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Nature Neuroscience

Sheila Alcantara Llaguno, Daochun Sun, Alicia M Pedraza, Elsa Vera, Zilai Wang, Dennis K Burns, Luis F Parada
The contribution of lineage identity and differentiation state to malignant transformation is controversial. We have previously shown that adult neural stem and early progenitor cells give origin to glioblastoma. Here we systematically assessed the tumor-initiating potential of adult neural populations at various stages of lineage progression. Cell type-specific tamoxifen-inducible Cre recombinase transgenes were used to target glioblastoma-relevant tumor suppressors Nf1, Trp53 and Pten in late-stage neuronal progenitors, neuroblasts and differentiated neurons...
February 18, 2019: Nature Neuroscience
Xiang Li, Qiongyi Zhao, Wei Wei, Quan Lin, Christophe Magnan, Michael R Emami, Luis E Wearick-Silva, Thiago W Viola, Paul R Marshall, Jiayu Yin, Sachithrani U Madugalle, Ziqi Wang, Sarah Nainar, Cathrine Broberg Vågbø, Laura J Leighton, Esmi L Zajaczkowski, Ke Ke, Rodrigo Grassi-Oliveira, Magnar Bjørås, Pierre F Baldi, Robert C Spitale, Timothy W Bredy
DNA modification is known to regulate experience-dependent gene expression. However, beyond cytosine methylation and its oxidated derivatives, very little is known about the functional importance of chemical modifications on other nucleobases in the brain. Here we report that in adult mice trained in fear extinction, the DNA modification N6-methyl-2'-deoxyadenosine (m6dA) accumulates along promoters and coding sequences in activated prefrontal cortical neurons. The deposition of m6dA is associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with extinction-induced gene expression...
February 18, 2019: Nature Neuroscience
Minjie Shen, Feifei Wang, Meng Li, Nirnath Sah, Michael E Stockton, Joseph J Tidei, Yu Gao, Tomer Korabelnikov, Sudharsan Kannan, Jason D Vevea, Edwin R Chapman, Anita Bhattacharyya, Henriette van Praag, Xinyu Zhao
Fragile X syndrome results from a loss of the RNA-binding protein fragile X mental retardation protein (FMRP). How FMRP regulates neuronal development and function remains unclear. Here we show that FMRP-deficient immature neurons exhibit impaired dendritic maturation, altered expression of mitochondrial genes, fragmented mitochondria, impaired mitochondrial function, and increased oxidative stress. Enhancing mitochondrial fusion partially rescued dendritic abnormalities in FMRP-deficient immature neurons. We show that FMRP deficiency leads to reduced Htt mRNA and protein levels and that HTT mediates FMRP regulation of mitochondrial fusion and dendritic maturation...
February 18, 2019: Nature Neuroscience
Philipp Homan, Ifat Levy, Eric Feltham, Charles Gordon, Jingchu Hu, Jian Li, Robert H Pietrzak, Steven Southwick, John H Krystal, Ilan Harpaz-Rotem, Daniela Schiller
The original and corrected figures are shown in the accompanying Author Correction.
February 13, 2019: Nature Neuroscience
Adrienne L Fairhall
No abstract text is available yet for this article.
February 11, 2019: Nature Neuroscience
Jean C Cruz Hernández, Oliver Bracko, Calvin J Kersbergen, Victorine Muse, Mohammad Haft-Javaherian, Maxime Berg, Laibaik Park, Lindsay K Vinarcsik, Iryna Ivasyk, Daniel A Rivera, Yiming Kang, Marta Cortes-Canteli, Myriam Peyrounette, Vincent Doyeux, Amy Smith, Joan Zhou, Gabriel Otte, Jeffrey D Beverly, Elizabeth Davenport, Yohan Davit, Charles P Lin, Sidney Strickland, Costantino Iadecola, Sylvie Lorthois, Nozomi Nishimura, Chris B Schaffer
Cerebral blood flow (CBF) reductions in Alzheimer's disease patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences for Alzheimer's disease pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to in wild-type animals, largely due to neutrophils that had adhered in capillary segments and blocked blood flow. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to both an immediate increase in CBF and rapidly improved performance in spatial and working memory tasks...
February 11, 2019: Nature Neuroscience
Jeffrey Weiler, Paul L Gribble, J Andrew Pruszynski
Motor behaviour is most efficiently controlled by correcting only disturbances that influence task success. It is currently thought that such control is computed within a transcortical feedback pathway. Here we show that, for postural hand control, even the fastest spinal feedback pathway can produce efficient corrective responses, forcing a re-evaluation of how the nervous system derives the control laws that support motor behavior.
February 11, 2019: Nature Neuroscience
Evandro F Fang, Yujun Hou, Konstantinos Palikaras, Bryan A Adriaanse, Jesse S Kerr, Beimeng Yang, Sofie Lautrup, Md Mahdi Hasan-Olive, Domenica Caponio, Xiuli Dan, Paula Rocktäschel, Deborah L Croteau, Mansour Akbari, Nigel H Greig, Tormod Fladby, Hilde Nilsen, M Zameel Cader, Mark P Mattson, Nektarios Tavernarakis, Vilhelm A Bohr
Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models. In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinson's disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)-dependent pathways...
February 11, 2019: Nature Neuroscience
A Emin Orhan, Wei Ji Ma
The original and corrected figures are shown in the accompanying Publisher Correction.
February 6, 2019: Nature Neuroscience
Freek van Ede, Sammi R Chekroud, Mark G Stokes, Anna C Nobre
Visual working memory enables us to hold onto past sensations in anticipation that these may become relevant for guiding future actions. Yet laboratory tasks have treated visual working memories in isolation from their prospective actions and have focused on the mechanisms of memory retention rather than utilization. To understand how visual memories become used for action, we linked individual memory items to particular actions and independently tracked the neural dynamics of visual and motor selection when memories became used for action...
February 4, 2019: Nature Neuroscience
Carl M Sellgren, Jessica Gracias, Bradley Watmuff, Jonathan D Biag, Jessica M Thanos, Paul B Whittredge, Ting Fu, Kathleen Worringer, Hannah E Brown, Jennifer Wang, Ajamete Kaykas, Rakesh Karmacharya, Carleton P Goold, Steven D Sheridan, Roy H Perlis
Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake...
February 4, 2019: Nature Neuroscience
Antoine Besnard, Yuan Gao, Michael TaeWoo Kim, Hannah Twarkowski, Alexander Keith Reed, Tomer Langberg, Wendy Feng, Xiangmin Xu, Dieter Saur, Larry S Zweifel, Ian Davison, Amar Sahay
Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus-CA3 circuit. Retrograde monosynaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock-responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field...
February 4, 2019: Nature Neuroscience
David M Howard, Mark J Adams, Toni-Kim Clarke, Jonathan D Hafferty, Jude Gibson, Masoud Shirali, Jonathan R I Coleman, Saskia P Hagenaars, Joey Ward, Eleanor M Wigmore, Clara Alloza, Xueyi Shen, Miruna C Barbu, Eileen Y Xu, Heather C Whalley, Riccardo E Marioni, David J Porteous, Gail Davies, Ian J Deary, Gibran Hemani, Klaus Berger, Henning Teismann, Rajesh Rawal, Volker Arolt, Bernhard T Baune, Udo Dannlowski, Katharina Domschke, Chao Tian, David A Hinds, Maciej Trzaskowski, Enda M Byrne, Stephan Ripke, Daniel J Smith, Patrick F Sullivan, Naomi R Wray, Gerome Breen, Cathryn M Lewis, Andrew M McIntosh
Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission...
February 4, 2019: Nature Neuroscience
Xiaoyang Yang, Beisi Xu, Brett Mulvey, Myron Evans, Samuel Jordan, Yong-Dong Wang, Vishwajeeth Pagala, Junmin Peng, Yiping Fan, Arishna Patel, Jamy C Peng
UTX is a chromatin modifier required for development and neural lineage specification, but how it controls these biological processes is unclear. To determine the molecular mechanisms of UTX, we identified novel UTX protein interaction partners. Here we show that UTX and 53BP1 directly interact and co-occupy promoters in human embryonic stem cells and differentiating neural progenitor cells. Human 53BP1 contains a UTX-binding site that diverges from its mouse homolog by 41%, and disruption of the 53BP1-UTX interaction abrogated human, but not mouse, neurogenesis in vitro...
February 4, 2019: Nature Neuroscience
Rebecca M Marton, Yuki Miura, Steven A Sloan, Qingyun Li, Omer Revah, Rebecca J Levy, John R Huguenard, Sergiu P Pașca
Investigating human oligodendrogenesis and the interaction of oligodendrocytes with neurons and astrocytes would accelerate our understanding of the mechanisms underlying white matter disorders. However, this is challenging because of the limited accessibility of functional human brain tissue. Here, we developed a new differentiation method of human induced pluripotent stem cells to generate three-dimensional brain organoids that contain oligodendrocytes as well as neurons and astrocytes, called human oligodendrocyte spheroids...
January 28, 2019: Nature Neuroscience
Diego Elgueda, Daniel Duque, Susanne Radtke-Schuller, Pingbo Yin, Stephen V David, Shihab A Shamma, Jonathan B Fritz
In higher sensory cortices, there is a gradual transformation from sensation to perception and action. In the auditory system, this transformation is revealed by responses in the rostral ventral posterior auditory field (VPr), a tertiary area in the ferret auditory cortex, which shows long-term learning in trained compared to naïve animals, arising from selectively enhanced responses to behaviorally relevant target stimuli. This enhanced representation is further amplified during active performance of spectral or temporal auditory discrimination tasks...
January 28, 2019: Nature Neuroscience
Andrew J Schork, Hyejung Won, Vivek Appadurai, Ron Nudel, Mike Gandal, Olivier Delaneau, Malene Revsbech Christiansen, David M Hougaard, Marie Bækved-Hansen, Jonas Bybjerg-Grauholm, Marianne Giørtz Pedersen, Esben Agerbo, Carsten Bøcker Pedersen, Benjamin M Neale, Mark J Daly, Naomi R Wray, Merete Nordentoft, Ole Mors, Anders D Børglum, Preben Bo Mortensen, Alfonso Buil, Wesley K Thompson, Daniel H Geschwind, Thomas Werge
There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study...
January 28, 2019: Nature Neuroscience
Michael J Yetman, Eric Washburn, Jung Ho Hyun, Fumitaka Osakada, Yasufumi Hayano, Hongkui Zeng, Edward M Callaway, Hyung-Bae Kwon, Hiroki Taniguchi
Functionally and anatomically distinct cortical substructures, such as areas or layers, contain different principal neuron (PN) subtypes that generate output signals representing particular information. Various types of cortical inhibitory interneurons (INs) differentially but coordinately regulate PN activity. Despite a potential determinant for functional specialization of PN subtypes, the spatial organization of IN subtypes that innervate defined PN subtypes remains unknown. Here we develop a genetic strategy combining a recombinase-based intersectional labeling method and rabies viral monosynaptic tracing, which enables subtype-specific visualization of cortical IN ensembles sending inputs to defined PN subtypes...
January 28, 2019: Nature Neuroscience
Laura A DeNardo, Cindy D Liu, William E Allen, Eliza L Adams, Drew Friedmann, Lisa Fu, Casey J Guenthner, Marc Tessier-Lavigne, Liqun Luo
Memories of fearful events can last a lifetime. The prelimbic (PL) cortex, a subregion of prefrontal cortex, plays a critical role in fear memory retrieval over time. Most studies have focused on acquisition, consolidation, and retrieval of recent memories, but much less is known about the neural mechanisms of remote memory. Using a new knock-in mouse for activity-dependent genetic labeling (TRAP2), we demonstrate that neuronal ensembles in the PL cortex are dynamic. PL neurons TRAPed during later memory retrievals are more likely to be reactivated and make larger behavioral contributions to remote memory retrieval compared to those TRAPed during learning or early memory retrieval...
January 28, 2019: Nature Neuroscience
Mirko Santello, Nicolas Toni, Andrea Volterra
Astrocytes serve important roles that affect recruitment and function of neurons at the local and network levels. Here we review the contributions of astrocyte signaling to synaptic plasticity, neuronal network oscillations, and memory function. The roles played by astrocytes are not fully understood, but astrocytes seem to contribute to memory consolidation and seem to mediate the effects of vigilance and arousal on memory performance. Understanding the role of astrocytes in cognitive processes may also advance our understanding of how these processes go awry in pathological conditions...
January 21, 2019: Nature Neuroscience
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