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基本了解有限对开发治疗精神障碍的有效临床应用构成了主要障碍。长期来看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大脑神经元回路的特性。表观遗传基因调控已经出现作为神经元回路动力学和行为变化的关键分子驱动因素。我们的初步数据表明 CHD7（一种主要在胚胎大脑中表达的染色质重塑因子）仍然富集成年小鼠前扣带皮层 (ACC) 2/3 层的兴奋性神经元。 ACC，一个地区在啮齿类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相关的行为。虽然 CHD7 在神经发育过程中的关键作用已被充分证实据记载，其在有丝分裂后神经元中的功能仍不清楚。我们的数据表明有丝分裂后删除来自 ACC 兴奋性神经元的 Chd7（称为 Chd7cKO）显着降低了先天焦虑水平。在此外，暴露于环境应激源的 Chd7cKO 小鼠 ACC 中的神经元活动显着增加低于野生型（WT）小鼠。有趣的是，这些现象仅在男性中观察到（而不是在男性中）雌性）小鼠，表明 CHD7 功能的性别二态性。我们的数据提供了第一个证据表明 CHD7 在有丝分裂后 ACC 神经元中在调节神经元活动和先天性焦虑中发挥重要作用。我们的主要目的是探究 CHD7 在控制复杂基因网络以调节突触中的作用 ACC 神经元及其下游目标的活动。在这个提案中，我们将首先确定CHD7如何调节终纹床核中 ACC 神经元及其下游靶标的活动（BNST）。我们的初步数据表明，CHD7 在维持适当的神经元活动中发挥着关键作用 ACC-BNST途径。接下来，我们将使用无偏高通量方法来确定 CHD7 控制有丝分裂后神经元中的复杂基因网络，以调节活性依赖性基因转录。最后，我们将研究 CHD7 活性如何受到参与 G 蛋白信号传导的相互作用伙伴的调节。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线索。对压力做出反应的电路。这些信息最终将有助于定义复杂的机制人类的情绪行为。