The Role of CHD7 in ACC neurons

CHD7 在 ACC 神经元中的作用

基本信息

批准号：
10511885
负责人：
KAI JIAO
金额：
$ 68.99万
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/10511885
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 Protein alpha Subunits, Gs GTP-Binding Proteins Gene Expression Gene Expression Regulation Genetic Transcription Goals Human Individual Knowledge Light 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-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 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理解有限为开发有效治疗精神障碍的有效临床应用的主要障碍。长期我们研究的目标是阐明有关分子特征和突触的知识差距控制压力反应的脑神经元电路的特性。表观遗传基因调节已经出现作为神经元电路动力学和行为变化的关键分子驱动器。我们的初步数据建议CHD7是主要在胚胎大脑中表达的染色质复制因子，保持富集在成年小鼠前扣带回皮层（ACC）的2/3层内的兴奋性神经元中。 ACC，一个地区在啮齿动物的内侧前额叶皮层中，在处理与情绪相关的信息和调节与焦虑有关的行为。尽管神经发育过程中CHD7的关键作用一直很好有记录，其在有丝分裂后神经元中的功能尚不清楚。我们的数据表明，有丝分裂后删除 ACC兴奋性神经元（称为CHD7CKO）的CHD7大大降低了先天焦虑水平。在此外，暴露于环境压力源的CHD7CKO小鼠ACC中的神经元活性显着低于野生型（WT）小鼠的低。有趣的是，这些现象仅在男性中观察到雌性）小鼠，表明CHD7功能的性二态性。我们的数据提供了第一个证据，表明 CHD7在有缺血后ACC神经元中的重要作用在调节神经元活动和先天焦虑中。我们的主要目标是询问CHD7在控制复杂基因网络以调节突触的角色 ACC神经元及其下游靶标的活动。在此提案中，我们将首先确定CHD7如何调节ACC神经元及其下游靶的活性（BNST）。我们的初步数据表明，CHD7在保持适当的神经元活动中起着至关重要的作用 ACC-BNST途径。接下来，我们将使用公正的高通量方法来确定CHD7的方式控制有丝分裂后神经元中复杂的基因网络，以调节活性依赖性基因转录。最后，我们将研究CHD7活性如何受到与G蛋白信号传导有关的相互作用伴侣的调节。如果成功，我们的研究将为神经元的分子基础和神经生理学提供新的启示应对压力的电路。这些信息最终将有助于定义复杂的机制人类的情感行为。