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 压力通过激活皮质激素来影响综合的激素，自主和行为反应 下丘脑（PVN）的室室核中释放因子（CRF）神经元。而CRF是 发给垂体以启动下丘脑 - 垂体 - 肾上腺（HPA）轴活动，我们发现了一个新的 CRF在PVN中作用的机制。 PVN中先前未表征的神经元种群 Express CRFR1，CRF的主要接收器，使其可以响应局部释放的肽。电路水平 分析表明，PVN CRFR1神经元在CRF神经元上恢复了突触，以提供对局部反馈 HPA轴，以及在磁性和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，在幼稚的动物中，这种局部微电路的功能 抑制HPA轴活性，与电生理学证据一致，表明CRFR1神经元可抑制 相邻神经元的突触。但是，在慢性应激的背景下，需要pVN内信号传导才能 保持HPA轴活性，表明CRFR1神经元潜在的CRF神经元活性。该提议是 专注于通过在PVN中建立CRF-CRFR1微电路的结构来解决这一悖论， 确定CRFR1神经元在塑造HPA轴响应和自主语气中的重要性 急性应力反应的反应，并探索微电路在慢性应激后如何变化以颠倒其影响 在HPA轴上。为了解决我们的假设，我们使用遗传引导的光学遗传学表达， 化学生成和病毒追踪工具来定义该新人群的解剖学和功能重要性 神经元。成功完成本提案中描述的实验将定义HPA的新方面 轴心调节和PVN输出的协调，这对于维持适当的压力至关重要 回答。这些信息将填补我们对神经电路如何影响PVN的空白 编排压力反应。此外，这种机制的失败可能解释了HPA轴如何 在抑郁症等疾病的一部分中变得过度活跃，以及在其他疾病中的低血管 暴露于强烈或慢性应激后，创伤应激障碍（PTSD）。