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

描述(申请人提供)：人们普遍认识到，控制应激激素功能的大脑系统的失调可能是导致严重抑郁症和其他与应激相关的疾病状态的基础。内侧前额叶皮质(MPFC)和海马体结构(HF)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的情绪和神经内分泌紊乱有关，也与慢性应激动物研究有关。多年来，由于无法揭示慢性应激后mPFC和HF抑制影响的复杂神经回路和机制，针对神经内分泌系统的干预措施一直缺乏进展。我们最近在终纹床核(ABST)的前部发现了一个离散的GABA能细胞群，作为边缘皮质和下丘脑室旁核(PVH)之间的双突触中继，并能够整合这些在急性情绪应激时对HPA输出的应激抑制影响，使我们能够直接研究这一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mPFC的神经可塑性(即树突/轴突收缩、突触/终末丢失)通过减少它们的神经支配，导致它们对HPA轴的正常抑制作用被破坏。 关键的双突触抑制继电器(例如，涉及Abst)到PVH。目的1将评估慢性可变应激暴露后HPA轴改变所涉及的这一新通路的参与，免疫毒素消融这些回路中的关键GABA能继电器将测试这一通路是否参与慢性应激诱导的内分泌改变。目的2将利用高分辨率显微镜、数字重建和体视学来评估慢性可变应激后mPFC/HF神经元的结构可塑性(树突、脊椎密度、轴突终末改变)，该结构针对HPA轴修饰所涉及的回路。目的3将测试阻断mPFC/HF中的GC受体是否会阻止电路特异性神经可塑性，进而防止慢性可变应激后HPA轴的过度活动。这些研究有望(A)确定慢性可变应激后HPA抑制影响的撤销所涉及的抑制性回路中断的基础，以及(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。希望在这项建议中识别新的神经解剖学靶点和潜在的细胞过程将有助于寻找更有效的应激相关精神和全身疾病的治疗方法。

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.