The Role of CHD7 in ACC neurons

CHD7 在 ACC 神经元中的作用

• 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
• 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

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理解有限 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 我们研究的目标是揭示关于分子特征和突触的知识差距， 控制对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器。我们的初步数据 提示主要在胚胎脑中表达的染色质重塑因子CHD 7仍然富集 在成年小鼠前扣带皮层（ACC）2/3层内的兴奋性神经元中。ACC，一个区域 在啮齿类动物的内侧前额叶皮层中，在处理与情绪有关的信息方面起着关键作用， 调节焦虑相关的行为虽然CHD 7在神经发育过程中的关键作用已经很好- 有文献记载，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，有丝分裂后缺失的 来自ACC兴奋性神经元的Chd 7（称为Chd 7 cKO）显著降低先天性焦虑水平。在 此外，暴露于环境应激物的Chd 7 cKO小鼠的ACC中的神经元活性显著降低。 低于野生型（WT）小鼠。有趣的是，这些现象只在男性中观察到（而不是在男性中观察到）。 雌性）小鼠，表明CHD 7功能的两性异形。我们的数据提供了第一个证据，表明 CHD 7在有丝分裂后ACC神经元中调节神经元活性和先天性焦虑中的重要作用。我们的首要 目的是询问CHD 7在控制复杂基因网络以调节突触中的作用。 ACC神经元及其下游靶点的活性。在这个建议中，我们将首先确定CHD 7如何 调节终纹床核中ACC神经元及其下游靶点的活性 （BNST）.我们的初步数据表明，CHD 7在维持正常的神经元活动中起着关键作用。 ACC-BNST通路。接下来，我们将使用无偏的高通量方法来确定CHD 7 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CHD 7的活性是如何通过参与G蛋白信号传导的相互作用伴侣来调节的。 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确定复杂的 人类的情感行为。