Circuit and cellular mechanisms of chronic stress-induced HPA axis hyperactivity

描述（由申请人提供）：人们普遍认识到，控制应激激素功能的脑系统的失调可能是严重抑郁症和其他应激相关疾病状态的发展的基础。内侧前额叶皮质（mPFC）和海马结构（HF）是负性调节下丘脑-垂体-肾上腺（HPA）轴，其功能障碍与抑郁症的情绪和神经内分泌紊乱以及慢性应激的动物研究有关。多年来，在开发针对神经内分泌系统的干预措施方面一直缺乏进展，这是由于无法解开慢性应激后mPFC和HF抑制影响撤回的复杂神经回路和机制。我们最近在终纹床核（aBST）的前亚部鉴定了一个离散的GABA能细胞群，作为边缘皮质和室旁下丘脑核（PVH）之间的双突触中继，并且能够在急性情绪应激期间整合这些应激抑制对HPA输出的影响，使我们能够直接检查这种新途径在控制抑郁症相关神经内分泌变化中的作用。我们假设慢性应激诱导的神经可塑性（即，树突/轴突回缩，突触/终末丢失）通过减少其神经支配，导致其对HPA轴的正常抑制作用中断 关键的双突触抑制中继（例如，涉及aBST）到PVH。目的1将评估慢性可变应激暴露后HPA轴修饰中涉及的这种新回路的参与，并且这些回路中关键GABA能中继的免疫毒素消融将测试慢性应激诱导的内分泌改变中该通路的参与。目标2将利用高分辨率显微镜、数字重建和体视学评估mPFC/HF神经元中的结构可塑性（树突、棘密度、轴突末端改变），特别是慢性可变应力后涉及HPA轴修饰的回路。目的3将测试在慢性可变应激后，阻断mPFC/HF中的GC受体是否会阻止回路特异性神经可塑性，进而防止HPA轴过度活跃。这些研究有望（a）确定慢性可变应激后HPA抑制作用消退所涉及的抑制回路中断的基础，（B）评估边缘皮质神经可塑性与慢性应激相关的内分泌异常之间的关系。我们希望，新的神经解剖学目标和潜在的细胞过程的识别，在这个建议将通知寻找更有效的治疗与压力有关的精神和系统性疾病。 公共卫生相关性：虽然人们普遍认为，控制应激激素功能的脑系统失调可能对理解重度抑郁症和其他应激相关疾病状态的病理生理学很重要，但其潜在机制仍然难以捉摸。该提议将（1）利用动物研究来显著增强我们对调节应激反应的脑回路组织的理解，以及（2）将有助于识别抑郁相关内分泌变化发展的新解剖靶点和细胞过程。在这样做的过程中，希望这些信息将有助于开发更有效的治疗与压力有关的精神和系统性疾病。

DESCRIPTION (provided by applicant): It is widely appreciated that dysregulation of brain systems controlling stress hormone function may underlie the development of major depression, and other stress-related disease states. The medial prefrontal cortex (mPFC) and hippocampal formation (HF) are known to negatively regulate the hypothalamo-pituitary-adrenal (HPA) axis, and their dysfunction is implicated in the mood and neuroendocrine disturbances in depression and in animal studies of chronic stress. Over the years, progress in developing interventions that target neuroendocrine systems has been lacking, due to the inability to unravel the complex neurocircuitry and mechanisms underlying the withdrawal of mPFC and HF restraining influences following chronic stress. Our recent identification of a discrete GABAergic cell group in the anterior subdivision of the bed nucleus of the stria terminalis (aBST), serves as a disynaptic relay between limbic cortical and the paraventricular hypothalamic nucleus (PVH), and is capable of integrating these stress-inhibitory influences over HPA output during acute emotional stress, allows us to directly examine the role of this novel pathway in controlling depression-related neuroendocrine changes. We hypothesize that chronic stress-induced neuroplasticity (i.e., dendritic/axonal retraction, synapse/terminal loss) in mPFC leads to a disruption in their normal restraining influences on the HPA axis, via decreasing their innervation of key disynaptic inhibitory relays (e.g., involving aBST) to PVH. Aim 1 will assess the involvement of this new circuit implicated in HPA axis modifications following chronic variable stress exposure, and immunotoxin ablation of key GABAergic relays in these circuits will test the involvement of this pathway in chronic stress-induced endocrine alterations. Aim 2 will utilize high- resolution microscopy, digital reconstructions, and stereology for the assessment of structural plasticity (dendritic, spine density, axon terminal alterations) in mPFC/HF neurons, specific to the circuitry implicated in HPA axis modifications, following chronic variable stress. Aim 3 will test whether blockade of GC receptors in mPFC/HF prevents circuit-specific neuroplasticity, and, in turn prevent HPA axis hyperactivity, following chronic variable stress. These studies are expected to (a) define a basis for inhibitory circuit disruptions implicated in the withdrawal of HPA restraining influences following chronic variable stress, and (b) to assess the relationship between limbic cortical neuroplasticity and the endocrine abnormalities associated with chronic stress. It is hoped that identification of novel neuroanatomical targets and underlying cellular processes in this proposal will inform the search for more effective treatments for stress-related psychiatric and systemic disorders. PUBLIC HEALTH RELEVANCE: While it is widely hypothesized that dysregulation of brain systems controlling stress hormone function may be important for understanding the pathophysiology of major depression and other stress-related disease states, their underlying mechanisms have remained elusive. This proposal will (1) utilize animal studies to significantly enhance our understanding of the organization of brain circuitry regulating the stress response, and (2), will help to identify novel anatomical targets and cellular processes underlying the development of depression- related endocrine changes. In doing so, it is hoped that this information will help in the development of more effective treatments of stress-related psychiatric and systemic illnesses.