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  1. Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders

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    Using large-scale analysis of protein interactions and bioinformatics, Li et al. describe the organization of the core-scaffold machinery of the postsynaptic density and its assembly in protein-interaction networks. The authors show how mutations associated with complex brain disorders are distributed along spatiotemporal protein complexes and modulate their protein interactions.

  2. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes

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    Microglia are the macrophages of the CNS, with innate neuroimmune function, and play important roles in tissue homeostasis, CNS development and neurodegeneration. Here human microglial gene expression profiles were generated. Human and mouse microglia were highly similar, except for aging-regulated genes, indicating that microglial aging differs between humans and mice.

  3. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems

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    The authors report two new engineered AAV capsids that efficiently deliver genes throughout the adult central and peripheral nervous systems after intravenous administration. Complementing these capsids is an AAV toolbox that enables cell morphology and genetic manipulation studies of defined neural cell types in transgenic or wild-type animals.

  4. Neural reactivations during sleep determine network credit assignment

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    A fundamental goal of learning is to establish neural patterns that cause desired behaviors. This paper demonstrates that sleep-dependent processing is required for credit assignment and the establishment of task-related activity reflecting the causal neuron-behavior relationship. Decoupling of spiking to sleep slow oscillations using optogenetics methods disrupted this process.

  5. Activation of cortical somatostatin interneurons prevents the development of neuropathic pain

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    Using in vivo calcium imaging in a mouse model of neuropathic pain, the authors found a persistent increase in the activity of somatosensory cortex pyramidal neurons following peripheral nerve injury. Repeated pharmacogenetic activation of somatostatin-expressing inhibitory neurons after injury not only corrected this abnormal cortical activity but also prevented the development of chronic pain.

  6. A causal account of the brain network computations underlying strategic social behavior

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    The authors show that transcranial magnetic disruption of the right temporoparietal junction decreases strategic behavior during competitive interactions. The altered behavior relates to neural activity changes both locally and in interconnected prefrontal areas. These brain networks may causally underlie the ability to predict the behavior of other agents.

  7. C9orf72 expansion disrupts ATM-mediated chromosomal break repair

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    An expanded repetition of a DNA sequence within the C9orf72 gene is the most common genetic cause for motor neuron disease and frontotemporal dementia. In this study, the authors show that this expansion causes increased genomic breaks and reduces the cell's ability to repair the breaks, ultimately leading to neuronal cell death.

  8. Reorganization of corticospinal output during motor learning

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    Corticospinal cells of the motor cortex act as a direct link between the cortex and movement-generating circuits within the spinal cord. The authors demonstrate that the relationship between activity of these cells and movement changes with time and learning, indicating a flexible cortical output to drive movements.

  9. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

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    Survey of postzygotic mosaic mutations (PZMs) in 5,947 trios with autism spectrum disorders (ASD) discovers differences in mutational properties between germline mutations and PZMs. Spatiotemporal analyses of the PZMs also revealed the association of the amygdala with ASD and implicated risk genes, including recurrent potential gain-of-function mutations in SMARCA4.

  10. A circuit-based mechanism underlying familiarity signaling and the preference for novelty

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    The mechanistic basis of how novel stimuli become familiar with repeated exposures has remained elusive. Molas et al. demonstrate that familiarity activates the interpeduncular nucleus, thereby reducing motivation to explore. Familiarity signaling in the interpeduncular nucleus is bidirectionally modulated by habenula and ventral tegmental area afferents to control novelty preference.

  11. PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1

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    The authors identify programmed cell death ligand-1 (PD-L1), an immunity suppressor produced by cancer cells, as a new pain inhibitor and a neuromodulator. They report that PD-L1 is produced by melanoma and normal neural tissues and that it inhibits acute and chronic pain. Via activation of PD-1, its receptor, PD-L1 decreases the excitability of nociceptive neurons in mouse and human dorsal root ganglia.

  12. Thalamic projections sustain prefrontal activity during working memory maintenance

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    Using pathway-specific optogenetic inhibition, the authors demonstrate that projections from the mediodorsal thalamus to prefrontal cortex support the maintenance of working memory, while prefrontal–thalamic projections support subsequent choice selection. Thalamo–prefrontal projections have a circuit-specific role in sustaining prefrontal delay-period activity, a neuronal signature required for successful task performance.

  13. Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus

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    Most cancer patients experience loss of appetite and feelings of illness, which contribute to cancer-related deaths and morbidity. The authors demonstrate that, in mice, activation of a subset of neurons in the parabrachial nucleus mediate cancer-induced anorexia and associated sickness behaviors.

  14. Gut microbiota is critical for the induction of chemotherapy-induced pain

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    Recent evidence supports a functional connection between gut microbiota and the nervous system. Here the authors show that gut microbiota plays a critical role in the development of chemotherapy-induced pain. This role of the microbiota is likely mediated, in part, by Tlr4 expressed on hematopoietic cells, including macrophages.

  15. The thalamic paradox

    Most thalamic research has focused on sensory transmission. Now three independent groups reveal the thalamus to be critical in behaviors linked to frontal cortex and the maintenance of persistent cortical activity during delays.
  16. The cellular mechanism for water detection in the mammalian taste system

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    The authors find that mammalian acid-sensing taste receptor cells, previously shown to be putative sour taste sensors, also mediate responses to water. Optogenetic activation of this population of cells in thirsty mice induced robust drinking response in the absence of water. This study shows that acid-sensing TRCs contribute to the detection of water in the oral cavity.

  17. Cortical gamma band synchronization through somatostatin interneurons

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    The authors establish a critical role for somatostatin interneurons in visually induced gamma oscillations in the primary visual cortex of mice. Optogenetic manipulations in awake animals, combined with an innovative computational model with multiple interneuron subtypes, provide a mechanism for the synchronization of neural firing across the retinotopic map.

  18. From eye movements to actions: how batsmen hit the ball

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    In cricket, a batsman watches a fast bowler's ball come toward him at a high and unpredictable speed, bouncing off ground of uncertain hardness. Although he views the trajectory for little more than half a second, he can accurately judge where and when the ball will reach him. Batsmen's eye movements monitor the moment when the ball is released, make a predictive saccade to the place where they expect it to hit the ground, wait for it to bounce, and follow its trajectory for 100–200 ms after the bounce. We show how information provided by these fixations may allow precise prediction of the ball's timing and placement. Comparing players with different skill levels, we found that a short latency for the first saccade distinguished good from poor batsmen, and that a cricket player's eye movement strategy contributes to his skill in the game.

  19. Germline Chd8 haploinsufficiency alters brain development in mouse

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    Strong genetic evidence points to a significant role for heterozygous mutations to general chromatin remodeling factors, such as CHD8, in autism. Gompers et al. combine genomic, neuroanatomical and behavioral approaches to present an initial integrative picture of transcriptional mechanisms and widespread impacts of Chd8 haploinsufficiency across brain development in mice.

  20. Rich cell-type-specific network topology in neocortical microcircuitry

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    To unravel structural regularities in neocortical networks, Gal et al. analyzed a biologically constrained model of a neocortical microcircuit. Using extended graph theory, they found multiple cell-type-specific wiring features, including small-word and rich-club topologies that might contribute to the large repertoire of computations performed by the neocortex.

  21. Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber

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    The authors demonstrate that optical fibers with tapered tips can homogenously illuminate either elongated brain structures or dynamically selected subregions. Tapered fibers achieve efficient optogenetic stimulation in vivo with minimal tissue damage. In addition, a single fiber can deliver light of multiple wavelengths to independently controlled regions.

  22. A fluoro-Nissl dye identifies pericytes as distinct vascular mural cells during in vivo brain imaging

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    No techniques exist for the precise identification of vascular pericytes. Here the authors identify and characterize a fluorescent dye that exclusively labels pericytes. Using this tool for intravital imaging of the mouse brain, the authors provide conclusive evidence that these cells are molecularly and functionally distinct from all other brain and vascular cells.

  23. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

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    The authors identified a protective genetic allele associated with lower PU.1 (SPI1) expression in myeloid cells by conducting a genome-wide scan of Alzheimer's disease (AD). PU.1 binds the promoters of AD-associated genes (e.g., CD33, MS4A4A & MS4A6A, TYROBP) and modulates their expression, suggesting it may reduce AD risk by regulating myeloid cell gene expression.

  24. Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior

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    Using calcium imaging and optogenetic manipulation in mice performing a working memory task, the authors show that delay activity in prefrontal cortex pyramidal neurons is crucial for task performance. Optogenetic activation of VIP interneurons enhances the neuronal representation of task-relevant information and improves the animal's memory retention.