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

描述（由申请人提供）：人们普遍认为，控制应激激素功能的脑系统失调可能是重度抑郁症和其他应激相关疾病的发展基础。内侧前额叶皮层（mPFC）和海马形成（HF）被认为对下丘脑-垂体-肾上腺（HPA）轴具有负性调节作用，它们的功能障碍与抑郁症和慢性应激动物研究中的情绪和神经内分泌紊乱有关。多年来，由于无法揭示慢性应激后mPFC和HF抑制影响退出的复杂神经回路和机制，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。我们最近在终纹床核（aBST）的前分支中发现了一个离散的gaba能细胞群，作为边缘皮层和室旁下丘脑核（PVH）之间的突触传递，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，使我们能够直接研究这一新途径在控制抑郁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/轴突缩回，突触/终端丢失）在mPFC中通过减少其神经支配，导致其对中枢轴的正常抑制作用被破坏

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.