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Nature Neuroscience

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https://www.readbyqxmd.com/read/28714954/c9orf72-expansion-disrupts-atm-mediated-chromosomal-break-repair
#1
Callum Walker, Saul Herranz-Martin, Evangelia Karyka, Chunyan Liao, Katherine Lewis, Waheba Elsayed, Vera Lukashchuk, Shih-Chieh Chiang, Swagat Ray, Padraig J Mulcahy, Mateusz Jurga, Ioannis Tsagakis, Tommaso Iannitti, Jayanth Chandran, Ian Coldicott, Kurt J De Vos, Mohamed K Hassan, Adrian Higginbottom, Pamela J Shaw, Guillaume M Hautbergue, Mimoun Azzouz, Sherif F El-Khamisy
Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA-RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks...
July 17, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28714953/gut-microbiota-is-critical-for-the-induction-of-chemotherapy-induced-pain
#2
Shiqian Shen, Grewo Lim, Zerong You, Weihua Ding, Peigen Huang, Chongzhao Ran, Jason Doheny, Peter Caravan, Samuel Tate, Kun Hu, Hyangin Kim, Michael McCabe, Bo Huang, Zhongcong Xie, Douglas Kwon, Lucy Chen, Jianren Mao
Chemotherapy-induced pain is a dose-limiting condition that affects 30% of patients undergoing chemotherapy. We found that gut microbiota promotes the development of chemotherapy-induced mechanical hyperalgesia. Oxaliplatin-induced mechanical hyperalgesia was reduced in germ-free mice and in mice pretreated with antibiotics. Restoring the microbiota of germ-free mice abrogated this protection. These effects appear to be mediated, in part, by TLR4 expressed on hematopoietic cells, including macrophages.
July 17, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28714952/a-circuit-based-mechanism-underlying-familiarity-signaling-and-the-preference-for-novelty
#3
Susanna Molas, Rubing Zhao-Shea, Liwang Liu, Steven R DeGroot, Paul D Gardner, Andrew R Tapper
Novelty preference (NP) is an evolutionarily conserved, essential survival mechanism often dysregulated in neuropsychiatric disorders. NP is mediated by a motivational dopamine signal that increases in response to novel stimuli, thereby driving exploration. However, the mechanism by which once-novel stimuli transition to familiar stimuli is unknown. Here we describe a neuroanatomical substrate for familiarity signaling, the interpeduncular nucleus (IPN) of the midbrain, which is activated as novel stimuli become familiar with multiple exposures...
July 17, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28714951/rates-distribution-and-implications-of-postzygotic-mosaic-mutations-in-autism-spectrum-disorder
#4
Elaine T Lim, Mohammed Uddin, Silvia De Rubeis, Yingleong Chan, Anne S Kamumbu, Xiaochang Zhang, Alissa M D'Gama, Sonia N Kim, Robert Sean Hill, Arthur P Goldberg, Christopher Poultney, Nancy J Minshew, Itaru Kushima, Branko Aleksic, Norio Ozaki, Mara Parellada, Celso Arango, Maria J Penzol, Angel Carracedo, Alexander Kolevzon, Christina M Hultman, Lauren A Weiss, Menachem Fromer, Andreas G Chiocchetti, Christine M Freitag, George M Church, Stephen W Scherer, Joseph D Buxbaum, Christopher A Walsh
We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10(-6)), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5...
July 17, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28692062/neural-reactivations-during-sleep-determine-network-credit-assignment
#5
Tanuj Gulati, Ling Guo, Dhakshin S Ramanathan, Anitha Bodepudi, Karunesh Ganguly
A fundamental goal of motor learning is to establish the neural patterns that produce a desired behavioral outcome. It remains unclear how and when the nervous system solves this 'credit assignment' problem. Using neuroprosthetic learning, in which we could control the causal relationship between neurons and behavior, we found that sleep-dependent processing was required for credit assignment and the establishment of task-related functional connectivity reflecting the casual neuron-behavior relationship. Notably, we observed a strong link between the microstructure of sleep reactivations and credit assignment, with downscaling of non-causal activity...
July 10, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28692061/a-causal-account-of-the-brain-network-computations-underlying-strategic-social-behavior
#6
Christopher A Hill, Shinsuke Suzuki, Rafael Polania, Marius Moisa, John P O'Doherty, Christian C Ruff
During competitive interactions, humans have to estimate the impact of their own actions on their opponent's strategy. Here we provide evidence that neural computations in the right temporoparietal junction (rTPJ) and interconnected structures are causally involved in this process. By combining inhibitory continuous theta-burst transcranial magnetic stimulation with model-based functional MRI, we show that disrupting neural excitability in the rTPJ reduces behavioral and neural indices of mentalizing-related computations, as well as functional connectivity of the rTPJ with ventral and dorsal parts of the medial prefrontal cortex...
July 10, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28671694/reorganization-of-corticospinal-output-during-motor-learning
#7
Andrew J Peters, Jun Lee, Nathan G Hedrick, Keelin O'Neil, Takaki Komiyama
Motor learning is accompanied by widespread changes within the motor cortex, but it is unknown whether these changes are ultimately funneled through a stable corticospinal output channel or whether the corticospinal output itself is plastic. We investigated the consistency of the relationship between corticospinal neuron activity and movement through in vivo two-photon calcium imaging in mice learning a lever-press task. Corticospinal neurons exhibited heterogeneous correlations with movement, with the majority of movement-modulated neurons decreasing activity during movement...
July 3, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28671693/transcriptomic-analysis-of-purified-human-cortical-microglia-reveals-age-associated-changes
#8
Thais F Galatro, Inge R Holtman, Antonio M Lerario, Ilia D Vainchtein, Nieske Brouwer, Paula R Sola, Mariana M Veras, Tulio F Pereira, Renata E P Leite, Thomas Möller, Paul D Wes, Mari C Sogayar, Jon D Laman, Wilfred den Dunnen, Carlos A Pasqualucci, Sueli M Oba-Shinjo, Erik W G M Boddeke, Suely K N Marie, Bart J L Eggen
Microglia are essential for CNS homeostasis and innate neuroimmune function, and play important roles in neurodegeneration and brain aging. Here we present gene expression profiles of purified microglia isolated at autopsy from the parietal cortex of 39 human subjects with intact cognition. Overall, genes expressed by human microglia were similar to those in mouse, including established microglial genes CX3CR1, P2RY12 and ITGAM (CD11B). However, a number of immune genes, not identified as part of the mouse microglial signature, were abundantly expressed in human microglia, including TLR, Fcγ and SIGLEC receptors, as well as TAL1 and IFI16, regulators of proliferation and cell cycle...
July 3, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28671696/spatiotemporal-profile-of-postsynaptic-interactomes-integrates-components-of-complex-brain-disorders
#9
Jing Li, Wangshu Zhang, Hui Yang, Daniel P Howrigan, Brent Wilkinson, Tade Souaiaia, Oleg V Evgrafov, Giulio Genovese, Veronica A Clementel, Jennifer C Tudor, Ted Abel, James A Knowles, Benjamin M Neale, Kai Wang, Fengzhu Sun, Marcelo P Coba
The postsynaptic density (PSD) contains a collection of scaffold proteins used for assembling synaptic signaling complexes. However, it is not known how the core-scaffold machinery associates in protein-interaction networks or how proteins encoded by genes involved in complex brain disorders are distributed through spatiotemporal protein complexes. Here using immunopurification, proteomics and bioinformatics, we isolated 2,876 proteins across 41 in vivo interactomes and determined their protein domain composition, correlation to gene expression levels and developmental integration to the PSD...
June 26, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28671695/engineered-aavs-for-efficient-noninvasive-gene-delivery-to-the-central-and-peripheral-nervous-systems
#10
Ken Y Chan, Min J Jang, Bryan B Yoo, Alon Greenbaum, Namita Ravi, Wei-Li Wu, Luis Sánchez-Guardado, Carlos Lois, Sarkis K Mazmanian, Benjamin E Deverman, Viviana Gradinaru
Adeno-associated viruses (AAVs) are commonly used for in vivo gene transfer. Nevertheless, AAVs that provide efficient transduction across specific organs or cell populations are needed. Here, we describe AAV-PHP.eB and AAV-PHP.S, capsids that efficiently transduce the central and peripheral nervous systems, respectively. In the adult mouse, intravenous administration of 1 × 10(11) vector genomes (vg) of AAV-PHP.eB transduced 69% of cortical and 55% of striatal neurons, while 1 × 10(12) vg of AAV-PHP.S transduced 82% of dorsal root ganglion neurons, as well as cardiac and enteric neurons...
June 26, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28671692/activation-of-cortical-somatostatin-interneurons-prevents-the-development-of-neuropathic-pain
#11
Joseph Cichon, Thomas J J Blanck, Wen-Biao Gan, Guang Yang
Neuropathic pain involves long-lasting modifications of pain pathways that result in abnormal cortical activity. How cortical circuits are altered and contribute to the intense sensation associated with allodynia is unclear. Here we report a persistent elevation of layer V pyramidal neuron activity in the somatosensory cortex of a mouse model of neuropathic pain. This enhanced pyramidal neuron activity was caused in part by increases of synaptic activity and NMDA-receptor-dependent calcium spikes in apical tuft dendrites...
June 26, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28671691/germline-chd8-haploinsufficiency-alters-brain-development-in-mouse
#12
Andrea L Gompers, Linda Su-Feher, Jacob Ellegood, Nycole A Copping, M Asrafuzzaman Riyadh, Tyler W Stradleigh, Michael C Pride, Melanie D Schaffler, A Ayanna Wade, Rinaldo Catta-Preta, Iva Zdilar, Shreya Louis, Gaurav Kaushik, Brandon J Mannion, Ingrid Plajzer-Frick, Veena Afzal, Axel Visel, Len A Pennacchio, Diane E Dickel, Jason P Lerch, Jacqueline N Crawley, Konstantinos S Zarbalis, Jill L Silverman, Alex S Nord
The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8(+/del5) mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8(+/del5) mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8(+/del5) mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling...
June 26, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28628104/active-dendritic-integration-as-a-mechanism-for-robust-and-precise-grid-cell-firing
#13
Christoph Schmidt-Hieber, Gabija Toleikyte, Laurence Aitchison, Arnd Roth, Beverley A Clark, Tiago Branco, Michael Häusser
Understanding how active dendrites are exploited for behaviorally relevant computations is a fundamental challenge in neuroscience. Grid cells in medial entorhinal cortex are an attractive model system for addressing this question, as the computation they perform is clear: they convert synaptic inputs into spatially modulated, periodic firing. Whether active dendrites contribute to the generation of the dual temporal and rate codes characteristic of grid cell output is unknown. We show that dendrites of medial entorhinal cortex neurons are highly excitable and exhibit a supralinear input-output function in vitro, while in vivo recordings reveal membrane potential signatures consistent with recruitment of active dendritic conductances...
June 19, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28628103/a-common-haplotype-lowers-pu-1-expression-in-myeloid-cells-and-delays-onset-of-alzheimer-s-disease
#14
Kuan-Lin Huang, Edoardo Marcora, Anna A Pimenova, Antonio F Di Narzo, Manav Kapoor, Sheng Chih Jin, Oscar Harari, Sarah Bertelsen, Benjamin P Fairfax, Jake Czajkowski, Vincent Chouraki, Benjamin Grenier-Boley, Céline Bellenguez, Yuetiva Deming, Andrew McKenzie, Towfique Raj, Alan E Renton, John Budde, Albert Smith, Annette Fitzpatrick, Joshua C Bis, Anita DeStefano, Hieab H H Adams, M Arfan Ikram, Sven van der Lee, Jorge L Del-Aguila, Maria Victoria Fernandez, Laura Ibañez, Rebecca Sims, Valentina Escott-Price, Richard Mayeux, Jonathan L Haines, Lindsay A Farrer, Margaret A Pericak-Vance, Jean Charles Lambert, Cornelia van Duijn, Lenore Launer, Sudha Seshadri, Julie Williams, Philippe Amouyel, Gerard D Schellenberg, Bin Zhang, Ingrid Borecki, John S K Kauwe, Carlos Cruchaga, Ke Hao, Alison M Goate
A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU...
June 19, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28628102/regulation-of-body-weight-and-energy-homeostasis-by-neuronal-cell-adhesion-molecule-1
#15
Thomas Rathjen, Xin Yan, Natalia L Kononenko, Min-Chi Ku, Kun Song, Leiron Ferrarese, Valentina Tarallo, Dmytro Puchkov, Gaga Kochlamazashvili, Sebastian Brachs, Luis Varela, Klara Szigeti-Buck, Chun-Xia Yi, Sonja C Schriever, Sudhir Gopal Tattikota, Anne Sophie Carlo, Mirko Moroni, Jan Siemens, Arnd Heuser, Louise van der Weyden, Andreas L Birkenfeld, Thoralf Niendorf, James F A Poulet, Tamas L Horvath, Matthias H Tschöp, Matthias Heinig, Mirko Trajkovski, Volker Haucke, Matthew N Poy
Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure...
June 19, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28628101/dynamic-illumination-of-spatially-restricted-or-large-brain-volumes-via-a-single-tapered-optical-fiber
#16
Ferruccio Pisanello, Gil Mandelbaum, Marco Pisanello, Ian A Oldenburg, Leonardo Sileo, Jeffrey E Markowitz, Ralph E Peterson, Andrea Della Patria, Trevor M Haynes, Mohamed S Emara, Barbara Spagnolo, Sandeep Robert Datta, Massimo De Vittorio, Bernardo L Sabatini
Optogenetics promises precise spatiotemporal control of neural processes using light. However, the spatial extent of illumination within the brain is difficult to control and cannot be adjusted using standard fiber optics. We demonstrate that optical fibers with tapered tips can be used to illuminate either spatially restricted or large brain volumes. Remotely adjusting the light input angle to the fiber varies the light-emitting portion of the taper over several millimeters without movement of the implant...
June 19, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28628100/hotspots-of-missense-mutation-identify-neurodevelopmental-disorder-genes-and-functional-domains
#17
Madeleine R Geisheker, Gabriel Heymann, Tianyun Wang, Bradley P Coe, Tychele N Turner, Holly A F Stessman, Kendra Hoekzema, Malin Kvarnung, Marie Shaw, Kathryn Friend, Jan Liebelt, Christopher Barnett, Elizabeth M Thompson, Eric Haan, Hui Guo, Britt-Marie Anderlid, Ann Nordgren, Anna Lindstrand, Geert Vandeweyer, Antonino Alberti, Emanuela Avola, Mirella Vinci, Stefania Giusto, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, Jacob J Michaelson, Zdenek Sedlacek, Gijs W E Santen, Hilde Peeters, Hakon Hakonarson, Eric Courchesne, Corrado Romano, R Frank Kooy, Raphael A Bernier, Magnus Nordenskjöld, Jozef Gecz, Kun Xia, Larry S Zweifel, Evan E Eichler
Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations...
June 19, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28604685/a-tnf-jnk-axl-erk-signaling-axis-mediates-primary-resistance-to-egfr-inhibition-in-glioblastoma
#18
Gao Guo, Ke Gong, Sonia Ali, Neha Ali, Shahzad Shallwani, Kimmo J Hatanpaa, Edward Pan, Bruce Mickey, Sandeep Burma, David H Wang, Santosh Kesari, Jann N Sarkaria, Dawen Zhao, Amyn A Habib
Aberrant epidermal growth factor receptor (EGFR) signaling is widespread in cancer, making the EGFR an important target for therapy. EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition has not been effective in treating this tumor. Here we propose that primary resistance to EGFR inhibition in glioma cells results from a rapid compensatory response to EGFR inhibition that mediates cell survival. We show that in glioma cells expressing either EGFR wild type or the mutant EGFRvIII, EGFR inhibition triggers a rapid adaptive response driven by increased tumor necrosis factor (TNF) secretion, which leads to activation in turn of c-Jun N-terminal kinase (JNK), the Axl receptor tyrosine kinase and extracellular signal-regulated kinases (ERK)...
June 12, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28604684/sensory-integration-and-neuromodulatory-feedback-facilitate-drosophila-mechanonociceptive-behavior
#19
Chun Hu, Meike Petersen, Nina Hoyer, Bettina Spitzweck, Federico Tenedini, Denan Wang, Alisa Gruschka, Lara S Burchardt, Emanuela Szpotowicz, Michaela Schweizer, Ananya R Guntur, Chung-Hui Yang, Peter Soba
Nociception is an evolutionarily conserved mechanism to encode and process harmful environmental stimuli. Like most animals, Drosophila melanogaster larvae respond to a variety of nociceptive stimuli, including noxious touch and temperature, with stereotyped escape responses through activation of multimodal nociceptors. How behavioral responses to these different modalities are processed and integrated by the downstream network remains poorly understood. By combining trans-synaptic labeling, ultrastructural analysis, calcium imaging, optogenetics and behavioral analyses, we uncovered a circuit specific for mechanonociception but not thermonociception...
June 12, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28604683/neural-signatures-of-dynamic-stimulus-selection-in-drosophila
#20
Yi Sun, Aljoscha Nern, Romain Franconville, Hod Dana, Eric R Schreiter, Loren L Looger, Karel Svoboda, Douglas S Kim, Ann M Hermundstad, Vivek Jayaraman
Many animals orient using visual cues, but how a single cue is selected from among many is poorly understood. Here we show that Drosophila ring neurons-central brain neurons implicated in navigation-display visual stimulus selection. Using in vivo two-color two-photon imaging with genetically encoded calcium indicators, we demonstrate that individual ring neurons inherit simple-cell-like receptive fields from their upstream partners. Stimuli in the contralateral visual field suppressed responses to ipsilateral stimuli in both populations...
June 12, 2017: Nature Neuroscience
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