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

慢性应激诱导的 HPA 轴过度活跃的回路和细胞机制

• 批准号: 8600188
• 负责人: JASON J RADLEY
• 金额: $ 36.97万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8600188
• 关键词: Ablation; Acute; Adrenal Glands; Adverse effects; Animals; Anterior; Atrophic; Brain; Cell physiology; Cells; Chronic; Chronic stress; Complement; Complex; Control Groups; Data; Dendritic Spines; Development; Disease; Emotional Stress; Endocrine; Exposure to; Functional disorder; Glutamates; Goals; Hippocampal Formation; Hormones; Human; Hyperactive behavior; Hypothalamic structure; Immunotoxins; Intervention; Label; Laser Scanning Confocal Microscopy; Major Depressive Disorder; Medial; Mental Depression; Microscopy; Modeling; Modification; Moods; Morphology; Neuronal Plasticity; Neurons; Neurosecretory Systems; Output; Pathway interactions; Pituitary Gland; Pituitary-Adrenal System; Prefrontal Cortex; Presynaptic Terminals; Prevention; Regulation; Reporting; Resolution; Role; Specificity; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; System; Testing; Time; Vertebral column; Withdrawal; Work; base; biological adaptation to stress; density; digital; effective therapy; experience; follow-up; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; hypercortisolemia; innovation; nerve supply; neural circuit; neuroimaging; novel; paraventricular nucleus; prevent; receptor; reconstruction; research study; response; stressor

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.

描述（由申请人提供）：人们普遍认为，控制应激激素功能的大脑系统的失调可能是重度抑郁症和其他与压力相关的疾病状态发展的基础。众所周知，内侧前额叶皮层 (mPFC) 和海马结构 (HF) 对下丘脑-垂体-肾上腺 (HPA) 轴具有负调节作用，它们的功能障碍与抑郁症和慢性应激的动物研究中的情绪和神经内分泌紊乱有关。多年来，由于无法阐明慢性应激后 mPFC 和 HF 抑制影响撤回的复杂神经回路和机制，针对神经内分泌系统的干预措施的开发一直缺乏进展。我们最近在终纹床核（aBST）的前细分中鉴定出离散的 GABA 能细胞群，作为边缘皮质和下丘脑室旁核（PVH）之间的突触中继，并且能够整合这些应激-急性情绪压力期间对 HPA 输出的抑制影响使我们能够直接检查这种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 mPFC 中慢性应激诱导的神经可塑性（即树突/轴突回缩、突触/末端丢失）通过减少其神经支配，导致其对 HPA 轴的正常抑制影响被破坏 关键的突触抑制中继（例如，涉及 aBST）到 PVH。目标 1 将评估这一新回路在慢性可变应激暴露后参与 HPA 轴修饰的情况，并且对这些回路中关键 GABA 能继电器的免疫毒素消融将测试该通路在慢性应激诱导的内分泌改变中的参与情况。目标 2 将利用高分辨率显微镜、数字重建和体视学来评估 mPFC/HF 神经元的结构可塑性（树突、脊柱密度、轴突末端改变），特别是在慢性可变应激后与 HPA 轴修饰有关的电路。目标 3 将测试 mPFC/HF 中 GC 受体的阻断是否可以防止环路特异性神经可塑性，进而防止慢性可变应激后的 HPA 轴过度活跃。这些研究预计将 (a) 确定与慢性可变应激后 HPA 抑制影响撤回有关的抑制回路中断的基础，以及 (b) 评估边缘皮质神经可塑性和与慢性应激相关的内分泌异常之间的关系。希望该提案中新的神经解剖学目标和潜在细胞过程的识别将为寻找更有效的治疗压力相关精神和全身性疾病的方法提供信息。