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  • Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-09-18
    Harald Prüss, Andrea Tedeschi, Aude Thiriot, Lydia Lynch, Scott M Loughhead, Susanne Stutte, Irina B Mazo, Marcel A Kopp, Benedikt Brommer, Christian Blex, Laura-Christin Geurtz, Thomas Liebscher, Andreas Niedeggen, Ulrich Dirnagl, Frank Bradke, Magdalena S Volz, Michael J DeVivo, Yuying Chen, Ulrich H von Andrian, Jan M Schwab

    Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus–pituitary–adrenal axis stimulation. Instead of consecutive hypothalamus–pituitary–adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.

    更新日期:2017-09-20
  • Esr1+ cells in the ventromedial hypothalamus control female aggression
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Koichi Hashikawa, Yoshiko Hashikawa, Robin Tremblay, Jiaxing Zhang, James E Feng, Alexander Sabol, Walter T Piper, Hyosang Lee, Bernardo Rudy, Dayu Lin

    As an essential means of resolving conflicts, aggression is expressed by both sexes but often at a higher level in males than in females. Recent studies suggest that cells in the ventrolateral part of the ventromedial hypothalamus (VMHvl) that express estrogen receptor-α (Esr1) and progesterone receptor are essential for male but not female mouse aggression. In contrast, here we show that VMHvlEsr1+ cells are indispensable for female aggression. This population was active when females attacked naturally. Inactivation of these cells reduced female aggression whereas their activation elicited attack. Additionally, we found that female VMHvl contains two anatomically distinguishable subdivisions that showed differential gene expression, projection and activation patterns after mating and fighting. These results support an essential role of the VMHvl in both male and female aggression and reveal the existence of two previously unappreciated subdivisions in the female VMHvl that are involved in distinct social behaviors.

    更新日期:2017-09-19
  • Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Danielle E Mor, Elpida Tsika, Joseph R Mazzulli, Neal S Gould, Hanna Kim, Malcolm J Daniels, Shachee Doshi, Preetika Gupta, Jennifer L Grossman, Victor X Tan, Robert G Kalb, Kim A Caldwell, Guy A Caldwell, John H Wolfe, Harry Ischiropoulos

    Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

    更新日期:2017-09-19
  • A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Linette Liqi Tan, Patric Pelzer, Céline Heinl, Wannan Tang, Vijayan Gangadharan, Herta Flor, Rolf Sprengel, Thomas Kuner, Rohini Kuner

    The identity of cortical circuits mediating nociception and pain is largely unclear. The cingulate cortex is consistently activated during pain, but the functional specificity of cingulate divisions, the roles at distinct temporal phases of central plasticity and the underlying circuitry are unknown. Here we show in mice that the midcingulate division of the cingulate cortex (MCC) does not mediate acute pain sensation and pain affect, but gates sensory hypersensitivity by acting in a wide cortical and subcortical network. Within this complex network, we identified an afferent MCC–posterior insula pathway that can induce and maintain nociceptive hypersensitivity in the absence of conditioned peripheral noxious drive. This facilitation of nociception is brought about by recruitment of descending serotonergic facilitatory projections to the spinal cord. These results have implications for our understanding of neuronal mechanisms facilitating the transition from acute to long-lasting pain.

    更新日期:2017-09-19
  • Modular organization of the brainstem noradrenaline system coordinates opposing learning states
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Akira Uematsu, Bao Zhen Tan, Edgar A Ycu, Jessica Sulkes Cuevas, Jenny Koivumaa, Felix Junyent, Eric J Kremer, Ilana B Witten, Karl Deisseroth, Joshua P Johansen

    Noradrenaline modulates global brain states and diverse behaviors through what is traditionally believed to be a homogeneous cell population in the brainstem locus coeruleus (LC). However, it is unclear how LC coordinates disparate behavioral functions. We report a modular LC organization in rats, endowed with distinct neural projection patterns and coding properties for flexible specification of opposing behavioral learning states. LC projection mapping revealed functionally distinct cell modules with specific anatomical connectivity. An amygdala-projecting ensemble promoted aversive learning, while an independent medial prefrontal cortex-projecting ensemble extinguished aversive responses to enable flexible behavior. LC neurons displayed context-dependent inter-relationships, with moderate, discrete activation of distinct cell populations by fear or safety cues and robust, global recruitment of most cells by strong aversive stimuli. These results demonstrate a modular organization in LC in which combinatorial activation modes are coordinated with projection- and behavior-specific cell populations, enabling adaptive tuning of emotional responding and behavioral flexibility.

    更新日期:2017-09-19
  • Reactivations of emotional memory in the hippocampus–amygdala system during sleep
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Gabrielle Girardeau, Ingrid Inema, György Buzsáki

    The consolidation of context-dependent emotional memory requires communication between the hippocampus and the basolateral amygdala (BLA), but the mechanisms of this process are unknown. We recorded neuronal ensembles in the hippocampus and BLA while rats learned the location of an aversive air puff on a linear track, as well as during sleep before and after training. We found coordinated reactivations between the hippocampus and the BLA during non-REM sleep following training. These reactivations peaked during hippocampal sharp wave–ripples (SPW-Rs) and involved a subgroup of BLA cells positively modulated during hippocampal SPW-Rs. Notably, reactivation was stronger for the hippocampus–BLA correlation patterns representing the run direction that involved the air puff than for the 'safe' direction. These findings suggest that consolidation of contextual emotional memory occurs during ripple-reactivation of hippocampus–amygdala circuits.

    更新日期:2017-09-12
  • Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Stacey M Glasgow, Jeffrey C Carlson, Wenyi Zhu, Lesley S Chaboub, Peng Kang, Hyun Kyoung Lee, Yoanne M Clovis, Brittney E Lozzi, Robert J McEvilly, Michael G Rosenfeld, Chad J Creighton, Soo-Kyung Lee, Carrie A Mohila, Benjamin Deneen

    Long-range enhancer interactions critically regulate gene expression, yet little is known about how their coordinated activities contribute to CNS development or how this may, in turn, relate to disease states. By examining the regulation of the transcription factor NFIA in the developing spinal cord, we identified long-range enhancers that recapitulate NFIA expression across glial and neuronal lineages in vivo. Complementary genetic studies found that Sox9–Brn2 and Isl1–Lhx3 regulate enhancer activity and NFIA expression in glial and neuronal populations. Chromatin conformation analysis revealed that these enhancers and transcription factors form distinct architectures within these lineages in the spinal cord. In glioma models, the glia-specific architecture is present in tumors, and these enhancers are required for NFIA expression and contribute to glioma formation. By delineating three-dimensional mechanisms of gene expression regulation, our studies identify lineage-specific chromatin architectures and associated enhancers that regulate cell fate and tumorigenesis in the CNS.

    更新日期:2017-09-12
  • Parallel encoding of recent visual experience and self-motion during navigation in Drosophila
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-09-04
    Hiroshi M Shiozaki, Hokto Kazama

    Animal navigation requires multiple types of information for decisions on directional heading. We identified neural processing channels that encode multiple cues during navigational decision-making in Drosophila melanogaster. In a flight simulator, we found that flies made directional choices on the basis of the location of a recently presented landmark. This experience-guided navigation was impaired by silencing neurons in the bulb (BU), a region in the central brain. Two-photon calcium imaging during flight revealed that the dorsal part of the BU encodes the location of a recent landmark, whereas the ventral part of the BU tracks self-motion reflecting turns. Photolabeling-based circuit tracing indicated that these functional compartments of the BU constitute adjacent, yet distinct, anatomical pathways that both enter the navigation center. Thus, the fly's navigation system organizes multiple types of information in parallel channels, which may compactly transmit signals without interference for decision-making during flight.

    更新日期:2017-09-04
  • An xQTL map integrates the genetic architecture of the human brain's transcriptome and epigenome
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-09-04
    Bernard Ng, Charles C White, Hans-Ulrich Klein, Solveig K Sieberts, Cristin McCabe, Ellis Patrick, Jishu Xu, Lei Yu, Chris Gaiteri, David A Bennett, Sara Mostafavi, Philip L De Jager

    An xQTL map integrates the genetic architecture of the human brain's transcriptome and epigenome Nature Neuroscience, Published online: 4 September 2017; doi:10.1038/nn.4632 This paper reports the availability of a new Resource with RNA-seq, DNA methylation and H3K9Ac QTL results from 411 brain samples. Many xQTL SNPs influence multiple molecular features, and the authors observe epigenetic mediation of eQTLs in some cases. Reanalyzing GWAS with an xQTL-weighted approach detected 20 new CNS disease susceptibility loci.

    更新日期:2017-09-04
  • Impaired hippocampal place cell dynamics in a mouse model of the 22q11.2 deletion
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-09-04
    Jeffrey D Zaremba, Anastasia Diamantopoulou, Nathan B Danielson, Andres D Grosmark, Patrick W Kaifosh, John C Bowler, Zhenrui Liao, Fraser T Sparks, Joseph A Gogos, Attila Losonczy

    Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca2+ imaging in hippocampal area CA1 of wild-type and Df(16)A+/− mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A+/− mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction.

    更新日期:2017-09-04
  • Seeing faces is necessary for face-domain formation
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-09-04
    Michael J Arcaro, Peter F Schade, Justin L Vincent, Carlos R Ponce, Margaret S Livingstone

    Here we report that monkeys raised without exposure to faces did not develop face domains, but did develop domains for other categories and did show normal retinotopic organization, indicating that early face deprivation leads to a highly selective cortical processing deficit. Therefore, experience must be necessary for the formation (or maintenance) of face domains. Gaze tracking revealed that control monkeys looked preferentially at faces, even at ages prior to the emergence of face domains, but face-deprived monkeys did not, indicating that face looking is not innate. A retinotopic organization is present throughout the visual system at birth, so selective early viewing behavior could bias category-specific visual responses toward particular retinotopic representations, thereby leading to domain formation in stereotyped locations in inferotemporal cortex, without requiring category-specific templates or biases. Thus, we propose that environmental importance influences viewing behavior, viewing behavior drives neuronal activity, and neuronal activity sculpts domain formation.

    更新日期:2017-09-04
  • Functions and dysfunctions of neocortical inhibitory neuron subtypes
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Ryoma Hattori, Kishore V Kuchibhotla, Robert C Froemke, Takaki Komiyama

    Neocortical inhibitory neurons exhibit remarkably diverse morphology, physiological properties and connectivity. Genetic access to molecularly defined subtypes of inhibitory neurons has aided their functional characterization in recent years. These studies have established that, instead of simply balancing excitatory neuron activity, inhibitory neurons actively shape excitatory circuits in a subtype-specific manner. We review the emerging view that inhibitory neuron subtypes perform context-dependent modulation of excitatory activity, as well as regulate experience-dependent plasticity of excitatory circuits. We then review the roles of neuromodulators in regulating the subtype-specific functions of inhibitory neurons. Finally, we discuss the idea that dysfunctions of inhibitory neuron subtypes may be responsible for various aspects of neurological disorders.

    更新日期:2017-09-04
  • Jamais vu all over again
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Rebecca D Burwell, Victoria L Templer

    Jamais vu all over again Nature Neuroscience, Published online: 29 August 2017; doi:10.1038/nn.4625 What is the basis for the feeling that someplace or someone is familiar? Molas et al. have identified brain structures involved in signaling familiarity, a necessary element for the expression of preference for novelty.

    更新日期:2017-09-04
  • Is population activity more than the sum of its parts?
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Jonathan W Pillow, Mikio C Aoi

    Is population activity more than the sum of its parts? Nature Neuroscience, Published online: 29 August 2017; doi:10.1038/nn.4627 A study introduces innovative ways to test whether neural population activity exhibits structure above and beyond that of its basic components.

    更新日期:2017-09-04
  • The Zika threat to the periphery
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Themasap A. Khan, Sergiu P. Paşca

    The Zika threat to the periphery Nature Neuroscience, Published online: 29 August 2017; doi:10.1038/nn.4633 Zika virus infection is associated with birth defects, including microcephaly, but also with disorders of peripheral nerves. Oh et al. use rodent and human cell models to explore how the virus affects the peripheral nervous system.

    更新日期:2017-09-04
  • Jamais vu all over again
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-29
    Rebecca D Burwell, Victoria L Templer

    What is the basis for the feeling that someplace or someone is familiar? Molas et al. have identified brain structures involved in signaling familiarity, a necessary element for the expression of preference for novelty.

    更新日期:2017-08-29
  • Loopholes in the DNA contract kill neurons
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-29
    Karl Herrup, Kai-Hei Tse, Hei-Man Chow

    Hexanucleotide repeat expansions in C9orf72 gene locus create double jeopardy, first by leading to DNA–RNA R-loops that spawn double-strand breaks and second by the synthesis of dipeptide repeats that hinder DNA repair. This two-pronged mechanism may explain neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia.

    更新日期:2017-08-29
  • The Zika threat to the periphery
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-29
    Themasap A. Khan, Sergiu P. Paşca

    Zika virus infection is associated with birth defects, including microcephaly, but also with disorders of peripheral nerves. Oh et al. use rodent and human cell models to explore how the virus affects the peripheral nervous system.

    更新日期:2017-08-29
  • Functions and dysfunctions of neocortical inhibitory neuron subtypes
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-29
    Ryoma Hattori, Kishore V Kuchibhotla, Robert C Froemke, Takaki Komiyama

    Neocortical inhibitory neurons exhibit remarkably diverse morphology, physiological properties and connectivity. Genetic access to molecularly defined subtypes of inhibitory neurons has aided their functional characterization in recent years. These studies have established that, instead of simply balancing excitatory neuron activity, inhibitory neurons actively shape excitatory circuits in a subtype-specific manner. We review the emerging view that inhibitory neuron subtypes perform context-dependent modulation of excitatory activity, as well as regulate experience-dependent plasticity of excitatory circuits. We then review the roles of neuromodulators in regulating the subtype-specific functions of inhibitory neurons. Finally, we discuss the idea that dysfunctions of inhibitory neuron subtypes may be responsible for various aspects of neurological disorders.

    更新日期:2017-08-29
  • Is population activity more than the sum of its parts?
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-29
    Jonathan W Pillow, Mikio C Aoi

    A study introduces innovative ways to test whether neural population activity exhibits structure above and beyond that of its basic components.

    更新日期:2017-08-29
  • Zika virus directly infects peripheral neurons and induces cell death
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-31
    Yohan Oh, Feiran Zhang, Yaqing Wang, Emily M Lee, In Young Choi, Hotae Lim, Fahimeh Mirakhori, Ronghua Li, Luoxiu Huang, Tianlei Xu, Hao Wu, Cui Li, Cheng-Feng Qin, Zhexing Wen, Qing-Feng Wu, Hengli Tang, Zhiheng Xu, Peng Jin, Hongjun Song, Guo-li Ming, Gabsang Lee

    Zika virus infection is associated with neurological disorders, yet few studies have directly examined its impact on the peripheral nervous system. Oh et al. show that Zika virus can infect peripheral neurons in the mouse in vivo, as well as human peripheral neurons in vitro, leading to increased cell death and transcriptional dysregulation.

    更新日期:2017-08-29
  • Gut microbiota is critical for the induction of chemotherapy-induced pain
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-17
    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

    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.

    更新日期:2017-08-29
  • Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-17
    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 = 5.4 × 10−3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

    更新日期:2017-08-29
  • C9orf72 expansion disrupts ATM-mediated chromosomal break repair
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-17
    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. We reveal that defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Virus-mediated expression of C9orf72-related RNA and dipeptide repeats in the mouse central nervous system increases double strand breaks and ATM defects and triggers neurodegeneration. These findings identify R-loops, double strand breaks and defective ATM-mediated repair as pathological consequences of C9orf72 expansions and suggest that C9orf72-linked neurodegeneration is driven at least partly by genomic instability.

    更新日期:2017-08-29
  • Necroptosis activation in Alzheimer's disease
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-24
    Antonella Caccamo, Caterina Branca, Ignazio S Piras, Eric Ferreira, Matthew J Huentelman, Winnie S Liang, Ben Readhead, Joel T Dudley, Elizabeth E Spangenberg, Kim N Green, Ramona Belfiore, Wendy Winslow, Salvatore Oddo

    Alzheimer's disease (AD) is characterized by severe neuronal loss; however, the mechanisms by which neurons die remain elusive. Necroptosis, a programmed form of necrosis, is executed by the mixed lineage kinase domain-like (MLKL) protein, which is triggered by receptor-interactive protein kinases (RIPK) 1 and 3. We found that necroptosis was activated in postmortem human AD brains, positively correlated with Braak stage, and inversely correlated with brain weight and cognitive scores. In addition, we found that the set of genes regulated by RIPK1 overlapped significantly with multiple independent AD transcriptomic signatures, indicating that RIPK1 activity could explain a substantial portion of transcriptomic changes in AD. Furthermore, we observed that lowering necroptosis activation reduced cell loss in a mouse model of AD. We anticipate that our findings will spur a new area of research in the AD field focused on developing new therapeutic strategies aimed at blocking its activation.

    更新日期:2017-08-29
  • Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-07
    Daisuke Ibi, Mario de la Fuente Revenga, Nebojsa Kezunovic, Carolina Muguruza, Justin M Saunders, Supriya A Gaitonde, José L Moreno, Maryum K Ijaz, Vishaka Santosh, Alexey Kozlenkov, Terrell Holloway, Jeremy Seto, Aintzane García-Bea, Mitsumasa Kurita, Grace E Mosley, Yan Jiang, Daniel J Christoffel, Luis F Callado, Scott J Russo, Stella Dracheva, Juan F López-Giménez, Yongchao Ge, Carlos R Escalante, J Javier Meana, Schahram Akbarian, George W Huntley, Javier González-Maeso

    Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.

    更新日期:2017-08-29
  • A circuit-based mechanism underlying familiarity signaling and the preference for novelty
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-17
    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. In mice, optogenetic silencing of IPN neurons increases salience of and interaction with familiar stimuli without affecting novelty responses, whereas photoactivation of the same neurons reduces exploration of novel stimuli mimicking familiarity. Bidirectional control of NP by the IPN depends on familiarity signals and novelty signals arising from excitatory habenula and dopaminergic ventral tegmentum inputs, which activate and reduce IPN activity, respectively. These results demonstrate that familiarity signals through unique IPN circuitry that opposes novelty seeking to control NP.

    更新日期:2017-08-29
  • Dorsal hippocampus contributes to model-based planning
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-31
    Kevin J Miller, Matthew M Botvinick, Carlos D Brody

    Planning can be defined as action selection that leverages an internal model of the outcomes likely to follow each possible action. Its neural mechanisms remain poorly understood. Here we adapt recent advances from human research for rats, presenting for the first time an animal task that produces many trials of planned behavior per session, making multitrial rodent experimental tools available to study planning. We use part of this toolkit to address a perennially controversial issue in planning: the role of the dorsal hippocampus. Although prospective hippocampal representations have been proposed to support planning, intact planning in animals with damaged hippocampi has been repeatedly observed. Combining formal algorithmic behavioral analysis with muscimol inactivation, we provide causal evidence directly linking dorsal hippocampus with planning behavior. Our results and methods open the door to new and more detailed investigations of the neural mechanisms of planning in the hippocampus and throughout the brain.

    更新日期:2017-08-29
  • Neural reactivations during sleep determine network credit assignment
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-10
    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. Decoupling of spiking to slow oscillations using optogenetic methods eliminated rescaling. Thus, our results suggest that coordinated firing during sleep is essential for establishing sparse activation patterns that reflect the causal neuron-behavior relationship.

    更新日期:2017-08-29
  • Functional dissection of signal and noise in MT and LIP during decision-making
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-24
    Jacob L Yates, Il Memming Park, Leor N Katz, Jonathan W Pillow, Alexander C Huk

    During perceptual decision-making, responses in the middle temporal (MT) and lateral intraparietal (LIP) areas appear to map onto theoretically defined quantities, with MT representing instantaneous motion evidence and LIP reflecting the accumulated evidence. However, several aspects of the transformation between the two areas have not been empirically tested. We therefore performed multistage systems identification analyses of the simultaneous activity of MT and LIP during individual decisions. We found that monkeys based their choices on evidence presented in early epochs of the motion stimulus and that substantial early weighting of motion was present in MT responses. LIP responses recapitulated MT early weighting and contained a choice-dependent buildup that was distinguishable from motion integration. Furthermore, trial-by-trial variability in LIP did not depend on MT activity. These results identify important deviations from idealizations of MT and LIP and motivate inquiry into sensorimotor computations that may intervene between MT and LIP.

    更新日期:2017-08-29
  • Adults with autism overestimate the volatility of the sensory environment
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-31
    Rebecca P Lawson, Christoph Mathys, Geraint Rees

    Insistence on sameness and intolerance of change are among the diagnostic criteria for autism spectrum disorder (ASD), but little research has addressed how people with ASD represent and respond to environmental change. Here, behavioral and pupillometric measurements indicated that adults with ASD are less surprised than neurotypical adults when their expectations are violated, and decreased surprise is predictive of greater symptom severity. A hierarchical Bayesian model of learning suggested that in ASD, a tendency to overlearn about volatility in the face of environmental change drives a corresponding reduction in learning about probabilistically aberrant events, thus putatively rendering these events less surprising. Participant-specific modeled estimates of surprise about environmental conditions were linked to pupil size in the ASD group, thus suggesting heightened noradrenergic responsivity in line with compromised neural gain. This study offers insights into the behavioral, algorithmic and physiological mechanisms underlying responses to environmental volatility in ASD.

    更新日期:2017-08-29
  • Structure in neural population recordings: an expected byproduct of simpler phenomena?
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-07
    Gamaleldin F Elsayed, John P Cunningham

    To what extent are population-level results an expected byproduct of simpler structure already known to exist in single neurons? Conventional controls are insufficient to perform this critical investigation. The authors developed a methodological framework to test the significance of population-level studies and apply it to prefrontal and motor cortices.

    更新日期:2017-08-29
  • High-dimensional, single-cell characterization of the brain's immune compartment
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-24
    Ben Korin, Tamar L Ben-Shaanan, Maya Schiller, Tania Dubovik, Hilla Azulay-Debby, Nadia T Boshnak, Tamar Koren, Asya Rolls

    Korin et al. use CyTOF mass cytometry to characterize immune cell populations in the naive mouse brain (parenchyma, choroid plexus and meninges). This single-cell analysis of cell-surface proteins reveals the presence and phenotype of distinctive immune populations in the mouse brain compartment.

    更新日期:2017-08-29
  • Memory reactivation improves visual perception
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Rotem Amar-Halpert, Rony Laor-Maayany, Shlomi Nemni, Jonathan D Rosenblatt, Nitzan Censor

    Human perception can improve through repeated practice, enabling perceptual learning. The authors report findings challenging the fundamental ‘practice makes perfect’ basis of procedural learning theory. They show that brief periods in which visual memory is reactivated are sufficient to improve basic perceptual thresholds, supporting a new account of perceptual learning dynamics.

    更新日期:2017-08-29
  • Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Petra Füger, Jasmin K Hefendehl, Karthik Veeraraghavalu, Ann-Christin Wendeln, Christine Schlosser, Ulrike Obermüller, Bettina M Wegenast-Braun, Jonas J Neher, Peter Martus, Shinichi Kohsaka, Martin Thunemann, Robert Feil, Sangram S Sisodia, Angelos Skodras, Mathias Jucker

    To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. The lifespan of brain microglia, however, remains uncertain, and reflects confounding factors in earlier assessments that were largely indirect. We genetically labeled single resident microglia in living mice and then used multiphoton microscopy to monitor these cells over time. Under homeostatic conditions, we found that neocortical resident microglia were long-lived, with a median lifetime of well over 15 months; thus, approximately half of these cells survive the entire mouse lifespan. While proliferation of resident neocortical microglia under homeostatic conditions was low, microglial proliferation in a mouse model of Alzheimer's β-amyloidosis was increased threefold. The persistence of individual microglia throughout the mouse lifespan provides an explanation for how microglial priming early in life can induce lasting functional changes and how microglial senescence may contribute to age-related neurodegenerative diseases.

    更新日期:2017-08-29
  • Glia initiate brain assembly through noncanonical Chimaerin–Furin axon guidance in C. elegans
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Georgia Rapti, Chang Li, Alan Shan, Yun Lu, Shai Shaham

    Brain assembly is hypothesized to begin when pioneer axons extend over non-neuronal cells, forming tracts guiding follower axons. Yet pioneer-neuron identities, their guidance substrates, and their interactions are not well understood. Here, using time-lapse embryonic imaging, genetics, protein-interaction, and functional studies, we uncover the early events of C. elegans brain assembly. We demonstrate that C. elegans glia are key for assembly initiation, guiding pioneer and follower axons using distinct signals. Pioneer sublateral neurons, with unique growth properties, anatomy, and innervation, cooperate with glia to mediate follower-axon guidance. We further identify a Chimaerin (CHIN-1)– Furin (KPC-1) double-mutant that severely disrupts assembly. CHIN-1 and KPC-1 function noncanonically, in glia and pioneer neurons, for guidance-cue trafficking. We exploit this bottleneck to define roles for glial Netrin and Semaphorin in pioneer- and follower-axon guidance, respectively, and for glial and pioneer-neuron Flamingo (CELSR) in follower-axon navigation. Taken together, our studies reveal previously undescribed glial roles in pioneer-axon guidance, suggesting conserved principles of brain assembly.

    更新日期:2017-08-29
  • Central amygdala circuits modulate food consumption through a positive-valence mechanism
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Amelia M Douglass, Hakan Kucukdereli, Marion Ponserre, Milica Markovic, Jan Gründemann, Cornelia Strobel, Pilar L Alcala Morales, Karl-Klaus Conzelmann, Andreas Lüthi, Rüdiger Klein

    The complex behaviors underlying reward seeking and consumption are integral to organism survival. The hypothalamus and mesolimbic dopamine system are key mediators of these behaviors, yet regulation of appetitive and consummatory behaviors outside of these regions is poorly understood. The central nucleus of the amygdala (CeA) has been implicated in feeding and reward, but the neurons and circuit mechanisms that positively regulate these behaviors remain unclear. Here, we defined the neuronal mechanisms by which CeA neurons promote food consumption. Using in vivo activity manipulations and Ca2+ imaging in mice, we found that GABAergic serotonin receptor 2a (Htr2a)-expressing CeA neurons modulate food consumption, promote positive reinforcement and are active in vivo during eating. We demonstrated electrophysiologically, anatomically and behaviorally that intra-CeA and long-range circuit mechanisms underlie these behaviors. Finally, we showed that CeAHtr2a neurons receive inputs from feeding-relevant brain regions. Our results illustrate how defined CeA neural circuits positively regulate food consumption.

    更新日期:2017-08-29
  • Selective inhibitory control of pyramidal neuron ensembles and cortical subnetworks by chandelier cells
    Nat. Neurosci. (IF 17.839) Pub Date : 
    Jiangteng Lu, Jason Tucciarone, Nancy Padilla-Coreano, Miao He, Joshua A Gordon, Z Josh Huang

    The neocortex comprises multiple information processing streams mediated by subsets of glutamatergic pyramidal cells (PCs) that receive diverse inputs and project to distinct targets. How GABAergic interneurons regulate the segregation and communication among intermingled PC subsets that contribute to separate brain networks remains unclear. Here we demonstrate that a subset of GABAergic chandelier cells (ChCs) in the prelimbic cortex, which innervate PCs at spike initiation site, selectively control PCs projecting to the basolateral amygdala (BLAPC) compared to those projecting to contralateral cortex (CCPC). These ChCs in turn receive preferential input from local and contralateral CCPCs as opposed to BLAPCs and BLA neurons (the prelimbic cortex–BLA network). Accordingly, optogenetic activation of ChCs rapidly suppresses BLAPCs and BLA activity in freely behaving mice. Thus, the exquisite connectivity of ChCs not only mediates directional inhibition between local PC ensembles but may also shape communication hierarchies between global networks.

    更新日期:2017-08-29
  • AAV-mediated direct in vivo CRISPR screen identifies functional suppressors in glioblastoma
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-14
    Ryan D Chow, Christopher D Guzman, Guangchuan Wang, Florian Schmidt, Mark W Youngblood, Lupeng Ye, Youssef Errami, Matthew B Dong, Michael A Martinez, Sensen Zhang, Paul Renauer, Kaya Bilguvar, Murat Gunel, Phillip A Sharp, Feng Zhang, Randall J Platt, Sidi Chen

    A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus–mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts. Co-mutation analysis identified co-occurring driver combinations such as B2m–Nf1, Mll3–Nf1 and Zc3h13–Rb1, which were subsequently validated using AAV minipools. Distinct from Nf1-mutant tumors, Rb1-mutant tumors are undifferentiated and aberrantly express homeobox gene clusters. The addition of Zc3h13 or Pten mutations altered the gene expression profiles of Rb1 mutants, rendering them more resistant to temozolomide. Our study provides a functional landscape of gliomagenesis suppressors in vivo.

    更新日期:2017-08-23
  • Analysis of genome-wide association data highlights candidates for drug repositioning in psychiatry
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-14
    Hon-Cheong So, Carlos Kwan-Long Chau, Wan-To Chiu, Kin-Sang Ho, Cho-Pong Lo, Stephanie Ho-Yue Yim, Pak-Chung Sham

    Knowledge of psychiatric disease genetics has advanced rapidly during the past decade with the advent of genome-wide association studies (GWAS). However, less progress has been made in harnessing these data to reveal new therapies. Here we propose a framework for drug repositioning by comparing transcriptomes imputed from GWAS data with drug-induced gene expression profiles from the Connectivity Map database and apply this approach to seven psychiatric disorders. We found a number of repositioning candidates, many supported by preclinical or clinical evidence. Repositioning candidates for a number of disorders were also significantly enriched for known psychiatric medications or therapies considered in clinical trials. For example, candidates for schizophrenia were enriched for antipsychotics, while those for bipolar disorder were enriched for both antipsychotics and antidepressants. These findings provide support for the usefulness of GWAS data in guiding drug discovery.

    更新日期:2017-08-23
  • Selective attention within the foveola
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-14
    Martina Poletti, Michele Rucci, Marisa Carrasco

    Efficient control of attentional resources and high-acuity vision are both fundamental for survival. Shifts in visual attention are known to covertly enhance processing at locations away from the center of gaze, where visual resolution is low. It is unknown, however, whether selective spatial attention operates where the observer is already looking—that is, within the high-acuity foveola, the small yet disproportionally important rod-free region of the retina. Using new methods for precisely controlling retinal stimulation, here we show that covert attention flexibly improves and speeds up both detection and discrimination at loci only a fraction of a degree apart within the foveola. These findings reveal a surprisingly precise control of attention and its involvement in fine spatial vision. They show that the commonly studied covert shifts of attention away from the fovea are the expression of a global mechanism that exerts its action across the entire visual field.

    更新日期:2017-08-23
  • Cerebellar granule cell replenishment postinjury by adaptive reprogramming of Nestin+ progenitors
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-14
    Alexandre Wojcinski, Andrew K Lawton, N Sumru Bayin, Zhimin Lao, Daniel N Stephen, Alexandra L Joyner

    Regeneration of several organs involves adaptive reprogramming of progenitors, but the intrinsic capacity of the developing brain to replenish lost cells remains largely unknown. Here we found that the developing cerebellum has unappreciated progenitor plasticity, since it undergoes near full growth and functional recovery following acute depletion of granule cells, the most plentiful neuron population in the brain. We demonstrate that following postnatal ablation of granule cell progenitors, Nestin-expressing progenitors, specified during mid-embryogenesis to produce astroglia and interneurons, switch their fate and generate granule neurons in mice. Moreover, Hedgehog signaling in two Nestin-expressing progenitor populations is crucial not only for the compensatory replenishment of granule neurons but also for scaling interneuron and astrocyte numbers. Thus, we provide insights into the mechanisms underlying robustness of circuit formation in the cerebellum and speculate that adaptive reprogramming of progenitors in other brain regions plays a greater role than appreciated in developmental regeneration.

    更新日期:2017-08-23
  • Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-07
    Daisuke Ibi, Mario de la Fuente Revenga, Nebojsa Kezunovic, Carolina Muguruza, Justin M Saunders, Supriya A Gaitonde, José L Moreno, Maryum K Ijaz, Vishaka Santosh, Alexey Kozlenkov, Terrell Holloway, Jeremy Seto, Aintzane García-Bea, Mitsumasa Kurita, Grace E Mosley, Yan Jiang, Daniel J Christoffel, Luis F Callado, Scott J Russo, Stella Dracheva, Juan F López-Giménez, Yongchao Ge, Carlos R Escalante, J Javier Meana, Schahram Akbarian, George W Huntley, Javier González-Maeso

    Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.

    更新日期:2017-08-23
  • Structure in neural population recordings: an expected byproduct of simpler phenomena?
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-08-07
    Gamaleldin F Elsayed, John P Cunningham

    Structure in neural population recordings: an expected byproduct of simpler phenomena? Nature Neuroscience, Published online: 7 August 2017; doi:10.1038/nn.4617 To what extent are population-level results an expected byproduct of simpler structure already known to exist in single neurons? Conventional controls are insufficient to perform this critical investigation. The authors developed a methodological framework to test the significance of population-level studies and apply it to prefrontal and motor cortices.

    更新日期:2017-08-23
  • Zika virus directly infects peripheral neurons and induces cell death
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-31
    Yohan Oh, Feiran Zhang, Yaqing Wang, Emily M Lee, In Young Choi, Hotae Lim, Fahimeh Mirakhori, Ronghua Li, Luoxiu Huang, Tianlei Xu, Hao Wu, Cui Li, Cheng-Feng Qin, Zhexing Wen, Qing-Feng Wu, Hengli Tang, Zhiheng Xu, Peng Jin, Hongjun Song, Guo-li Ming, Gabsang Lee

    Zika virus infection is associated with neurological disorders, yet few studies have directly examined its impact on the peripheral nervous system. Oh et al. show that Zika virus can infect peripheral neurons in the mouse in vivo, as well as human peripheral neurons in vitro, leading to increased cell death and transcriptional dysregulation.

    更新日期:2017-08-20
  • Gut microbiota is critical for the induction of chemotherapy-induced pain
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-17
    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

    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.

    更新日期:2017-08-20
  • Adults with autism overestimate the volatility of the sensory environment
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-31
    Rebecca P Lawson, Christoph Mathys, Geraint Rees

    Insistence on sameness and intolerance of change are among the diagnostic criteria for autism spectrum disorder (ASD), but little research has addressed how people with ASD represent and respond to environmental change. Here, behavioral and pupillometric measurements indicated that adults with ASD are less surprised than neurotypical adults when their expectations are violated, and decreased surprise is predictive of greater symptom severity. A hierarchical Bayesian model of learning suggested that in ASD, a tendency to overlearn about volatility in the face of environmental change drives a corresponding reduction in learning about probabilistically aberrant events, thus putatively rendering these events less surprising. Participant-specific modeled estimates of surprise about environmental conditions were linked to pupil size in the ASD group, thus suggesting heightened noradrenergic responsivity in line with compromised neural gain. This study offers insights into the behavioral, algorithmic and physiological mechanisms underlying responses to environmental volatility in ASD.

    更新日期:2017-08-20
  • Dorsal hippocampus contributes to model-based planning
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-31
    Kevin J Miller, Matthew M Botvinick, Carlos D Brody

    Planning can be defined as action selection that leverages an internal model of the outcomes likely to follow each possible action. Its neural mechanisms remain poorly understood. Here we adapt recent advances from human research for rats, presenting for the first time an animal task that produces many trials of planned behavior per session, making multitrial rodent experimental tools available to study planning. We use part of this toolkit to address a perennially controversial issue in planning: the role of the dorsal hippocampus. Although prospective hippocampal representations have been proposed to support planning, intact planning in animals with damaged hippocampi has been repeatedly observed. Combining formal algorithmic behavioral analysis with muscimol inactivation, we provide causal evidence directly linking dorsal hippocampus with planning behavior. Our results and methods open the door to new and more detailed investigations of the neural mechanisms of planning in the hippocampus and throughout the brain.

    更新日期:2017-08-20
  • Necroptosis activation in Alzheimer's disease
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-24
    Antonella Caccamo, Caterina Branca, Ignazio S Piras, Eric Ferreira, Matthew J Huentelman, Winnie S Liang, Ben Readhead, Joel T Dudley, Elizabeth E Spangenberg, Kim N Green, Ramona Belfiore, Wendy Winslow, Salvatore Oddo

    Alzheimer's disease (AD) is characterized by severe neuronal loss; however, the mechanisms by which neurons die remain elusive. Necroptosis, a programmed form of necrosis, is executed by the mixed lineage kinase domain-like (MLKL) protein, which is triggered by receptor-interactive protein kinases (RIPK) 1 and 3. We found that necroptosis was activated in postmortem human AD brains, positively correlated with Braak stage, and inversely correlated with brain weight and cognitive scores. In addition, we found that the set of genes regulated by RIPK1 overlapped significantly with multiple independent AD transcriptomic signatures, indicating that RIPK1 activity could explain a substantial portion of transcriptomic changes in AD. Furthermore, we observed that lowering necroptosis activation reduced cell loss in a mouse model of AD. We anticipate that our findings will spur a new area of research in the AD field focused on developing new therapeutic strategies aimed at blocking its activation.

    更新日期:2017-08-20
  • Functional dissection of signal and noise in MT and LIP during decision-making
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-24
    Jacob L Yates, Il Memming Park, Leor N Katz, Jonathan W Pillow, Alexander C Huk

    During perceptual decision-making, responses in the middle temporal (MT) and lateral intraparietal (LIP) areas appear to map onto theoretically defined quantities, with MT representing instantaneous motion evidence and LIP reflecting the accumulated evidence. However, several aspects of the transformation between the two areas have not been empirically tested. We therefore performed multistage systems identification analyses of the simultaneous activity of MT and LIP during individual decisions. We found that monkeys based their choices on evidence presented in early epochs of the motion stimulus and that substantial early weighting of motion was present in MT responses. LIP responses recapitulated MT early weighting and contained a choice-dependent buildup that was distinguishable from motion integration. Furthermore, trial-by-trial variability in LIP did not depend on MT activity. These results identify important deviations from idealizations of MT and LIP and motivate inquiry into sensorimotor computations that may intervene between MT and LIP.

    更新日期:2017-08-20
  • Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-17
    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, Autism Sequencing Consortium, 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 = 5.4 × 10−3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

    更新日期:2017-08-20
  • A circuit-based mechanism underlying familiarity signaling and the preference for novelty
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-17
    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. In mice, optogenetic silencing of IPN neurons increases salience of and interaction with familiar stimuli without affecting novelty responses, whereas photoactivation of the same neurons reduces exploration of novel stimuli mimicking familiarity. Bidirectional control of NP by the IPN depends on familiarity signals and novelty signals arising from excitatory habenula and dopaminergic ventral tegmentum inputs, which activate and reduce IPN activity, respectively. These results demonstrate that familiarity signals through unique IPN circuitry that opposes novelty seeking to control NP.

    更新日期:2017-08-20
  • C9orf72 expansion disrupts ATM-mediated chromosomal break repair
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-17
    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. We reveal that defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Virus-mediated expression of C9orf72-related RNA and dipeptide repeats in the mouse central nervous system increases double strand breaks and ATM defects and triggers neurodegeneration. These findings identify R-loops, double strand breaks and defective ATM-mediated repair as pathological consequences of C9orf72 expansions and suggest that C9orf72-linked neurodegeneration is driven at least partly by genomic instability.

    更新日期:2017-08-20
  • Neural reactivations during sleep determine network credit assignment
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-10
    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. Decoupling of spiking to slow oscillations using optogenetic methods eliminated rescaling. Thus, our results suggest that coordinated firing during sleep is essential for establishing sparse activation patterns that reflect the causal neuron-behavior relationship.

    更新日期:2017-08-20
  • High-dimensional, single-cell characterization of the brain's immune compartment
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-24
    Ben Korin, Tamar L Ben-Shaanan, Maya Schiller, Tania Dubovik, Hilla Azulay-Debby, Nadia T Boshnak, Tamar Koren, Asya Rolls

    Korin et al. use CyTOF mass cytometry to characterize immune cell populations in the naive mouse brain (parenchyma, choroid plexus and meninges). This single-cell analysis of cell-surface proteins reveals the presence and phenotype of distinctive immune populations in the mouse brain compartment.

    更新日期:2017-08-20
  • Helping EGFR inhibition to block cancer
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-26
    Rolf Warta, Christel Herold-Mende

    Effectiveness of EGFR treatment is impaired through an early adaptive response. TNF–JNK–Axl–ERK signaling contributes to this primary resistance to EGFR inhibition and might serve as novel target to improve EGFR inhibition.

    更新日期:2017-07-28
  • VIP cortical conductors set the tone for chronic pain
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-26
    Erika K Harding, Michael W Salter

    Loss of inhibition in a circuit in the primary somatosensory cortex that controls the activity of layer 5 neurons drives pain hypersensitivity. Restoring this inhibition resets the inhibitory–excitatory balance, producing analgesia.

    更新日期:2017-07-28
  • Is the boss watching?
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-26
    Amit Etkin

    A combination of computational modeling, neuroimaging and a causal manipulation of brain activity in humans reveals how the brain represents beliefs about how our choices will affect those of others we interact with.

    更新日期:2017-07-28
  • CREATEd viruses go global
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-07-26
    Keisuke Yonehara, Botond Roska

    A Cre-dependent capsid selection method, CREATE, was used to produce adeno-associated viral vectors that allow gene delivery to the entire central and peripheral nervous systems, with multicolor labeling of single cells.

    更新日期:2017-07-28
  • Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains
    Nat. Neurosci. (IF 17.839) Pub Date : 2017-06-19
    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. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.

    更新日期:2017-07-28
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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