Intra-PVN CRF signaling control of HPA axis activity and autonomic tone

PVN 内 CRF 信号控制 HPA 轴活动和自主神经张力

• 批准号: 9519214
• 负责人: NICHOLAS J JUSTICE
• 金额: $ 36.88万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-17 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9519214
• 关键词: Acute; Address; Affect; Anatomy; Animals; Architecture; Back; Brain; Cardiovascular Diseases; Cells; Chronic stress; Complement; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Coupled; Data; Disease; Electrophysiology (science); Exposure to; Failure; Feedback; Genetic; Glucocorticoids; Grant; Hormonal; Hormones; Hyperactive behavior; Hypothalamic structure; Inhibitory Synapse; Justice; Maintenance; Measures; Mediating; Mental Depression; Metabolic Diseases; Molecular; Monitor; Neurons; Neurosecretory Systems; Obesity; Output; Pattern; Peptides; Pituitary Gland; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Preparation; Psyche structure; Rabies; Regulation; Rest; Role; Shapes; Signal Transduction; Site; Slice; Stress; Synapses; Transgenic Organisms; Viral; acute stress; behavioral response; biological adaptation to stress; cell type; experimental study; gain of function; gamma-Aminobutyric Acid; hypothalamic-pituitary-adrenal axis; indexing; insight; loss of function; magnocellular; median eminence; neural circuit; neuropsychiatric disorder; novel; optogenetics; paraventricular nucleus; release factor; response; stress resilience; tool

Project Summary Stress induces an integrated hormonal, autonomic, and behavioral response by activating Corticotropin Releasing Factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVN). While CRF is released to the pituitary to initiate Hypothalamic-Pituitary-Adrenal (HPA) axis activity, we have discovered a new mechanism in which CRF acts in the PVN. A previously uncharacterized population of neurons in the PVN express CRFR1, the primary receptor for CRF, allowing them to respond to locally released peptide. Circuit level analysis suggests that PVN CRFR1 neurons synapse back on CRF neurons to provide local feedback to the HPA axis, and synapse on magnocellular and pre-autonomic neurons to coordinate neuroendocrine and autonomic responses. Our preliminary data indicate that in naïve animals, this local microcircuit functions to inhibit HPA axis activity, consistent with electrophysiological evidence that CRFR1 neurons make inhibitory synapses on neighboring neurons. However, in the context of chronic stress, intra-PVN signaling is required to maintain HPA axis activity, indicating that CRFR1 neurons potentiate CRF neuron activity. This proposal is focused on resolving this paradox by establishing the architecture of a CRF-CRFR1 microcircuit in the PVN, determining the importance of CRFR1 neurons in shaping HPA axis responses and autonomic tone in the context of acute stress responses, and exploring how the microcircuit changes after chronic stress to invert its influence on the HPA axis. In order to address our hypotheses, we use genetically guided expression of optogenetic, chemogenetic, and viral tracing tools to define the anatomical and functional importance of this new population of neurons. Successful completion of the experiments described in this proposal will define a new facet of HPA axis regulation and coordination of PVN output that is essential for the maintenance of appropriate stress responses. This information will fill a gap in our understanding of how neural circuits impinge on the PVN to orchestrate the stress response. Moreover, failure of this mechanism potentially explains how the HPA axis becomes hyperactive in a subset of diseases such as depression, and hypoactive in other diseases like Post- Traumatic Stress Disorder (PTSD), after exposure to intense or chronic stress.

项目摘要 应激通过激活促肾上腺皮质激素诱导综合的激素、自主神经和行为反应 下丘脑室旁核（PVN）中的CRF神经元。虽然CRF是 释放到垂体启动下丘脑-垂体-肾上腺（HPA）轴活动，我们发现了一个新的 CRF作用于PVN的机制。PVN中以前未表征的神经元群体 表达CRF的主要受体CRFR 1，使它们能够对局部释放的肽做出反应。电路级 分析表明，PVN CRFR 1神经元突触回到CRF神经元上，以提供局部反馈。 HPA轴，以及大细胞和前自主神经元上的突触，以协调神经内分泌和 自主反应我们的初步数据表明，在幼稚动物中，这种局部微电路的功能是 抑制HPA轴活性，这与CRFR 1神经元抑制HPA轴活性电生理学证据一致， 神经突触的连接然而，在慢性应激的情况下，需要PVN内信号传导， 维持HPA轴活性，表明CRFR 1神经元增强CRF神经元活性。这项建议是 专注于通过在PVN中建立CRF-CRFR 1微电路的架构来解决这个矛盾， 确定CRFR 1神经元在形成HPA轴反应和自主神经张力中的重要性 急性应激反应，并探讨如何微电路的变化后，慢性应激，以扭转其影响 在HPA轴上。为了解决我们的假设，我们使用遗传引导的光遗传学表达， 化学遗传学和病毒追踪工具，以确定这一新群体的解剖学和功能重要性 的神经元。成功完成本提案中所述的实验将定义HPA的一个新方面 PVN输出的轴调节和协调对于维持适当的应力至关重要 应答这些信息将填补我们对神经回路如何影响PVN的理解中的空白， 协调压力反应此外，这种机制的失败可能解释了HPA轴如何 在抑郁症等疾病的子集中变得过度活跃，在其他疾病中变得功能减退，如后抑郁症。 创伤性应激障碍（PTSD），暴露于强烈或慢性压力后。