w/T2w ratio between PD and controls (p < 0.0001). The SNc T1w/T2w ratio had high sensitivity (0.908) and specificity (0.80) to separate PD and controls (area under the curve [AUC] = 0.926), even for PDE patients (AUC = 0.901, sensitivity = 0.857, specificity = 0.857). These results were validated in the second cohort.

Interpretation

The T1w/T2w ratio can detect PD‐related changes in the SNc and may be used as a novel, parsimonious in vivo biomarker for the disease, particularly for early stage patients, with high translational value for clinical practice and research. ANN NEUROL 2019;85:96–104.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Brain state–dependent stimulation boosts functional recovery following stroke

Objective

Adjuvant protocols devised to enhance motor recovery in subacute stroke patients have failed to show benefits with respect to classic therapeutic interventions. Here, we evaluate the efficacy of a novel brain state–dependent intervention based on known mechanisms of memory and learning that is integrated as part of the weekly rehabilitation program in subacute stroke patients.

Methods

Twenty‐four hospitalized subacute stroke patients were randomly assigned to 2 intervention groups: (1) the associative group received 30 pairings of a peripheral electrical nerve stimulus (ES) such that the generated afferent volley arrived precisely during the most active phase of the motor cortex as patients attempted to perform a movement; and (2) in the control group, the ES intensity was too low to generate a stimulation of the nerve. Functional (including the lower extremity Fugl–Meyer assessment [LE‐FM; primary outcome measure]) and neurophysiological (changes in motor evoked potentials [MEPs]) assessments were performed prior to and following the intervention period.

Results

The associative group significantly improved functional recovery with respect to the control group (median [interquartile range] LE‐FM improvement = 6.5 [3.5–8.25] and 3 [0.75–3], respectively; p = 0.029). Significant increases in MEP amplitude were seen following all sessions in the associative group only (p ≤ 0.006).

Interpretation

This is the first evidence of a clinical effect of a neuromodulatory intervention in the subacute phase of stroke. This was evident with relatively few repetitions in comparison to available techniques, making it a clinically viable approach. The results indicate the potential of the proposed neuromodulation system in daily clinical routine for stroke rehabilitation. ANN NEUROL 2019;85:84–95.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Reduced brain amyloid burden in elderly patients with narcolepsy type 1

Objective

To determine whether brain amyloid burden in elderly patients with narcolepsy type 1 (NT1) is lower than in controls, and to assess in patients with NT1 the relationships between amyloid burden, cerebral spinal fluid (CSF) markers of Alzheimer disease (AD), CSF orexin‐A, and cognitive profile.

Methods

Cognitive and ¹⁸F‐florbetapir positron emission tomography (PET) data were compared in patients with NT1 aged ≥ 65 years (n = 23) and in age‐ and sex‐matched controls free of clinical dementia selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 69) and the Multi‐Domain Intervention Alzheimer's Prevention Trial (MAPT‐18F AV45‐PET; n = 23) cohorts. The standardized uptake values (SUVs) of the cortical retention index for 6 regions of interest were computed and averaged to create a mean SUV ratio normalized to 3 subcortical reference regions (cerebellum, pons, and a composite region). A cortical/cerebellum SUV ratio ≥ 1.17 defined positive PET amyloid.

Results

Lower cortical amyloid burden was observed in the NT1 than in the ADNI and MAPT‐AV45 groups (mean cortical/cerebellum SUV ratios = 0.95 ± 0.15, 1.11 ± 0.18 [p < 0.0001], and 1.14 ± 0.17 [p = 0.0005], respectively). Similar results were obtained with all subcortical reference regions and for all cortical regions of interest, except cingulum. Only 1 patient with NT1 (4.4%) had positive PET amyloid compared with 27.5% in the ADNI and 30.4% in the MAPT‐AV45 group. In the NT1 group, cortical or regional amyloid load was not associated with CSF orexin‐A, CSF AD biomarkers, or neuropsychological profile.

Interpretation

Lower brain amyloid burden, assessed by ¹⁸F‐florbetapir PET, in patients with NT1 suggests delayed appearance of amyloid plaques. ANN NEUROL 2019;85:74–83.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Neural basis of induced phantom limb pain relief

Objective

Phantom limb pain (PLP) is notoriously difficult to treat, partly due to an incomplete understanding of PLP‐related disease mechanisms. Noninvasive brain stimulation (NIBS) is used to modulate plasticity in various neuropathological diseases, including chronic pain. Although NIBS can alleviate neuropathic pain (including PLP), both disease and treatment mechanisms remain tenuous. Insight into the mechanisms underlying both PLP and NIBS‐induced PLP relief is needed for future implementation of such treatment and generalization to related conditions.

Methods

We used a within‐participants, double‐blind, and sham‐controlled design to alleviate PLP via task‐concurrent NIBS over the primary sensorimotor missing hand cortex (S1/M1). To specifically influence missing hand signal processing, amputees performed phantom hand movements during anodal transcranial direct current stimulation. Brain activity was monitored using neuroimaging during and after NIBS. PLP ratings were obtained throughout the week after stimulation.

Results

A single session of intervention NIBS significantly relieved PLP, with effects lasting at least 1 week. PLP relief associated with reduced activity in the S1/M1 missing hand cortex after stimulation. Critically, PLP relief and reduced S1/M1 activity correlated with preceding activity changes during stimulation in the mid‐ and posterior insula and secondary somatosensory cortex (S2).

Interpretation

The observed correlation between PLP relief and decreased S1/M1 activity confirms our previous findings linking PLP with increased S1/M1 activity. Our results further highlight the driving role of the mid‐ and posterior insula, as well as S2, in modulating PLP. Lastly, our novel PLP intervention using task‐concurrent NIBS opens new avenues for developing treatment for PLP and related pain conditions. ANN NEUROL 2019;85:59–73.

in Wiley: Annals of Neurology: Table of Contents on January 22, 2019 10:57 AM.
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Relationship of the Acoustic Startle Response and Its Modulation to Adaptive and Maladaptive Behaviors in Typically Developing Children and Those With Autism Spectrum Disorders: A Pilot Study
Ken Ebishima, Hidetoshi Takahashi, Andrew Stickley, Takayuki Nakahachi, Tomiki Sumiyoshi, Yoko Kamio
in Frontiers in Human Neuroscience | New and Recent Articles on January 22, 2019 06:00 AM.
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The Suppression of Irrelevant Semantic Representations in Parkinson’s Disease
Megan L. Isaacs, Katie L. McMahon, Anthony J. Angwin, David A. Copland
in Frontiers in Human Neuroscience | New and Recent Articles on January 22, 2019 06:00 AM.
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Subcutaneous Administration of PDGF-AA Improves the Functional Recovery After Spinal Cord Injury
Xue-Yan Guo, Fei-Xiang Duan, Jing Chen, Ying Wang, Rui Wang, Lin Shen, Qi Qi, Zhi-Quan Jiang, An-You Zhu, Jin Xi, He-Zuo Lü, Jian-Guo Hu
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 22, 2019 06:00 AM.
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Loss of Neurofascin-186 Disrupts Alignment of AnkyrinG Relative to Its Binding Partners in the Axon Initial Segment
Scott A. Alpizar, Arielle L. Baker, Allan T. Gulledge, Michael B. Hoppa
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 22, 2019 06:00 AM.
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Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of β-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer’s Disease
Yu Wang, Jia Xia, Mengjun Shen, Yifan Zhou, Zhe Wu, Yuhuan Shi, Jianrong Xu, Lina Hou, Rui Zhang, Zhuibai Qiu, Qiong Xie, Hongzhuan Chen, Yongfang Zhang, Hao Wang
in Frontiers in Aging Neuroscience | New and Recent Articles on January 22, 2019 06:00 AM.
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A General Model of Ion Passive Transmembrane Transport Based on Ionic Concentration
Vincent Qiqian Wang, Shenquan Liu
in Frontiers in Computational Neuroscience | New and Recent Articles on January 22, 2019 06:00 AM.
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Cortical Layer and Spectrotemporal Architecture of Epileptiform Activity in vivo in a Mouse Model of Focal Cortical Malformation
Anthony J. Williams, Qian-Quan Sun
in Frontiers in Neural Circuits | New and Recent Articles on January 22, 2019 06:00 AM.
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Adaptive Stimulus Design for Dynamic Recurrent Neural Network Models
R. Ozgur Doruk, Kechen Zhang
in Frontiers in Neural Circuits | New and Recent Articles on January 22, 2019 06:00 AM.
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Collicular cortex watches movies

Collicular cortex watches movies
Collicular cortex watches movies, Published online: 22 January 2019; doi:10.1038/s41583-019-0123-7
Neurons in the mouse postrhinal cortex receive visual inputs from the superior colliculus and respond to visual motion independently of the primary visual cortex.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 22, 2019 12:00 AM.
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A toolbox of IgG subclass-switched recombinant monoclonal antibodies for enhanced multiplex immunolabeling of brain
Generating recombinant monoclonal antibodies (R-mAbs) from mAb-producing hybridomas offers numerous advantages that increase the effectiveness, reproducibility, and transparent reporting of research. We report here the generation of a novel resource in the form of a library of recombinant R-mAbs validated for neuroscience research. We cloned immunoglobulin G (IgG) variable domains from cryopreserved hybridoma cells and input them into an integrated pipeline for expression and validation of functional R-mAbs. To improve efficiency over standard protocols, we eliminated aberrant Sp2/0-Ag14 hybridoma-derived variable light transcripts using restriction enzyme treatment. Further, we engineered a plasmid backbone that allows for switching of the IgG subclasses without altering target binding specificity to generate R-mAbs useful in simultaneous multiplex labeling experiments not previously possible. The method was also employed to rescue IgG variable sequences and generate functional R-mAbs from a non-viable cryopreserved hybridoma. All R-mAb sequences and plasmids will be archived and disseminated from open source suppliers.
in eLife: latest articles on January 22, 2019 12:00 AM.
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Absence of TGFβ signaling in retinal microglia induces retinal degeneration and exacerbates choroidal neovascularization
Constitutive TGFβ signaling is important in maintaining retinal neurons and blood vessels and is a factor contributing to the risk for age-related macular degeneration (AMD), a retinal disease involving neurodegeneration and microglial activation. How TGFβ signaling to microglia influences pathological retinal neuroinflammation is unclear. We discovered that ablation of the TGFβ receptor, TGFBR2, in retinal microglia of adult mice induced abnormal microglial numbers, distribution, morphology, and activation status, and promoted a pathological microglial gene expression profile. TGFBR2-deficient retinal microglia induced secondary gliotic changes in Müller cells, neuronal apoptosis, and decreased light-evoked retinal function reflecting abnormal synaptic transmission. While retinal vasculature was unaffected, TGFBR2-deficient microglia demonstrated exaggerated responses to laser-induced injury that was associated with increased choroidal neovascularization, a hallmark of advanced exudative AMD. These findings demonstrate that deficiencies in TGFβ-mediated microglial regulation can drive neuroinflammatory contributions to AMD-related neurodegeneration and neovascularization, highlighting TGFβ signaling as a potential therapeutic target.
in eLife: latest articles on January 22, 2019 12:00 AM.
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Factors affecting template switch recombination associated with restarted DNA replication
Homologous recombination helps ensure the timely completion of genome duplication by restarting collapsed replication forks. This beneficial function is not without risk however, as replication restarted by homologous recombination is prone to template switching (TS) that can generate deleterious genome rearrangements associated with diseases such as cancer. In a previous paper (Nguyen et al., 2015), we established an assay for studying TS in Schizosaccharomyces pombe. Here, we advance this work by showing that TS is detected up to 75 kb downstream of a collapsed replication fork and can be triggered by head-on collision between the restarted fork and RNA Polymerase III transcription. The Pif1 DNA helicase, Pfh1, promotes efficient restart and also suppresses TS. A further three conserved helicases (Fbh1, Rqh1 and Srs2) strongly suppress TS, but there is no change in TS frequency in cells lacking Fml1 or Mus81. We discuss how these factors likely influence TS.
in eLife: latest articles on January 22, 2019 12:00 AM.
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Generality and opponency of rostromedial tegmental (RMTg) roles in valence processing
The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine (DA) neurons, has been hypothesized to be broadly activated by aversive stimuli. However, this encoding pattern has only been demonstrated for a limited number of stimuli, and the RMTg influence on ventral tegmental (VTA) responses to aversive stimuli is untested. Here, we found that RMTg neurons are broadly excited by aversive stimuli of different sensory modalities and inhibited by reward-related stimuli. These stimuli include visual, auditory, somatosensory and chemical aversive stimuli, as well as “opponent” motivational states induced by removal of sustained rewarding or aversive stimuli. These patterns are consistent with broad encoding of negative valence in a subset of RMTg neurons. We further found that valence-encoding RMTg neurons preferentially project to the DA-rich VTA versus other targets, and excitotoxic RMTg lesions greatly reduce aversive stimulus-induced inhibitions in VTA neurons, particularly putative DA neurons, while also impairing conditioned place aversion to multiple aversive stimuli. Together, our findings indicate a broad RMTg role in encoding aversion and driving VTA responses and behavior.
in eLife: latest articles on January 22, 2019 12:00 AM.
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Molecular safeguarding of CRISPR gene drive experiments
CRISPR-based homing gene drives have sparked both enthusiasm and deep concerns due to their potential for genetically altering entire species. This raises the question about our ability to prevent the unintended spread of such drives from the laboratory into a natural population. Here, we experimentally demonstrate the suitability of synthetic target site drives as well as split drives as flexible safeguarding strategies for gene drive experiments by showing that their performance closely resembles that of standard homing drives in Drosophila melanogaster. Using our split drive system, we further find that maternal deposition of both Cas9 and gRNA is required to form resistance alleles in the early embryo and that maternally-deposited Cas9 alone can power germline drive conversion in individuals that lack a genomic source of Cas9.
in eLife: latest articles on January 22, 2019 12:00 AM.
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Gut microbiota density influences host physiology and is shaped by host and microbial factors
To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn’s disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.
in eLife: latest articles on January 22, 2019 12:00 AM.
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High-molecular-weight polymers from dietary fiber drive aggregation of particulates in the murine small intestine
The lumen of the small intestine (SI) is filled with particulates: microbes, therapeutic particles, and food granules. The structure of this particulate suspension could impact uptake of drugs and nutrients and the function of microorganisms; however, little is understood about how this suspension is re-structured as it transits the gut. Here, we demonstrate that particles spontaneously aggregate in SI luminal fluid ex vivo. We find that mucins and immunoglobulins are not required for aggregation. Instead, aggregation can be controlled using polymers from dietary fiber in a manner that is qualitatively consistent with polymer-induced depletion interactions, which do not require specific chemical interactions. Furthermore, we find that aggregation is tunable; by feeding mice dietary fibers of different molecular weights, we can control aggregation in SI luminal fluid. This work suggests that the molecular weight and concentration of dietary polymers play an underappreciated role in shaping the physicochemical environment of the gut.
in eLife: latest articles on January 22, 2019 12:00 AM.
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The Crohn’s disease polymorphism, ATG16L1 T300A, alters the gut microbiota and enhances the local Th1/Th17 response
Inflammatory bowel disease (IBD) is driven by dysfunction between host genetics, the microbiota, and immune system. Knowledge gaps remain regarding how IBD genetic risk loci drive gut microbiota changes. The Crohn’s disease risk allele ATG16L1 T300A results in abnormal Paneth cells due to decreased selective autophagy, increased cytokine release, and decreased intracellular bacterial clearance. To unravel the effects of ATG16L1 T300A on the microbiota and immune system, we employed a gnotobiotic model using human fecal transfers into ATG16L1 T300A knock-in mice. We observed increases in Bacteroides ovatus and Th1 and Th17 cells in ATG16L1 T300A mice. Association of altered Schaedler flora mice with B. ovatus specifically increased Th17 cells selectively in ATG16L1 T300A knock-in mice. Changes occur before disease onset, suggesting that ATG16L1 T300A contributes to dysbiosis and immune infiltration prior to disease symptoms. Our work provides insight for future studies on IBD subtypes, IBD patient treatment and diagnostics.
in eLife: latest articles on January 22, 2019 12:00 AM.
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Quantitative analysis of auxin sensing in leaf primordia argues against proposed role in regulating leaf dorsoventrality
Dorsoventrality in leaves has been shown to depend on the pre-patterned expression of KANADI and HD-ZIPIII genes within the plant shoot apical meristem (SAM). However, it has also been proposed that asymmetric auxin levels within initiating leaves help establish leaf polarity, based in part on observations of the DII auxin sensor. By analyzing and quantifying the expression of the R2D2 auxin sensor, we find that there is no obvious asymmetry in auxin levels during Arabidopsis leaf development. We further show that the mDII control sensor also exhibits an asymmetry in expression in developing leaf primordia early on, while it becomes more symmetric at a later developmental stage as reported previously. Together with other recent findings, our results argue against the importance of auxin asymmetry in establishing leaf polarity.
in eLife: latest articles on January 22, 2019 12:00 AM.
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Ion Channels and Receptors as Determinants of Microglial Function
Microglia provide immune surveillance of the CNS. They display diverse behaviors, including nondirectional and directed motility of their processes, phagocytosis of targets such as dying neurons or superfluous synapses, and generation of reactive oxygen species (ROS) and cytokines. Many of these functions are mediated by ion channels and cell surface receptors, the expression of which varies with the many morphological and functional states that microglial cells can adopt. Recent progress in understanding microglial function has been facilitated by applying classical cell physiological techniques in situ, such as patch-clamping and live imaging, and cell-specific transcriptomic analyses.
in Trends in Neurosciences on January 22, 2019 12:00 AM.
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Structured Odorant Response Patterns across a Complete Olfactory Receptor Neuron Population
The combinatorial olfactory code conveys odor stimulus features in an entangled manner. Si et al. uncover structure and statistical properties in ORN responses that allow separated representations of odor features and shine light on the mechanism of molecular recognition by olfactory receptors.
in Neuron on January 22, 2019 12:00 AM.
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A Network for Computing Value Equilibrium in the Human Medial Prefrontal Cortex
Humans often need to maintain equilibrium between competing goals. Juechems et al. show that a region in the rostral ACC monitors this equilibrium, whereas the vmPFC encodes the redress in imbalance between goals incurred by choice.
in Neuron on January 22, 2019 12:00 AM.
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C99, not beta-amyloid, is associated with selective death of vulnerable neurons in Alzheimer\'s disease.
Amyloid Precursor Protein (APP) and its cleavage product beta-amyloid are widely believed to be key players in the development of Alzheimer's disease (AD). However, the distribution of amyloid deposits in the brain does not correlate well with disease progression. Therefore, it seemed possible that APP metabolites other than beta-amyloid might make a strong contribution to AD pathology. We developed a sensitive assay adapted to the detection of C99, an intermediate in the conversion of APP to beta-amyloid. Brain tissue sections were obtained from patients suffering from sporadic AD and non-demented controls. Our results demonstrate that C99 levels, but not Abeta levels, correlate with the degree of vulnerability to neurodegeneration and cognitive impairment in patients suffering from AD.
in bioRxiv Subject Collection: Neuroscience on January 22, 2019 12:00 AM.
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Attentional amplification of neural codes for number independent of other quantities along the dorsal visual stream
Humans and other animals base important decisions on estimates of number, and intraparietal cortex is thought to provide a crucial substrate of this ability. However, it remains debated whether an independent neuronal processing mechanism underlies this 'number sense', or whether number is instead judged indirectly on the basis of other quantitative features. We performed high-resolution 7 Tesla fMRI while adult human volunteers attended either to the numerosity or to an orthogonal dimension (average item size) of visual dot arrays. Numerosity explained a significant amount of variance in activation patterns, above and beyond non-numerical dimensions. Its representation was progressively enhanced along the dorsal visual pathway and was selectively amplified by attention when task relevant. These results reveal a dedicated extraction mechanism for numerosity that operates independently of other quantitative dimensions of the stimuli, and suggest that later stages along the dorsal stream are most important for the explicit manipulation of numerical quantity.
in bioRxiv Subject Collection: Neuroscience on January 22, 2019 12:00 AM.
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Association between premorbid body mass index and amyotrophic lateral sclerosis: causal inference through genetic approaches
Background: Inverse association between premorbid body mass index (BMI) and amyotrophic lateral sclerosis (ALS) has been discovered in observational studies; however, whether this association is causal remains largely unknown. Methods: We employed a two-sample Mendelian randomization approach to evaluate the causal relationship of genetically increased BMI with the risk of ALS. The analyses were implemented using summary statistics obtained for the independent instruments identified from large-scale genome-wide association studies of BMI (up to ~770,000 individuals) and ALS (up to ~81,000 individuals). The causal relationship between BMI and ALS was estimated using inverse-variance weighted methods and was further validated through extensive complementary and sensitivity analyses. Findings: Using 1,031 instruments strongly related to BMI, the causal effect of per one standard deviation increase of BMI was estimated to be 1.04 (95% CI 0.97~1.11, p=0.275) in the European population. The null association between BMI and ALS discovered in the European population also held in the East Asian population and was robust against various modeling assumptions and outlier biases. Additionally, the Egger-regression and MR-PRESSO ruled out the possibility of horizontal pleiotropic effects of instruments. Interpretation: Our results do not support the causal role of genetically increased or decreased BMI on the risk of ALS.
in bioRxiv Subject Collection: Neuroscience on January 22, 2019 12:00 AM.
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Multi-frequency tACS has lasting effects on neural synchrony and audiovisual responses
BACKGROUND: In cortical networks, synchronized oscillatory activity of neuronal populations enables communication, and its disturbance is related to a range of pathologies. Transcranial alternating current stimulation (tACS) has been explored as a flexible, noninvasive tool for the modulation and restoration of synchronized oscillatory signals. While numerous studies have addressed cognitive or behavioural effects of electrical stimulation, the neural changes underlying the effects of tACS and their persistence after stimulation offset have remained unclear. OBJECTIVE: Here, we screened for lasting aftereffects of prolonged tACS on intrinsic network activity and audiovisual processing in the anesthetized ferret brain. METHODS: Electrical stimulation was applied via subcutaneous wire electrodes. Current waveforms were synthesized from two frequencies in the alpha or gamma range, respectively. Flashes and clicks were used for audiovisual stimulation. Electrocorticographic recordings from an extended network including occipital, temporal and parietal cortical areas were obtained before and after tACS. RESULTS: Changes in local synchrony (continuous and spike-triggered power of LFP), synchrony across recording sites (imaginary coherence) and altered dynamics of sensory response-features (peak-to-peak amplitude, extremum latency) following electrical stimulation consistently point to a synchronizing effect of tACS that can outlast stimulation offset by at least 10 min. Gamma-band tACS proved particularly effective. In line with previous reports on cross-frequency interactions, we observed effects on coherence and power of baseline activity at frequencies other than the ones targeted by tACS. These cross-frequency interactions appeared to underlie the strengthening and stabilizing effect on audiovisual responses. CONCLUSION: We demonstrate aftereffects of tACS on synchrony and stimulus processing in an extended cortical network, measured intracranially in a setting that resembles tACS stimulation in humans. The data provide direct evidence for the efficacy of tACS as a tool for sustained modulation of cortical network dynamics.
in bioRxiv Subject Collection: Neuroscience on January 22, 2019 12:00 AM.
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Neural Function in DCC Mutation Carriers with and without Mirror Movements

Abstract

Objective

Recently identified mutations of the axon guidance molecule receptor gene, DCC, present an opportunity to investigate, in living human brain, mechanisms affecting neural connectivity and the basis of mirror movements, involuntary contralateral responses that mirror voluntary unilateral actions. We hypothesized that haploinsufficient DCC ^+/‐ mutation carriers with mirror movements would exhibit decreased DCC mRNA expression, a functional ipsilateral corticospinal tract, greater “mirroring” motor representations, and reduced interhemispheric inhibition. DCC ^+/‐ mutation carriers without mirror movements might exhibit some of these features.

Methods

The participants (n=52) included 13 DCC ^+/‐ mutation carriers with mirror movements, 7 DCC ^+/‐ mutation carriers without mirror movements, 13 relatives without the mutation or mirror movements, and 19 unrelated healthy volunteers. The multimodal approach comprised quantitative real time polymerase chain reaction, transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) under resting and task conditions, and measures of white matter integrity.

Results

Mirror movements were associated with reduced DCC mRNA expression, increased ipsilateral TMS‐induced motor evoked potentials, increased fMRI responses in the “mirroring” M1 and cerebellum, and markedly reduced interhemispheric inhibition. The DCC ^+/‐ mutation, irrespective of mirror movements, was associated with reduced functional connectivity and white matter integrity.

Interpretation

Diverse connectivity abnormalities were identified in mutation carriers with and without mirror movements, but corticospinal effects and decreased peripheral DCC mRNA appeared driven by the mirror movement phenotype.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on January 21, 2019 05:39 PM.
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The impact of amyloid‐beta and tau on prospective cognitive decline in older individuals

Objectives

Amyloid‐beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated.

Methods

One hundred thirty‐seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aβ (¹¹C‐Pittsburgh compound B) and tau (¹⁸F‐flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aβ PET measures were assessed in regions of interest (ROIs) as well as vertex‐wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites.

Results

Higher levels of Aβ and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aβ was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aβ. A significant interaction between tau and Aβ was observed in both ROI and map‐level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies.

Interpretation

Our results are consistent with the supposition that both Aβ and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1–3

in Wiley: Annals of Neurology: Table of Contents on January 21, 2019 05:36 PM.
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Transgenerational transmission of enhanced ocular dominance plasticity from enriched mice to their non-enriched offspring
Abstract
In recent years, evidence has accumulated that non-Mendelian transgenerational inheritance of qualities acquired through experience is possible. In particular, it has been shown that raising rodents in a so-called enriched environment (EE) can not only modify the animals’ behaviour and increase their susceptibility to activity-dependent neuronal network changes, but also influences both behaviour and neuronal plasticity of the non-enriched offspring. Here, we tested whether such a transgenerational transmission can also be observed in the primary visual cortex (V1) using ocular dominance (OD) plasticity after monocular deprivation (MD) as a paradigm. While OD-plasticity after 7 days of MD is absent in standard-cage (SC) raised mice beyond postnatal day (P) 110, it is present lifelong in EE-raised mice. Using intrinsic signal optical imaging to visualize cortical activity, we confirm these previous observations and additionally show that OD-plasticity is not only preserved in adult EE-mice but also in their adult non-enriched offspring: mice born to enriched parents, but raised in SCs at least until P110 displayed similar OD-shifts towards the open eye after 7 days of MD as age-matched EE-raised animals. Furthermore, testing the offspring of EE-female versus EE-males with SC-mating partners revealed that only pups of EE-females, but not of EE-males, preserved OD-plasticity into adulthood, suggesting that the life experiences of the mother have a greater impact on the continued V1-plasticity of the offspring. The OD-plasticity of the non-enriched pups of EE-mothers was, however, mechanistically different from that of non-enriched pups of EE-parents or EE-mice.
Significance statement Recently evidence is accumulating that life experiences and thus acquired qualities of parents can be transmitted across generations in a non-Mendelian fashion and have a significant impact on the fitness of offspring. Raising mice in a so-called enriched environment with enhanced opportunities for social interaction, voluntary physical exercise and explorative behaviour has been shown to boost cortical plasticity. Our results now show that the plasticity-promoting effect of enrichment on ocular dominance plasticity, a well-established plasticity paradigm in a primary sensory cortex, can also be transmitted from enriched parents to their non-enriched offspring. Thus cortical plasticity is not only influenced by an animal’s life experiences but can also be modified by the life experiences of its parents.

in RSS PAP on January 21, 2019 05:30 PM.
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Non-invasive High Frequency Median Nerve Stimulation Effectively Suppresses Olfactory Intensity Perception in Healthy Males
Ashim Maharjan, Mei Peng, Yusuf O. Cakmak
in Frontiers in Human Neuroscience | New and Recent Articles on January 21, 2019 06:00 AM.
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Small Molecule Modulators of the Circadian Molecular Clock With Implications for Neuropsychiatric Diseases
Hyo Kyeong Cha, Sooyoung Chung, Hye Young Lim, Jong-Wha Jung, Gi Hoon Son
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 21, 2019 06:00 AM.
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General Principles of Neuronal Co-transmission: Insights From Multiple Model Systems
Erik Svensson, John Apergis-Schoute, Geoffrey Burnstock, Michael P. Nusbaum, David Parker, Helgi B. Schiöth
in Frontiers in Neural Circuits | New and Recent Articles on January 21, 2019 06:00 AM.
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Brain Derived Neurotrophic Factor (BDNF) Delays Onset of Pathogenesis in Transgenic Mouse Model of Spinocerebellar Ataxia Type 1 (SCA1)
Aaron Mellesmoen, Carrie Sheeler, Austin Ferro, Orion Rainwater, Marija Cvetanovic
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 21, 2019 06:00 AM.
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Less Is More – Estimation of the Number of Strides Required to Assess Gait Variability in Spatially Confined Settings
Daniel Kroneberg, Morad Elshehabi, Anne-Christiane Meyer, Karen Otte, Sarah Doss, Friedemann Paul, Susanne Nussbaum, Daniela Berg, Andrea A. Kühn, Walter Maetzler, Tanja Schmitz-Hübsch
in Frontiers in Aging Neuroscience | New and Recent Articles on January 21, 2019 06:00 AM.
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Astrocyte function from information processing to cognition and cognitive impairment

Astrocyte function from information processing to cognition and cognitive impairment
Astrocyte function from information processing to cognition and cognitive impairment, Published online: 21 January 2019; doi:10.1038/s41593-018-0325-8
Volterra et al. review evidence that astrocyte-generated signals participate in recruitment and function of neuronal networks underlying memory performance and that signal abnormalities under pathological conditions contribute to cognitive impairment.
in Nature Neuroscience - Issue - nature.com science feeds on January 21, 2019 12:00 AM.
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Microvascular endothelial cells engulf myelin debris and promote macrophage recruitment and fibrosis after neural injury

Microvascular endothelial cells engulf myelin debris and promote macrophage recruitment and fibrosis after neural injury
Microvascular endothelial cells engulf myelin debris and promote macrophage recruitment and fibrosis after neural injury, Published online: 21 January 2019; doi:10.1038/s41593-018-0324-9
Blood vessels help macrophage entry. Zhou et al. show that activated microvessels serve as critical portals for macrophage entry to boost inflammation after spinal cord injury.
in Nature Neuroscience - Issue - nature.com science feeds on January 21, 2019 12:00 AM.
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Acute silencing of hippocampal CA3 reveals a dominant role in place field responses

Acute silencing of hippocampal CA3 reveals a dominant role in place field responses
Acute silencing of hippocampal CA3 reveals a dominant role in place field responses, Published online: 21 January 2019; doi:10.1038/s41593-018-0321-z
Previous studies have suggested that cortical input can drive spatially tuned responses in hippocampal CA1 neurons. Here we use acute inactivation to demonstrate that CA3 is the predominant driver of CA1 responses under normal conditions.
in Nature Neuroscience - Issue - nature.com science feeds on January 21, 2019 12:00 AM.
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Neural computations of threat in the aftermath of combat trauma

Neural computations of threat in the aftermath of combat trauma
Neural computations of threat in the aftermath of combat trauma, Published online: 21 January 2019; doi:10.1038/s41593-018-0315-x
PTSD symptom severity in combat veterans was associated with enhanced sensitivity to prediction errors and lower neural tracking of value and learning rate, providing evidence for neurocomputational contributions to trauma-related psychopathology.
in Nature Neuroscience - Issue - nature.com science feeds on January 21, 2019 12:00 AM.
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A diverse range of factors affect the nature of neural representations underlying short-term memory

A diverse range of factors affect the nature of neural representations underlying short-term memory
A diverse range of factors affect the nature of neural representations underlying short-term memory, Published online: 21 January 2019; doi:10.1038/s41593-018-0314-y
Two qualitatively different neural mechanisms for maintaining information in short-term memory, experimentally observed in animal studies, emerge as part of a spectrum of solutions in recurrent neural networks trained on short-term memory tasks.
in Nature Neuroscience - Issue - nature.com science feeds on January 21, 2019 12:00 AM.
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Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell–derived cortical interneurons from subjects with schizophrenia

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell–derived cortical interneurons from subjects with schizophrenia
Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell–derived cortical interneurons from subjects with schizophrenia, Published online: 21 January 2019; doi:10.1038/s41593-018-0313-z
Shao et al. report that interneurons derived from iPSCs from schizophrenia patients have altered protocadherin expression and synaptic and arborization deficits. A PKC inhibitor, acting downstream of protocadherin, reversed the arborization deficit.
in Nature Neuroscience - Issue - nature.com science feeds on January 21, 2019 12:00 AM.
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Human cognition involves the dynamic integration of neural activity and neuromodulatory systems

Human cognition involves the dynamic integration of neural activity and neuromodulatory systems
Human cognition involves the dynamic integration of neural activity and neuromodulatory systems, Published online: 21 January 2019; doi:10.1038/s41593-018-0312-0
Neuronal activity across task states converges onto a low-dimensional manifold. Flow within this attractor space covaries with network-level topology, fluid intelligence, and regional differences in the density of neuromodulatory receptors.
in Nature Neuroscience - Issue - nature.com science feeds on January 21, 2019 12:00 AM.
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Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus–CA3 projection

Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus–CA3 projection
Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus–CA3 projection, Published online: 21 January 2019; doi:10.1038/s41593-018-0311-1
Zhou et al. show that NCORs regulate memory and synaptic plasticity through a GABAergic hypothalamus–hippocampus projection in mice, and that variants in NCOR1 and NCOR2 are linked to intellectual disability and neurodevelopmental defects in humans.
in Nature Neuroscience - Issue - nature.com science feeds on January 21, 2019 12:00 AM.
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Primed Track, high-fidelity lineage tracing in mouse pre-implantation embryos using primed conversion of photoconvertible proteins
Accurate lineage reconstruction of mammalian pre-implantation development is essential for inferring the earliest cell fate decisions. Lineage tracing using global fluorescence labeling techniques is complicated by increasing cell density and rapid embryo rotation, which hampers automatic alignment and accurate cell tracking of obtained four-dimensional imaging data sets. Here, we exploit the advantageous properties of primed convertible fluorescent proteins (pr-pcFPs) to simultaneously visualize the global green and the photoconverted red population in order to minimize tracking uncertainties over prolonged time windows. Confined primed conversion of H2B-pr-mEosFP-labeled nuclei combined with light-sheet imaging greatly facilitates segmentation, classification, and tracking of individual nuclei from the 4-cell stage up to the blastocyst. Using green and red labels as fiducial markers, we computationally correct for rotational and translational drift, reduce overall data size, and accomplish high-fidelity lineage tracing even for increased imaging time intervals – addressing major concerns in the field of volumetric embryo imaging.
in eLife: latest articles on January 21, 2019 12:00 AM.
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Building bigger beta-barrels
The range of barrel-shaped proteins found in the outer membrane of certain bacteria evolved through multiple pathways.
in eLife: latest articles on January 21, 2019 12:00 AM.
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Computational modeling of brainstem circuits controlling locomotor frequency and gait
A series of recent studies identified key structures in the mesencephalic locomotor region and the caudal brainstem of mice involved in the initiation and control of slow (exploratory) and fast (escape-type) locomotion and gait. Yet, how these brainstem centers interact with each other and with the spinal locomotor circuits is poorly understood. In a previous model (Danner et al., 2017), we suggested that commissural and long propriospinal interneurons are the main targets for brainstem inputs adjusting gait. Here, by extending our previous model, we propose a connectome of the brainstem-spinal circuitry and suggest a mechanistic explanation of the operation of brainstem structures and their roles in controlling speed and gait. We suggest that brainstem control of locomotion is mediated by two pathways, one controlling locomotor speed via connections to rhythm generating circuits in the spinal cord and the other providing gait control by targeting commissural and long propriospinal interneurons.
in eLife: latest articles on January 21, 2019 12:00 AM.
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Reduced White Matter Fiber Density in Autism Spectrum Disorder

Abstract
Differences in brain networks and underlying white matter abnormalities have been suggested to underlie symptoms of autism spectrum disorder (ASD). However, robustly characterizing microstructural white matter differences has been challenging. In the present study, we applied an analytic technique that calculates structural metrics specific to differently-oriented fiber bundles within a voxel, termed “fixels”. Fixel-based analyses were used to compare diffusion-weighted magnetic resonance imaging data from 25 individuals with ASD (mean age = 16.8 years) and 27 typically developing age-matched controls (mean age = 16.9 years). Group comparisons of fiber density (FD) and bundle morphology were run on a fixel-wise, tract-wise, and global white matter (GWM) basis. We found that individuals with ASD had reduced FD, suggestive of decreased axonal count, in several major white matter tracts, including the corpus callosum (CC), bilateral inferior frontal-occipital fasciculus, right arcuate fasciculus, and right uncinate fasciculus, as well as a GWM reduction. Secondary analyses assessed associations with social impairment in participants with ASD, and showed that lower FD in the splenium of the CC was associated with greater social impairment. Our findings suggest that reduced FD could be the primary microstructural white matter abnormality in ASD.
in Cerebral Cortex Open Access on January 21, 2019 12:00 AM.
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Plasticity in Adult Mouse Visual Cortex Following Optic Nerve Injury

Abstract
Optic nerve (ON) injury is an established model of axonal injury which results in retrograde degeneration and death of retinal ganglion cells as well anterograde loss of transmission and Wallerian degeneration of the injured axons. While the local impact of ON crush has been extensively documented we know comparatively little about the functional changes that occur in higher visual structures such as primary visual cortex (V1). We explored the extent of adult cortical plasticity using ON crush in aged mice. V1 function of the contralateral hemisphere was assessed longitudinally by intrinsic signal imaging and 2-photon calcium imaging before and after ON crush. Functional imaging demonstrated an immediate shift in V1 ocular dominance towards the ipsilateral, intact eye, due to the expected almost complete loss of responses to contralateral eye stimulation. Surprisingly, within 2 weeks we observed a delayed increase in ipsilateral eye responses. Additionally, spontaneous activity in V1 was reduced, similar to the lesion projection zone after retinal lesions. The observed changes in V1 activity indicate that severe ON injury in adulthood evokes cortical plasticity not only cross-modally but also within the visual cortex; this plasticity may be best compared with that seen after retinal lesions.
in Cerebral Cortex Open Access on January 21, 2019 12:00 AM.
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Selective Modulation of Early Visual Cortical Activity by Movement Intention

Abstract
The primate visual system contains myriad feedback projections from higher- to lower-order cortical areas, an architecture that has been implicated in the top-down modulation of early visual areas during working memory and attention. Here we tested the hypothesis that these feedback projections also modulate early visual cortical activity during the planning of visually guided actions. We show, across three separate human functional magnetic resonance imaging (fMRI) studies involving object-directed movements, that information related to the motor effector to be used (i.e., limb, eye) and action goal to be performed (i.e., grasp, reach) can be selectively decoded—prior to movement—from the retinotopic representation of the target object(s) in early visual cortex. We also find that during the planning of sequential actions involving objects in two different spatial locations, that motor-related information can be decoded from both locations in retinotopic cortex. Together, these findings indicate that movement planning selectively modulates early visual cortical activity patterns in an effector-specific, target-centric, and task-dependent manner. These findings offer a neural account of how motor-relevant target features are enhanced during action planning and suggest a possible role for early visual cortex in instituting a sensorimotor estimate of the visual consequences of movement.
in Cerebral Cortex Advance Access on January 21, 2019 12:00 AM.
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Sequence Variation Associated with SLC12A5 Gene Expression Is Linked to Brain Structure and Function in Healthy Adults

Abstract
A single-nucleotide polymorphism in the promoter region of the Matrix Metalloproteinase-9 (MMP9) gene, rs3918242, has been shown to affect MMP9 expression in macrophages and was associated with schizophrenia by two independent groups. However, rs3918242's effects on MMP9 expression were not replicable in cell lines or brain tissue. Additionally, publically available data indicate that rs3918242 genotype is related not to MMP9 expression, but rather to expression of SLC12A5, a nearby gene coding for a K+/Cl- cotransporter, whose expression has also been related to schizophrenia. Here, we studied brain structure and function in healthy participants stratified by rs3918242 genotype using structural MRI (N = 298), functional MRI during an N-back working memory task (N = 554), and magnetoencephalography (MEG) during the same task (N = 190). We found rs3918242 was associated with gray matter volume (GMV) in the insula and dorsolateral prefrontal cortex bilaterally, closely replicated in discovery and replication samples; and with inferior parietal lobule (IPL) GMV when the samples were meta-analytically combined. Additionally, using both fMRI and MEG, rs3918242 was associated with right IPL working memory-related activation, replicated in two cohorts and across imaging modalities. These convergent results provide further impetus for examinations of the relationship of SLC12A5 with brain structure and function in neuropsychiatric disease.
in Cerebral Cortex Advance Access on January 21, 2019 12:00 AM.
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Biological Characteristics of Connection-Wise Resting-State Functional Connectivity Strength

Abstract
Functional connectivity is defined as the statistical dependency of neurophysiological activity between 2 separate brain areas. To investigate the biological characteristics of resting-state functional connectivity (rsFC)—and in particular the significance of connection-wise variation in time-series correlations—rsFC was compared with strychnine-based connectivity measured in the macaque. Strychnine neuronography is a historical technique that induces activity in cortical areas through means of local administration of the substance strychnine. Strychnine causes local disinhibition through GABA suppression and leads to subsequent activation of functional pathways. Multiple resting-state fMRI recordings were acquired in 4 macaques (examining in total 299 imaging runs) from which a group-averaged rsFC matrix was constructed. rsFC was observed to be higher (P < 0.0001) between region-pairs with a strychnine-based connection as compared with region-pairs with no strychnine-based connection present. In particular, higher resting-state connectivity was observed in connections that were relatively stronger (weak < moderate < strong; P < 0.01) and in connections that were bidirectional (P < 0.0001) instead of unidirectional in strychnine-based connectivity. Our results imply that the level of correlation between brain areas as extracted from resting-state fMRI relates to the strength of underlying interregional functional pathways.
in Cerebral Cortex Advance Access on January 21, 2019 12:00 AM.
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Spontaneous Brain Activity Predicts Task-Evoked Activity During Animate Versus Inanimate Touch

Abstract
The spontaneous activity of the brain is characterized by an elaborate temporal structure with scale-free properties as indexed by the power law exponent (PLE). We test the hypothesis that spontaneous brain activity modulates task-evoked activity during interactions with animate versus inanimate stimuli. For this purpose, we developed a paradigm requiring participants to actively touch either animate (real hand) or inanimate (mannequin hand) stimuli. Behaviorally, participants perceived the animate target as closer in space, temporally more synchronous with their own self, and more personally relevant, compared with the inanimate. Neuronally, we observed a modulation of task-evoked activity by animate versus inanimate interactions in posterior insula, in medial prefrontal cortex, comprising anterior cingulate cortex, and in medial superior frontal gyrus. Among these regions, an increased functional connectivity was shown between posterior insula and perigenual anterior cingulate cortex (PACC) during animate compared with inanimate interactions and during resting state. Importantly, PLE during spontaneous brain activity in PACC correlated positively with PACC task-evoked activity during animate versus inanimate stimuli. In conclusion, we demonstrate that brain spontaneous activity in PACC can be related to the distinction between animate and inanimate stimuli and thus might be specifically tuned to align our brain with its animate environment.
in Cerebral Cortex Advance Access on January 21, 2019 12:00 AM.
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Neural Coding of Contact Events in Somatosensory Cortex

Abstract
Manual interactions with objects require precise and rapid feedback about contact events. These tactile signals are integrated with motor plans throughout the neuraxis to achieve dexterous object manipulation. To better understand the role of somatosensory cortex in interactions with objects, we measured, using chronically implanted arrays of electrodes, the responses of populations of somatosensory neurons to skin indentations designed to simulate the initiation, maintenance, and termination of contact with an object. First, we find that the responses of somatosensory neurons to contact onset and offset dwarf their responses to maintenance of contact. Second, we show that these responses rapidly and reliably encode features of the simulated contact events—their timing, location, and strength—and can account for the animals’ performance in an amplitude discrimination task. Third, we demonstrate that the spatiotemporal dynamics of the population response in cortex mirror those of the population response in the nerves. We conclude that the responses of populations of somatosensory neurons are well suited to encode contact transients and are consistent with a role of somatosensory cortex in signaling transitions between task subgoals.
in Cerebral Cortex Advance Access on January 21, 2019 12:00 AM.
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Thalamocortical Afferents Innervate the Cortical Subplate much Earlier in Development in Primate than in Rodent

Abstract
The current model, based on rodent data, proposes that thalamocortical afferents (TCA) innervate the subplate towards the end of cortical neurogenesis. This implies that the laminar identity of cortical neurons is specified by intrinsic instructions rather than information of thalamic origin. In order to determine whether this mechanism is conserved in the primates, we examined the growth of thalamocortical (TCA) and corticofugal afferents in early human and monkey fetal development. In the human, TCA, identified by secretagogin, calbindin, and ROBO1 immunoreactivity, were observed in the internal capsule of the ventral telencephalon as early as 7–7.5 PCW, crossing the pallial/subpallial boundary (PSB) by 8 PCW before the calretinin immunoreactive corticofugal fibers do. Furthermore, TCA were observed to be passing through the intermediate zone and innervating the presubplate of the dorsolateral cortex, and already by 10–12 PCW TCAs were occupying much of the cortex. Observations at equivalent stages in the marmoset confirmed that this pattern is conserved across primates. Therefore, our results demonstrate that in primates, TCAs innervate the cortical presubplate at earlier stages than previously demonstrated by acetylcholinesterase histochemistry, suggesting that pioneer thalamic afferents may contribute to early cortical circuitry that can participate in defining cortical neuron phenotypes.
in Cerebral Cortex Open Access on January 21, 2019 12:00 AM.
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Detection of Multiway Gamma Coordination Reveals How Frequency Mixing Shapes Neural Dynamics
In nonlinear systems, converging oscillatory inputs undergo frequency mixing, resulting in additional oscillations in the system’s response. Neural recordings exhibit spectral properties predicted by this process suggesting that not all oscillations originate from synaptic inputs rhythmically active at corresponding frequencies.
in Neuron on January 21, 2019 12:00 AM.
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Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models
This study tests the E-I ratio hypothesis of autism in four mouse models. All show increased E-I ratio, but E-I changes are precisely coordinated to stabilize synaptic depolarization and spiking, not increase them. E-I changes therefore appear compensatory in autism.
in Neuron on January 21, 2019 12:00 AM.
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Loss of EPAC2 results in altered synaptic composition of dendritic spines and excitatory and inhibitory balance
EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras) and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of EPAC2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice (Epac2-/-) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo. In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2+/+ or Epac2-/- mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2-/- mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered of expression of vesicular glutamate transporter 1 (VGluT1) and vesicular GABA transporter (VGAT), indicating a potential imbalance in excitatory/inhibitory inputs onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo. These data provide evidence that EPAC2 is required for the correct composition of synapses and that loss of this protein could result in an imbalance of excitatory and inhibitory synapses.
in bioRxiv Subject Collection: Neuroscience on January 21, 2019 12:00 AM.
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Characterization of neuronal synaptopodin reveals a myosin V-dependent mechanism of synaptopodin clustering at the post-synaptic sites
The spine apparatus (SA) is an endoplasmic reticulum-related organelle which is present in a subset of dendritic spines in cortical and pyramidal neurons. The synaptopodin protein localizes between the stacks of the spine apparatus and is essential for the formation of this unique organelle. Although several studies have demonstrated the significance of the SA and synaptopodin in calcium homeostasis and plasticity of dendritic spines, it is still unclear what factors contribute to its stability at the synapse and whether the SA is locally formed or it is actively delivered to the spines. In this study we show that synaptopodin clusters are stable at their locations. We found no evidence of active microtubule-based transport for synaptopodin. Instead new clusters were emerging in the spines, which we interpret as the SA being assembled on-site. Furthermore, using super-resolution microscopy we show a tight association of synaptopodin with actin filaments. We identify the actin-based motor proteins myosin V and VI as novel interaction partners of synaptopodin and demonstrate that myosin V is important for the formation and/or maintenance of the SA.
in bioRxiv Subject Collection: Neuroscience on January 21, 2019 12:00 AM.
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Intrinsic spine dynamics are critical for recurrent network learning in models with and without autism spectrum disorder
It is often assumed that Hebbian synaptic plasticity forms a cell assembly, a mutually interacting group of neurons that encodes memory. However, in recurrently connected networks with pure Hebbian plasticity, cell assemblies typically diverge or fade under ongoing changes of synaptic strength. Previously assumed mechanisms that stabilize cell assemblies do not robustly reproduce the experimentally reported unimodal and long-tailed distribution of synaptic strengths. Here, we show that augmenting Hebbian plasticity with experimentally observed intrinsic spine dynamics can stabilize cell assemblies and reproduce the distribution of synaptic strengths. Moreover, we posit that strong intrinsic spine dynamics impair learning performance. Our theory explains how excessively strong spine dynamics, experimentally observed in several animal models of autism spectrum disorder, impair learning associations in the brain.
in bioRxiv Subject Collection: Neuroscience on January 21, 2019 12:00 AM.
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Regionally diffuse muscle pain-hypersensitivity in humans during acute muscle pain
Background: We have previously shown that an intramuscular infusion of 5% hypertonic saline (HS) produces a painful response to normally innocuous stimuli applied to overlying and adjacent skin regions. In the current study, we explored whether a similar interaction could be observed between adjacent, contralateral and remote muscles. Indeed, widespread muscle pain-hypersensitivity is a hallmark of chronic pain conditions such as fibromyalgia. Methods: 5% HS was infused into the flexor carpi ulnaris (FCU) muscle to develop a stable baseline pain (n=30). In separate experiments, each of the three test locations (n=10 per site), the adjacent abductor digiti minimi (ADM), contralateral FCU and contralateral tibialis anterior (TA) (part 1-3, respectively), 50uL of 0.9% normal saline (NS) was infused (in triplicate) prior to, during and following HS-induced muscle pain. Results: Under control conditions (no background pain), the infusion of NS was imperceptible by all subjects. In the presence of HS-induced background pain (FCU), in part 1 the NS co-infusion into ADM increased overall pain by 17%. This was replicated in the contralateral FCU (part 2) with a 12% pain increase, and in the TA (part 3) with a 15% pain increase in response to the NS co-infusions. Notably, over 80% of subjects perceived the NS-induced increase in pain at the HS-infusion location (FCU) rather than the NS-infusion location (adjacent, contralateral and remote). Conclusions: Intramuscular infusion of HS results in pain-hypersensitivity to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.
in bioRxiv Subject Collection: Neuroscience on January 21, 2019 12:00 AM.
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Longitudinal Trajectory of Early Functional Recovery in Patients with First Episode Psychosis
There is a large variability in the recovery trajectory and outcome of first episode of psychosis [FEP] patients. To date, individuals outcome trajectories at early stage of illness and potential risk factors associated with a poor outcome trajectory are largely unknown. This study aims to apply three separate predictors (positive symptoms, negative symptoms, and soft neurological signs) to identify homogeneous function outcome trajectories in patients with FEP using objective data-driven methods, and to explore the potential risk /protective factors associated with each trajectory. Methods: A total of 369 first episode patients (93% antipsychotic naive) were included in the baseline assessments and followed-up at 4-8 weeks, 6 months, and 1 year. K means cluster modelling for longitudinal data (kml3d) was used to identify distinct, homogeneous clusters of functional outcome trajectories. Patients with at least 3 assessments were included in the trajectory analyses (N=129). The Scale for the Assessment of Negative Symptoms (SANS), Scale for the Assessment of Positive Symptoms (SAPS), and Neurological examination abnormalities (NEA) were used as predictors against Global Assessment of Functioning Scale (GAF). Results: In each of the three predictor models, four distinct functional outcome trajectories emerged: Poor, Intermediate, Good and Catch-up. Individuals with male gender; ethnic minority status; low premorbid adjustment; low executive function/IQ, low SES, personality disorder, substance use history may be risk factors for poor recovery. Conclusions: Functioning recovery in individuals with FEP is heterogeneous, although distinct recovery profiles are apparent. Data-driven trajectory analysis can facilitate better characterization of individual longitudinal patterns of functioning recovery.
in bioRxiv Subject Collection: Neuroscience on January 21, 2019 12:00 AM.
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Synapse-specific Opioid Modulation of Thalamo-cortico-striatal Circuits
The medial thalamus (MThal), anterior cingulate cortex (ACC) and striatum play important roles in affective-motivational pain processing and reward learning. Opioids affect both pain and reward through uncharacterized modulation of this circuitry. This study examined opioid actions on glutamate transmission between these brain regions in mouse. Mu-opioid receptor (MOR) agonists potently inhibited MThal inputs without affecting ACC inputs to individual striatal medium spiny neurons (MSNs). MOR activation also inhibited MThal inputs to the pyramidal neurons in the ACC. In contrast, delta-opioid receptor (DOR) agonists disinhibited ACC pyramidal neuron responses to MThal inputs by suppressing local feed-forward GABA signaling from parvalbumin-positive interneurons. As a result, DOR activation in the ACC facilitated poly-synaptic (thalamo-cortico-striatal) excitation of MSNs by MThal inputs. These results suggest that opioid effects on pain and reward may be shaped by the relative selectivity of opioid drugs to the specific circuit components.
in bioRxiv Subject Collection: Neuroscience on January 21, 2019 12:00 AM.
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Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum.
The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the aggregation of Tau and TDP-43 in frontotemporal dementia, and to the heterogeneity of clinical disease. We used positron emission tomography in vivo with (a) [11C]PK-11195, a marker of activated microglia and a proxy index of neuroinflammation, and (b) [18F]AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and diseases associated with TDP-43 protein aggregation, and which is used as a surrogate marker of non-{beta}-amyloid protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant frontotemporal dementia, 11 with the semantic variant of primary progressive aphasia and 10 with the non-fluent variant of primary progressive aphasia), 28 of whom underwent both [18F]AV-1451 and [11C]PK-11195 PET, and matched controls (14 for [18F]AV-1451 and 15 for [11C]PK-11195). We used univariate region-of-interest analyses, and multivariate analysis of the distribution of binding that explicitly control for individual differences in ligand affinity for TDP-43 and different Tau isoforms. We found differences between patients and controls in frontotemporal regions for both neuroinflammation and protein aggregation, and a strong positive correlation between these two processes in all disease groups. Despite this regional co-localisation, the multivariate distribution of [11C]PK-11195 binding related better to clinical heterogeneity than did the distribution of [18F]AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate group classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.
in bioRxiv Subject Collection: Neuroscience on January 21, 2019 12:00 AM.
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Observing the origins of human brain development: Automated processing of fetal fMRI
Fetal resting-state functional magnetic resonance imaging (rs-fMRI) has emerged as a critical new approach for characterizing brain network development before birth. Despite rapid and widespread growth of this approach, at present we lack neuroimaging analysis pipelines suited to address the unique challenges inherent in this data type. Here, we present a comprehensive fetal data processing pipeline with provision of full code, and solve the most challenging processing step, rapid and accurate isolation of the fetal brain from surrounding tissue across thousands of non-stationary 3D brain images. Leveraging our library of more than 1,000 manually traced fetal fMRI images, we trained a Convolutional Neural Network (CNN) that achieved excellent accuracy (>90%) across two held-out test sets from separate populations. Furthermore, we unite the auto-masking model with a full processing pipeline and report methodology, performance, and comparison to available alternatives. This work represents the first open source, automated, start-to-finish processing pipeline for fetal fMRI data.
in bioRxiv Subject Collection: Neuroscience on January 21, 2019 12:00 AM.
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Automated Pupillometry to Detect Command Following in Neurological Patients: A Proof-of-Concept Study
Background: Levels of consciousness in patients with acute and chronic brain injury are notoriously underestimated. Paradigms based on electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) may detect covert consciousness in unresponsive patients but are subject to logistical challenges and the need for advanced statistical analysis. Methods: To assess the feasibility of automated pupillometry for the detection of command following, we enrolled 20 healthy volunteers and 48 patients with a wide range of neurological disorders, including 7 patients in the intensive care unit (ICU), who were asked to engage in mental arithmetic. Results: Fourteen of 20 (70%) healthy volunteers and 17 of 43 (39.5%) neurological patients, including 1 in the ICU, fulfilled prespecified criteria for command following by showing pupillary dilations during [≥] 4 of 5 arithmetic tasks. None of the 5 sedated and unconscious ICU patients passed this threshold. Conclusions: Automated pupillometry combined with mental arithmetic appears to be a promising paradigm for the detection of covert consciousness in people with brain injury. We plan to build on this study by focusing on non-communicating ICU patients in whom the level of consciousness is unknown. If some of these patients show reproducible pupillary dilation during mental arithmetic, this would suggest that the present paradigm can reveal conscious awareness in unresponsive patients in whom standard investigations have failed to detect signs of covert consciousness.
in bioRxiv Subject Collection: Neuroscience on January 21, 2019 12:00 AM.
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Learning in visual regions as support for the bias in future value-driven choice
Learning biases decision-making towards higher expected outcomes. Cognitive theories describe this through the tracking of value and outcome evaluations within striatum and prefrontal cortex. Decisions however first require processing of sensory input, and to-date, far less is known about the learning perception interplay. This fMRI study (N=43), relates visual BOLD responses to value-beliefs during choice, and, signed prediction errors after outcomes. To understand these relationships, which co-occurred in striatum, we next evaluated relevance with the prediction of future value-based choices, using a separate transfer-phase with learning already established. We decoded choice outcomes with a 69% accuracy with a machine learning algorithm that was given trial-by-trial BOLD from visual regions alongside traditional prefrontal, and striatal regions. Importantly, this decoding of value-driven choice outcomes again showed an important role for visual activity. These results raise the intriguing possibility that value learning in visual cortex is supportive for the striatal bias towards valued options.
in bioRxiv Subject Collection: Neuroscience on January 21, 2019 12:00 AM.
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Neuronal identity control by terminal selectors in worms, flies, and chordates

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Oliver Hobert, Paschalis Kratsios
How do post-mitotic neurons acquire and maintain their terminal identity? Genetic mutant analysis in the nematode Caenorhabditis elegans has revealed common molecular programs that control neuronal identity. Neuron type-specific combinations of transcription factors, called terminal selectors, act as master regulatory factors to initiate and maintain terminal identity programs through direct regulation of neuron type-specific effector genes. We will provide here an update on recent studies that solidify the terminal selector concept in worms, flies and chordates. We will also describe how the terminal selector concept has been expanded by recent work in C. elegans to explain neuronal subtype diversification and plasticity of neuronal identity.

in ScienceDirect Publication: Current Opinion in Neurobiology on January 20, 2019 06:00 PM.
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Factors predicting cessation of status epilepticus in clinical practice – data from a prospective observational registry (SENSE)

Abstract

Objective

To investigate the initial termination rate of status epilepticus (SE) in a large observational study, and to explore associated variables.

Methods

Data of adults treated for SE were collected prospectively in centers in Germany, Austria, and Switzerland, during 4.5 years. Incident episodes of 1,049 patients were analyzed using uni‐ and multivariate statistics to determine factors predicting cessation of SE within 1 hour (for generalized convulsive SE, GCSE) and 12 hours (for non‐GCSE) of initiating treatment.

Results

Median age at SE onset was 70 years; most frequent etiologies were remote (32%) and acute (31%). GCSE was documented in 43%. Median latency between SE onset and first treatment was 30 minutes in GCSE and 150 minutes in non‐GCSE. The first intravenous compound was a benzodiazepine in 86% in GCSE, and 73% in non‐GCSE. Bolus doses of the first treatment step were lower than recommended by current guidelines in 76% of the GCSE patients and 78% of the non‐GCSE patients. In 319 GCSE patients (70%), SE was ongoing 1 hour after initiating treatment, and in 342 non‐GCSE patients (58%) 12 hours after initiating treatment. Multivariate Cox regression demonstrated that the use of benzodiazepines as first treatment step, and a higher cumulative dose of anticonvulsants within the first period of treatment were associated with shorter time to cessation of SE for both groups.

Interpretation

In clinical practice, treatment guidelines were not followed in a substantial proportion of patients. This under‐dosing correlated with lack of cessation of SE. Our data suggest that sufficiently dosed benzodiazepines should be used as first treatment step.

This article is protected by copyright. All rights reserved.

in Wiley: Annals of Neurology: Table of Contents on January 20, 2019 11:25 AM.
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In vivo metabotropic glutamate receptor type 5 abnormalities localize the epileptogenic zone in mesial temporal lobe epilepsy

Objective

Surgical specimens from patients with mesial temporal lobe epilepsy (MTLE) show abnormalities in tissue concentrations of metabotropic glutamate receptor type 5 (mGluR5). To clarify whether these abnormalities are specific to the epileptogenic zone (EZ), we characterized in vivo whole‐brain mGluR5 availability in MTLE patients using positron emission tomography (PET) and [¹¹C]ABP688, a radioligand that binds specifically to the mGluR5 allosteric site.

Methods

Thirty‐one unilateral MTLE patients and 30 healthy controls underwent [¹¹C]ABP688 PET. We compared partial volume corrected [¹¹C]ABP688 nondisplaceable binding potentials (BP_ND) between groups using region‐of‐interest and whole‐brain voxelwise analyses. [¹⁸F]Fluorodeoxyglucose (FDG) PET was acquired in 15 patients, for whom we calculated asymmetry indices of [¹¹C]ABP688 BP_ND and [¹⁸F]FDG uptake to compare lateralization and localization differences.

Results

[¹¹C]ABP688 BP_ND was focally reduced in the epileptogenic hippocampal head and amygdala (p < 0.001). Patients with hippocampal atrophy showed more extensive abnormalities, including the ipsilateral temporal neocortex (p = 0.006). [¹¹C]ABP688 BP_ND showed interhemispheric differences of higher magnitude and discriminated the epileptogenic structures more accurately when compared to [¹⁸F]FDG uptake, which showed more widespread hypometabolism. Among 23 of 25 operated patients with >1 year of follow‐up, 13 were seizure‐free (Engel Ia) and showed significantly lower [¹¹C]ABP688 BP_ND in the ipsilateral entorhinal cortex.

Interpretation

[¹¹C]ABP688 PET provides a focal biomarker for the EZ in MTLE with higher spatial accuracy compared to [¹⁸F]FDG PET. Focally reduced mGluR5 availability in the EZ might reflect receptor internalization or conformational changes in response to excessive extracellular glutamate, supporting a potential role for mGluR5 as therapeutic target in human MTLE. Ann Neurol 2019; 1–11

in Wiley: Annals of Neurology: Table of Contents on January 20, 2019 11:24 AM.
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Multimodal cell type correspondence by intersectional mFISH in intact tissues
Defining a complete set of cell types within the cortex requires reconciling disparate results achieved through diverging methodologies. To address this correspondence problem, multiple methodologies must be applied to the same cells in multiple single-cell experiments. Here we present an approach in which spatial transcriptomics using multiplexed fluorescence in situ hybridization (mFISH) on tissue previously interrogated through two-photon optogenetic mapping of synaptic connectivity can resolve the anatomical, transcriptomic, connectomic, electrophysiological, and morphological characteristics of single cells within the mouse cortex.
in bioRxiv Subject Collection: Neuroscience on January 20, 2019 12:00 AM.
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Modular structure of human olfactory receptor codes reflects the bases of odor perception
The circuits of olfactory signaling are reminiscent of complex computational devices. The olfactory receptor code, which represents the responses of receptors elicited by olfactory stimuli, is effectively an input code for the neural computation of odor sensing. Here, analyzing a recent dataset of the responses of human olfactory receptors (ORs) to odorants, we show that the space of human olfactory receptor codes is partitioned into a modular structure where groups of receptors are "labeled" for key olfactory features. The existence of such independent and sizable receptor groups implies a significant dimensional reduction in the space of human odor perception. Our data-driven statistical analysis of receptor codes leads to a valuable discovery that human olfaction works by hybridizing both the combinatorial coding and labeled line strategies, even at the early stage of signal processing.
in bioRxiv Subject Collection: Neuroscience on January 20, 2019 12:00 AM.
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Distinct role of flexible and stable encoding in sequential working memory
The serial-position effect in working memory is considered important for studying how a sequence of sensory information can be retained and manipulated simultaneously in neural memory circuits. Here, via a precise analysis of the primacy and recency effects in human psychophysical experiments, we propose that stable and flexible coding take distinct roles of retaining and updating information in working memory, and that their combination induces serial-position effects spontaneously. We found that stable encoding retains memory to induce the primacy effect, while flexible encoding used for learning new inputs induces the recency effect. A model simulation based on human data, confirmed that a neural network with both flexible and stable synapses could reproduce the major characteristics of serial-position effects. Our new prediction, that the control of resource allocation by flexible-stable coding balance can modulate memory performance in sequence-specific manner, was supported by pre-cued memory performance data in humans.
in bioRxiv Subject Collection: Neuroscience on January 20, 2019 12:00 AM.
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Prospective, brain-wide labeling of neuronal subclasses with enhancer-driven AAVs
Labeling and perturbation of specific cell types in multicellular systems has transformed our ability to understand them. The rapid pace of cell type identification by new single-cell analysis methods has not been met with efficient access to these newly discovered types. To enable access to specific neural populations in the mouse cortex, we have collected single cell chromatin accessibility data from select cell types. We clustered the single cell data and mapped them to single cell transcriptomics to identify highly specific enhancers for cell subclasses. These enhancers, when cloned into AAVs and delivered to the brain by retro-orbital injections, enable transgene expression in specific cell subclasses throughout the mouse brain. This approach will enable functional investigation of cell types in the mouse cortex and beyond.
in bioRxiv Subject Collection: Neuroscience on January 20, 2019 12:00 AM.
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Feeling left out or just surprised? Neural correlates of social exclusion and expectancy violations in adolescence
Social belonging and affiliation are important human drives that impact decision-making and health outcomes. While neural responses to social exclusion are increasingly well-characterized, studies rarely identify whether these responses reflect the affective distress or expectancy violation associated with exclusion. The present study compares neural responses to exclusion and over-inclusion, a similarly unexpected social occurrence that violates fair play expectations, but does not involve rejection, with a focus on implications for models of dorsal anterior cingulate cortex (dACC) function. In an fMRI adaptation of the Cyberball paradigm with human adolescents 11.1-17.7 years of age (N=69), we employed parametric modulators to examine scaling of neural signal with cumulative exclusion and inclusion events. The use of parametric modulators overcomes arbitrary definitions of condition onsets and offsets imposed on fluid, continuous gameplay. In support of the notion that the dACC plays a role in processing affective distress, this region exhibited greater signal with cumulative exclusion than cumulative inclusion events. However, this difference was partly driven by diminished signal accompanying cumulative inclusion, a finding that does not conform to either affective distress or expectancy violation model predictions. Additionally, we found that signal in the insula and dorsomedial prefrontal cortex scaled uniquely with social exclusion and over-inclusion, respectively, while conjunction analyses revealed that the rostromedial prefrontal cortex and left intraparietal sulcus responded similarly to both conditions. These findings shed light on which neural regions may exhibit patterns of differential sensitivity to exclusion or over-inclusion, as well as those that are more broadly engaged by both types of social interaction.
in bioRxiv Subject Collection: Neuroscience on January 20, 2019 12:00 AM.
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Ten Simple Rules for avoiding and resolving conflicts with your colleagues

by Fran Lewitter, Philip E. Bourne, Teresa K. Attwood

in PLOS Computational Biology: New Articles on January 18, 2019 10:00 PM.
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OpenCASA: A new open-source and scalable tool for sperm quality analysis

by Carlos Alquézar-Baeta, Silvia Gimeno-Martos, Sara Miguel-Jiménez, Pilar Santolaria, Jesús Yániz, Inmaculada Palacín, Adriana Casao, José Álvaro Cebrián-Pérez, Teresa Muiño-Blanco, Rosaura Pérez-Pé
In the field of assisted reproductive techniques (ART), computer-assisted sperm analysis (CASA) systems have proved their utility and potential for assessing sperm quality, improving the prediction of the fertility potential of a seminal dose. Although most laboratories and scientific centers use commercial systems, in the recent years certain free and open-source alternatives have emerged that can reduce the costs that research groups have to face. However, these open-source alternatives cannot analyze sperm kinetic responses to different stimuli, such as chemotaxis, thermotaxis or rheotaxis. In addition, the programs released to date have not usually been designed to encourage the scalability and the continuity of software development. We have developed an open-source CASA software, called OpenCASA, which allows users to study three classical sperm quality parameters: motility, morphodmetry and membrane integrity (viability) and offers the possibility of analyzing the guided movement response of spermatozoa to different stimuli (useful for chemotaxis, thermotaxis or rheotaxis studies) or different motile cells such as bacteria, using a single software. This software has been released in a Version Control System at Github. This platform will allow researchers not only to download the software but also to be involved in and contribute to further developments. Additionally, a Google group has been created to allow the research community to interact and discuss OpenCASA. For validation of the OpenCASA software, we analysed different simulated sperm populations (for chemotaxis module) and evaluated 36 ejaculates obtained from 12 fertile rams using other sperm analysis systems (for motility, membrane integrity and morphology modules). The results were compared with those obtained by Open-CASA using the Pearson’s correlation and Bland-Altman tests, obtaining a high level of correlation in all parameters and a good agreement between the different used methods and the OpenCASA. With this work, we propose an open-source project oriented to the development of a new software application for sperm quality analysis. This proposed software will use a minimally centralized infrastructure to allow the continued development of its modules by the research community.
in PLOS Computational Biology: New Articles on January 18, 2019 10:00 PM.
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Brain Vital Signs: Expanding From the Auditory to Visual Modality
Gabriela M. Pawlowski, Sujoy Ghosh-Hajra, Shaun D. Fickling, Careesa C. Liu, Xiaowei Song, Stephen Robinovitch, Sam M. Doesburg, Ryan C. N. D'Arcy
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 18, 2019 06:00 PM.
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Dynamic Computational Model of the Human Spinal Cord Connectome
Neural Computation, Volume 31, Issue 2, Page 388-416, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Functional Diversity in the Retina Improves the Population Code
Neural Computation, Volume 31, Issue 2, Page 270-311, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Accelerating Nonnegative Matrix Factorization Algorithms Using Extrapolation
Neural Computation, Volume 31, Issue 2, Page 417-439, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Learning Invariant Features in Modulatory Networks through Conflict and Ambiguity
Neural Computation, Volume 31, Issue 2, Page 344-387, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Calculating the Mutual Information between Two Spike Trains
Neural Computation, Volume 31, Issue 2, Page 330-343, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Modeling the Correlated Activity of Neural Populations: A Review
Neural Computation, Volume 31, Issue 2, Page 233-269, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Systems of Bounded Rational Agents with Information-Theoretic Constraints
Neural Computation, Volume 31, Issue 2, Page 440-476, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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Equivalence of Equilibrium Propagation and Recurrent Backpropagation
Neural Computation, Volume 31, Issue 2, Page 312-329, February 2019.

in MIT Press: Neural Computation: Table of Contents on January 18, 2019 06:29 AM.
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The Effects of Family Socioeconomic Status on Psychological and Neural Mechanisms as Well as Their Sex Differences
Hikaru Takeuchi, Yasuyuki Taki, Rui Nouchi, Ryoishi Yokoyama, Yuka Kotozaki, Seishu Nakagawa, Atsushi Sekiguchi, Kunio Iizuka, Yuki Yamamoto, Sugiko Hanawa, Tsuyoshi Araki, Carlos Makoto Miyauchi, Kohei Sakaki, Takayuki Nozawa, Shigeyuki Ikeda, Susumu Yokota, Daniele Magistro, Yuko Sassa, Ryuta Kawashima
in Frontiers in Human Neuroscience | New and Recent Articles on January 18, 2019 06:00 AM.
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Identification of Altered Developmental Pathways in Human Juvenile HD iPSC With 71Q and 109Q Using Transcriptome Profiling
Karolina Świtońska, Wojciech J. Szlachcic, Luiza Handschuh, Paweł Wojciechowski, Łukasz Marczak, Michał Stelmaszczuk, Marek Figlerowicz, Maciej Figiel
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 18, 2019 06:00 AM.
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Predicting Illusory Contours Without Extracting Special Image Features
Albert Yankelovich, Hedva Spitzer
in Frontiers in Computational Neuroscience | New and Recent Articles on January 18, 2019 06:00 AM.
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Age Related Decline in Cortical Multifocal Flash VEP: Latency Increases Shown to Be Predominately Magnocellular
Alyse Brown, Molly Corner, David Crewther, Sheila Crewther
in Frontiers in Aging Neuroscience | New and Recent Articles on January 18, 2019 06:00 AM.
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A Manifold Regularized Multi-Task Learning Model for IQ Prediction from Multiple fMRI Paradigms. (arXiv:1901.05913v1 [q-bio.QM])

Multi-modal brain functional connectivity (FC) data have shown great potential for providing insights into individual variations in behavioral and cognitive traits. The joint learning of multi-modal imaging data can utilize the intrinsic association, and thus can boost the learning performance. Although several multi-task based learning models have already been proposed by viewing the feature learning on each modality as one task, most of them ignore the geometric structure information inherent in the modalities, which may play an important role in extracting discriminative features. In this paper, we propose a new manifold regularized multi-task learning model by simultaneously considering between-subject and between-modality relationships. Besides employing a group-sparsity regularizer to jointly select a few common features across multiple tasks (modalities), we design a novel manifold regularizer to preserve the structure information both within and between modalities in our model. This will make our model more adaptive for realistic data analysis. Our model is then validated on the Philadelphia Neurodevelopmental Cohort dataset, where we regard our modalities as functional MRI (fMRI) data collected under two paradigms. Specifically, we conduct experimental studies on fMRI based FC network data in two task conditions for intelligence quotient (IQ) prediction. The results demonstrate that our proposed model can not only achieve improved prediction performance, but also yield a set of IQ-relevant biomarkers.

in q-bio.NC updates on arXiv.org on January 18, 2019 01:30 AM.
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Early Salient Region Selection Does Not Drive Rapid Visual Categorization. (arXiv:1901.04908v1 [cs.CV] CROSS LISTED)

The current dominant visual processing paradigm in both human and machine research is the feedforward, layered hierarchy of neural-like processing elements. Within this paradigm, visual saliency is seen by many to have a specific role, namely that of early selection. Early selection is thought to enable very fast visual performance by limiting processing to only the most relevant candidate portions of an image. Though this strategy has indeed led to improved processing time efficiency in machine algorithms, at least one set of critical tests of this idea has never been performed with respect to the role of early selection in human vision. How would the best of the current saliency models perform on the stimuli used by experimentalists who first provided evidence for this visual processing paradigm? Would the algorithms really provide correct candidate sub-images to enable fast categorization on those same images? Here, we report on a new series of tests of these questions whose results suggest that it is quite unlikely that such an early selection process has any role in human rapid visual categorization.

in q-bio.NC updates on arXiv.org on January 18, 2019 01:30 AM.
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Identification of a bilirubin receptor that may mediate a component of cholestatic itch
Various pathologic conditions result in jaundice, a yellowing of the skin due to a buildup of bilirubin. Patients with jaundice commonly report experiencing an intense non-histaminergic itch. Despite this association, the pruritogenic capacity of bilirubin itself has not been explored, and no bilirubin receptor has been identified. Here, we demonstrate that pathophysiologic levels of bilirubin excite peripheral itch sensory neurons and elicit pruritus through MRGPRs, a family of G-protein coupled receptors expressed in primary sensory neurons. Bilirubin binds and activates two MRGPRs, mouse MRGPRA1 and human MRGPRX4. In two mouse models of pathologic hyperbilirubinemia, we show that genetic deletion of either Mrgpra1 or Blvra, the gene that encodes the bilirubin-producing enzyme, attenuates itch. Similarly, plasma isolated from hyperbilirubinemic patients evoked itch in wild-type animals but not Mrgpra1^-/- animals. Removing bilirubin decreased the pruritogenic capacity of patient plasma. Based on these data, targeting MRGPRs is a promising strategy for alleviating jaundice-associated itch.
in eLife: latest articles on January 18, 2019 12:00 AM.
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HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4⁺CD8⁺ thymocytes for CD4-lineage commitment
CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.
in eLife: latest articles on January 18, 2019 12:00 AM.
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Neuronal morphologies built for reliable physiology in a rhythmic motor circuit
It is often assumed that highly-branched neuronal structures perform compartmentalized computations. Instead, the Gastric Mill (GM) neuron in the crustacean stomatogastric ganglion (STG) operates like a single electrotonic compartment, despite having thousands of branch points and total cable length >10 mm (Otopalik et al., 2017a, b). We now show: 1) that compact electrotonic architecture is generalizable to other STG neuron types, 2) these neurons present direction-insensitive, linear voltage integration, suggesting they pool synaptic inputs across their neuronal structures. 3) Simulations of 720 cable models spanning a broad range of geometries and passive properties show that compact electrotonus, linear integration, and directional insensitivity in STG neurons arise from their neurite geometries (diameters tapering from 10-20 µm to < 2 µm at their terminal tips). A broad parameter search reveals multiple morphological and biophysical solutions for achieving different degrees of passive electrotonic decrement and computational strategies in the absence of active properties.
in eLife: latest articles on January 18, 2019 12:00 AM.
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Cellular cartography of the organ of Corti based on optical tissue clearing and machine learning
The highly organized spatial arrangement of sensory hair cells in the organ of Corti is essential for inner ear function. Here, we report a new analytical pipeline, based on optical clearing of tissue, for the construction of a single-cell resolution map of the organ of Corti. A sorbitol-based optical clearing method enabled imaging of the entire cochlea at subcellular resolution. High-fidelity detection and analysis of all hair cell positions along the entire longitudinal axis of the organ of Corti were performed automatically by machine learning–based pattern recognition. Application of this method to samples from young, adult, and noise-exposed mice extracted essential information regarding cellular pathology, including longitudinal and radial spatial characteristics of cell loss, implying that multiple mechanisms underlie clustered cell loss. Our method of cellular mapping is effective for system-level phenotyping of the organ of Corti under both physiological and pathological conditions.
in eLife: latest articles on January 18, 2019 12:00 AM.
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A conserved filamentous assembly underlies the structure of the meiotic chromosome axis
The meiotic chromosome axis plays key roles in meiotic chromosome organization and recombination, yet the underlying protein components of this structure are highly diverged. Here, we show that 'axis core proteins' from budding yeast (Red1), mammals (SYCP2/SYCP3), and plants (ASY3/ASY4) are evolutionarily related and play equivalent roles in chromosome axis assembly. We first identify 'closure motifs' in each complex that recruit meiotic HORMADs, the master regulators of meiotic recombination. We next find that axis core proteins form homotetrameric (Red1) or heterotetrameric (SYCP2:SYCP3 and ASY3:ASY4) coiled-coil assemblies that further oligomerize into micron-length filaments. Thus, the meiotic chromosome axis core in fungi, mammals, and plants shares a common molecular architecture, and likely also plays conserved roles in meiotic chromosome axis assembly and recombination control.
in eLife: latest articles on January 18, 2019 12:00 AM.
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Multiple factors maintain assembled trans-SNARE complexes in the presence of NSF and aSNAP
Neurotransmitter release requires formation of trans-SNARE complexes between the synaptic vesicle and plasma membranes, which likely underlies synaptic vesicle priming to a release-ready state. It is unknown whether Munc18-1, Munc13-1, complexin-1 and synaptotagmin-1 are important for priming because they mediate trans-SNARE complex assembly and/or because they prevent trans-SNARE complex disassembly by NSF-aSNAP, which can lead to de-priming. Here we show that trans-SNARE complex formation in the presence of NSF-aSNAP requires both Munc18-1 and Munc13-1, as proposed previously, and is facilitated by synaptotagmin-1. Our data also show that Munc18-1, Munc13-1, complexin-1 and likely synaptotagmin-1 contribute to maintaining assembled trans-SNARE complexes in the presence of NSF-aSNAP. We propose a model whereby Munc18-1 and Munc13-1 are critical not only for mediating vesicle priming but also for precluding de-priming by preventing trans-SNARE complex disassembly; in this model, complexin-1 also impairs de-priming, while synaptotagmin-1 may assist in priming and hinder de-priming.
in eLife: latest articles on January 18, 2019 12:00 AM.
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Essential metabolism for a minimal cell
JCVI-syn3A, a robust minimal cell with a 543 kbp genome and 493 genes, provides a versatile platform to study the basics of life. Using the vast amount of experimental information available on its precursor, Mycoplasma mycoides capri, we assembled a near-complete metabolic network with 98% of enzymatic reactions supported by annotation or experiment. The model agrees well with genome-scale in vivo transposon mutagenesis experiments, showing a Matthews correlation coefficient of 0.59. The genes in the reconstruction have a high in vivo essentiality or quasi-essentiality of 92% (68% essential), compared to 79% in silico essentiality. This coherent model of the minimal metabolism in JCVI-syn3A at the same time also points toward specific open questions regarding the minimal genome of JCVI-syn3A, which still contains many genes of generic or completely unclear function. In particular, the model, its comparison to in vivo essentiality and proteomics data yield specific hypotheses on gene functions and metabolic capabilities; and provide suggestions for several further gene removals. In this way, the model and its accompanying data guide future investigations of the minimal cell. Finally, the identification of 30 essential genes with unclear function will motivate the search for new biological mechanisms beyond metabolism.
in eLife: latest articles on January 18, 2019 12:00 AM.
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Domain-specific working memory, but not dopamine-related genetic variability, shapes reward-based motor learning
The addition of rewarding feedback to motor learning tasks has been shown to increase the retention of learning, spurring interest in the possible utility for rehabilitation. However, laboratory-based motor tasks employing rewarding feedback have repeatedly been shown to lead to great inter-individual variability in performance. Understanding the causes of such variability is vital for maximising the potential benefits of reward-based motor learning. Thus, in this pre-registered study, we assessed whether spatial (SWM), verbal (VWM) and mental rotation (RWM) working memory capacity as well as dopamine-related genetic profiles could predict performance in two reward-based motor tasks, using a large cohort of participants (N=241). The first task assessed participant's ability to follow a hidden and slowly shifting reward region based on hit/miss (binary) feedback. The second task investigated participant's capacity to preserve performance with binary feedback after adapting to the shift with full visual feedback. Our results demonstrate that SWM strongly predicts a participant's capacity to reliably reproduce a successful motor action, measured as change in reach angle following reward, while RWM predicted a participant's propensity to express an explicit strategy when required to make large adjustments in reach angle. Therefore, both SWM and RWM were reliable predictors of success during reward-based motor learning. Change in reach direction following failure was also a strong predictor of success rate, although we observed no consistent relationship with any type of working memory. Surprisingly, no dopamine-related genotypes predicted performance. Therefore, working memory capacity plays a pivotal in determining individual ability in reward-based motor learning.
in bioRxiv Subject Collection: Neuroscience on January 18, 2019 12:00 AM.
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Thermodynamic model of gene regulation for the Or59b olfactory receptor in <i>Drosophila</i>

by Alejandra González, Shadi Jafari, Alberto Zenere, Mattias Alenius, Claudio Altafini
Complex eukaryotic promoters normally contain multiple cis-regulatory sequences for different transcription factors (TFs). The binding patterns of the TFs to these sites, as well as the way the TFs interact with each other and with the RNA polymerase (RNAp), lead to combinatorial problems rarely understood in detail, especially under varying epigenetic conditions. The aim of this paper is to build a model describing how the main regulatory cluster of the olfactory receptor Or59b drives transcription of this gene in Drosophila. The cluster-driven expression of this gene is represented as the equilibrium probability of RNAp being bound to the promoter region, using a statistical thermodynamic approach. The RNAp equilibrium probability is computed in terms of the occupancy probabilities of the single TFs of the cluster to the corresponding binding sites, and of the interaction rules among TFs and RNAp, using experimental data of Or59b expression to tune the model parameters. The model reproduces correctly the changes in RNAp binding probability induced by various mutation of specific sites and epigenetic modifications. Some of its predictions have also been validated in novel experiments.
in PLOS Computational Biology: New Articles on January 17, 2019 10:00 PM.
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Modeling cell line-specific recruitment of signaling proteins to the insulin-like growth factor 1 receptor

by Keesha E. Erickson, Oleksii S. Rukhlenko, Md Shahinuzzaman, Kalina P. Slavkova, Yen Ting Lin, Ryan Suderman, Edward C. Stites, Marian Anghel, Richard G. Posner, Dipak Barua, Boris N. Kholodenko, William S. Hlavacek
Receptor tyrosine kinases (RTKs) typically contain multiple autophosphorylation sites in their cytoplasmic domains. Once activated, these autophosphorylation sites can recruit downstream signaling proteins containing Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains, which recognize phosphotyrosine-containing short linear motifs (SLiMs). These domains and SLiMs have polyspecific or promiscuous binding activities. Thus, multiple signaling proteins may compete for binding to a common SLiM and vice versa. To investigate the effects of competition on RTK signaling, we used a rule-based modeling approach to develop and analyze models for ligand-induced recruitment of SH2/PTB domain-containing proteins to autophosphorylation sites in the insulin-like growth factor 1 (IGF1) receptor (IGF1R). Models were parameterized using published datasets reporting protein copy numbers and site-specific binding affinities. Simulations were facilitated by a novel application of model restructuration, to reduce redundancy in rule-derived equations. We compare predictions obtained via numerical simulation of the model to those obtained through simple prediction methods, such as through an analytical approximation, or ranking by copy number and/or K_D value, and find that the simple methods are unable to recapitulate the predictions of numerical simulations. We created 45 cell line-specific models that demonstrate how early events in IGF1R signaling depend on the protein abundance profile of a cell. Simulations, facilitated by model restructuration, identified pairs of IGF1R binding partners that are recruited in anti-correlated and correlated fashions, despite no inclusion of cooperativity in our models. This work shows that the outcome of competition depends on the physicochemical parameters that characterize pairwise interactions, as well as network properties, including network connectivity and the relative abundances of competitors.
in PLOS Computational Biology: New Articles on January 17, 2019 10:00 PM.
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Ten simple rules on how to create open access and reproducible molecular simulations of biological systems

by Arne Elofsson, Berk Hess, Erik Lindahl, Alexey Onufriev, David van der Spoel, Anders Wallqvist

in PLOS Computational Biology: New Articles on January 17, 2019 10:00 PM.
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STRFs in primary auditory cortex emerge from masking-based statistics of natural sounds

by Abdul-Saboor Sheikh, Nicol S. Harper, Jakob Drefs, Yosef Singer, Zhenwen Dai, Richard E. Turner, Jörg Lücke
We investigate how the neural processing in auditory cortex is shaped by the statistics of natural sounds. Hypothesising that auditory cortex (A1) represents the structural primitives out of which sounds are composed, we employ a statistical model to extract such components. The input to the model are cochleagrams which approximate the non-linear transformations a sound undergoes from the outer ear, through the cochlea to the auditory nerve. Cochleagram components do not superimpose linearly, but rather according to a rule which can be approximated using the max function. This is a consequence of the compression inherent in the cochleagram and the sparsity of natural sounds. Furthermore, cochleagrams do not have negative values. Cochleagrams are therefore not matched well by the assumptions of standard linear approaches such as sparse coding or ICA. We therefore consider a new encoding approach for natural sounds, which combines a model of early auditory processing with maximal causes analysis (MCA), a sparse coding model which captures both the non-linear combination rule and non-negativity of the data. An efficient truncated EM algorithm is used to fit the MCA model to cochleagram data. We characterize the generative fields (GFs) inferred by MCA with respect to in vivo neural responses in A1 by applying reverse correlation to estimate spectro-temporal receptive fields (STRFs) implied by the learned GFs. Despite the GFs being non-negative, the STRF estimates are found to contain both positive and negative subfields, where the negative subfields can be attributed to explaining away effects as captured by the applied inference method. A direct comparison with ferret A1 shows many similar forms, and the spectral and temporal modulation tuning of both ferret and model STRFs show similar ranges over the population. In summary, our model represents an alternative to linear approaches for biological auditory encoding while it captures salient data properties and links inhibitory subfields to explaining away effects.
in PLOS Computational Biology: New Articles on January 17, 2019 10:00 PM.
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Sequential infection experiments for quantifying innate and adaptive immunity during influenza infection

by Ada W. C. Yan, Sophie G. Zaloumis, Julie A. Simpson, James M. McCaw
Laboratory models are often used to understand the interaction of related pathogens via host immunity. For example, recent experiments where ferrets were exposed to two influenza strains within a short period of time have shown how the effects of cross-immunity vary with the time between exposures and the specific strains used. On the other hand, studies of the workings of different arms of the immune response, and their relative importance, typically use experiments involving a single infection. However, inferring the relative importance of different immune components from this type of data is challenging. Using simulations and mathematical modelling, here we investigate whether the sequential infection experiment design can be used not only to determine immune components contributing to cross-protection, but also to gain insight into the immune response during a single infection. We show that virological data from sequential infection experiments can be used to accurately extract the timing and extent of cross-protection. Moreover, the broad immune components responsible for such cross-protection can be determined. Such data can also be used to infer the timing and strength of some immune components in controlling a primary infection, even in the absence of serological data. By contrast, single infection data cannot be used to reliably recover this information. Hence, sequential infection data enhances our understanding of the mechanisms underlying the control and resolution of infection, and generates new insight into how previous exposure influences the time course of a subsequent infection.
in PLOS Computational Biology: New Articles on January 17, 2019 10:00 PM.
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Not all cortical expansions are the same: the coevolution of the neocortex and the dorsal thalamus in mammals

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Andrew C Halley, Leah Krubitzer
A central question in comparative neurobiology concerns how evolution has produced brains with expanded neocortices, composed of more areas with unique connectivity and functional properties. Some mammalian lineages, such as primates, exhibit exceptionally large cortices relative to the amount of sensory inputs from the dorsal thalamus, and this expansion is associated with a larger number of distinct cortical areas, composing a larger proportion of the cortical sheet. We propose a link between the organization of the neocortex and its expansion relative to the size of the dorsal thalamus, based on a combination of work in comparative neuroanatomy and experimental research.

in ScienceDirect Publication: Current Opinion in Neurobiology on January 17, 2019 06:00 PM.
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Presetting of the Corticospinal Excitability in the Tibialis Anterior Muscle in Relation to Prediction of the Magnitude and Direction of Postural Perturbations
Kimiya Fujio, Hiroki Obata, Noritaka Kawashima, Kimitaka Nakazawa
in Frontiers in Human Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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A Versatile and Open-Source Rapid LED Switching System for One-Photon Imaging and Photo-Activation
Arne Battefeld, Marko A. Popovic, Dirk van der Werf, Maarten H. P. Kole
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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Entorhinal Neurons Exhibit Cue Locking in Rodent VR
Giulio Casali, Sarah Shipley, Charlie Dowell, Robin Hayman, Caswell Barry
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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The Neuroprotector Benzothiazepine CGP37157 Extends Lifespan in C. elegans Worms
Paloma García-Casas, Jessica Arias-del-Val, Pilar Alvarez-Illera, Aneta Wojnicz, Cristobal de los Ríos, Rosalba I. Fonteriz, Mayte Montero, Javier Alvarez
in Frontiers in Aging Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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Differential Associations of IL-4 With Hippocampal Subfields in Mild Cognitive Impairment and Alzheimer’s Disease
Virginia Boccardi, Eric Westman, Luca Pelini, Olof Lindberg, J-Sebastian Muehlboeck, Andrew Simmons, Roberto Tarducci, Piero Floridi, Pietro Chiarini, Hilkka Soininen, Iwona Kloszewska, Magda Tsolaki, Bruno Vellas, Christian Spenger, Lars-Olof Wahlund, Simon Lovestone, Patrizia Mecocci
in Frontiers in Aging Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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Fragile-X Syndrome Is Associated With NMDA Receptor Hypofunction and Reduced Dendritic Complexity in Mature Dentate Granule Cells
Suk-Yu Yau, Luis Bettio, Jason Chiu, Christine Chiu, Brian R. Christie
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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EZH2 Influences mdDA Neuronal Differentiation, Maintenance and Survival
Iris Wever, Lars von Oerthel, Cindy M. R. J. Wagemans, Marten P. Smidt
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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The Degree of Modulation of Beta Band Activity During Motor Planning Is Related to Trait Impulsivity
Charidimos Tzagarakis, Andrew Thompson, Robert D. Rogers, Giuseppe Pellizzer
in Frontiers in Integrative Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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The Effect of Dual Task on Attentional Performance in Children With ADHD
Simona Caldani, Milena Razuk, Mathilde Septier, José Angelo Barela, Richard Delorme, Eric Acquaviva, Maria Pia Bucci
in Frontiers in Integrative Neuroscience | New and Recent Articles on January 17, 2019 06:00 AM.
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Quantum Structures in Human Decision-making: Towards Quantum Expected Utility. (arXiv:1811.00875v1 [cs.AI] CROSS LISTED)

{\it Ellsberg thought experiments} and empirical confirmation of Ellsberg preferences pose serious challenges to {\it subjective expected utility theory} (SEUT). We have recently elaborated a quantum-theoretic framework for human decisions under uncertainty which satisfactorily copes with the Ellsberg paradox and other puzzles of SEUT. We apply here the quantum-theoretic framework to the {\it Ellsberg two-urn example}, showing that the paradox can be explained by assuming a state change of the conceptual entity that is the object of the decision ({\it decision-making}, or {\it DM}, {\it entity}) and representing subjective probabilities by quantum probabilities. We also model the empirical data we collected in a DM test on human participants within the theoretic framework above. The obtained results are relevant, as they provide a line to model real life, e.g., financial and medical, decisions that show the same empirical patterns as the two-urn experiment.

in q-bio.NC updates on arXiv.org on January 17, 2019 01:30 AM.
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Synapse maintenance is impacted by ATAT-2 tubulin acetyltransferase activity and the RPM-1 signaling hub
Synapse formation is comprised of target recognition, synapse assembly, and synapse maintenance. Maintaining established synaptic connections is essential for generating functional circuitry and synapse instability is a hallmark of neurodegenerative disease. While many molecules impact synapse formation generally, we know little about molecules that affect synapse maintenance in vivo. Using genetics and developmental time course analysis in C. elegans, we show that the a-tubulin acetyltransferase ATAT-2 and the signaling hub RPM-1 are required presynaptically to maintain stable synapses. Importantly, the enzymatic acetyltransferase activity of ATAT-2 is required for synapse maintenance. Our analysis revealed that RPM-1 is a hub in a genetic network composed of ATAT-2, PTRN-1 and DLK-1. In this network, ATAT-2 functions independent of the DLK-1 MAPK and likely acts downstream of RPM-1. Thus, our study reveals an important role for tubulin acetyltransferase activity in presynaptic maintenance, which occurs via the RPM-1/ATAT-2 pathway.
in eLife: latest articles on January 17, 2019 12:00 AM.
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A Bundle of Mechanisms: Inner-Ear Hair-Cell Mechanotransduction
In the inner ear, the deflection of hair bundles, the sensory organelles of hair cells, activates mechanically-gated channels (MGCs). Hair bundles monitor orientation of the head, its angular and linear acceleration, and detect sound. Force applied to MGCs is shaped by intrinsic hair-bundle properties, by the mechanical load on the bundle, and by the filter imparted by the environment of the hair bundle. Channel gating and adaptation, the ability of the bundle to reset its operating point, contribute to hair-bundle mechanics.
in Trends in Neurosciences on January 17, 2019 12:00 AM.
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Long-Range Guidance of Spinal Commissural Axons by Netrin1 and Sonic Hedgehog from Midline Floor Plate Cells
Recent studies have queried the role of netrin1 from floor plate (FP-netrin1) in guiding commissural axons. Wu et al. show that, in spinal cord, FP-netrin1 is required and acts at long range to guide commissural axons, collaborating with Shh.
in Neuron on January 17, 2019 12:00 AM.
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Synergistic Activity of Floor-Plate- and Ventricular-Zone-Derived Netrin-1 in Spinal Cord Commissural Axon Guidance
Moreno-Bravo et al. use a conditional-knockout strategy and light sheet fluorescence microscopy to show that netrin-1 from ventricular zone progenitors and netrin-1 from the floor plate cooperate to guide spinal cord commissural axons to and across the midline.
in Neuron on January 17, 2019 12:00 AM.
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Correction to: Computing reward prediction errors and learning valence in the insect mushroom body
Following the publication of the original article [1], it was highlighted that an old version of the text for abstract P252 was published, thereby causing the text to no longer correspond with Fig. 1.
in Most Recent Articles: BMC Neuroscience on January 17, 2019 12:00 AM.
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The Effect of Fucoidan on Cellular Oxidative Stress and the CatD-Bax Signaling Axis in MN9D Cells Damaged by 1-Methyl-4-Phenypyridinium
Zhigang Liang, Zhuli Liu, Xuwen Sun, Manli Tao, Xiao Xiao, Guoping Yu, Xiaomin Wang
in Frontiers in Aging Neuroscience | New and Recent Articles on January 16, 2019 06:00 PM.
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Erratum: Prekop et al., "Sox14 Is Required for a Specific Subset of Cerebello-Olivary Projections"

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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A Proposed Mechanism for Spontaneous Transitions between Interictal and Ictal Activity

Epileptic networks are characterized by two outputs: brief interictal spikes and rarer, more prolonged seizures. Although either output state is readily modeled in silico and induced experimentally, the transition mechanisms are unknown, in part because no models exhibit both output states spontaneously. In silico small-world neural networks were built using single-compartment neurons whose physiological parameters were derived from dual whole-cell recordings of pyramidal cells in organotypic hippocampal slice cultures that were generating spontaneous seizure-like activity. In silico, neurons were connected by abundant local synapses and rare long-distance synapses. Activity-dependent synaptic depression and gradual recovery delimited synchronous activity. Full synaptic recovery engendered interictal population spikes that spread via long-distance synapses. When synaptic recovery was incomplete, postsynaptic neurons required coincident activation of multiple presynaptic terminals to reach firing threshold. Only local connections were sufficiently dense to spread activity under these conditions. This coalesced network activity into traveling waves whose velocity varied with synaptic recovery. Seizures were comprised of sustained traveling waves that were similar to those recorded during experimental and human neocortical seizures. Sustained traveling waves occurred only when wave velocity, network dimensions, and the rate of synaptic recovery enabled wave reentry into previously depressed areas at precisely ictogenic levels of synaptic recovery. Wide-field, cellular-resolution GCamP7b calcium imaging demonstrated similar initial patterns of activation in the hippocampus, although the anatomical distribution of traveling waves of synaptic activation was altered by the pattern of synaptic connectivity in the organotypic hippocampal cultures.

SIGNIFICANCE STATEMENT When computerized distributed neural network models are required to generate both features of epileptic networks (i.e., spontaneous interictal population spikes and seizures), the network structure is substantially constrained. These constraints provide important new hypotheses regarding the nature of epileptic networks and mechanisms of seizure onset.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Tau Accumulation in Clinically Normal Older Adults Is Associated with Hippocampal Hyperactivity

Animal studies demonstrate that hyperactive neurons facilitate early accumulation and spread of tau and amyloid-β proteins in the pathological cascade of Alzheimer's disease (AD). Human neuroimaging studies have linked hippocampal hyperactivity to amyloid-β accumulation, apolipoprotein 4 (APOE4) and clinical progression from prodromal AD to clinical dementia. The relationship between hippocampal hyperactivity and early AD molecular pathology (amyloid-β and tau accumulation) before clinical symptoms remains to be elucidated. Here, we studied 120 clinically normal older humans (80 females/40 males) enrolled in the Harvard Aging Brain Study. We measured functional magnetic resonance imaging (fMRI) activity during successful memory encoding and amyloid-β accumulation with PiB-positron emission tomography imaging. Additionally, we measured tau accumulation using AV1451 PET imaging in a subset of 87 participants. In this subset, we found that inferior temporal tau accumulation was associated with increased fMRI activity in the hippocampus, but showed no clear association with amyloid. Together, the findings support a hypothetical model of the evolution of preclinical AD that place hippocampal hyperactivity concurrent with spread of tau pathology to neocortical regions before clinical impairment.

SIGNIFICANCE STATEMENT The circumstances under which the hippocampus becomes hyperactive in preclinical stages of Alzheimer's disease (AD) have thus far remained elusive. Recent advances in positron emission tomography (PET) tracers now enable in vivo characterization of amyloid-β and tau accumulation. Here, we combine amyloid and tau PET with functional magnetic resonance imaging (fMRI) to examine the association between Alzheimer's disease pathology and memory-related brain activity in clinically normal older adults. We found an association between increased hippocampal activity and tau accumulation in the inferior temporal cortex. These data suggest that the pathogenesis of hippocampal hyperactivity occurs concurrent with the spread of tau pathology from the entorhinal cortex to the neocortex, before the clinical manifestations of Alzheimer's disease.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA–BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D_2/3 PET assessment using [¹¹C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D_2/3 receptors to BOLD response in the thalamo–striatal–cortical circuit, which supports WM functioning. Critically, the DA–BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA–BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA–BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.

SIGNIFICANCE STATEMENT Dopamine (DA) is a major neuromodulator in the CNS and plays a key role in several cognitive processes via modulating the blood oxygenation level-dependent (BOLD) signal. Some studies have shown a link between DA and BOLD, whereas others have failed to observe such a relationship. A possible reason for the discrepancy is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. We examined the relationship of DA to BOLD response during working memory under three load conditions and found that the DA–BOLD association is expressed in a load-dependent fashion. These findings may help explain the disproportionate impairment evident in more effortful cognitive tasks in normal aging and in those suffering dopamine-dependent neurodegenerative diseases (e.g., Parkinson's disease).

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Electrical Stimulation Over Human Posterior Parietal Cortex Selectively Enhances the Capacity of Visual Short-Term Memory

Visual short-term memory (VSTM) provides an on-line mental space for incoming sensory information to be temporally maintained to carry out complex behavioral tasks. Despite its essential functions, the capacity at which VSTM could maintain sensory information is limited (i.e., VSTM can hold only about three to four visual items at once). Moreover, the quality of sensory representation (i.e., precision) degrades as more information has to be maintained in VSTM. Correlational evidence suggests that the level and the pattern of neural activity measured in the posterior parietal cortex (PPC) track both VSTM capacity and precision. However, the causal contributions of the PPC to these different VSTM operations are unclear. Here, we tested whether stimulating the PPC with transcranial direct current stimulation (tDCS) could increase VSTM capacity or precision. We found that stimulating the PPC in male and female human participants selectively enhanced VSTM capacity when the number of memory items exceeded capacity limit, without significant effects on VSTM precision. Moreover, this enhancement of VSTM capacity is region specific as stimulating the prefrontal cortex did not change VSTM capacity or precision. Null stimulation effects in the sensory memory condition confirmed that the tDCS-induced enhancement of VSTM capacity was not simply due to changes in sensory or attentional processes. Altogether, these results provide causal evidence suggesting that the PPC has a more dominant role in supporting the storage capacity of VSTM compared with maintaining the quality of sensory representations. Furthermore, tDCS could be used as a promising noninvasive method to enhance this PPC VSTM-related function.

SIGNIFICANCE STATEMENT Correlational evidence from neuroimaging and electrophysiology suggests that the posterior parietal cortex (PPC) supports the storage capacity of visual short-term memory (VSTM) and the precision of sensory representations maintained in VSTM. However, the causal contributions of the PPC to these different VSTM functions were unclear. Here, we found that electrical stimulation over the PPC selectively enhanced VSTM capacity without changing VSTM precision. Overall, our findings suggest that the PPC has a dominant and causal role in supporting the storage capacity of VSTM.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Balancing Prediction and Sensory Input in Speech Comprehension: The Spatiotemporal Dynamics of Word Recognition in Context

Spoken word recognition in context is remarkably fast and accurate, with recognition times of ~200 ms, typically well before the end of the word. The neurocomputational mechanisms underlying these contextual effects are still poorly understood. This study combines source-localized electroencephalographic and magnetoencephalographic (EMEG) measures of real-time brain activity with multivariate representational similarity analysis to determine directly the timing and computational content of the processes evoked as spoken words are heard in context, and to evaluate the respective roles of bottom-up and predictive processing mechanisms in the integration of sensory and contextual constraints. Male and female human participants heard simple (modifier-noun) English phrases that varied in the degree of semantic constraint that the modifier (W1) exerted on the noun (W2), as in pairs, such as "yellow banana." We used gating tasks to generate estimates of the probabilistic predictions generated by these constraints as well as measures of their interaction with the bottom-up perceptual input for W2. Representation similarity analysis models of these measures were tested against electroencephalographic and magnetoencephalographic brain data across a bilateral fronto-temporo-parietal language network. Consistent with probabilistic predictive processing accounts, we found early activation of semantic constraints in frontal cortex (LBA45) as W1 was heard. The effects of these constraints (at 100 ms after W2 onset in left middle temporal gyrus and at 140 ms in left Heschl's gyrus) were only detectable, however, after the initial phonemes of W2 had been heard. Within an overall predictive processing framework, bottom-up sensory inputs are still required to achieve early and robust spoken word recognition in context.

SIGNIFICANCE STATEMENT Human listeners recognize spoken words in natural speech contexts with remarkable speed and accuracy, often identifying a word well before all of it has been heard. In this study, we investigate the brain systems that support this important capacity, using neuroimaging techniques that can track real-time brain activity during speech comprehension. This makes it possible to locate the brain areas that generate predictions about upcoming words and to show how these expectations are integrated with the evidence provided by the speech being heard. We use the timing and localization of these effects to provide the most specific account to date of how the brain achieves an optimal balance between prediction and sensory input in the interpretation of spoken language.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors in male rats, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of G_q signaling, but not G_s signaling, in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory G_i/o signaling in DA neurons blunted the reinforcing and priming effects of cocaine, reduced stress-potentiated reinstatement, and altered behavioral strategies for cocaine seeking and taking. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein-signaling cascades, and DA neuron efferent targets, highlighting their multifaceted roles in addiction.

SIGNIFICANCE STATEMENT G-protein-coupled receptors are crucial modulators of ventral tegmental area (VTA) dopamine neuron activity, but how this metabotropic signaling impacts the complex roles of dopamine in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs (designer receptors exclusively activated by designer drugs) during a variety of cocaine-seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. G_q and G_s stimulation activated dopamine neurons, but only G_q stimulation robustly enhanced cocaine seeking. G_i/o inhibitory signaling reduced some, but not all, types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and point to potential new approaches for intervening in these processes to treat addiction.

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Ipsilateral-Dominant Control of Limb Movements in Rodent Posterior Parietal Cortex

It is well known that the posterior parietal cortex (PPC) and frontal motor cortices in primates preferentially control voluntary movements of contralateral limbs. The PPC of rats has been defined based on patterns of thalamic and cortical connectivity. The anatomical characteristics of this area suggest that it may be homologous to the PPC of primates. However, its functional roles in voluntary forelimb movements have not been well understood, particularly in the lateralization of motor limb representation; that is, the limb-specific activity representations for right and left forelimb movements. We examined functional spike activity of the PPC and two motor cortices, the primary motor cortex (M1) and the secondary motor cortex (M2), when head-fixed male rats performed right or left unilateral movements. Unlike primates, PPC neurons in rodents were found to preferentially represent ipsilateral forelimb movements, in contrast to the contralateral preference of M1 and M2 neurons. Consistent with these observations, optogenetic activation of PPC and motor cortices, respectively, evoked ipsilaterally and contralaterally biased forelimb movements. Finally, we examined the effects of optogenetic manipulation on task performance. PPC or M1 inhibition by optogenetic GABA release shifted the behavioral limb preference contralaterally or ipsilaterally, respectively. In addition, weak optogenetic PPC activation, which was insufficient to evoke motor responses by itself, shifted the preference ipsilaterally; although similar M1 activation showed no effects on task performance. These paradoxical observations suggest that the PPC plays evolutionarily different roles in forelimb control between primates and rodents.

SIGNIFICANCE STATEMENT In rodents, the primary and secondary motor cortices (M1 and M2, respectively) are involved in voluntary movements with contralateral preference. However, it remains unclear whether and how the posterior parietal cortex (PPC) participates in controlling multiple limb movements. We recorded functional activity from these areas using a behavioral task to monitor movements of the right and left forelimbs separately. PPC neurons preferentially represented ipsilateral forelimb movements and optogenetic PPC activation evoked ipsilaterally biased forelimb movements. Optogenetic PPC inhibition via GABA release shifted the behavioral limb preference contralaterally during task performance, whereas weak optogenetic PPC activation, which was insufficient to evoke motor responses by itself, shifted the preference ipsilaterally. Our findings suggest rodent PPC contributes to ipsilaterally biased motor response and/or planning.

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{alpha}2A-Adrenergic Receptor Activation Decreases Parabrachial Nucleus Excitatory Drive onto BNST CRF Neurons and Reduces Their Activity In Vivo

Stress contributes to numerous psychiatric disorders. Corticotropin releasing factor (CRF) signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of α_2A-adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that α- and β-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that α_2A-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α_2A-AR is a G_i-linked GPCR, we assessed the impact of activating the G_i-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced Fos in BNST Crh neurons. Further, using Prkcd as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the coexpression of Prkcd/Crh in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that α_2A-AR activation suppresses the in vivo activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons.

SIGNIFICANCE STATEMENT Stress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated α_2A-AR agonist guanfacine reduces activity of these cells in vivo, and reduces excitatory PBN inputs onto these cells ex vivo. Additionally, we uncover a novel sex-dependent coexpression of Prkcd with Crh in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between norepinephrine and CRF, and point to an action by which guanfacine may reduce negative affective responses.

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AGRP Neurons Project to the Medial Preoptic Area and Modulate Maternal Nest-Building

AGRP (agouti-related neuropeptide) expressing inhibitory neurons sense caloric needs of an animal to coordinate homeostatic feeding. Recent evidence suggests that AGRP neurons also suppress competing actions and motivations to mediate adaptive behavioral selection during starvation. Here, in adult mice of both sexes we show that AGRP neurons form inhibitory synapses onto ~30% neurons in the medial preoptic area (mPOA), a region critical for maternal care. Remarkably, optogenetically stimulating AGRP neurons decreases maternal nest-building while minimally affecting pup retrieval, partly recapitulating suppression of maternal behaviors during food restriction. In parallel, optogenetically stimulating AGRP projections to the mPOA or to the paraventricular nucleus of hypothalamus but not to the LHA (lateral hypothalamus area) similarly decreases maternal nest-building. Chemogenetic inhibition of mPOA neurons that express Vgat (vesicular GABA transporter), the population targeted by AGRP terminals, also decreases maternal nest-building. In comparison, chemogenetic inhibition of neurons in the LHA that express vesicular glutamate transporter 2, another hypothalamic neuronal population critical for feeding and innate drives, is ineffective. Importantly, nest-building during low temperature thermal challenge is not affected by optogenetic stimulation of AGRP->mPOA projections. Finally, via optogenetic activation and inhibition we show that distinctive subsets of mPOA Vgat+ neurons likely underlie pup retrieval and maternal nest-building. Together, these results show that AGRP neurons can modulate maternal nest-building, in part through direct projections to the mPOA. This study corroborates other recent discoveries and underscores the broad functions that AGRP neurons play in antagonizing rivalry motivations to modulate behavioral outputs during hunger.

SIGNIFICANCE STATEMENT In order for animals to initiate ethologically appropriate behaviors, they must typically decide between behavioral repertoires driven by multiple and often conflicting internal states. How neural pathways underlying individual behaviors interact to coherently modulate behavioral outputs, in particular to achieve a proper balance between behaviors that serve immediate individual needs versus those that benefit the propagation of the species, remains poorly understood. Here, by investigating projections from a neuronal population known to drive hunger behaviors to a brain region critical for maternal care, we show that activation of AGRP->mPOA projections in females dramatically inhibits maternal nest-building while leaving mostly intact pup retrieval behavior. Our findings shed new light on neural organization of behaviors and neural mechanisms that coordinate behavioral selection.

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Locus Coeruleus Phasic, But Not Tonic, Activation Initiates Global Remapping in a Familiar Environment

Locus coeruleus (LC) neurons, the source of hippocampal norepinephrine (NE), are activated by novelty and changes in environmental contingencies. Based on the role of monoamines in reconfiguring invertebrate networks, and data from mammalian systems, a network reset hypothesis for the effects of LC activation has been proposed. We used the cellular compartmental analysis of temporal FISH technique based on the cellular distribution of immediate early genes to examine the effect of LC activation and inactivation, on regional hippocampal maps in male rats, when LC activity was manipulated just before placement in a second familiar (A/A) and/or novel environment (A/B). We found that bilateral phasic, but not tonic, activation of LC reset hippocampal maps in the A/A condition, whereas silencing the LC with clonidine before placement in the A/B condition blocked map reset and a familiar map emerged in the dentate gyrus, proximal and distal CA1, and CA3c. However, CA3a and CA3b encoded the novel environment. These results support a role for phasic LC responses in generating novel hippocampal sequences during memory encoding and, potentially, memory updating. The silencing experiments suggest that novel environments may not be recognized as different by dentate gyrus and CA1 without LC input. The functional distinction between phasic and tonic LC activity argues that these parameters are critical for determining network changes. These data are consistent with the hippocampus activating internal network representations to encode novel experiential episodes and suggest LC input is critical for this role.

SIGNIFICANCE STATEMENT Burst activation of the broadly projecting novelty signaling system of the locus coeruleus initiates new network representations throughout the hippocampus despite unchanged external environments. Tonic activation does not alter network representations in the same condition. This suggests differences in the temporal parameters of neuromodulator network activation are critical for neuromodulator function. Silencing this novelty signaling system prevented the appearance of new network representations in a novel environment. Instead, familiar representations were expressed in a subset of hippocampal areas, with another subset encoding the novel environment. This "being in two places at once" argues for independent functional regions within the hippocampus. These experiments strengthen the view that internal states are major determinants of the brain's construction of environmental representations.

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Occurrence of Hippocampal Ripples is Associated with Activity Suppression in the Mediodorsal Thalamic Nucleus

Forming reliable memories requires coordinated activity within distributed brain networks. At present, neural mechanisms underlying systems-level consolidation of declarative memory beyond the hippocampal–prefrontal interactions remain largely unexplored. The mediodorsal thalamic nucleus (MD) is reciprocally connected with the medial prefrontal cortex (mPFC) and also receives inputs from parahippocampal regions. The MD may thus modulate functional connectivity between the hippocampus and the mPFC at different stages of information processing. Here, we characterized, in freely behaving Sprague Dawley male rats, the MD neural activity around hippocampal ripples, indicators of memory replay and hippocampal–cortical information transfer. Overall, the MD firing rate was transiently (0.76 ± 0.06 s) decreased around ripples, with the MD activity suppression preceding the ripple onset for 0.41 ± 0.04 s (range, 0.01–0.95 s). The degree of MD modulation correlated with ripple amplitude, differed across behavioral states, and also depended on the dynamics of hippocampal–cortical population activity. The MD suppression was the strongest and the most consistent during awake ripples. During non–rapid eye movement sleep, MD firing rate decreased around spindle-uncoupled ripples, but increased around spindle-coupled ripples. Our results suggest a competitive interaction between the thalamocortical and hippocampal–cortical networks supporting "on-line" and "off-line" information processing, respectively. We hypothesize that thalamic activity suppression during spindle-uncoupled ripples is favorable for memory replay, as it reduces interference from sensory relay. In turn, the thalamic input during hippocampal–cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer. Both predictions need to be tested in future experiments.

SIGNIFICANCE STATEMENT Systems mechanisms of declarative memory consolidation beyond the hippocampal–prefrontal interactions remain largely unexplored. The connectivity of the mediodorsal thalamic nucleus (MD) with extrahippocampal regions and with medial prefrontal cortex underlies its role in execution of diverse cognitive functions. However, little is known about the MD involvement in "off-line" consolidation. We found that MD neural activity was transiently suppressed around hippocampal ripples, except for ripples co-occurring with sleep spindles, when the MD activity was elevated. The thalamic activity suppression at times of spindle-uncoupled ripples may be favorable for memory replay, as it reduces interference with sensory relay. In turn, the thalamic input during hippocampal–cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer.

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Histamine H1 Receptor Contributes to Vestibular Compensation

Vestibular compensation is responsible for the spontaneous recovery of postural, locomotor, and oculomotor dysfunctions in patients with peripheral vestibular lesion or posterior circulation stroke. Mechanism investigation of vestibular compensation is of great importance in both facilitating recovery of vestibular function and understanding the postlesion functional plasticity in the adult CNS. Here, we report that postsynaptic histamine H1 receptor contributes greatly to facilitating vestibular compensation. The expression of H1 receptor is restrictedly increased in the ipsilesional rather than contralesional GABAergic projection neurons in the medial vestibular nucleus (MVN), one of the most important centers for vestibular compensation, in unilateral labyrinthectomized male rats. Furthermore, H1 receptor mediates an asymmetric excitation of the commissural GABAergic but not glutamatergic neurons in the ipsilesional MVN, which may help to rebalance bilateral vestibular systems and promote vestibular compensation. Selective blockage of H1 receptor in the MVN significantly retards the recovery of both static and dynamic vestibular symptoms following unilateral labyrinthectomy, and remarkably attenuates the facilitation of betahistine, whose effect has traditionally been attributed to its antagonistic action on the presynaptic H3 receptor, on vestibular compensation. These results reveal a previously unknown role for histamine H1 receptor in vestibular compensation and amelioration of vestibular motor deficits, as well as an involvement of H1 receptor in potential therapeutic effects of betahistine. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery in the CNS, but also a novel potential therapeutic target for vestibular disorders.

SIGNIFICANCE STATEMENT Vestibular disorders manifest postural imbalance, nystagmus, and vertigo. Vestibular compensation is critical for facilitating recovery from vestibular disorders, and of great importance in understanding the postlesion functional plasticity in the adult CNS. Here, we show that postsynaptic H1 receptor in the medial vestibular nucleus (MVN) contributes greatly to the recovery of both static and dynamic symptoms following unilateral vestibular lesion. H1 receptor selectively mediates the asymmetric activation of commissural inhibitory system in the ipsilesional MVN and actively promotes vestibular compensation. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery of CNS, but also a novel potential therapeutic target for promoting vestibular compensation and ameliorating vestibular disorders.

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Dendritic Spines in Early Postnatal Fragile X Mice Are Insensitive to Novel Sensory Experience

Autism spectrum disorders are often associated with atypical sensory processing and sensory hypersensitivity, which can lead to maladaptive behaviors, such as tactile defensiveness. Such altered sensory perception in autism spectrum disorders could arise from disruptions in experience-dependent maturation of circuits during early brain development. Here, we tested the hypothesis that synaptic structures of primary somatosensory cortex (S1) neurons in Fragile X syndrome (FXS), which is a common inherited cause of autism, are not modulated by novel sensory information during development. We used chronic in vivo two-photon microscopy to image dendritic spines and axon "en passant" boutons of layer 2/3 pyramidal neurons in S1 of male and female WT and Fmr1 KO mice, a model of FXS. We found that a brief (overnight) exposure to dramatically enhance sensory inputs in the second postnatal week led to a significant increase in spine density in WT mice, but not in Fmr1 KO mice. In contrast, axon "en passant" boutons dynamics were impervious to this novel sensory experience in mice of both genotypes. We surmise that the inability of Fmr1 KO mice to modulate postsynaptic dynamics in response to increased sensory input, at a time when sensory information processing first comes online in S1 cortex, could play a role in altered sensory processing in FXS.

SIGNIFICANCE STATEMENT Very few longitudinal in vivo imaging studies have investigated synaptic structure and dynamics in early postnatal mice. Moreover, those studies tend to focus on the effects of sensory input deprivation, a process that rarely occurs during normal brain development. Early postnatal imaging experiments are critical because a variety of neurodevelopmental disorders, including those characterized by autism, could result from alterations in how circuits are shaped by incoming sensory inputs during critical periods of development. In this study, we focused on a mouse model of Fragile X syndrome and demonstrate how dendritic spines are insensitive to a brief period of novel sensory experience.

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Nociceptor Translational Profiling Reveals the Ragulator-Rag GTPase Complex as a Critical Generator of Neuropathic Pain

Nociceptors, sensory neurons in the DRG that detect damaging or potentially damaging stimuli, are key drivers of neuropathic pain. Injury to these neurons causes activation of translation regulation signaling, including the mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase interacting kinase (MNK) eukaryotic initiation factor (eIF) 4E pathways. This is a mechanism driving changes in excitability of nociceptors that is critical for the generation of chronic pain states; however, the mRNAs that are translated to lead to this plasticity have not been elucidated. To address this gap in knowledge, we used translating ribosome affinity purification in male and female mice to comprehensively characterize mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain (CIPN) caused by paclitaxel treatment. This unbiased method creates a new resource for the field, confirms many findings in the CIPN literature and also find extensive evidence for new target mechanisms that may cause CIPN. We provide evidence that an underlying mechanism of CIPN is sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling. This demonstrates a novel translation regulation signaling circuit wherein MNK1-eIF4E activity drives mTORC1 via control of RagA translation. CIPN and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We identify a novel translational circuit for the genesis of neuropathic pain caused by chemotherapy with important implications for therapeutics.

SIGNIFICANCE STATEMENT Neuropathic pain affects up to 10% of the population, but its underlying mechanisms are incompletely understood, leading to poor treatment outcomes. We used translating ribosome affinity purification technology to create a comprehensive translational profile of DRG nociceptors in naive mice and at the peak of neuropathic pain induced by paclitaxel treatment. We reveal new insight into how mechanistic target of rapamycin complex 1 is activated in neuropathic pain pointing to a key role of MNK1-eIF4E-mediated translation of a complex of mRNAs that control mechanistic target of rapamycin complex 1 signaling at the surface of the lysosome. We validate this finding using genetic and pharmacological techniques. Our work strongly suggests that MNK1-eIF4E signaling drives CIPN and that a drug in human clinical trials, eFT508, may be a new therapeutic for neuropathic pain.

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Resilience to Pain: A Peripheral Component Identified Using Induced Pluripotent Stem Cells and Dynamic Clamp

Pain is a complex process that involves both detection in the peripheral nervous system and perception in the CNS. Individual-to-individual differences in pain are well documented, but not well understood. Here we capitalized on inherited erythromelalgia (IEM), a well characterized human genetic model of chronic pain, and studied a unique family containing related IEM subjects with the same disease-causing Na_V1.7 mutation, which is known to make dorsal root ganglion (DRG) neurons hyperexcitable, but different pain profiles (affected son with severe pain, affected mother with moderate pain, and an unaffected father). We show, first, that, at least in some cases, relative sensitivity to pain can be modeled in subject-specific induced pluripotent stem cell (iPSC)-derived sensory neurons in vitro; second, that, in some cases, mechanisms operating in peripheral sensory neurons contribute to interindividual differences in pain; and third, using whole exome sequencing (WES) and dynamic clamp, we show that it is possible to pinpoint a specific variant of another gene, KCNQ in this particular kindred, that modulates the excitability of iPSC-derived sensory neurons in this family. While different gene variants may modulate DRG neuron excitability and thereby contribute to interindividual differences in pain in other families, this study shows that subject-specific iPSCs can be used to model interindividual differences in pain. We further provide proof-of-principle that iPSCs, WES, and dynamic clamp can be used to investigate peripheral mechanisms and pinpoint specific gene variants that modulate pain signaling and contribute to interindividual differences in pain.

SIGNIFICANCE STATEMENT Individual-to-individual differences in pain are well documented, but not well understood. In this study, we show, first, that, at least in some cases, relative sensitivity to pain can be modeled in subject-specific induced pluripotent stem cell-derived sensory neurons in vitro; second, that, in some cases, mechanisms operating in peripheral sensory neurons contribute to interindividual differences in pain; and third, using whole exome sequencing and dynamic clamp, we show that it is possible to pinpoint a specific gene variant that modulates pain signaling and contributes to interindividual differences in pain.

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This Week in The Journal

in Journal of Neuroscience current issue on January 16, 2019 05:40 PM.
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Gut Microbes Join the Social Network
The gut microbiome is increasingly implicated in the regulation of social behavior across model organisms. In this issue of Neuron, Sgritta et al. (2018) examine the role of the gut microbiome in social reward circuits and sociability in three mouse models of autism spectrum disorder.
in Neuron on January 16, 2019 12:00 AM.
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A TREK to Translate Genetics to Mechanisms of Migraine
In this issue of Neuron, Royal et al. (2018) find that a mutant form of the TRESK ion channel linked to migraine undergoes alternative translation to produce an inhibitory protein that blocks TREK channels, leading to neuronal hyperexcitability and migraine in rodents.
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Engram Excitement
Engram cells can encode and switch between multiple mnemonic functions, but how they intrinsically do so is unknown. Pignatelli, Ryan, and colleagues show that upon memory recall, the engram’s excitability is transiently elevated, allowing its bearer to adapt to changing environments.
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The Puzzling Pulvinar
The functional role of the pulvinar, with its widespread cortical connectivity, has remained elusive. In this issue of Neuron, Jaramillo et al. (2019) provide a computational roadmap for how the pulvinar might influence various cognitive behaviors across multiple large-scale networks.
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Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer’s Disease
(Neuron 99, 925–940.e1–e7; September 5, 2018)
in Neuron on January 16, 2019 12:00 AM.
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Crosstalk of Local Translation and Mitochondria: Powering Plasticity in Axons and Dendrites
Two papers in Cell uncover reciprocal crosstalk of local translation and mitochondria in neurons. Rangaraju et al. (2019) observe tethered compartments of stable mitochondria in dendrites that provide a local energy supply for mRNA translation at synapses. Cioni et al. (2019) report a novel association of axonal RNA granules with Rab7a-late endosomes that provides a platform for local translation supporting mitochondria.
in Neuron on January 16, 2019 12:00 AM.
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Expectancy-Related Changes in Dopaminergic Error Signals Are Impaired by Cocaine Self-Administration
In the current study, Takahashi et al. show that prior cocaine use causes lasting changes in dopaminergic errors, consistent with diminished predictive input. These changes may play a role in long-term sequellae of drug use, such as relapse, which define addiction.
in Neuron on January 16, 2019 12:00 AM.
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On identifying collective displacements in apo-proteins that reveal eventual binding pathways

by Dheeraj Dube, Navjeet Ahalawat, Himanshu Khandelia, Jagannath Mondal, Surajit Sengupta
Binding of small molecules to proteins often involves large conformational changes in the latter, which open up pathways to the binding site. Observing and pinpointing these rare events in large scale, all-atom, computations of specific protein-ligand complexes, is expensive and to a great extent serendipitous. Further, relevant collective variables which characterise specific binding or un-binding scenarios are still difficult to identify despite the large body of work on the subject. Here, we show that possible primary and secondary binding pathways can be discovered from short simulations of the apo-protein without waiting for an actual binding event to occur. We use a projection formalism, introduced earlier to study deformation in solids, to analyse local atomic displacements into two mutually orthogonal subspaces—those which are “affine” i.e. expressible as a homogeneous deformation of the native structure, and those which are not. The susceptibility to non-affine displacements among the various residues in the apo- protein is then shown to correlate with typical binding pathways and sites crucial for allosteric modifications. We validate our observation with all-atom computations of three proteins, T4-Lysozyme, Src kinase and Cytochrome P450.
in PLOS Computational Biology: New Articles on January 15, 2019 10:00 PM.
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The finite state projection based Fisher information matrix approach to estimate information and optimize single-cell experiments

by Zachary R Fox, Brian Munsky
Modern optical imaging experiments not only measure single-cell and single-molecule dynamics with high precision, but they can also perturb the cellular environment in myriad controlled and novel settings. Techniques, such as single-molecule fluorescence in-situ hybridization, microfluidics, and optogenetics, have opened the door to a large number of potential experiments, which begs the question of how to choose the best possible experiment. The Fisher information matrix (FIM) estimates how well potential experiments will constrain model parameters and can be used to design optimal experiments. Here, we introduce the finite state projection (FSP) based FIM, which uses the formalism of the chemical master equation to derive and compute the FIM. The FSP-FIM makes no assumptions about the distribution shapes of single-cell data, and it does not require precise measurements of higher order moments of such distributions. We validate the FSP-FIM against well-known Fisher information results for the simple case of constitutive gene expression. We then use numerical simulations to demonstrate the use of the FSP-FIM to optimize the timing of single-cell experiments with more complex, non-Gaussian fluctuations. We validate optimal simulated experiments determined using the FSP-FIM with Monte-Carlo approaches and contrast these to experiment designs chosen by traditional analyses that assume Gaussian fluctuations or use the central limit theorem. By systematically designing experiments to use all of the measurable fluctuations, our method enables a key step to improve co-design of experiments and quantitative models.
in PLOS Computational Biology: New Articles on January 15, 2019 10:00 PM.
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Sexually dimorphic vasopressin cells modulate social investigation and communication in sex-specific ways
Abstract
The neuropeptide arginine-vasopressin (AVP) has long been implicated in the regulation of social behavior and communication, but precisely which AVP cell groups are involved is largely unknown. To address if the sexually dimorphic AVP cell group in the bed nucleus of the stria terminalis (BNST) is important for social communication, we deleted BNST AVP cells by viral delivery of a Cre-dependent caspase-3 cell-death construct in AVP-iCre positive mice using AVP-iCre negative littermate as controls, and assessed social, sexual, aggressive and anxiety-related behaviors. In males, lesioning BNST AVP cells reduced social investigation of other males and increased urine marking in the presence of a live female, without altering ultrasonic vocalizations, resident-intruder aggression, copulatory behavior, anxiety, or investigation of females or their odor cues. In females, which have significantly fewer AVP cells in the BNST, these injections influenced copulatory behavior but otherwise had minimal effects on social behavior and communication, indicating that these cells contribute to sex differences in social behavioral function.
Significance Statement Despite over thirty years of indirect evidence implicating sexually-dimorphic arginine vasopressin (AVP) cells within the bed nucleus of the stria terminalis (BNST) in the control of social and anxiety-related behavior in mammals, the function of these cells has never been directly tested. Here, we show that deletion of these cells in male, but not female, mice reduce investigation of same-sex conspecifics and alter social communication without changing aggressive and anxiety-related behaviors. Although AVP cell deletion in the BNST did not alter male copulatory behavior, it impaired female sexual behavior. These results indicate that sexually-dimorphic AVP cells in the BNST drive specific aspects of sexually-differentiated social investigation, behavior, and communication.

in RSS PAP on January 15, 2019 05:35 PM.
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Modern genomic tools reveal the structural and cellular diversity of cnidarian nervous systems

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Fabian Rentzsch, Celina Juliano, Brigitte Galliot
Cnidarians shared a common ancestor with bilaterians more than 600 million years ago. This sister group relationship gives them an informative phylogenetic position for understanding the fascinating morphological and molecular cell type diversity of bilaterian nervous systems. Moreover, cnidarians display novel features such as endodermal neurogenesis and independently evolved centralizations, which provide a platform for understanding the evolution of nervous system innovations. In recent years, the application of modern genomic tools has significantly advanced our understanding of cnidarian nervous system structure and function. For example, transgenic reporter lines and gene knockdown experiments in several cnidarian species reveal a significant degree of conservation in the neurogenesis gene regulatory program, while single cell RNA sequencing projects are providing a much deeper understanding of cnidarian neural cell type diversity. At the level of neural function, the physiological properties of ion channels have been described and calcium imaging of the nervous system in whole animals has allowed for the identification of neural circuits underlying specific behaviours. Cnidarians have arrived in the modern era of molecular neurobiology and are primed to provide exciting new insights into the early evolution of nervous systems.

in ScienceDirect Publication: Current Opinion in Neurobiology on January 15, 2019 12:00 PM.
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The Relevancy of Data Regarding the Metabolism of Iron to Our Understanding of Deregulated Mechanisms in ALS; Hypotheses and Pitfalls
Camille Petillon, Rudolf Hergesheimer, Hervé Puy, Philippe Corcia, Patrick Vourc’h, Christian Andres, Zoubida Karim, Hélène Blasco
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 15, 2019 12:00 PM.
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The Transcription Factor Function of Parkin: Breaking the Dogma
Cristine Alves da Costa, Eric Duplan, Lila Rouland, Frédéric Checler
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 15, 2019 12:00 PM.
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Abnormal Cortico-Cerebellar Functional Connectivity in Autism Spectrum Disorder
Taiane Coelho Ramos, Joana Bisol Balardin, João Ricardo Sato, André Fujita
in Frontiers in Systems Neuroscience | New and Recent Articles on January 15, 2019 12:00 PM.
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Synaptotagmin Ca2+ Sensors and Their Spatial Coupling to Presynaptic Cav Channels in Central Cortical Synapses
Grit Bornschein, Hartmut Schmidt
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 15, 2019 12:00 PM.
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Visual and Vestibular Inputs Affect Muscle Synergies Responsible for Body Extension and Stabilization in Sit-to-Stand Motion
Kazunori Yoshida, Qi An, Arito Yozu, Ryosuke Chiba, Kaoru Takakusaki, Hiroshi Yamakawa, Yusuke Tamura, Atsushi Yamashita, Hajime Asama
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 15, 2019 12:00 PM.
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Advances in Nano Neuroscience: From Nanomaterials to Nanotools
Niccolò Paolo Pampaloni, Michele Giugliano, Denis Scaini, Laura Ballerini, Rossana Rauti
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 15, 2019 12:00 PM.
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A Novel Optimization Framework to Improve the Computational Cost of Muscle Activation Prediction for a Neuromusculoskeletal System
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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Advancing System Performance with Redundancy: From Biological to Artificial Designs
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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State-Space Representations of Deep Neural Networks
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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Gradient Descent with Identity Initialization Efficiently Learns Positive-definite Linear Transformations by Deep Residual Networks
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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Scalable and Flexible Unsupervised Feature Selection
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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Forgetting Memories and Their Attractiveness
Neural Computation, Ahead of Print.

in MIT Press: Neural Computation: Table of Contents on January 15, 2019 06:17 AM.
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EEG-Based Neurocognitive Metrics May Predict Simulated and On-Road Driving Performance in Older Drivers
Greg Rupp, Chris Berka, Amir H. Meghdadi, Marija Stevanović Karić, Marc Casillas, Stephanie Smith, Theodore Rosenthal, Kevin McShea, Emily Sones, Thomas D. Marcotte
in Frontiers in Human Neuroscience | New and Recent Articles on January 15, 2019 06:00 AM.
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Cerebellum, Predictions and Errors
Laurentiu S. Popa, Timothy J. Ebner
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 15, 2019 06:00 AM.
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Executive Functions in Alzheimer Disease: A Systematic Review
Angela Guarino, Francesca Favieri, Ilaria Boncompagni, Francesca Agostini, Micaela Cantone, Maria Casagrande
in Frontiers in Aging Neuroscience | New and Recent Articles on January 15, 2019 06:00 AM.
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Cannabinoid Ligands Targeting TRP Channels
Chanté Muller, Paula Morales, Patricia H. Reggio
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 15, 2019 06:00 AM.
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Increased Vesicular Monoamine Transporter 2 (VMAT2) and Dopamine Transporter (DAT) Expression in Adolescent Brain Development: A Longitudinal Micro-PET/CT Study in Rodent
Donglang Jiang, Xiuhong Lu, Zijing Li, Nicklas Rydberg, Chuantao Zuo, Fangyu Peng, Fengchun Hua, Yihui Guan, Fang Xie
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 15, 2019 06:00 AM.
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Dominant Patterns of Information Flow in the Propagation of the Neuromagnetic Somatosensory Steady-State Response
Vasily A. Vakorin, Bernhard Ross, Sam M. Doesburg, Urs Ribary, Anthony R. McIntosh
in Frontiers in Neural Circuits | New and Recent Articles on January 15, 2019 06:00 AM.
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How to correctly quantify neuronal phase-response curves from noisy recordings. (arXiv:1901.04399v1 [q-bio.NC])

At the level of individual neurons, various coding properties can be inferred from the input-output relationship of a cell. For small inputs, this relation is captured by the phase-response curve (PRC), which measures the effect of a small perturbation on the timing of the subsequent spike. Experimentally, however, an accurate experimental estimation of PRCs is challenging. Despite elaborate measurement efforts, experimental PRC estimates often cannot be related to those from modeling studies. In particular, experimental PRCs rarely resemble the generic PRC expected close to spike initiation, which is indicative of the underlying spike-onset bifurcation. Here, we show for conductance-based model neurons that the correspondence between theoretical and measured phase-response curve is lost when the stimuli used for the estimation are too large. In this case, the derived phase-response curve is distorted beyond recognition and takes on a generic shape that reflects the measurement protocol, but not the real neuronal dynamics. We discuss how to identify appropriate stimulus strengths for perturbation and noise-stimulation methods, which permit to estimate PRCs that reliably reflect the spike-onset bifurcation -- a task that is particularly difficult if a lower bound for the stimulus amplitude is dictated by prominent intrinsic neuronal noise.

in q-bio.NC updates on arXiv.org on January 15, 2019 01:30 AM.
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Optimal decoding of dynamic stimuli encoded by heterogeneous populations of spiking neurons - a closed form approximation. (arXiv:1901.04094v1 [q-bio.NC])

Neural decoding may be formulated as dynamic state estimation (filtering) based on point process observations, a generally intractable problem. Numerical sampling techniques are often practically useful for the decoding of real neural data. However, they are less useful as theoretical tools for modeling and understanding sensory neural systems, since they lead to limited conceptual insight about optimal encoding and decoding strategies. We consider sensory neural populations characterized by a distribution over neuron parameters. We develop an analytically tractable Bayesian approximation to optimal filtering based on the observation of spiking activity, that greatly facilitates the analysis of optimal encoding in situations deviating from common assumptions of uniform coding. Continuous distributions are used to approximate large populations with few parameters, resulting in a filter whose complexity does not grow with the population size, and allowing optimization of population parameters rather than individual tuning functions. Numerical comparison with particle filtering demonstrates the quality of the approximation. The analytic framework leads to insights which are difficult to obtain from numerical algorithms, and is consistent with biological observations about the distribution of sensory cells' preferred stimuli.

in q-bio.NC updates on arXiv.org on January 15, 2019 01:30 AM.
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Formation of three-dimensional auditory space. (arXiv:1901.03990v1 [q-bio.NC])

Human listeners need to permanently interact with their three-dimensional (3-D) environment. To this end, they require efficient perceptual mechanisms to form a sufficiently accurate 3-D auditory space. In this chapter, we discuss the formation of the 3-D auditory space from various perspectives. The aim is to show the link between cognition, acoustics, neurophysiology, and psychophysics, when it comes to spatial hearing. First, we present recent cognitive concepts for creating internal models of the complex auditory environment. Second, we describe the acoustic signals available at our ears and discuss the spatial information they convey. Third, we look into neurophysiology, seeking for the neural substrates of the 3-D auditory space. Finally, we elaborate on psychophysical spatial tasks and percepts that are possible just because of the formation of the auditory space.

in q-bio.NC updates on arXiv.org on January 15, 2019 01:30 AM.
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Publisher Correction: Midbrain activity can explain perceptual decisions during an attention task

Publisher Correction: Midbrain activity can explain perceptual decisions during an attention task
Publisher Correction: Midbrain activity can explain perceptual decisions during an attention task, Published online: 15 January 2019; doi:10.1038/s41593-018-0319-6
Publisher Correction: Midbrain activity can explain perceptual decisions during an attention task
in Nature Neuroscience - Issue - nature.com science feeds on January 15, 2019 12:00 AM.
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The control of release probability at nerve terminals

The control of release probability at nerve terminals
The control of release probability at nerve terminals, Published online: 15 January 2019; doi:10.1038/s41583-018-0111-3
Neurosecretion is controlled by SNAREs and SNARE-binding proteins and is initiated by the influx of Ca2+ ions through voltage-gated calcium channels (VGCCs). In this Review, Dittman and Ryan discuss progress in our understanding of the molecular mechanisms underlying the function of VGCCs and fusion machinery.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 15, 2019 12:00 AM.
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Functional Synaptic Architecture of Callosal Inputs in Mouse Primary Visual Cortex
Lee et al. examine the functional synaptic organization of callosal projections onto layer 2/3 pyramidal neurons in the primary visual cortices of mice. They find that callosal and intra-cortical inputs with similar orientation preference cluster together on short dendritic segments.
in Neuron on January 15, 2019 12:00 AM.
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Cholinergic Interneurons Amplify Thalamostriatal Excitation of Striatal Indirect Pathway Neurons in Parkinson’s Disease Models
Tanimura et al. found that motor-learning deficits in a mouse model of PD were triggered by adaptations in the thalamostriatal circuitry. Cholinergic interneuron activation of nicotinic acetylcholine receptors on thalamostriatal axons was key to the adaptation.
in Neuron on January 15, 2019 12:00 AM.
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PAIRUP-MS: Pathway analysis and imputation to relate unknowns in profiles from mass spectrometry-based metabolite data

by Yu-Han H. Hsu, Claire Churchhouse, Tune H. Pers, Josep M. Mercader, Andres Metspalu, Krista Fischer, Kristen Fortney, Eric K. Morgen, Clicerio Gonzalez, Maria E. Gonzalez, Tonu Esko, Joel N. Hirschhorn
Metabolomics is a powerful approach for discovering biomarkers and for characterizing the biochemical consequences of genetic variation. While untargeted metabolite profiling can measure thousands of signals in a single experiment, many biologically meaningful signals cannot be readily identified as known metabolites nor compared across datasets, making it difficult to infer biology and to conduct well-powered meta-analyses across studies. To overcome these challenges, we developed a suite of computational methods, PAIRUP-MS, to match metabolite signals across mass spectrometry-based profiling datasets and to generate metabolic pathway annotations for these signals. To pair up signals measured in different datasets, where retention times (RT) are often not comparable or even available, we implemented an imputation-based approach that only requires mass-to-charge ratios (m/z). As validation, we treated each shared known metabolite as an unmatched signal and showed that PAIRUP-MS correctly matched 70–88% of these metabolites from among thousands of signals, equaling or outperforming a standard m/z- and RT-based approach. We performed further validation using genetic data: the most stringent set of matched signals and shared knowns showed comparable consistency of genetic associations across datasets. Next, we developed a pathway reconstitution method to annotate unknown signals using curated metabolic pathways containing known metabolites. We performed genetic validation for the generated annotations, showing that annotated signals associated with gene variants were more likely to be enriched for pathways functionally related to the genes compared to random expectation. Finally, we applied PAIRUP-MS to study associations between metabolites and genetic variants or body mass index (BMI) across multiple datasets, identifying up to ~6 times more significant signals and many more BMI-associated pathways compared to the standard practice of only analyzing known metabolites. These results demonstrate that PAIRUP-MS enables analysis of unknown signals in a robust, biologically meaningful manner and provides a path to more comprehensive, well-powered studies of untargeted metabolomics data.
in PLOS Computational Biology: New Articles on January 14, 2019 10:00 PM.
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Deep image reconstruction from human brain activity

by Guohua Shen, Tomoyasu Horikawa, Kei Majima, Yukiyasu Kamitani
The mental contents of perception and imagery are thought to be encoded in hierarchical representations in the brain, but previous attempts to visualize perceptual contents have failed to capitalize on multiple levels of the hierarchy, leaving it challenging to reconstruct internal imagery. Recent work showed that visual cortical activity measured by functional magnetic resonance imaging (fMRI) can be decoded (translated) into the hierarchical features of a pre-trained deep neural network (DNN) for the same input image, providing a way to make use of the information from hierarchical visual features. Here, we present a novel image reconstruction method, in which the pixel values of an image are optimized to make its DNN features similar to those decoded from human brain activity at multiple layers. We found that our method was able to reliably produce reconstructions that resembled the viewed natural images. A natural image prior introduced by a deep generator neural network effectively rendered semantically meaningful details to the reconstructions. Human judgment of the reconstructions supported the effectiveness of combining multiple DNN layers to enhance the visual quality of generated images. While our model was solely trained with natural images, it successfully generalized to artificial shapes, indicating that our model was not simply matching to exemplars. The same analysis applied to mental imagery demonstrated rudimentary reconstructions of the subjective content. Our results suggest that our method can effectively combine hierarchical neural representations to reconstruct perceptual and subjective images, providing a new window into the internal contents of the brain.
in PLOS Computational Biology: New Articles on January 14, 2019 10:00 PM.
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Transsacadic Information and Corollary Discharge in Local Field Potentials of Macaque V1
Michael A. Paradiso, Seth Akers-Campbell, Octavio Ruiz, James E. Niemeyer, Stuart Geman, Jackson Loper
in Frontiers in Integrative Neuroscience | New and Recent Articles on January 14, 2019 06:00 PM.
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EEG Phase Synchronization in Persons With Depression Subjected to Transcranial Magnetic Stimulation
Urszula Zuchowicz, Agata Wozniak-Kwasniewska, David Szekely, Elzbieta Olejarczyk, Olivier David
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 14, 2019 06:00 PM.
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Postmeal optogenetic inhibition of dorsal or ventral hippocampal pyramidal neurons increases future intake
Abstract
Memory of a recently eaten meal can serve as a powerful mechanism for controlling future eating behavior because it provides a record of intake that likely outlasts most physiological signals generated by the meal. In support, impairing the encoding of a meal in humans increases the amount ingested at the next eating episode. However, the brain regions that mediate the inhibitory effects of memory on future intake are unknown. In the present study, we tested the hypothesis that dorsal (dHC) and ventral hippocampal (vHC) glutamatergic pyramidal neurons play a critical role in the inhibition of energy intake during the postprandial period by optogenetically inhibiting these neurons at specific times relative to a meal. Male Sprague-Dawley rats were given viral vectors containing CaMKIIα-eArchT3.0-eYFP or CaMKIIα-GFP and fiber optic probes into dHC of one hemisphere and vHC of the other. Compared to intake on a day in which illumination was not given, inhibition of dHC or vHC glutamatergic neurons after the end of a chow, sucrose, or saccharin meal accelerated the onset of the next meal and increased the amount consumed during that next meal when the neurons were no longer inhibited. Inhibition given during a meal did not affect the amount consumed during that meal or the next one but did hasten meal initiation. These data show that dHC and vHC glutamatergic neuronal activity during the postprandial period is critical for limiting subsequent ingestion and suggest that these neurons inhibit future intake by consolidating the memory of the preceding meal.
Significance statement Memory of a recently eaten meal provides a lasting record of recent intake and limits subsequent ingestion; however, the neural mechanisms underlying these mnemonic effects remain unknown. Here, we show that optogenetic inhibition of dorsal or ventral hippocampal pyramidal neurons induced after the end of a sucrose, chow or saccharin meal, when the memory of the meal would be undergoing consolidation, accelerated the initiation of the next meal and, importantly, increased the amount consumed during that next meal when the neurons were no longer inhibited. These findings show that principal hippocampal neurons limit future intake and suggest that they do so by consolidating the memory of the preceding meal.

in RSS PAP on January 14, 2019 05:49 PM.
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Cell-Type-Specific Changes in Intrinsic Excitability in the Subiculum following Learning and Exposure to Novel Environmental Contexts
Abstract
The subiculum is the main target of the hippocampal region CA1 and is the principle output region of the hippocampus. The subiculum is critical to learning and memory, although it has been relatively understudied. There are two functional types of principle neurons within the subiculum: regular spiking (RS) and burst spiking (BS) neurons. To determine whether these cell types are differentially modified by learning-related experience, we performed whole-cell patch clamp recordings from male mouse brain slices following contextual fear conditioning (FC) and memory retrieval relative to a number of control behavioral paradigms. RS cells, but not BS cells, displayed a greater degree of experience-related plasticity in intrinsic excitability measures [afterhyperpolarization (AHP), input resistance (R_input), current required to elicit a spike], with fear conditioned animals having generally more excitable RS cells compared to naïve controls. Furthermore, we found that the relative proportion of RS to BS neurons is modified by the type of exposure, with the lowest proportion of BS subicular cells occurring in animals that underwent contextual FC followed by a retrieval test. These studies indicate that pyramidal neurons in the subiculum undergo experience- and learning-related plasticity in intrinsic properties in a cell-type-specific manner. As BS and RS cells are thought to convey distinct types of information, this plasticity may be particularly important in encoding, consolidating, and recalling spatial information by modulating information flow from the hippocampus to cortical regions.

in eNeuro current issue on January 14, 2019 05:30 PM.
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PINK1 Interacts with VCP/p97 and Activates PKA to Promote NSFL1C/p47 Phosphorylation and Dendritic Arborization in Neurons

While PTEN-induced kinase 1 (PINK1) is well characterized for its role in mitochondrial homeostasis, much less is known concerning its ability to prevent synaptodendritic degeneration. Using unbiased proteomic methods, we identified valosin-containing protein (VCP) as a major PINK1-interacting protein. RNAi studies demonstrate that both VCP and its cofactor NSFL1C/p47 are necessary for the ability of PINK1 to increase dendritic complexity. Moreover, PINK1 regulates phosphorylation of p47, but not the VCP co-factor UFD1. Although neither VCP nor p47 interact directly with PKA, we found that PINK1 binds and phosphorylates the catalytic subunit of PKA at T197 [PKA_cat(pT197)], a site known to activate the PKA holoenzyme. PKA in turn phosphorylates p47 at a novel site (S176) to regulate dendritic complexity. Given that PINK1 physically interacts with both the PKA holoenzyme and the VCP-p47 complex to promote dendritic arborization, we propose that PINK1 scaffolds a novel PINK1-VCP-PKA-p47 signaling pathway to orchestrate dendritogenesis in neurons. These findings highlight an important mechanism by which proteins genetically implicated in Parkinson’s disease (PD; PINK1) and frontotemporal dementia (FTD; VCP) interact to support the health and maintenance of neuronal arbors.

in eNeuro current issue on January 14, 2019 05:30 PM.
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Longitudinal Changes in Semantic Concreteness in Semantic Variant Primary Progressive Aphasia (svPPA)
Abstract
This study examines longitudinal changes in the concreteness of nouns produced by human patients with semantic variant primary progressive aphasia (svPPA). Cross-sectional studies show that patients with svPPA demonstrate severe loss of concrete noun knowledge linked to atrophy of the left ventral temporal lobe. It is unknown how disease spread and duration affect the magnitude of the concreteness impairment in svPPA. We evaluate longitudinal spoken production of concrete nouns in svPPA, and relate this to changes in longitudinal MRI measures of gray matter (GM). Noun concreteness in svPPA is compared to that of behavioral variant frontotemporal dementia (bvFTD) patients, who typically demonstrate highly concrete speech. We elicited naturalistic speech samples at two time points (time 1 and time 2) in patients with svPPA (n = 11) and bvFTD (n = 15) through descriptions of the Cookie Theft picture and evaluated each spoken noun for concreteness. Compared to bvFTD patients whose noun production remained highly concrete throughout the testing period, mixed-effects models revealed that noun concreteness significantly decreased as disease progressed in svPPA. We also measured longitudinal changes to GM in a subset of svPPA patients (n = 7), who showed significant decline in the left and right temporal and frontal regions. Regression analyses revealed that longitudinal GM atrophy in the right fusiform and parahippocampal gyri and the left superior temporal gyrus was related to decreasing noun concreteness. These results suggest that progressive atrophy of the ventral temporal lobe in svPPA contributes to declining concrete noun production over time.

in eNeuro current issue on January 14, 2019 05:30 PM.
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The Positive Brain – Resting State Functional Connectivity in Highly Vital and Flourishing Individuals
Florens Goldbeck, Alina Haipt, David Rosenbaum, Tim Rohe, Andreas J. Fallgatter, Martin Hautzinger, Ann-Christine Ehlis
in Frontiers in Human Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Analysis of Metabolic Alterations Related to Pathogenic Process of Diabetic Encephalopathy Rats
Minjian Dong, Mengqian Ren, Chen Li, Xi Zhang, Changwei Yang, Liangcai Zhao, Hongchang Gao
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Chronic Ethanol Consumption Impairs the Tactile-Evoked Long-Term Depression at Cerebellar Molecular Layer Interneuron-Purkinje Cell Synapses in vivo in Mice
Da-Yong Li, Yan-Hua Bing, Chun-Ping Chu, Xun Cui, Song-Biao Cui, De-Lai Qiu, Li-Da Su
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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A Flow Cytometry-Based Approach for the Isolation and Characterization of Neural Stem Cell Primary Cilia
Sara Monaco, Katja Baur, Andrea Hellwig, Gabriele Hölzl-Wenig, Claudia Mandl, Francesca Ciccolini
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Sirtuin 1 and Autophagy Attenuate Cisplatin-Induced Hair Cell Death in the Mouse Cochlea and Zebrafish Lateral Line
Jiaqi Pang, Hao Xiong, Ting Zhan, Gui Cheng, Haiying Jia, Yongyi Ye, Zhongwu Su, Hongyu Chen, Hanqing Lin, Lan Lai, Yongkang Ou, Yaodong Xu, Suijun Chen, Qiuhong Huang, Maojin Liang, Yuexin Cai, Xueyuan Zhang, Xiaoding Xu, Yiqing Zheng, Haidi Yang
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Increased DJ-1 and α-Synuclein in Plasma Neural-Derived Exosomes as Potential Markers for Parkinson’s Disease
Zhen-Hua Zhao, Zhi-Ting Chen, Rui-Ling Zhou, Xu Zhang, Qin-Yong Ye, Yin-Zhou Wang
in Frontiers in Aging Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Circular RNA Expression Alteration and Bioinformatics Analysis in Rats After Traumatic Spinal Cord Injury
Chuan Qin, Chang-Bin Liu, De-Gang Yang, Feng Gao, Xin Zhang, Chao Zhang, Liang-Jie Du, Ming-Liang Yang, Jian-Jun Li
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Common CHD8 Genomic Targets Contrast With Model-Specific Transcriptional Impacts of CHD8 Haploinsufficiency
A. Ayanna Wade, Kenneth Lim, Rinaldo Catta-Preta, Alex S. Nord
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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White Matter Microstructure Associations of Cognitive and Visuomotor Control in Children: A Sensory Processing Perspective
Annie Brandes-Aitken, Joaquin A. Anguera, Yi-Shin Chang, Carly Demopoulos, Julia P. Owen, Adam Gazzaley, Pratik Mukherjee, Elysa J. Marco
in Frontiers in Integrative Neuroscience | New and Recent Articles on January 14, 2019 06:00 AM.
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Test-Retest Reliability of Diffusion Measures Extracted Along White Matter Language Fiber Bundles Using HARDI-Based Tractography
Mariem Boukadi, Karine Marcotte, Christophe Bedetti, Jean-Christophe Houde, Alex Desautels, Samuel Deslauriers-Gauthier, Marianne Chapleau, Arnaud Boré, Maxime Descoteaux, Simona M. Brambati
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 14, 2019 06:00 AM.
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A Clinical Report of Two Cases of Cryptogenic Brain Abscess and a Relevant Literature Review
Wei Zhou, Xuefei Shao, Xiaochun Jiang
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 14, 2019 06:00 AM.
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Crosstalk Between Autophagy and Cerebral Ischemia
Yulin Sun, Yuanhan Zhu, Xiaojun Zhong, Xinle Chen, Jun Wang, Guozheng Ying
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 14, 2019 06:00 AM.
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Modeling the Effect of Environmental Geometries on Grid Cell Representations
Samyukta Jayakumar, Rukhmani Narayanamurthy, Reshma Ramesh, Karthik Soman, Vignesh Muralidharan, V. Srinivasa Chakravarthy
in Frontiers in Neural Circuits | New and Recent Articles on January 14, 2019 06:00 AM.
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The Organization and Connections of Second Somatosensory Cortex in the Agouti
Lucidia F. Santiago, Marco Aurelio M. Freire, Cristovam W. Picanço-Diniz, João G. Franca, Antonio Pereira
in Frontiers in Neuroanatomy | New and Recent Articles on January 14, 2019 06:00 AM.
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DIVE: A spatiotemporal progression model of brain pathology in neurodegenerative disorders. (arXiv:1901.03553v1 [cs.CV])

Here we present DIVE: Data-driven Inference of Vertexwise Evolution. DIVE is an image-based disease progression model with single-vertex resolution, designed to reconstruct long-term patterns of brain pathology from short-term longitudinal data sets. DIVE clusters vertex-wise biomarker measurements on the cortical surface that have similar temporal dynamics across a patient population, and concurrently estimates an average trajectory of vertex measurements in each cluster. DIVE uniquely outputs a parcellation of the cortex into areas with common progression patterns, leading to a new signature for individual diseases. DIVE further estimates the disease stage and progression speed for every visit of every subject, potentially enhancing stratification for clinical trials or management. On simulated data, DIVE can recover ground truth clusters and their underlying trajectory, provided the average trajectories are sufficiently different between clusters. We demonstrate DIVE on data from two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Dementia Research Centre (DRC), UK, containing patients with Posterior Cortical Atrophy (PCA) as well as typical Alzheimer's disease (tAD). DIVE finds similar spatial patterns of atrophy for tAD subjects in the two independent datasets (ADNI and DRC), and further reveals distinct patterns of pathology in different diseases (tAD vs PCA) and for distinct types of biomarker data: cortical thickness from Magnetic Resonance Imaging (MRI) vs amyloid load from Positron Emission Tomography (PET). Finally, DIVE can be used to estimate a fine-grained spatial distribution of pathology in the brain using any kind of voxelwise or vertexwise measures including Jacobian compression maps, fractional anisotropy (FA) maps from diffusion imaging or other PET measures. DIVE source code is available online: https://github.com/mrazvan22/dive

in q-bio.NC updates on arXiv.org on January 14, 2019 01:30 AM.
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Progress in Brain Computer Interfaces: Challenges and Trends. (arXiv:1901.03442v1 [cs.HC])

Brain computer interfaces (BCI) provide a direct communication link between the brain and a computer or other external devices. They offer an extended degree of freedom either by strengthening or by substituting human peripheral working capacity and have potential applications in various fields such as rehabilitation, affective computing, robotics, gaming and artificial intelligence. Significant research efforts on a global scale have delivered common platforms for technology standardization and help tackle highly complex and nonlinear brain dynamics and related feature extraction and classification challenges. Psycho-neurophysiological phenomena and their impact on brain signals impose another challenge for BCI researchers to transform the technology from laboratory experiments to plug-and-play daily life. This review summarizes progress in BCI field and highlights critical challenges.

in q-bio.NC updates on arXiv.org on January 14, 2019 01:30 AM.
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Time is just a memory

Time is just a memory
Time is just a memory, Published online: 14 January 2019; doi:10.1038/s41593-018-0331-x
Experience unfolds continuously in time, but we remember discrete sequences of events. In this issue of Nature Neuroscience, Montchal et al. describe brain activity patterns that predict how well people remember precisely when recent events occurred. Converging evidence suggests that homologous neural machinery structures temporal representations in rats and people.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Task representations in neural networks trained to perform many cognitive tasks

Task representations in neural networks trained to perform many cognitive tasks
Task representations in neural networks trained to perform many cognitive tasks, Published online: 14 January 2019; doi:10.1038/s41593-018-0310-2
Prefrontal cortex can be flexibly engaged in many different tasks. Yang et al. trained an artificial neural network to solve 20 cognitive tasks. Functionally specialized modules and compositional representations emerged in the network after training.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Cortical microcircuitry of performance monitoring

Cortical microcircuitry of performance monitoring
Cortical microcircuitry of performance monitoring, Published online: 14 January 2019; doi:10.1038/s41593-018-0309-8
Concurrently recording neural spiking across cortical layers in a medial frontal area with EEG reveals the microcircuitry of error and reward signals, showing how neural circuits can realize executive control and produce error-related negativity.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Active control of arousal by a locus coeruleus GABAergic circuit

Active control of arousal by a locus coeruleus GABAergic circuit
Active control of arousal by a locus coeruleus GABAergic circuit, Published online: 14 January 2019; doi:10.1038/s41593-018-0305-z
The authors describe a local population of GABAergic neurons that directly inhibits locus coeruleus noradrenergic neurons. They show how this circuit regulates arousal gain and tone.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Precise temporal memories are supported by the lateral entorhinal cortex in humans

Precise temporal memories are supported by the lateral entorhinal cortex in humans
Precise temporal memories are supported by the lateral entorhinal cortex in humans, Published online: 14 January 2019; doi:10.1038/s41593-018-0303-1
In the lateral entorhinal cortex, high-precision judgments related to timing were associated with greater blood-oxygen-level-dependent fMRI activity than low-precision time judgments. This brain region may be involved in memory for when events occur.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair

ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair
ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair, Published online: 14 January 2019; doi:10.1038/s41593-018-0300-4
Klim et al. illuminate pathomechanisms of ALS using pluripotent stem cells to identify transcripts altered in human motor neurons by perturbations to ALS protein TDP-43, finding the microtubule regulator STMN2 highly sensitive to TDP-43 malfunctions.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Neuronal brain-region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric trait heritability

Neuronal brain-region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric trait heritability
Neuronal brain-region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric trait heritability, Published online: 14 January 2019; doi:10.1038/s41593-018-0297-8
An extensive profile of DNA methylation in neuronal and non-neuronal cells across four brain regions is reported, showing that differential epigenetic marks are enriched for DNA variants associated with neuropsychiatric traits.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration

Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration
Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration, Published online: 14 January 2019; doi:10.1038/s41593-018-0293-z
The mRNA encoding stathmin-2, a protein implicated in axonal growth, is shown to be widely suppressed by premature polyadenylation in both sporadic and C9orf72 ALS through a mechanism directly dependent on loss of nuclear TDP-43 in motor neurons.
in Nature Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis

Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis
Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis, Published online: 14 January 2019; doi:10.1038/s41583-018-0113-1
Understanding the complex interplay of cells that protect neurons early in Alzheimer disease but later contribute to neurodegeneration is important for developing effective therapeutics. In this Review, Henstridge and colleagues discuss the contributions of multiple cell types to disease pathogenesis.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 14, 2019 12:00 AM.
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Ionotropic Receptors Specify the Morphogenesis of Phasic Sensors Controlling Rapid Thermal Preference in Drosophila
Budelli et al. find Drosophila thermoregulatory behavior is driven by a combination of heating and cooling detectors rather than hot- and cold-labeled lines. They further show Ionotropic Receptors not only confer thermosensitivity but also specify the thermoreceptor’s complex dendritic morphology.
in Neuron on January 14, 2019 12:00 AM.
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Oligodendrocyte Progenitor Cells Become Regionally Diverse and Heterogeneous with Age
Spitzer et al. show that oligodendrocyte progenitor cells (OPCs) acquire ion channels and sensitivity to neuronal activity that differ between region and age. The onset and decline of ion channels follow developmental milestones. This heterogeneity indicates different functional states of OPCs.
in Neuron on January 14, 2019 12:00 AM.
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Correction: clusterExperiment and RSEC: A Bioconductor package and framework for clustering of single-cell and other large gene expression datasets

by The PLOS Computational Biology Staff

in PLOS Computational Biology: New Articles on January 11, 2019 10:00 PM.
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Hypomyelination and Oligodendroglial Alterations in a Mouse Model of Autism Spectrum Disorder
Mariana Graciarena, Araceli Seiffe, Brahim Nait-Oumesmar, Amaicha M. Depino
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 11, 2019 06:00 PM.
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Dual-Model Radiomic Biomarkers Predict Development of Mild Cognitive Impairment Progression to Alzheimer’s Disease
Hucheng Zhou, Jiehui Jiang, Jiaying Lu, Min Wang, Huiwei Zhang, Chuantao Zuo, Alzheimer’s Disease Neuroimaging Initiative
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 11, 2019 06:00 PM.
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Pain-Related Fear--Dissociable Neural Sources of Different Fear Constructs
Abstract
Fear of pain demonstrates significant prognostic value regarding the development of persistent musculoskeletal pain and disability. Its assessment often relies on self-report measures of pain-related fear by a variety of questionnaires. However, based either on "fear of movement/(re)injury/kinesiophobia," "fear avoidance beliefs," or "pain anxiety," pain-related fear constructs plausibly differ while it is unclear how specific the questionnaires are in assessing these different constructs. Furthermore, the relationship of pain-related fear to other anxiety measures such as state or trait anxiety remains ambiguous. Advances in neuroimaging such as machine learning on brain activity patterns recorded by functional magnetic resonance imaging might help to dissect commonalities or differences across pain-related fear constructs. We applied a pattern regression approach in 20 human patients with nonspecific chronic low back pain to reveal predictive relationships between fear-related neural pattern information and different pain-related fear questionnaires. More specifically, the applied multiple kernel learning approach allowed the generation of models to predict the questionnaire scores based on a hierarchical ranking of fear-related neural patterns induced by viewing videos of activities potentially harmful for the back. We sought to find evidence for or against overlapping pain-related fear constructs by comparing the questionnaire prediction models according to their predictive abilities and associated neural contributors. By demonstrating evidence of nonoverlapping neural predictors within fear-processing regions, the results underpin the diversity of pain-related fear constructs. This neuroscientific approach might ultimately help to further understand and dissect psychological pain-related fear constructs.

in eNeuro current issue on January 11, 2019 05:30 PM.
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Neuronal Correlations in MT and MST Impair Population Decoding of Opposite Directions of Random Dot Motion
Abstract
The study of neuronal responses to random-dot motion patterns has provided some of the most valuable insights into how the activity of neurons is related to perception. In the opposite directions of motion paradigm, the motion signal strength is decreased by manipulating the coherence of random dot patterns to examine how well the activity of single neurons represents the direction of motion. To extend this paradigm to populations of neurons, studies have used modelling based on data from pairs of neurons, but several important questions require further investigation with larger neuronal datasets. We recorded neuronal populations in the middle temporal (MT) and medial superior temporal (MST) areas of anaesthetized marmosets with electrode arrays, while varying the coherence of random dot patterns in two opposite directions of motion (left and right). Using the spike rates of simultaneously recorded neurons, we decoded the direction of motion at each level of coherence with linear classifiers. We found that the presence of correlations had a detrimental effect to decoding performance, but that learning the correlation structure produced better decoding performance compared to decoders that ignored the correlation structure. We also found that reducing motion coherence increased neuronal correlations, but decoders did not need to be optimized for each coherence level. Finally, we showed that decoder weights depend of left-right selectivity at 100% coherence, rather than the preferred direction. These results have implications for understanding how the information encoded by populations of neurons is affected by correlations in spiking activity.

in eNeuro current issue on January 11, 2019 05:30 PM.
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Gamma oscillations in the basolateral amygdala: biophysical mechanisms and computational consequences
Abstract
The basolateral nucleus of the amygdala (BL) is thought to support numerous emotional behaviors through specific microcircuits. These are often thought to be comprised of feedforward networks of principal cells and interneurons. Neither well-understood nor often considered are recurrent and feedback connections, which likely engender oscillatory dynamics within BL. Indeed, oscillations in the gamma frequency range (40-100 Hz) are known to occur in the BL, and yet their origin and effect on local circuits remains unknown. To address this, we constructed a biophysically and anatomically detailed model of the rat BL and its local field potential based on the physiological and anatomical literature, along with in vivo and in vitro data we collected on the activities of neurons within the rat BL. Remarkably, the model produced intermittent gamma oscillations (~50-70 Hz) whose properties matched those recorded in vivo, including their entrainment of spiking. BL gamma-band oscillations were generated by the intrinsic circuitry, depending upon reciprocal interactions between principal cells and fast-spiking interneurons, while connections within these cell types affected the rhythm’s frequency. The model allowed us to conduct experimentally impossible tests to characterize the synaptic and spatial properties of gamma. The entrainment of individual neurons to gamma depended on the number of afferent connections they received, and gamma bursts were spatially restricted in the BL. Importantly, the gamma rhythm synchronized principal cells and mediated competition between ensembles. Together, these results indicate that the recurrent connectivity of BL expands its computational and communication repertoire.
Significant Statement Using in vitro and in vivo data we develop the first large-scale biophysically and anatomically realistic model of the basolateral amygdala nucleus (BL), which reproduces the dynamics of the in vivo local field potential (LFP). Significantly, it predicts that BL intrinsically generates the transient gamma oscillations observed in vivo. The model permitted exploration of the poorly understood synaptic mechanisms underlying gamma genesis in BL, and the model's ability to compute LFPs at arbitrary numbers of recording sites provided insights into the characteristics of the spatial properties of gamma bursts. Furthermore, we show how gamma synchronizes principal cells to overcome their low firing rates while simultaneously promoting competition, potentially impacting their afferent selectivity and efferent drive, and thus emotional behavior.

in RSS PAP on January 11, 2019 05:16 PM.
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Decreased Intrinsic Functional Connectivity in First-Episode, Drug-Naive Adolescents With Generalized Anxiety Disorder
Fan Yang, Linlin Fan, Tianyi Zhai, Ying Lin, Yuyin Wang, Junji Ma, Mei Liao, Yan Zhang, Lingjiang Li, Linyan Su, Zhengjia Dai
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 12:00 PM.
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A Neurophysiological and Behavioral Assessment of Interventions Targeting Attention Bias and Sense of Control in Binge Drinking
Jessica E. Langbridge, Richard D. Jones, Juan J. Canales
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 12:00 PM.
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Memory Integration as a Challenge to the Consolidation/Reconsolidation Hypothesis: Similarities, Differences and Perspectives
Pascale Gisquet-Verrier, David C. Riccio
in Frontiers in Systems Neuroscience | New and Recent Articles on January 11, 2019 12:00 PM.
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Machine Learning Models for Multiparametric Glioma Grading With Quantitative Result Interpretations
Xiuying Wang, Dingqian Wang, Zhigang Yao, Bowen Xin, Bao Wang, Chuanjin Lan, Yejun Qin, Shangchen Xu, Dazhong He, Yingchao Liu
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 11, 2019 12:00 PM.
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Transcytosis to Cross the Blood Brain Barrier, New Advancements and Challenges
Victor M. Pulgar
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 11, 2019 12:00 PM.
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Tracking Neural Progenitor Cell Migration in the Rodent Brain Using Magnetic Resonance Imaging
Christiane L. Mallett, Dorela D. Shuboni-Mulligan, Erik M. Shapiro
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 11, 2019 12:00 PM.
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Tool Embodiment: The Tool’s Output Must Match the User’s Input
Veronica Weser, Dennis R. Proffitt
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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A Review of Acute Aerobic Exercise and Transcranial Direct Current Stimulation Effects on Cognitive Functions and Their Potential Synergies
Fabian Steinberg, Nils Henrik Pixa, Felipe Fregni
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Effects of Reciprocal Ia Inhibition on Contraction Intensity of Co-contraction
Ryo Hirabayashi, Mutsuaki Edama, Sho Kojima, Masatoshi Nakamura, Wataru Ito, Emi Nakamura, Takanori Kikumoto, Hideaki Onishi
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Improving Relationships by Elevating Positive Illusion and the Underlying Psychological and Neural Mechanisms
Hongwen Song, Yongjun Zhang, Lin Zuo, Xueli Chen, Gui Cao, Federico d’Oleire Uquillas, Xiaochu Zhang
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Current Status and Issues Regarding Pre-processing of fNIRS Neuroimaging Data: An Investigation of Diverse Signal Filtering Methods Within a General Linear Model Framework
Paola Pinti, Felix Scholkmann, Antonia Hamilton, Paul Burgess, Ilias Tachtsidis
in Frontiers in Human Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Targeting MAPK Pathways by Naringenin Modulates Microglia M1/M2 Polarization in Lipopolysaccharide-Stimulated Cultures
Bei Zhang, Yi-Zheng Wei, Guo-Qing Wang, Dai-Di Li, Jing-Shan Shi, Feng Zhang
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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The Role of BDNF in Peripheral Nerve Regeneration: Activity-Dependent Treatments and Val66Met
Claire Emma McGregor, Arthur W. English
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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The Expression of Transcription Factors Mecp2 and CREB Is Modulated in Inflammatory Pelvic Pain
Alison Xiaoqiao Xie, Xiao-Qing Pan, Randall B. Meacham, Anna P. Malykhina
in Frontiers in Systems Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Neuropeptides Exert Neuroprotective Effects in Alzheimer's Disease
Xin-Yi Chen, Yi-Feng Du, Lei Chen
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 11, 2019 06:00 AM.
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Clinical Value of Machine Learning in the Automated Detection of Focal Cortical Dysplasia Using Quantitative Multimodal Surface-Based Features
Jia-Jie Mo, Jian-Guo Zhang, Wen-Ling Li, Chao Chen, Na-Jing Zhou, Wen-Han Hu, Chao Zhang, Yao Wang, Xiu Wang, Chang Liu, Bao-Tian Zhao, Jun-Jian Zhou, Kai Zhang
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 11, 2019 06:00 AM.
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A Framework for Intelligence and Cortical Function Based on Grid Cells in the Neocortex
Jeff Hawkins, Marcus Lewis, Mirko Klukas, Scott Purdy, Subutai Ahmad
in Frontiers in Neural Circuits | New and Recent Articles on January 11, 2019 06:00 AM.
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DEFiNE: A Method for Enhancement and Quantification of Fluorescently Labeled Axons
Jeanne M. Powell, Nicholas W. Plummer, Erica L. Scappini, Charles J. Tucker, Patricia Jensen
in Frontiers in Neuroanatomy | New and Recent Articles on January 11, 2019 06:00 AM.
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Toward a Common Terminology for the Thalamus
Jürgen K. Mai, Milan Majtanik
in Frontiers in Neuroanatomy | New and Recent Articles on January 11, 2019 06:00 AM.
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COMPASS: An Open-Source, General-Purpose Software Toolkit for Computational Psychiatry
Ali Yousefi, Angelique C. Paulk, Ishita Basu, Jonathan L. Mirsky, Darin D. Dougherty, Emad N. Eskandar, Uri T. Eden, Alik S. Widge
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 11, 2019 06:00 AM.
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An Analysis of the Accuracy of the P300 BCI. (arXiv:1901.03299v1 [eess.SP])

The P300 Brain-Computer Interface (BCI) is a well-established communication channel for severely disabled people. The P300 event-related potential is mostly characterized by its amplitude or its area, which correlate with the spelling accuracy of the P300 speller. Here, we introduce a novel approach for estimating the efficiency of this BCI by considering the P300 signal-to-noise ratio (SNR), a parameter that estimates the spatial and temporal noise levels and has a significantly stronger correlation with spelling accuracy. Furthermore, we suggest a Gaussian noise model, which utilizes the P300 event-related potential SNR to predict spelling accuracy under various conditions for LDA-based classification. We demonstrate the utility of this analysis using real data and discuss its potential applications, such as speeding up the process of electrode selection.

in q-bio.NC updates on arXiv.org on January 11, 2019 01:30 AM.
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Brain Electrical Stimulation for Animal Navigation. (arXiv:1901.02943v1 [q-bio.NC])

The brain stimulation and its widespread use is one of the most important subjects in studies of neurophysiology. In brain electrical stimulation methods, following the surgery and electrode implantation, electrodes send electrical impulses to the specific targets in the brain. The use of this stimulation method is provided therapeutic benefits for treatment chronic pain, essential tremor, Parkinsons disease, major depression, and neurological movement disorder syndrome (dystonia). One area in which advancements have been recently made is in controlling the movement and navigation of animals in a specific pathway. It is important to identify brain targets in order to stimulate appropriate brain regions for all the applications listed above. An animal navigation system based on brain electrical stimulation is used to develop new behavioral models for the aim of creating a platform for interacting with the animal nervous system in the spatial learning task. In the context of animal navigation the electrical stimulation has been used either as creating virtual sensation for movement guidance or virtual reward for movement motivation. In this paper, different approaches and techniques of brain electrical stimulation for this application has been reviewed.

Keywords: Rat Robot, Brain Computer Interface, Electrical Stimulation, Cyborg Intelligence, Brain to Brain Interface

in q-bio.NC updates on arXiv.org on January 11, 2019 01:30 AM.
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Revealing interpretable object representations from human behavior. (arXiv:1901.02915v1 [stat.ML])

To study how mental object representations are related to behavior, we estimated sparse, non-negative representations of objects using human behavioral judgments on images representative of 1,854 object categories. These representations predicted a latent similarity structure between objects, which captured most of the explainable variance in human behavioral judgments. Individual dimensions in the low-dimensional embedding were found to be highly reproducible and interpretable as conveying degrees of taxonomic membership, functionality, and perceptual attributes. We further demonstrated the predictive power of the embeddings for explaining other forms of human behavior, including categorization, typicality judgments, and feature ratings, suggesting that the dimensions reflect human conceptual representations of objects beyond the specific task.

in q-bio.NC updates on arXiv.org on January 11, 2019 01:30 AM.
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Whole genomes define concordance of matched primary, xenograft, and organoid models of pancreas cancer

by Deena M. A. Gendoo, Robert E. Denroche, Amy Zhang, Nikolina Radulovich, Gun Ho Jang, Mathieu Lemire, Sandra Fischer, Dianne Chadwick, Ilinca M. Lungu, Emin Ibrahimov, Ping-Jiang Cao, Lincoln D. Stein, Julie M. Wilson, John M. S. Bartlett, Ming-Sound Tsao, Neesha Dhani, David Hedley, Steven Gallinger, Benjamin Haibe-Kains
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of the molecular heterogeneity of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 ‘trios’ of matched primary tumour, PDX, and PDO. We developed a pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Tumour-model comparisons of mutations displayed single-gene concordance across major PDAC driver genes, but relatively poor agreement across the greater mutational load. Genome-wide and chromosome-centric analysis of structural variation (SV) events highlights previously unrecognized concordance across chromosomes that demonstrate clustered SV events. We found that polyploidy presented a major challenge when assessing copy number changes; however, ploidy-corrected copy number states suggest good agreement between donor-model pairs. Collectively, our investigations highlight that while PDXs and PDOs may serve as tractable and transplantable systems for probing the molecular properties of PDAC, these models may best serve selective analyses across different levels of genomic complexity.
in PLOS Computational Biology: New Articles on January 10, 2019 10:00 PM.
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Computational translation of genomic responses from experimental model systems to humans

by Douglas K. Brubaker, Elizabeth A. Proctor, Kevin M. Haigis, Douglas A. Lauffenburger
The high failure rate of therapeutics showing promise in mouse models to translate to patients is a pressing challenge in biomedical science. Though retrospective studies have examined the fidelity of mouse models to their respective human conditions, approaches for prospective translation of insights from mouse models to patients remain relatively unexplored. Here, we develop a semi-supervised learning approach for inference of disease-associated human differentially expressed genes and pathways from mouse model experiments. We examined 36 transcriptomic case studies where comparable phenotypes were available for mouse and human inflammatory diseases and assessed multiple computational approaches for inferring human biology from mouse datasets. We found that semi-supervised training of a neural network identified significantly more true human biological associations than interpreting mouse experiments directly. Evaluating the experimental design of mouse experiments where our model was most successful revealed principles of experimental design that may improve translational performance. Our study shows that when prospectively evaluating biological associations in mouse studies, semi-supervised learning approaches, combining mouse and human data for biological inference, provide the most accurate assessment of human in vivo disease processes. Finally, we proffer a delineation of four categories of model system-to-human “Translation Problems” defined by the resolution and coverage of the datasets available for molecular insight translation and suggest that the task of translating insights from model systems to human disease contexts may be better accomplished by a combination of translation-minded experimental design and computational approaches.
in PLOS Computational Biology: New Articles on January 10, 2019 10:00 PM.
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Improvement of Mesenchymal Stem Cell Immunomodulatory Properties by Heat-Killed Propionibacterium acnes via TLR2
Gabriela da Paz Silveira, Mayari Eika Ishimura, Daniela Teixeira, Layla Tesla Galindo, Agnes Araujo Sardinha, Marimelia Porcionatto, Ieda Maria Longo-Maugéri
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 10, 2019 06:00 PM.
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Corrigendum: Dysregulation of MicroRNAs and Target Genes Networks in Peripheral Blood of Patients With Sporadic Amyotrophic Lateral Sclerosis
Maria Liguori, Nicoletta Nuzziello, Alessandro Introna, Arianna Consiglio, Flavio Licciulli, Eustachio D'Errico, Antonio Scarafino, Eugenio Distaso, Isabella L. Simone
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 10, 2019 06:00 PM.
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Distinct Stress Response and Altered Striatal Transcriptome in Alpha-Synuclein Overexpressing Mice
Zinah Wassouf, Thomas Hentrich, Nicolas Casadei, Mirko Jaumann, Marlies Knipper, Olaf Riess, Julia M. Schulze-Hentrich
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 10, 2019 06:00 PM.
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Trigeminal nerve transection-induced neuroplastic changes in the somatosensory and insular cortices in a rat ectopic pain model
Abstract
The primary sensory cortex processes competitive sensory inputs. Ablation of these competitive inputs induces neuroplastic changes in local cortical circuits. However, information concerning cortical plasticity induced by a disturbance of competitive nociceptive inputs is limited. Nociceptive information from the maxillary and mandibular molar pulps converges at the border between the ventral secondary somatosensory cortex (S2) and insular oral region (IOR), therefore S2/IOR is a suitable target for examining the cortical changes induced by a disturbance of noxious inputs, which often causes neuropathic pain and allodynia. We focused on the plastic changes in S2/IOR excitation in a model of rats subjected to inferior alveolar nerve transection (IANX). Our optical imaging using a voltage-sensitive dye revealed that the maxillary molar pulp stimulation-induced excitatory propagation was expanded 1-2 weeks after IANX at the macroscopic level. At the cellular level, based on Ca²⁺ imaging using two-photon microscopy, the amplitude of the Ca²⁺ responses and the number of responding neurons in S2/IOR increased in both excitatory and inhibitory neurons. The in vitro laser scanning photostimulation revealed that layer II/III pyramidal and GABAergic fast-spiking neurons in S2/IOR received larger excitatory inputs from layer IV in the IANX models, which supports the findings obtained by the macroscopic and microscopic optical imaging. Furthermore, the inhibitory postsynaptic inputs to the pyramidal neurons were decreased in the IANX models, suggesting suppression of inhibitory synaptic transmission onto excitatory neurons. These results suggest that IANX induces plastic changes in S2/IOR by changing the local excitatory and inhibitory circuits. (246/250 words)
Significance statement The inferior alveolar nerve (IAN), a mandibular branch of the trigeminal nerve, innervates the orofacial region, including the tooth pulps. IAN transection (IANX) induces allodynia in the maxillary nerve-projecting region. This study demonstrates the facilitation of excitatory propagation in the secondary somatosensory cortex (S2) and insular oral region (IOR) following maxillary molar tooth pulp stimulation in IANX rats. Both pyramidal and fast-spiking neurons in layer II/III S2/IOR of IANX rats received larger glutamatergic excitatory inputs from the deeper layers. Reduction of GABA_A receptor-mediated IPSCs in pyramidal neurons of IANX rats may contribute to the facilitated excitation in S2/IOR. These findings suggest that GABAergic neurons in S2/IOR could be a therapeutic target for ectopic pain in the orofacial region. (118/120 words)

in RSS PAP on January 10, 2019 05:23 PM.
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Methamphetamine self-administration elicits sex related changes in postsynaptic glutamate transmission in the prefrontal cortex
Abstract
Pre-clinical and clinical research has shown that females are more vulnerable to the rewarding effects of stimulants, and it has been proposed that estrogens may play a role in this enhanced sensitivity; however sex differences in methamphetamine (METH)-induced neuroplasticity have not been explored. To address this gap in knowledge we recorded from the prelimbic area of the prefrontal cortex (PFC) of male and females rats following long access METH self-administration (SA) and investigated the resulting long-term synaptic neuroadaptations. Males and females took similar amounts of METH during self-administration; however, female rats exhibit significant synaptic baseline differences when compared to males. Furthermore, females exhibited a significant increase in evoked excitatory currents. This increase in evoked glutamate was correlated with increases in NMDA currents and was not affected by application of a GluN2B selective blocker. We propose that METH SA selectively upregulates GluN2B-lacking NMDAR in the PFC of female rats. Our results may provide a mechanistic explanation for the sex differences reported for METH addiction in females.
Significance Statement The rate of methamphetamine (METH) addiction is second only to heroin, and use trends are on the rise. Like other drugs of abuse, there are known sex differences in METH addiction, however if these differences result from sex differences in pharmacokinetics, neurophysiology, and/or drug-induced neuroplasticity has not been established. Here we assessed METH self-administration induced neuroadaptations in synaptic physiology using electrophysiological measures in prefrontal cortical brain slices of male and female rats. We are the first to report, to our knowledge, that cortical baseline and METH-induced synaptic responses are different between male and female rats. Our results may provide a mechanistic explanation for the sex differences reported for METH addiction in females and highlight the possibility that sex-specific treatment strategies may be required to address METH-induced neuroplasticity.

in RSS PAP on January 10, 2019 05:23 PM.
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Isoflurane inhibits dopaminergic synaptic vesicle exocytosis coupled to CaV2.1 and CaV2.2 in rat midbrain neurons
ABSTRACT
Volatile anesthetics affect neuronal signaling by poorly understood mechanisms. Activation of central dopaminergic pathways has been implicated in emergence from general anesthesia. The volatile anesthetic isoflurane differentially inhibits glutamatergic and GABAergic synaptic vesicle exocytosis by reducing presynaptic Ca²⁺ influx without affecting the Ca²⁺-exocytosis relationship, but its effects on dopaminergic exocytosis are unclear. We tested the hypothesis that isoflurane inhibits exocytosis in dopaminergic neurons. We used electrical stimulation or depolarization by elevated extracellular KCl to evoke exocytosis measured by quantitative live-cell fluorescence imaging in cultured rat ventral tegmental area neurons. Using trains of electrically evoked action potentials (APs), isoflurane inhibited exocytosis in dopaminergic neurons to a greater extent (30 ± 4% inhibition; p < 0.0001) than in non-dopaminergic neurons (15 ± 5% inhibition; p = 0.014). Isoflurane also inhibited exocytosis evoked by elevated KCl in dopaminergic neurons (35 ± 6% inhibition; p = 0.0007), but not in non-dopaminergic neurons (2 ± 4% inhibition). Pharmacological isolation of presynaptic Ca²⁺ channel subtypes showed that isoflurane inhibited KCl-evoked exocytosis mediated exclusively by either Ca_V2.1 (P/Q-type Ca²⁺ channels) (30 ± 5% inhibition; p = 0.0002) or by Ca_V2.2 (N-type Ca²⁺ channels) (35 ± 11% inhibition; p = 0.015). Additionally, isoflurane inhibited single AP-evoked Ca²⁺ influx by 41 ± 3% and single AP-evoked exocytosis by 34 ± 6%. Comparable reductions in exocytosis and Ca²⁺ influx were produced by lowering extracellular [Ca²⁺]. Thus, isoflurane inhibits exocytosis from dopaminergic neurons by a mechanism distinct from that in non-dopaminergic neurons involving reduced Ca²⁺ entry through Ca_V2.1 and/or Ca_V2.2.
SIGNIFICANCE STATEMENT Despite their medical importance, the mechanisms of action of general anesthetics have not been fully elucidated. Isoflurane, a widely used volatile anesthetic, inhibits voltage-gated sodium channels and differentially inhibits synaptic vesicle exocytosis depending on neurotransmitter phenotype. Here we show that in dopaminergic neurons of the ventral tegmental area isoflurane acts via a sodium channel-independent mechanism to inhibit synaptic vesicle exocytosis in proportion to reduced presynaptic Ca²⁺ flux mediated by Ca_V2.1 and/or Ca_V2.2, in contrast to its effects in non-dopaminergic neurons. These findings provide a synaptic mechanism for the observed role of reduced dopamine release in anesthetic-induced unconsciousness, and implicate presynaptic Ca²⁺ channels of dopaminergic neurons as important targets of isoflurane.

in RSS PAP on January 10, 2019 05:23 PM.
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Multimodal Characterization of Neural Networks Using Highly Transparent Electrode Arrays

Transparent and flexible materials are attractive for a wide range of emerging bioelectronic applications. These include neural interfacing devices for both recording and stimulation, where low electrochemical electrode impedance is valuable. Here the conducting polymer poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is used to fabricate electrodes that are small enough to allow unencumbered optical access for imaging a large cell population with two-photon (2P) microscopy, yet provide low impedance for simultaneous high quality recordings of neural activity in vivo. To demonstrate this, pathophysiological activity was induced in the mouse cortex using 4-aminopyridine (4AP), and the resulting electrical activity was detected with the PEDOT:PSS-based probe while imaging calcium activity directly below the probe area. The induced calcium activity of the neuronal network as measured by the fluorescence change in the cells correlated well with the electrophysiological recordings from the cortical grid of PEDOT:PSS microelectrodes. Our approach provides a valuable vehicle for complementing classical high temporal resolution electrophysiological analysis with optical imaging.

in eNeuro current issue on January 10, 2019 05:11 PM.
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Nociceptin/Orphanin-FQ Inhibits Gonadotropin-Releasing Hormone Neurons via G-Protein-Gated Inwardly Rectifying Potassium Channels
Abstract
The pulsatile release of gonadotropin-releasing hormone (GnRH) is a key feature of the hypothalamic–pituitary–gonadal axis. Kisspeptin neurons in the arcuate nucleus (ARC) trigger GnRH neuronal activity, but how GnRH neurons return to baseline electrical activity is unknown. Nociceptin/orphanin-FQ (OFQ) is an inhibitory neuromodulator. ARC proopiomelanocortin (POMC) neurons, known to receive inputs from ARC kisspeptin neurons, contact GnRH neurons and coexpress OFQ in the rat. In the present study, the effect of OFQ(1-13) on GnRH neurons was determined in the mouse. We identified transcripts for the OFQ receptor [opioid receptor like 1 (ORL1)] in GnRH neurons, and, using two-model systems (explants and slices), we found that OFQ exerted a potent inhibition on GnRH neurons, with or without excitatory inputs. We confirmed that the inhibition was mediated by ORL1 via G_i/o-protein coupling. The inhibition, occurring independently of levels of intracellular cyclic adenosine monophosphate, was sensitive to inwardly rectifying potassium channels. The only specific blocker of G_i/o-protein-coupled inwardly rectifying potassium (GIRK) channels, tertiapin-Q (TPNQ), was ineffective in the inhibition of OFQ. Two GIRK activators, one sharing the binding site of TPNQ and one active only on GIRK1-containing GIRK channels, failed to trigger an inhibition. In contrast, protein kinase C phosphorylation activation, known to inhibit GIRK2-mediated currents, prevented the OFQ inhibition. These results indicate a specific combination of GIRK subunits, GIRK2/3 in GnRH neurons. In vivo, double-labeled OFQ/POMC fibers were found in the vicinity of GnRH neurons, and OFQ fibers apposed GnRH neurons. Together, this study brings to light a potent neuromodulator of GnRH neurons.

in eNeuro current issue on January 10, 2019 05:11 PM.
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Single cell RNA-sequencing: replicability of cell types

Publication date: June 2019
Source: Current Opinion in Neurobiology, Volume 56
Author(s): Megan Crow, Jesse Gillis
Recent technical advances have enabled transcriptomics experiments at an unprecedented scale, and single-cell profiles from neural tissue are accumulating rapidly. There has been considerable effort to use these profiles to understand cell diversity, primarily through unsupervised clustering and differential expression analysis. However, current practices to validate these findings vary. In this review, we describe recent efforts to evaluate clusters from single-cell RNA-sequencing data, and provide a framework for considering current evidence and practices in terms of their capacity to establish principles of cell biology. Single-cell RNA-sequencing has already transformed neuroscience. By facilitating detailed comparative and genetic perturbation analyses, it may provide the tools to uncover fundamental mechanisms of neural diversity throughout the tree of life.

in ScienceDirect Publication: Current Opinion in Neurobiology on January 10, 2019 12:00 PM.
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Correlated MRI and Ultramicroscopy (MR-UM) of Brain Tumors Reveals Vast Heterogeneity of Tumor Infiltration and Neoangiogenesis in Preclinical Models and Human Disease
Michael O. Breckwoldt, Julia Bode, Felix Sahm, Thomas Krüwel, Gergely Solecki, Artur Hahn, Peter Wirthschaft, Anna S. Berghoff, Maximilian Haas, Varun Venkataramani, Andreas von Deimling, Wolfgang Wick, Christel Herold-Mende, Sabine Heiland, Michael Platten, Martin Bendszus, Felix T. Kurz, Frank Winkler, Björn Tews
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 10, 2019 12:00 PM.
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Parkinsonian Neurotoxins Impair the Pro-inflammatory Response of Glial Cells
Neus Rabaneda-Lombarte, Efren Xicoy-Espaulella, Joan Serratosa, Josep Saura, Carme Solà
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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High-Altitude Cognitive Impairment Is Prevented by Enriched Environment Including Exercise via VEGF Signaling
Christina Koester-Hegmann, Harkaitz Bengoetxea, Dmitry Kosenkov, Markus Thiersch, Thomas Haider, Max Gassmann, Edith M. Schneider Gasser
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Extracellular Vesicles Secreted by Astroglial Cells Transport Apolipoprotein D to Neurons and Mediate Neuronal Survival Upon Oxidative Stress
Raquel Pascua-Maestro, Esperanza González, Concepción Lillo, Maria D. Ganfornina, Juan Manuel Falcón-Pérez, Diego Sanchez
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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CSF1R Stimulation Promotes Increased Neuroprotection by CD11c+ Microglia in EAE
Agnieszka Wlodarczyk, Anouk Benmamar-Badel, Oriane Cédile, Kirstine Nolling Jensen, Isabella Kramer, Nick Boe Elsborg, Trevor Owens
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Choice of Alternative Polyadenylation Sites, Mediated by the RNA-Binding Protein Elavl3, Plays a Role in Differentiation of Inhibitory Neuronal Progenitors
Elena Grassi, Roberto Santoro, Alessandro Umbach, Anna Grosso, Salvatore Oliviero, Francesco Neri, Luciano Conti, Ugo Ala, Paolo Provero, Ferdinando DiCunto, Giorgio R. Merlo
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Commentary: Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer's Disease
Janusz K. Rybakowski
in Frontiers in Aging Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Precuneus Dysfunction in Parkinson’s Disease With Mild Cognitive Impairment
Xiuqin Jia, Ying Li, Kuncheng Li, Peipeng Liang, Xiaolan Fu
in Frontiers in Aging Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Experience-Dependent Effects of Muscimol-Induced Hippocampal Excitation on Mnemonic Discrimination
Sarah A. Johnson, Sean M. Turner, Katelyn N. Lubke, Tara L. Cooper, Kaeli E. Fertal, Jennifer L. Bizon, Andrew P. Maurer, Sara N. Burke
in Frontiers in Systems Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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A Key Role for Subiculum-Fornix Connectivity in Recollection in Older Age
Naomi Hartopp, Paul Wright, Nicola J. Ray, Tavia E. Evans, Claudia Metzler-Baddeley, John P. Aggleton, Michael J. O’Sullivan
in Frontiers in Systems Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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What Can Computational Models Contribute to Neuroimaging Data Analytics?
Oleksandr V. Popovych, Thanos Manos, Felix Hoffstaedter, Simon B. Eickhoff
in Frontiers in Systems Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Topological Properties of Resting-State fMRI Functional Networks Improve Machine Learning-Based Autism Classification
Amirali Kazeminejad, Roberto C. Sotero
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 10, 2019 06:00 AM.
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Tau and mTOR: The Hotspots for Multifarious Diseases in Alzheimer's Development
Zeba Mueed, Pallavi Tandon, Sanjeev Kumar Maurya, Ravi Deval, Mohammad A. Kamal, Nitesh Kumar Poddar
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 10, 2019 06:00 AM.
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Quantitative Analyses Help in Choosing Between Simultaneous vs. Separate EEG and fMRI
Maarten Schrooten, Rik Vandenberghe, Ronald Peeters, Patrick Dupont
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 10, 2019 06:00 AM.
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Optimizing Data for Modeling Neuronal Responses
Peter Zeidman, Samira M. Kazan, Nick Todd, Nikolaus Weiskopf, Karl J. Friston, Martina F. Callaghan
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 10, 2019 06:00 AM.
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Targeting Polyamine Oxidase to Prevent Excitotoxicity-Induced Retinal Neurodegeneration
Prahalathan Pichavaram, Chithra Devi Palani, Chintan Patel, Zhimin Xu, Esraa Shosha, Abdelrahman Y. Fouda, Ruth B. Caldwell, Subhadra Priya Narayanan
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 10, 2019 06:00 AM.
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A Single-Cell Level and Connectome-Derived Computational Model of the Drosophila Brain
Yu-Chi Huang, Cheng-Te Wang, Ta-Shun Su, Kuo-Wei Kao, Yen-Jen Lin, Chao-Chun Chuang, Ann-Shyn Chiang, Chung-Chuan Lo
in Frontiers in Neuroinformatics | New and Recent Articles on January 10, 2019 06:00 AM.
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Modeling the Encoding of Saccade Kinematic Metrics in the Purkinje Cell Layer of the Cerebellar Vermis
Hari Teja Kalidindi, Thomas George Thuruthel, Cecilia Laschi, Egidio Falotico
in Frontiers in Computational Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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Saccade Velocity Driven Oscillatory Network Model of Grid Cells
Ankur Chauhan, Karthik Soman, V. Srinivasa Chakravarthy
in Frontiers in Computational Neuroscience | New and Recent Articles on January 10, 2019 06:00 AM.
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duneuro - A software toolbox for forward modeling in neuroscience. (arXiv:1901.02874v3 [cs.MS] UPDATED)

This paper describes duneuro, a software toolbox for forward modeling in neuroscience. Its purpose is to provide extendible and easy-to-use interfaces and enable a closer integration into existing analysis pipelines. It provides implementations of fitted and unfitted finite element methods and makes use of the Dune framework. The forward problems consist of the electroencephalography (EEG) and magnetoencephalography (MEG) forward problems. For the incorporation into existing analysis pipelines, Python and Matlab interfaces are provided. The practical use is demonstrated on a source analysis example of evoked potentials.

in q-bio.NC updates on arXiv.org on January 10, 2019 01:30 AM.
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Visual novelty, curiosity, and intrinsic reward in machine learning and the brain. (arXiv:1901.02478v1 [q-bio.NC])

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 q-bio.NC updates on arXiv.org on January 10, 2019 01:30 AM.
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HCN2 Channels in Cholinergic Interneurons of Nucleus Accumbens Shell Regulate Depressive Behaviors
Cheng et al. show that decreased expression and function of HCN2 channels cause reduced ChI tonic activity in NAc shell that leads to depressive phenotypes. Targeting HCN2 channels to enhance ChI activity is sufficient to rescue depression.
in Neuron on January 10, 2019 12:00 AM.
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Rostral and Caudal Ventral Tegmental Area GABAergic Inputs to Different Dorsal Raphe Neurons Participate in Opioid Dependence
Li and Li et al. dissect the microcircuits between VTA GABAergic neurons and DRN neurons, identifying distinct pathways that specifically modulate morphine reward without affecting the analgesic effects of morphine.
in Neuron on January 10, 2019 12:00 AM.
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A computational knowledge-base elucidates the response of <i>Staphylococcus aureus</i> to different media types

by Yara Seif, Jonathan M. Monk, Nathan Mih, Hannah Tsunemoto, Saugat Poudel, Cristal Zuniga, Jared Broddrick, Karsten Zengler, Bernhard O. Palsson
S. aureus is classified as a serious threat pathogen and is a priority that guides the discovery and development of new antibiotics. Despite growing knowledge of S. aureus metabolic capabilities, our understanding of its systems-level responses to different media types remains incomplete. Here, we develop a manually reconstructed genome-scale model (GEM-PRO) of metabolism with 3D protein structures for S. aureus USA300 str. JE2 containing 854 genes, 1,440 reactions, 1,327 metabolites and 673 3-dimensional protein structures. Computations were in 85% agreement with gene essentiality data from random barcode transposon site sequencing (RB-TnSeq) and 68% agreement with experimental physiological data. Comparisons of computational predictions with experimental observations highlight: 1) cases of non-essential biomass precursors; 2) metabolic genes subject to transcriptional regulation involved in Staphyloxanthin biosynthesis; 3) the essentiality of purine and amino acid biosynthesis in synthetic physiological media; and 4) a switch to aerobic fermentation upon exposure to extracellular glucose elucidated as a result of integrating time-course of quantitative exo-metabolomics data. An up-to-date GEM-PRO thus serves as a knowledge-based platform to elucidate S. aureus’ metabolic response to its environment.
in PLOS Computational Biology: New Articles on January 09, 2019 10:00 PM.
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Using the drug-protein interactome to identify anti-ageing compounds for humans

by Matías Fuentealba, Handan Melike Dönertaş, Rhianna Williams, Johnathan Labbadia, Janet M. Thornton, Linda Partridge
Advancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established their association with ageing at multiple levels of biological action including pathways, functions and protein interactions. Finally, combining all the data, we calculated a ranked list of drugs that identified tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.
in PLOS Computational Biology: New Articles on January 09, 2019 10:00 PM.
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Electrophysiological Correlates of Absolute Pitch in a Passive Auditory Oddball Paradigm: a Direct Replication Attempt
Abstract
Humans with absolute pitch (AP) are able to effortlessly name the pitch class of a sound without an external reference. The association of labels with pitches cannot be entirely suppressed even if it interferes with task demands. This suggests a high level of automaticity of pitch labeling in AP. The automatic nature of AP was further investigated in a study by Rogenmoser et al. (2015). Using a passive auditory oddball paradigm in combination with electroencephalography, they observed electrophysiological differences between musicians with and without AP in response to piano tones. Specifically, the AP musicians showed a smaller P3a, an event-related potential (ERP) component presumably reflecting early attentional processes. In contrast, they did not find group differences in the mismatch negativity (MMN), an ERP component associated with auditory memory processes. They concluded that early cognitive processes are facilitated in AP during passive listening and are more important for AP than the preceding sensory processes. In our direct replication study on a larger sample of musicians with (n = 54, 27 females, 27 males) and without (n = 50, 24 females, 26 males) AP, we successfully replicated the non-significant effects of AP on the MMN. However, we could not replicate the significant effects for the P3a. Additional Bayes factor analyses revealed moderate to strong evidence (Bayes factor > 3) for the null hypothesis for both MMN and P3a. Therefore, the results of this replication study do not support the postulated importance of cognitive facilitation in AP during passive tone listening.

in eNeuro current issue on January 09, 2019 05:30 PM.
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Erratum: Chariker et al., "Rhythm and Synchrony in a Cortical Network Model"

in Journal of Neuroscience current issue on January 09, 2019 05:30 PM.
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Top-down and Bottom-up Regulated Auditory Phantom Perception

Auditory phantom percepts such as tinnitus are associated with auditory deafferentation. The idea is that auditory deafferentation limits the amount of information the brain can acquire to make sense of the world. Because of this, auditory deafferentation increases the uncertainty of the auditory environment. To minimize uncertainty, the deafferented brain will attempt to obtain or fill in the missing information. A proposed multiphase compensation model suggests two distinct types of bottom-up related tinnitus: an auditory cortex related tinnitus and a parahippocampal cortex related tinnitus. The weakness of this model is that it cannot explain why some people without hearing loss develop tinnitus, whereas conversely others with hearing loss do not develop tinnitus. In this human study, we provide evidence for a top-down type of tinnitus associated with a deficient noise-cancelling mechanism. A total of 72 participants (age: 40.96 ± 7.67 years; males: 48; females: 24) were recruited for this study. We demonstrate that top-down related tinnitus is related to a change in the pregenual anterior cingulate cortex that corresponds to increased activity in the auditory cortex. This is in accordance with the idea that tinnitus can have different generators as proposed in a recent model that suggests that different compensation mechanisms at a cortical level can be linked to phantom percepts.

SIGNIFICANCE STATEMENT Chronic tinnitus affects 15% of the population worldwide. The term "tinnitus" however represents a highly heterogeneous condition, as evidenced by the fact that there are no effective treatments or even an adequate understanding of the underlying neural mechanisms. Consistent with this idea, our research shows that tinnitus indeed has different subtypes related to hearing loss. In a human study tightly controlled for hearing loss, we establish a tinnitus subtype associated with a deficient top-down noise-cancelling mechanism, which distinguishes it from bottom-up subtypes. We demonstrate that top-down related tinnitus relates to a change in the pregenual anterior cingulate cortex that corresponds to increased activity in the auditory cortex, whereas bottom-up tinnitus instead relates to changes in the parahippocampal cortex.

in Journal of Neuroscience current issue on January 09, 2019 05:30 PM.
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Directing Voluntary Temporal Attention Increases Fixational Stability

Our visual input is constantly changing, but not all moments are equally relevant. Visual temporal attention, the prioritization of visual information at specific points in time, increases perceptual sensitivity at behaviorally relevant times. The dynamic processes underlying this increase are unclear. During fixation, humans make small eye movements called microsaccades, and inhibiting microsaccades improves perception of brief stimuli. Here, we investigated whether temporal attention changes the pattern of microsaccades in anticipation of brief stimuli. Human observers (female and male) judged stimuli presented within a short sequence. Observers were given either an informative precue to attend to one of the stimuli, which was likely to be probed, or an uninformative (neutral) precue. We found strong microsaccadic inhibition before the stimulus sequence, likely due to its predictable onset. Critically, this anticipatory inhibition was stronger when the first target in the sequence (T1) was precued (task-relevant) than when the precue was uninformative. Moreover, the timing of the last microsaccade before T1 and the first microsaccade after T1 shifted such that both occurred earlier when T1 was precued than when the precue was uninformative. Finally, the timing of the nearest pre- and post-T1 microsaccades affected task performance. Directing voluntary temporal attention therefore affects microsaccades, helping to stabilize fixation at the most relevant moments over and above the effect of predictability. Just as saccading to a relevant stimulus can be an overt correlate of the allocation of spatial attention, precisely timed gaze stabilization can be an overt correlate of the allocation of temporal attention.

SIGNIFICANCE STATEMENT We pay attention at moments in time when a relevant event is likely to occur. Such temporal attention improves our visual perception, but how it does so is not well understood. Here, we discovered a new behavioral correlate of voluntary, or goal-directed, temporal attention. We found that the pattern of small fixational eye movements called microsaccades changes around behaviorally relevant moments in a way that stabilizes the position of the eyes. Microsaccades during a brief visual stimulus can impair perception of that stimulus. Therefore, such fixation stabilization may contribute to the improvement of visual perception at attended times. This link suggests that, in addition to cortical areas, subcortical areas mediating eye movements may be recruited with temporal attention.

in Journal of Neuroscience current issue on January 09, 2019 05:30 PM.
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Neural Substrates of Cognitive Motor Interference During Walking; Peripheral and Central Mechanisms
Emad Al-Yahya, Wala’ Mahmoud, Daan Meester, Patrick Esser, Helen Dawes
in Frontiers in Human Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Parietal Activation Associated With Target-Directed Right Hand Movement Is Lateralized by Mirror Feedback to the Ipsilateral Hemisphere
Thushini Manuweera, Mathew Yarossi, Sergei Adamovich, Eugene Tunik
in Frontiers in Human Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Neural Network Connectivity During Post-encoding Rest: Linking Episodic Memory Encoding and Retrieval
Okka J. Risius, Oezguer A. Onur, Julian Dronse, Boris von Reutern, Nils Richter, Gereon R. Fink, Juraj Kukolja
in Frontiers in Human Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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EEG Frequency Bands in Psychiatric Disorders: A Review of Resting State Studies
Jennifer J. Newson, Tara C. Thiagarajan
in Frontiers in Human Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Idebenone Alleviates Neuroinflammation and Modulates Microglial Polarization in LPS-Stimulated BV2 Cells and MPTP-Induced Parkinson’s Disease Mice
Aijuan Yan, Zhihua Liu, Lu Song, Xijin Wang, Yu Zhang, Na Wu, Jingya Lin, Ying Liu, Zhenguo Liu
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Activin Receptor-Like Kinase 1 Combined With VEGF-A Affects Migration and Proliferation of Endothelial Cells From Sporadic Human Cerebral AVMs
Qiang Hao, Hao Wang, Jun-Lin Lu, Li Ma, Xiao-Lin Chen, Xun Ye, Ya-Hui Zhao, Ming-Tao Li, Yu Chen, Yuan-Li Zhao
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Expression of Tmem119/Sall1 and Ccr2/CD69 in FACS-Sorted Microglia- and Monocyte/Macrophage-Enriched Cell Populations After Intracerebral Hemorrhage
Qian Li, Xi Lan, Xiaoning Han, Jian Wang
in Frontiers in Cellular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Locus Coeruleus Optogenetic Light Activation Induces Long-Term Potentiation of Perforant Path Population Spike Amplitude in Rat Dentate Gyrus
Meghan A. L. Quinlan, Vanessa M. Strong, Darlene M. Skinner, Gerard M. Martin, Carolyn W. Harley, Susan G. Walling
in Frontiers in Systems Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Disruption of Otoferlin Alters the Mode of Exocytosis at the Mouse Inner Hair Cell Ribbon Synapse
Hideki Takago, Tomoko Oshima-Takago, Tobias Moser
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Oleoylethanolamide, Neuroinflammation, and Alcohol Abuse
Laura Orio, Francisco Alen, Francisco Javier Pavón, Antonia Serrano, Borja García-Bueno
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Ferroptosis Contributes to Isoflurane Neurotoxicity
Yimeng Xia, Xiaoyun Sun, Yan Luo, Creed M. Stary
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Expression and Roles of the Immunoglobulin Superfamily Recognition Molecule Sidekick1 in Mouse Retina
Masahito Yamagata, Joshua R. Sanes
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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An Excitatory/Inhibitory Switch From Asymmetric Sensory Neurons Defines Postsynaptic Tuning for a Rapid Response to NaCl in Caenorhabditis elegans
Masahiro Kuramochi, Motomichi Doi
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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PKR: A Kinase to Remember
Shunit Gal-Ben-Ari, Iliana Barrera, Marcelo Ehrlich, Kobi Rosenblum
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Analysis of α-Synuclein Pathology in PINK1 Knockout Rat Brains
Rose B. Creed, Matthew S. Goldberg
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 09, 2019 06:00 AM.
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Impact of Caffeine Consumption on Type 2 Diabetes-Induced Spatial Memory Impairment and Neurochemical Alterations in the Hippocampus
João M. N. Duarte, Cecilia Skoug, Henrique B. Silva, Rui A. Carvalho, Rolf Gruetter, Rodrigo A. Cunha
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 09, 2019 06:00 AM.
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Impact of Traumatic Brain Injury on Neurogenesis
Laura B. Ngwenya, Steve C. Danzer
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on January 09, 2019 06:00 AM.
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Radiation Induces Distinct Changes in Defined Subpopulations of Neural Stem and Progenitor Cells in the Adult Hippocampus
Olga A. Mineyeva, Dmitri V. Bezriadnov, Alexander V. Kedrov, Alexander A. Lazutkin, Konstantin V. Anokhin, Grigori N. Enikolopov
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on January 09, 2019 06:00 AM.
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The Evaluation of Dynamic FDG-PET for Detecting Epileptic Foci and Analyzing Reduced Glucose Phosphorylation in Refractory Epilepsy
Yongxiang Tang, Jeih-San Liow, Zhimin Zhang, Jian Li, Tingting Long, Yulai Li, Beisha Tang, Shuo Hu
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 09, 2019 06:00 AM.
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Longitudinal Connectomes as a Candidate Progression Marker for Prodromal Parkinson’s Disease
Óscar Peña-Nogales, Timothy M. Ellmore, Rodrigo de Luis-García, Jessika Suescun, Mya C. Schiess, Luca Giancardo
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 09, 2019 06:00 AM.
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Memory Reinforcement and Attenuation by Activating the Human Locus Coeruleus via Transcutaneous Vagus Nerve Stimulation
Niels Hansen
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 09, 2019 06:00 AM.
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Bio-inspired Analysis of Deep Learning on Not-So-Big Data Using Data-Prototypes
Thalita F. Drumond, Thierry Viéville, Frédéric Alexandre
in Frontiers in Computational Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Understanding Sensory Information Processing Through Simultaneous Multi-area Population Recordings
Elizabeth Zavitz, Nicholas S. C. Price
in Frontiers in Neural Circuits | New and Recent Articles on January 09, 2019 06:00 AM.
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Relationship Between DTI Metrics and Cognitive Function in Alzheimer’s Disease
Chantel D. Mayo, Mauricio A. Garcia-Barrera, Erin L. Mazerolle, Lesley J. Ritchie, John D. Fisk, Jodie R. Gawryluk, Alzheimer’s Disease Neuroimaging Initiative
in Frontiers in Aging Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Differences in Cognitive-Motor Interference in Older Adults While Walking and Performing a Visual-Verbal Stroop Task
Bettina Wollesen, Claudia Voelcker-Rehage
in Frontiers in Aging Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Metabolite Profile of Alzheimer’s Disease in the Frontal Cortex as Analyzed by HRMAS 1H NMR
Yuzhong Zhang, Zhou Liu, Bing Ji, Lijian Liu, Shaoxiong Wu, Xiaowu Liu, Silun Wang, Liya Wang
in Frontiers in Aging Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Two-Photon Uncaging of Glutamate
Graham C. R. Ellis-Davies
in Frontiers in Synaptic Neuroscience | New and Recent Articles on January 09, 2019 06:00 AM.
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Neural-network simulations of memory consolidation and reconsolidation. (arXiv:1901.02270v3 [q-bio.NC] UPDATED)

In the mammalian brain newly acquired memories depend on the hippocampus for maintenance and recall, but over time these functions are taken over by the neocortex through a process called systems consolidation. However, reactivation of a consolidated memory can induce a brief period of temporary hippocampus-dependence, followed by return to hippocampus-independence. Here we present a computational model that uses simulation of recently described mechanisms of synaptic plasticity to account for findings from the systems consolidation/reconsolidation literature and to make predictions for future research.

in q-bio.NC updates on arXiv.org on January 09, 2019 01:30 AM.
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Extracting impedance changes from a frequency multiplexed signal during neural activity in sciatic nerve of rat: preliminary study in-vitro. (arXiv:1901.02068v1 [q-bio.NC])

Objective: Establish suitable frequency spacing and demodulation steps to use when extracting impedance changes from frequency division multiplexed (FDM) carrier signals in peripheral nerve. Approach: Experiments were performed in-vitro on cadavers immediately following euthanasia. Neural activity was evoked via stimulation of nerves in the hind paw, while carrier signals were injected, and recordings obtained, with a dual ring nerve cuff implanted on the sciatic nerve. Frequency analysis of recorded compound action potentials (CAPs) and extracted impedance changes, with the latter obtained using established demodulation methods, were used to determine suitable frequency spacing of carrier signals, and bandpass filter (BPF) bandwidth and order, for a frequency multiplexed signal. Main results: CAPs and impedance changes were dominant in the frequency band 200 to 500 Hz and 100 to 200 Hz, respectively. A Tukey window was introduced to remove ringing from Gibbs phenomena. A +/- 750 Hz BPF bandwidth was selected to encompass 99.99 % of the frequency power of the impedance change. Modelling predicted a minimum BPF order of 16 for 2 kHz spacing, and 10 for 4 kHz spacing, were required to avoid ringing from the neighbouring carrier signal, while FDM experiments verified BPF orders of 12 and 8, respectively, were required. With a notch filter centred on the neighbouring signal, a BPF order of at least 6 or 4 was required for 2 and 4 kHz, respectively. Significance: The results establish drive frequency spacing and demodulation settings for use in FDM electrical impedance tomography (EIT) experiments, as well as a framework for their selection, and, for the first time, demonstrates the viability of FDM-EIT of neural activity on peripheral nerve, which will be a central aspect of future real-time neural-EIT systems and EIT-based neural prosthetics interfaces.

in q-bio.NC updates on arXiv.org on January 09, 2019 01:30 AM.
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Differential NOVA2-Mediated Splicing in Excitatory and Inhibitory Neurons Regulates Cortical Development and Cerebellar Function
cTag-CLIP provides a next-generation strategy to profile functional protein:RNA interactions at cell-specific resolution in vivo. Saito et al. show that differential NOVA2 regulatory actions on alternative splicing coupled to intron removal in different neurons.
in Neuron on January 09, 2019 12:00 AM.
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Spectral Imprints of Working Memory for Everyday Associations in the Frontoparietal Network
Elizabeth L. Johnson, David King-Stephens, Peter B. Weber, Kenneth D. Laxer, Jack J. Lin, Robert T. Knight
in Frontiers in Systems Neuroscience | New and Recent Articles on January 08, 2019 06:00 PM.
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18F-FDG-PET Detects Drastic Changes in Brain Metabolism in the Tg4–42 Model of Alzheimer’s Disease
Caroline Bouter, Philipp Henniges, Timon N. Franke, Caroline Irwin, Carsten Oliver Sahlmann, Marius E. Sichler, Nicola Beindorff, Thomas A. Bayer, Yvonne Bouter
in Frontiers in Aging Neuroscience | New and Recent Articles on January 08, 2019 06:00 PM.
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A Computational Model of Dual Competition between the Basal Ganglia and the Cortex
Abstract
We propose a model that includes interactions between the cortex, the basal ganglia (BG), and the thalamus based on a dual competition. We hypothesize that the striatum, the subthalamic nucleus (STN), the internal globus pallidus (GPi), the thalamus, and the cortex are involved in closed feedback loops through the hyperdirect and direct pathways. These loops support a competition process that results in the ability of BG to make a cognitive decision followed by a motor one. Considering lateral cortical interactions, another competition takes place inside the cortex allowing the latter to make a cognitive and a motor decision. We show how this dual competition endows the model with two regimes. One is driven by reinforcement learning and the other by Hebbian learning. The final decision is made according to a combination of these two mechanisms with a gradual transfer from the former to the latter. We confirmed these theoretical results on primates (Macaca mulatta) using a novel paradigm predicted by the model.

in eNeuro current issue on January 08, 2019 05:30 PM.
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The systemDrive: a Multisite, Multiregion Microdrive with Independent Drive Axis Angling for Chronic Multimodal Systems Neuroscience Recordings in Freely Behaving Animals

A multielectrode system that can address widely separated targets at multiple sites across multiple brain regions with independent implant angling is needed to investigate neural function and signaling in systems and circuits of small animals. Here, we present the systemDrive, a novel multisite, multiregion microdrive that is capable of moving microwire electrode bundles into targets along independent and nonparallel drive trajectories. Our design decouples the stereotaxic surgical placement of individual guide cannulas for each trajectory from the placement of a flexible drive structure. This separation enables placement of many microwire multitrodes along widely spaced and independent drive axes with user-set electrode trajectories and depths from a single microdrive body, and achieves stereotaxic precision with each. The system leverages tight tube–cannula tolerances and geometric constraints on flexible drive axes to ensure concentric alignment of electrode bundles within guide cannulas. Additionally, the headmount and microdrive both have an open-center design to allow for the placement of additional sensing modalities. This design is the first, in the context of small rodent chronic research, to provide the capability to finely position microwires through multiple widely distributed cell groups, each with stereotaxic precision, along arbitrary and nonparallel trajectories that are not restricted to emanate from a single source. We demonstrate the use of the systemDrive in male Long–Evans rats to observe simultaneous single-unit and multiunit activity from multiple widely separated sleep–wake regulatory brainstem cell groups, along with cortical and hippocampal activity, during free behavior over multiple many-day continuous recording periods.

in eNeuro current issue on January 08, 2019 05:30 PM.
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An Empirical Comparison of Meta- and Mega-Analysis With Data From the ENIGMA Obsessive-Compulsive Disorder Working Group
Premika S. W. Boedhoe, Martijn W. Heymans, Lianne Schmaal, Yoshinari Abe, Pino Alonso, Stephanie H. Ameis, Alan Anticevic, Paul D. Arnold, Marcelo C. Batistuzzo, Francesco Benedetti, Jan C. Beucke, Irene Bollettini, Anushree Bose, Silvia Brem, Anna Calvo, Rosa Calvo, Yuqi Cheng, Kang Ik K. Cho, Valentina Ciullo, Sara Dallaspezia, Damiaan Denys, Jamie D. Feusner, Kate D. Fitzgerald, Jean-Paul Fouche, Egill A. Fridgeirsson, Patricia Gruner, Gregory L. Hanna, Derrek P. Hibar, Marcelo Q. Hoexter, Hao Hu, Chaim Huyser, Neda Jahanshad, Anthony James, Norbert Kathmann, Christian Kaufmann, Kathrin Koch, Jun Soo Kwon, Luisa Lazaro, Christine Lochner, Rachel Marsh, Ignacio Martínez-Zalacaín, David Mataix-Cols, José M. Menchón, Luciano Minuzzi, Astrid Morer, Takashi Nakamae, Tomohiro Nakao, Janardhanan C. Narayanaswamy, Seiji Nishida, Erika L. Nurmi, Joseph O'Neill, John Piacentini, Fabrizio Piras, Federica Piras, Y. C. Janardhan Reddy, Tim J. Reess, Yuki Sakai, Joao R. Sato, H. Blair Simpson, Noam Soreni, Carles Soriano-Mas, Gianfranco Spalletta, Michael C. Stevens, Philip R. Szeszko, David F. Tolin, Guido A. van Wingen, Ganesan Venkatasubramanian, Susanne Walitza, Zhen Wang, Je-Yeon Yun, ENIGMA-OCD Working-Group , Paul M. Thompson, Dan J. Stein, Odile A. van den Heuvel, Jos W. R. Twisk
in Frontiers in Neuroinformatics | New and Recent Articles on January 08, 2019 12:00 PM.
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On the Influence of Structural Connectivity on the Correlation Patterns and Network Synchronization
Parisa Sadat Nazemi, Yousef Jamali
in Frontiers in Computational Neuroscience | New and Recent Articles on January 08, 2019 12:00 PM.
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Minimal Circuit Model of Reward Prediction Error Computations and Effects of Nicotinic Modulations
Nicolas Deperrois, Victoria Moiseeva, Boris Gutkin
in Frontiers in Neural Circuits | New and Recent Articles on January 08, 2019 12:00 PM.
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Differences in Gene Expression Profiles and Phenotypes of Differentiated SH-SY5Y Neurons Stably Overexpressing Mitochondrial Ferritin
Anarmaa Mendsaikhan, Shigeko Takeuchi, Douglas G. Walker, Ikuo Tooyama
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 08, 2019 06:00 AM.
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Mitochondrial Calcium Transporters Mediate Sensitivity to Noise-Induced Losses of Hair Cells and Cochlear Synapses
Xianren Wang, Yuanping Zhu, Haishan Long, Song Pan, Hao Xiong, Qiaojun Fang, Kayla Hill, Ruosha Lai, Hu Yuan, Su-Hua Sha
in Frontiers in Molecular Neuroscience | New and Recent Articles on January 08, 2019 06:00 AM.
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Oculomotor and Inhibitory Control in Dyslexia
Thomas D. W. Wilcockson, Diako Mardanbegi, Peter Sawyer, Hans Gellersen, Baiqiang Xia, Trevor J. Crawford
in Frontiers in Systems Neuroscience | New and Recent Articles on January 08, 2019 06:00 AM.
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The Cortical States of Wakefulness
James F. A. Poulet, Sylvain Crochet
in Frontiers in Systems Neuroscience | New and Recent Articles on January 08, 2019 06:00 AM.
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Effects of High-Definition Transcranial Direct Current Stimulation (HD-tDCS) of the Intraparietal Sulcus and Dorsolateral Prefrontal Cortex on Working Memory and Divided Attention
Stevan Nikolin, Shani Lauf, Colleen K. Loo, Donel Martin
in Frontiers in Integrative Neuroscience | New and Recent Articles on January 08, 2019 06:00 AM.
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Ceruloplasmin Plays a Neuroprotective Role in Cerebral Ischemia
Fari Ryan, Juan G. Zarruk, Lena Lößlein, Samuel David
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 08, 2019 06:00 AM.
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Postnatal Development of NPY and Somatostatin-28 Peptidergic Populations in the Human Angular Bundle
Sandra Cebada-Sánchez, Pilar Marcos Rabal, Ana María Insausti, Ricardo Insausti
in Frontiers in Neuroanatomy | New and Recent Articles on January 08, 2019 06:00 AM.
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Hacking the Brain: Triggering Neuroplasticity for Enhancing Musical Talent. (arXiv:1901.01362v1 [q-bio.NC])

In this paper, we analyze the cognitive improvements that can be achieved through hacking the brain and using neuroplasticity. Not all cases of neuroplasticity are useful, but exposure to gaming, for example, has proven conducive for learning. We will discuss cortical magnification and receptive field sizes, as well as topographic brain maps in the context of neuroplasticity. We finally propose more studies to be performed to improve musical talent and musical abilities.

in q-bio.NC updates on arXiv.org on January 08, 2019 01:30 AM.
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Publisher Correction: Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry

Publisher Correction: Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry
Publisher Correction: Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry, Published online: 08 January 2019; doi:10.1038/s41593-018-0306-y
Publisher Correction: Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry
in Nature Neuroscience - Issue - nature.com science feeds on January 08, 2019 12:00 AM.
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Hippocampal Neurogenesis Reduces the Dimensionality of Sparsely Coded Representations to Enhance Memory Encoding
Anthony J. DeCostanzo, Chi Chung Alan Fung, Tomoki Fukai
in Frontiers in Computational Neuroscience | New and Recent Articles on January 07, 2019 06:00 PM.
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Deep Learning Based Attenuation Correction of PET/MRI in Pediatric Brain Tumor Patients: Evaluation in a Clinical Setting
Claes Nøhr Ladefoged, Lisbeth Marner, Amalie Hindsholm, Ian Law, Liselotte Højgaard, Flemming Littrup Andersen
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 07, 2019 06:00 AM.
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Dynamic Alterations in Spontaneous Neural Activity in Multiple Brain Networks in Subacute Stroke Patients: A Resting-State fMRI Study
Jing Chen, Dalong Sun, Yonghui Shi, Wei Jin, Yanbin Wang, Qian Xi, Chuancheng Ren
in Frontiers in Neuroscience | Brain Imaging Methods section | New and Recent Articles on January 07, 2019 06:00 AM.
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An Integrative Approach to Treat Parkinson's Disease: Ukgansan Complements L-Dopa by Ameliorating Dopaminergic Neuronal Damage and L-Dopa-Induced Dyskinesia in Mice
Eugene Huh, Jin Gyu Choi, Yeomoon Sim, Myung Sook Oh
in Frontiers in Aging Neuroscience | New and Recent Articles on January 07, 2019 06:00 AM.
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Gestational Exposure to Particulate Matter 2.5 (PM2.5) Leads to Spatial Memory Dysfunction and Neurodevelopmental Impairment in Hippocampus of Mice Offspring
Xinrui Zheng, Xia Wang, Tingting Wang, Hongxia Zhang, Hongjuan Wu, Can Zhang, Li Yu, Yingjun Guan
in Frontiers in Neuroscience | Neurogenesis section | New and Recent Articles on January 07, 2019 06:00 AM.
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Manganese Enhanced MRI for Use in Studying Neurodegenerative Diseases
Galit Saar, Alan P. Koretsky
in Frontiers in Neural Circuits | New and Recent Articles on January 07, 2019 06:00 AM.
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A Dual Role Hypothesis of the Cortico-Basal-Ganglia Pathways: Opponency and Temporal Difference Through Dopamine and Adenosine
Kenji Morita, Yasuo Kawaguchi
in Frontiers in Neural Circuits | New and Recent Articles on January 07, 2019 06:00 AM.
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Centrifugal Inputs to the Main Olfactory Bulb Revealed Through Whole Brain Circuit-Mapping
Krishnan Padmanabhan, Fumitaka Osakada, Anna Tarabrina, Erin Kizer, Edward M. Callaway, Fred H. Gage, Terrence J. Sejnowski
in Frontiers in Neuroanatomy | New and Recent Articles on January 07, 2019 06:00 AM.
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Back to baseline: sleep recalibrates synapses

Back to baseline: sleep recalibrates synapses
Back to baseline: sleep recalibrates synapses, Published online: 07 January 2019; doi:10.1038/s41593-018-0327-6
In 2008, Vyazovskiy et al. published a seminal study demonstrating that sleep induces a widespread downscaling of synapses that counters the synaptic upscaling that occurred during prior wakefulness. The study laid the groundwork for current research into the ‘where’ and ‘when’ of homeostatic neuronal network regulation during sleep.
in Nature Neuroscience - Issue - nature.com science feeds on January 07, 2019 12:00 AM.
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Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE

Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE, Published online: 07 January 2019; doi:10.1038/s41593-018-0296-9
Loss of Trem2 function increases early amyloidogenesis by preventing microglial activation and clustering around amyloid seeds. As a consequence of reduced microglial ApoE production in the absence of Trem2 function, amyloid plaques contain less ApoE.
in Nature Neuroscience - Issue - nature.com science feeds on January 07, 2019 12:00 AM.
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Hemispheric Module-Specific Influence of the X Chromosome on White Matter Connectivity: Evidence from Girls with Turner Syndrome

Abstract
Turner syndrome (TS) is caused by the congenital absence of all or part of one of the X chromosomes in females, offering a valuable human “knockout model” to study the functioning patterns of the X chromosome in the human brain. Little is known about whether and how the loss of the X chromosome influences the brain structural wiring patterns in human. We acquired a multimodal MRI dataset and cognitive assessments from 22 girls with TS and 21 age-matched control girls to address these questions. Hemispheric white matter (WM) networks and modules were derived using refined diffusion MRI tractography. Statistical comparisons revealed a reduced topological efficiency of both hemispheric networks and bilateral parietal modules in TS girls. Specifically, the efficiency of right parietal module significantly mediated the effect of the X chromosome on working memory performance, indicating that X chromosome loss impairs working memory performance by disrupting this module. Additionally, TS girls showed structural and functional connectivity decoupling across specific within- and between-modular connections, predominantly in the right hemisphere. These findings provide novel insights into the functional pathways in the brain that are regulated by the X chromosome and highlight a module-specific genetic contribution to WM connectivity in the human brain.
in Cerebral Cortex Advance Access on January 07, 2019 12:00 AM.
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I See Your Effort: Force-Related BOLD Effects in an Extended Action Execution–Observation Network Involving the Cerebellum

Abstract
Action observation (AO) is crucial for motor planning, imitation learning, and social interaction, but it is not clear whether and how an action execution–observation network (AEON) processes the effort of others engaged in performing actions. In this functional magnetic resonance imaging (fMRI) study, we used a “squeeze ball” task involving different grip forces to investigate whether AEON activation showed similar patterns when executing the task or observing others performing it. Both in action execution, AE (subjects performed the visuomotor task) and action observation, AO (subjects watched a video of the task being performed by someone else), the fMRI signal was detected in cerebral and cerebellar regions. These responses showed various relationships with force mapping onto specific areas of the sensorimotor and cognitive systems. Conjunction analysis of AE and AO was repeated for the “0th” order and linear and nonlinear responses, and revealed multiple AEON nodes remapping the detection of actions, and also effort, of another person onto the observer’s own cerebrocerebellar system. This result implies that the AEON exploits the cerebellum, which is known to process sensorimotor predictions and simulations, performing an internal assessment of forces and integrating information into high-level schemes, providing a crucial substrate for action imitation.
in Cerebral Cortex Advance Access on January 07, 2019 12:00 AM.
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Enhanced Population Coding for Rewarded Choices in the Medial Frontal Cortex of the Mouse

Abstract
Instrumental behavior is characterized by the selection of actions based on the degree to which they lead to a desired outcome. However, we lack a detailed understanding of how rewarded actions are reinforced and preferentially implemented. In rodents, the medial frontal cortex is hypothesized to play an important role in this process, based in part on its capacity to encode chosen actions and their outcomes. We therefore asked how neural representations of choice and outcome might interact to facilitate instrumental behavior. To investigate this question, we imaged neural ensemble activity in layer 2/3 of the secondary motor region (M2) while mice engaged in a two-choice auditory discrimination task with probabilistic outcomes. Correct choices could result in one of three reward amounts (single, double or omitted reward), which allowed us to measure neural and behavioral effects of reward magnitude, as well as its categorical presence or absence. Single-unit and population decoding analyses revealed a consistent influence of outcome on choice signals in M2. Specifically, rewarded choices were more robustly encoded relative to unrewarded choices, with little dependence on the exact magnitude of reinforcement. Our results provide insight into the integration of past choices and outcomes in the rodent brain during instrumental behavior.
in Cerebral Cortex Advance Access on January 07, 2019 12:00 AM.
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Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms
The mesolimbic hypothesis has been a central dogma of schizophrenia for decades, positing that aberrant functioning of midbrain dopamine projections to limbic regions causes psychotic symptoms. Recently, however, advances in neuroimaging techniques have led to the unanticipated finding that dopaminergic dysfunction in schizophrenia is greatest within nigrostriatal pathways, implicating the dorsal striatum in the pathophysiology and calling into question the mesolimbic theory. At the same time our knowledge of striatal anatomy and function has progressed, suggesting new mechanisms via which striatal dysfunction may contribute to the symptoms of schizophrenia.
in Trends in Neurosciences on January 06, 2019 12:00 AM.
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Inhibitory effect of ultrasonic stimulation on the voltage-dependent potassium currents in rat hippocampal CA1 neurons
Transcranial ultrasonic stimulation is a novel noninvasive tool for neuromodulation, and has high spatial resolution and deep penetration. Although it can increase excitation of neurons, its effects on neuron ...
in Most Recent Articles: BMC Neuroscience on January 05, 2019 12:00 AM.
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Royal Jelly Alleviates Cognitive Deficits and β-Amyloid Accumulation in APP/PS1 Mouse Model Via Activation of the cAMP/PKA/CREB/BDNF Pathway and Inhibition of Neuronal Apoptosis
Mengmeng You, Yongming Pan, Yichen Liu, Yifan Chen, Yuqi Wu, Juanjuan Si, Kai Wang, Fuliang Hu
in Frontiers in Aging Neuroscience | New and Recent Articles on January 04, 2019 06:00 PM.
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Activity patterns in the neuropil of striatal cholinergic interneurons in freely moving mice represent their collective spiking dynamics
Abstract
Cholinergic interneurons (CINs) are believed to form synchronous cell assemblies that modulate the striatal microcircuitry and possibly orchestrate local dopamine release. We expressed GCaMP6s, a genetically encoded calcium indicator (GECIs), selectively in CINs, and used microendoscopes to visualize the putative CIN assemblies in the dorsal striatum of freely moving mice. The GECI fluorescence signal from the dorsal striatum was composed of signals from individual CIN somata that were engulfed by a widespread fluorescent neuropil. Bouts of synchronous activation of the cholinergic neuropil revealed patterns of activity that preceded the signal from individual somata. To investigate the nature of the neuropil signal and why it precedes the somatic signal, we target-patched GECI-expressing CINs in acute striatal slices in conjunction with multiphoton imaging or wide-field imaging that emulates the microendoscopes’ specifications. The ability to detect fluorescent transients associated with individual action potential was constrained by the long decay constant of GECIs (relative to common inorganic dyes) to slowly firing (< 2 spikes/s) CINs. The microendoscopes’ resolving power and sampling rate further diminished this ability. Additionally, we found that only back-propagating action potentials but not synchronous optogenetic activation of thalamic inputs elicited observable calcium transients in CIN dendrites. Our data suggest that only bursts of CIN activity (but not their tonic firing) are visible using endoscopic imaging, and that the neuropil patterns are a physiological measure of the collective recurrent CIN network spiking activity.
Significance Statement Cholinergic interneurons (CINs) are key modulators of the striatal microcircuitry that are necessary for assigning action value and behavioral flexibility. We present a first endoscopic imaging study of multiple molecularly identified CINs in freely moving mice. We reveal the presence of activity patterns in the CIN neuropil. We then use ex vivo electrophysiological and imaging techniques to show that the neuropil signal is the integrated fluorescence arising from the axo-dendritic arbors of CINs dispersed throughout the striatum. We conclude that the neuropil signal acts as a mean-field readout of the striatal CIN network activity.

in RSS PAP on January 04, 2019 05:39 PM.
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Neuron-Specific Gene 2 (NSG2) encodes an AMPA receptor interacting protein that modulates excitatory neurotransmission
Abstract
Neurons have evolved a number of unique protein-coding genes that regulate trafficking of protein complexes within small organelles throughout dendrites axons. Neuron specific gene 2 (NSG2) encodes for one of the most abundant proteins in the nervous system during perinatal development. NSG2 belongs to a family of small neuronal endosomal proteins but its function has remained uncharacterized to date. Here we show that NSG2 is found in discrete punctae restricted to the somatodendritic arbors of developing mouse and human neurons, and a significant proportion of NSG2 punctae colocalize with postsynaptic HOMER1 and surface-expressed AMPARs at excitatory synapses. Immunoprecipitation revealed that NSG2 physically interacts with both the GluA1 and GluA2 AMPAR subunits in mouse brain. Knockout of NSG2 in mouse hippocampal neurons selectively impaired the frequency of miniature excitatory postsynaptic currents (mEPSCs) and caused alterations in PSD95 expression at postsynaptic densities. In contrast, NSG2 overexpression caused a significant increase in the amplitude of mEPSCs as well as GluA2 surface expression. Thus, NSG2 functions as an AMPAR-binding protein that is required for normal synapse formation and/or maintenance, and has unique functions compared with other NSG family members.
Significance Statement Due to their morphological and functional complexity, neurons have evolved specialized proteins like those of the neuron-specific gene family (NSG1-3). Important developmental and synaptic functions have been attributed to NSG1/NEEP21 and NSG3/Calcyon while the function of NSG2/HMP19/NVTA2 has remained uncharacterized. Here we show that NSG2 localizes to a large proportion of excitatory synapses, interacts with AMPARs, and modulates their surface expression during synaptogenesis. Alterations of NSG2 expression affected both the amplitude and frequency of excitatory neurotransmission that is not compensated for by other NSG family members. Thus, NSG2 appears critical for excitatory synapse formation and/or maintenance and forced expression can promote increased synaptic efficacy.

in RSS PAP on January 04, 2019 05:39 PM.
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Wave Turbulence and Energy Cascade in the Hippocampus
Alex Sheremet, Yu Qin, Jack P. Kennedy, Yuchen Zhou, Andrew P. Maurer
in Frontiers in Systems Neuroscience | New and Recent Articles on January 04, 2019 06:00 AM.
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Altered Functional Connectivity of Cerebello-Cortical Circuit in Multiple System Atrophy (Cerebellar-Type)
Shan Ren, Hao Zhang, Weimin Zheng, Ming Liu, Fang Gao, Zhiqun Wang, Zhigang Chen
in Frontiers in Neuroscience | Neurodegeneration section | New and Recent Articles on January 04, 2019 06:00 AM.
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Electrophysiology Meets Printed Electronics: The Beginning of a Beautiful Friendship
Lilah Inzelberg, Yael Hanein
in Frontiers in Neuroscience | Neural Technology section | New and Recent Articles on January 04, 2019 06:00 AM.
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Deconstructing cortical folding: genetic, cellular and mechanical determinants

Deconstructing cortical folding: genetic, cellular and mechanical determinants
Deconstructing cortical folding: genetic, cellular and mechanical determinants, Published online: 04 January 2019; doi:10.1038/s41583-018-0112-2
Why is the human cerebral cortex folded? Llinares-Benadero and Borrell provide an overview of the mechanical, cellular and molecular factors — and the interactions among them — that influence cortical folding in gyrencephalic species.
in Nature Reviews Neuroscience - Issue - nature.com science feeds on January 04, 2019 12:00 AM.
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Cortical Dysmaturation in Congenital Heart Disease
Congenital heart disease (CHD) is among the most common birth defects. Children with CHD frequently display long-term intellectual and behavioral disability. Emerging evidence indicates that cardiac anomalies lead to a reduction in cerebral oxygenation, which appears to profoundly impact on the maturation of cerebral regions responsible for higher-order cognitive functions. In this review we focus on the potential mechanisms by which dysregulation of cortical neuronal development during early life may lead to the significant cognitive impairments that commonly occur in children with CHD.
in Trends in Neurosciences on January 04, 2019 12:00 AM.
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Nestin Regulates Neurogenesis in Mice Through Notch Signaling From Astrocytes to Neural Stem Cells

Abstract
The intermediate filament (nanofilament) protein nestin is a marker of neural stem cells, but its role in neurogenesis, including adult neurogenesis, remains unclear. Here, we investigated the role of nestin in neurogenesis in adult nestin-deficient (Nes^–/–) mice. We found that the proliferation of Nes^–/– neural stem cells was not altered, but neurogenesis in the hippocampal dentate gyrus of Nes^–/– mice was increased. Surprisingly, the proneurogenic effect of nestin deficiency was mediated by its function in the astrocyte niche. Through its role in Notch signaling from astrocytes to neural stem cells, nestin negatively regulates neuronal differentiation and survival; however, its expression in neural stem cells is not required for normal neurogenesis. In behavioral studies, nestin deficiency in mice did not affect associative learning but was associated with impaired long-term memory.
in Cerebral Cortex Advance Access on January 03, 2019 12:00 AM.
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The modulation effect of non-invasive brain stimulation on cognitive function in patients with mild cognitive impairment: a systematic review and meta-analysis of randomized controlled trials
To prevent and control dementia, many scholars have focused on the transition stage between normal ageing and dementia, mild cognitive impairment (MCI) which is a key interventional target for dementia. Studie...
in Most Recent Articles: BMC Neuroscience on January 03, 2019 12:00 AM.

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