The Role of CHD7 in ACC neurons

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程序构成了主要障碍。长期的 我们研究的目标是阐明关于分子签名和突触的知识差距 控制应激反应的脑神经回路的特性。表观遗传基因调控已经出现 作为神经回路动力学和行为改变的关键分子驱动因素。我们的初步数据 提示CHD7，一种主要在胚胎大脑中表达的染色质重塑因子，仍然丰富 在成年小鼠前扣带回(ACC)2/3层内的兴奋性神经元中。行政协调委员会，一个地区 在啮齿动物的内侧前额叶皮质内，在处理与情绪有关的信息和 调节与焦虑相关的行为。虽然CHD7在神经发育中的关键作用一直很好- 据文献记载，它在有丝分裂后神经元中的功能尚不清楚。我们的数据表明，有丝分裂后缺失的 来自ACC兴奋性神经元的CHD7(简称Chd7cKO)显著降低了先天焦虑水平。在……里面 此外，暴露于环境应激源的Chd7cKO小鼠的ACC中的神经元活动显著 低于野生型(WT)小鼠。有趣的是，这些现象只在男性身上观察到(而不是 雌性)小鼠，表明CHD7功能的性别二型性。我们的数据提供了第一个证据表明 CHD7在有丝分裂后ACC神经元调节神经元活动和先天焦虑中的重要作用。我们的初选 目的是询问CHD7在控制复杂的基因网络调节突触中的作用 ACC神经元及其下游靶点的活性。在这份提案中，我们将首先确定CHD7如何 调节终纹床核ACC神经元及其下游靶点的活动 (英国国家安全局)。我们的初步数据表明，CHD7在维持正常的神经元活动中起着关键作用。 ACC-BNST途径。接下来，我们将使用无偏见的高吞吐量方法来确定CHD7 控制有丝分裂后神经元中的复杂基因网络，以调节活性依赖的基因转录。最后， 我们将研究CHD7活性是如何由参与G蛋白信号转导的相互作用伙伴调节的。 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。 对压力做出反应的回路。这些信息最终将有助于确定复杂的基础机制 人类的情绪行为。

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.