Abstract：
:In Huntington's disease (HD), expansion of CAG codons in the huntingtin gene (HTT) leads to the aberrant formation of protein aggregates and the differential degeneration of striatal medium spiny neurons (MSNs). Modeling HD using patient-specific MSNs has been challenging, as neurons differentiated from induced pluripotent stem cells are free of aggregates and lack an overt cell death phenotype. Here we generated MSNs from HD patient fibroblasts through microRNA-based direct neuronal conversion, bypassing the induction of pluripotency and retaining age signatures of the original fibroblasts. We found that patient MSNs consistently exhibited mutant HTT (mHTT) aggregates, mHTT-dependent DNA damage, mitochondrial dysfunction and spontaneous degeneration in culture over time. We further provide evidence that erasure of age stored in starting fibroblasts or neuronal conversion of presymptomatic HD patient fibroblasts results in differential manifestation of cellular phenotypes associated with HD, highlighting the importance of age in modeling late-onset neurological disorders.
journal_name
Nat Neuroscijournal_title
Nature neuroscienceauthors
Victor MB,Richner M,Olsen HE,Lee SW,Monteys AM,Ma C,Huh CJ,Zhang B,Davidson BL,Yang XW,Yoo ASdoi
10.1038/s41593-018-0075-7subject
Has Abstractpub_date
2018-03-01 00:00:00pages
341-352issue
3eissn
1097-6256issn
1546-1726pii
10.1038/s41593-018-0075-7journal_volume
21pub_type
杂志文章abstract：:Breathing is a bilaterally synchronous behavior that relies on a respiratory rhythm generator located in the brainstem. An essential component of this generator is the preBötzinger complex (preBötC), which paces inspirations. Little is known about the developmental origin of the interneuronal populations forming the p...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2622
更新日期：2010-09-01 00:00:00
abstract：:Hippocampal CA1 pyramidal neurons have frequently been regarded as a homogeneous cell population in biophysical, pharmacological and modeling studies. We found robust differences between pyramidal neurons residing in the deep and superficial CA1 sublayers in rats. Compared with their superficial peers, deep pyramidal ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2894
更新日期：2011-08-07 00:00:00
abstract：:In mammals, olfaction is often used to distinguish individuals on the basis of their unique odor types (genetically programmed body odors). Parental-offspring recognition behavior is mediated, in part, by learning and processing of different odor types and is crucial for reproductive success. Maternal recognition beha...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2550
更新日期：2010-06-01 00:00:00
abstract：:The identification of distinct cell types in the basal ganglia has been critical to our understanding of basal ganglia function and the treatment of neurological disorders. The external globus pallidus (GPe) is a key contributor to motor suppressing pathways in the basal ganglia, yet its neuronal heterogeneity has rem...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.4559
更新日期：2017-06-01 00:00:00
abstract：:The output of cortical columns is routed to different downstream targets via distinct pathways: cortico-cortical and cortico-subcortical. It is as yet unclear what roles these pathways play in perception, and which cellular and circuit mechanisms regulate their gating. We recently showed that activation of the apical ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/s41593-020-0677-8
更新日期：2020-10-01 00:00:00
abstract：:Remembering a past experience can, surprisingly, cause forgetting. Forgetting arises when other competing traces interfere with retrieval and inhibitory control mechanisms are engaged to suppress the distraction they cause. This form of forgetting is considered to be adaptive because it reduces future interference. Th...
journal_title：Nature neuroscience
pub_type： 杂志文章
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更新日期：2015-04-01 00:00:00
abstract：:Neural stem and progenitor cells (NSCs/NPCs) give rise to neurons, astrocytes and oligodendrocytes. However, the mechanisms underlying the decision of a stem cell to either self-renew or differentiate are incompletely understood. We demonstrate here that Fbw7 (F-box and WD repeat domain containing-7), the substrate re...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2644
更新日期：2010-11-01 00:00:00
abstract：:Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in viv...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2862
更新日期：2011-07-10 00:00:00
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journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/85191
更新日期：2001-03-01 00:00:00
abstract：:Fear renewal, a widely pursued model of post-traumatic stress disorder and phobias, refers to the context-specific relapse of conditioned fear after extinction. However, its molecular mechanisms are largely unknown. We found that renewal-inducing stimuli, generally believed to be insufficient to induce synaptic plasti...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3491
更新日期：2013-10-01 00:00:00
abstract：:Histone deacetylases (HDACs) are major epigenetic regulators. We show that HDAC1 and HDAC2 functions are critical for myelination of the peripheral nervous system. Using mouse genetics, we have ablated Hdac1 and Hdac2 specifically in Schwann cells, resulting in massive Schwann cell loss and virtual absence of myelin i...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2762
更新日期：2011-04-01 00:00:00
abstract：:Shared neural variability is ubiquitous in cortical populations. While this variability is presumed to arise from overlapping synaptic input, its precise relationship to local circuit architecture remains unclear. We combine computational models and in vivo recordings to study the relationship between the spatial stru...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.4433
更新日期：2017-01-01 00:00:00
abstract：:Sensorimotor integration is crucial to perception and motor control. How and where this process takes place in the brain is still largely unknown. Here we analyze the cerebellar contribution to sensorimotor integration in the whisker system of mice. We identify an area in the cerebellum where cortical sensory and moto...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3773
更新日期：2014-09-01 00:00:00
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journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/72985
更新日期：2000-03-01 00:00:00
abstract：:We demonstrate a form of long-term depression (LTD) in the perirhinal cortex that relies on interaction between different glutamate receptors. Group II metabotropic glutamate (mGlu) receptors facilitated group I mGlu receptor-mediated increases in intracellular calcium. This facilitation plus NMDA receptor activation ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/72093
更新日期：2000-02-01 00:00:00
abstract：:Sensory systems create neural representations of environmental stimuli and these representations can be associated with other stimuli through learning. Are spike patterns the neural representations that get directly associated with reinforcement during conditioning? In the moth Manduca sexta, we found that odor presen...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2192
更新日期：2008-10-01 00:00:00
abstract：:Much of the information processing in the brain occurs at the level of local circuits; however, the mechanisms underlying their initial development are poorly understood. We sought to examine the early development and plasticity of local excitatory circuits in the optic tectum of Xenopus laevis tadpoles. We found that...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn2076
更新日期：2008-04-01 00:00:00
abstract：:Blood vessels in the nervous system have traditionally been considered neutral bystanders that only passively adapt their structure and function in response to the needs of neural cells. Emerging evidence suggests, however, that vessels and angiogenic molecules actively participate in the pathogenesis of neurological ...
journal_title：Nature neuroscience
pub_type： 杂志文章,评审
doi：10.1038/nn.2947
更新日期：2011-10-26 00:00:00
abstract：:Phosphoinositide 3 kinase enhancer (PIKE) is a recently identified nuclear GTPase that activates nuclear phosphoinositide 3-kinase (PI3 kinase). We have identified, cloned and characterized a new form of PIKE, designated PIKE-L, which, unlike the nuclear PIKE-S, localizes to both the cytoplasm and the nucleus. We demo...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1134
更新日期：2003-11-01 00:00:00
abstract：:Two studies in this issue show that the protein MeCP2, which is implicated in Rett syndrome, also critically regulates behavioral responses to psychostimulants. Although the two studies highlight different mechanisms of MeCP2 in regulating these behaviors, both underscore the importance of epigenetic mechanisms in est...
journal_title：Nature neuroscience
pub_type： 评论,新闻
doi：10.1038/nn0910-1039
更新日期：2010-09-01 00:00:00
abstract：:Neuroscientists increasingly analyze the joint activity of multineuron recordings to identify population-level structures believed to be significant and scientifically novel. Claims of significant population structure support hypotheses in many brain areas. However, these claims require first investigating the possibi...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.4617
更新日期：2017-09-01 00:00:00
abstract：:Nucleus accumbens (NAc) dopamine is widely implicated in mediating the reinforcing effects of drugs of abuse. However, the precise function of the NAc itself in drug self-administration has been difficult to establish. Here we show a neural double-dissociation of the behavioral processes that underlie cocaine self-adm...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1217
更新日期：2004-04-01 00:00:00
abstract：:Differentiation of CNS glia is regulated by Notch signaling through neuron-glia interaction. Here, we identified Delta/Notch-like EGF-related receptor (DNER), a neuron-specific transmembrane protein, as a previously unknown ligand of Notch during cellular morphogenesis of Bergmann glia in the mouse cerebellum. DNER bi...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1492
更新日期：2005-07-01 00:00:00
abstract：:Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose causes are still poorly understood. To identify additional genetic risk factors, we assessed the role of de novo mutations in ALS by sequencing the exomes of 47 ALS patients and both of their unaffected parents (n = 141 exomes). We fo...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3412
更新日期：2013-07-01 00:00:00
abstract：:Class I histone deacetylases (HDACs) Hdac1 and Hdac2 can associate together in protein complexes with transcriptional factors such as methyl-CpG-binding protein 2 (MeCP2). Given their high degree of sequence identity, we examined whether Hdac1 and Hdac2 were functionally redundant in mature mouse brain. We demonstrate...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.4395
更新日期：2016-11-01 00:00:00
abstract：:Active dendritic integration is thought to enrich the computational power of central neurons. However, a direct role of active dendritic processing in the execution of defined neuronal computations in intact neural networks has not been established. Here we used multi-site electrophysiological recording techniques to ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3565
更新日期：2013-12-01 00:00:00
abstract：:Every year in the United States, an estimated 500,000 babies are born preterm (before 37 completed weeks of gestation), and this number is rising, along with the recognition of brain injuries due to preterm delivery. A common underlying pathogenesis appears to be perinatal hypoxia induced by immature lung development,...
journal_title：Nature neuroscience
pub_type： 杂志文章,评审
doi：10.1038/nn.3604
更新日期：2014-03-01 00:00:00
abstract：:Precise apposition of pre- to postsynaptic specializations is required for optimal function of chemical synapses, but little is known about how it is achieved. At the skeletal neuromuscular junction, active zones (transmitter release sites) in the nerve terminal lie directly opposite junctional folds in the postsynapt...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/88414
更新日期：2001-06-01 00:00:00
abstract：:We examined enhancement of synaptic transmission by neurotrophins at the presynaptic level. In a synaptosomal preparation, brain-derived neurotrophic factor (BDNF) increased mitogen-activated protein (MAP) kinase-dependent synapsin I phosphorylation and acutely facilitated evoked glutamate release. PD98059, used to in...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/73888
更新日期：2000-04-01 00:00:00
abstract：:Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor-expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3625
更新日期：2014-02-01 00:00:00
