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The Role of CHD7 in ACC neurons

CHD7 在 ACC 神经元中的作用

基本信息

批准号：
10700139
负责人：
KAI JIAO
金额：
$ 69.95万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700139
关键词：
Adult Affect Anterior Anxiety Axon Behavior Behavioral Binding Sites Brain CHD7 gene Cell Nucleus ChIP-seq Chromatin Chromatin Remodeling Factor Complex Data Development Embryo Epigenetic Process Excitatory Synapse Exposure to Female GTP-Binding Proteins Gene Expression Gene Expression Regulation Genetic Transcription Goals Human Individual Knowledge Maps Medial Mental Health Mental disorders Molecular Molecular Profiling Moods Mus Neurons Nuclear Pathway interactions Play Prefrontal Cortex Process Property Regulation Research Rodent Role Sampling Signal Transduction Signaling Molecule Signaling Protein Stress Structure of terminal stria nuclei of preoptic region Synapses Testing Wild Type Mouse anxiety reduction anxiety-related behavior base behavioral response biological adaptation to stress cingulate cortex clinical application emotional behavior environmental stressor epigenetic regulation epigenome epigenomics excitatory neuron experience gene network improved male multiple omics neurodevelopment neuronal circuitry neurophysiology novel postmitotic response sexual dimorphism transcriptome

项目摘要

A limited fundamental understanding of the cellular and molecular mechanisms underlying complex behaviors poses a major barrier for development of effective clinical applications to treat mental disorders. The long-term goal of our research is to shed light on the gaps in knowledge regarding the molecular signatures and synaptic properties of brain neuronal circuits that control responses to stress. Epigenetic gene regulation has emerged as a key molecular driver underlying neuronal circuit dynamics and behavioral changes. Our preliminary data suggest that CHD7, a chromatin-remodeling factor primarily expressed in the embryonic brain, remains enriched in excitatory neurons within layer 2/3 of the anterior cingulate cortex (ACC) in adult mice. The ACC, a region within the medial prefrontal cortex in rodents, plays critical roles in processing mood-related information and modulating anxiety-related behaviors. While critical roles for CHD7 during neural development have been well- documented, its function in postmitotic neurons remains unclear. Our data suggest that postmitotic deletion of Chd7 from ACC excitatory neurons (referred to as Chd7cKO) significantly reduced innate anxiety levels. In addition, neuronal activity in the ACC of Chd7cKO mice exposed to an environmental stressor was significantly lower than that in wild type (WT) mice. Intriguingly, these phenomena were observed only in male (and not female) mice, indicating sexual dimorphism of CHD7 function. Our data provide the first evidence suggesting an essential role for CHD7 in postmitotic ACC neurons in regulating neuronal activity and innate anxiety. Our primary objectives are to interrogate the role of CHD7 in controlling a complex gene network to regulate the synaptic activity of ACC neurons and their downstream targets. In this proposal, we will first determine how CHD7 regulates the activity of ACC neurons and their downstream targets in the bed nucleus of the stria terminalis (BNST). Our preliminary data suggest that CHD7 plays a critical role in maintaining proper neuronal activity in the ACC-BNST pathway. Next, we will use unbiased high-throughput approaches to determine how CHD7 controls a complex gene network in postmitotic neurons to regulate activity-dependent gene transcription. Finally, we will investigate how CHD7 activity is regulated by an interacting partner that is involved in G protein signaling. If successful, our research will shed new light on the molecular underpinnings and neurophysiology of neuronal circuits that respond to stress. Such information will ultimately help define mechanisms underlying complex emotional behaviors in humans.

对复杂行为背后的细胞和分子机制的有限基本理解