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）：广泛理解的是，控制应激激素功能的大脑系统失调可能是严重抑郁症和其他与压力有关的疾病状态的发展。已知内侧前额叶皮层（MPFC）和海马形成（HF）对下丘脑 - 垂体 - 肾上腺（HPA）轴负调节，其功能障碍与抑郁症和慢性胁迫动物研究中的情绪和神经内分泌干扰有关。多年来，由于无法揭示MPFC戒断和HF限制性影响的慢性压力后，靶向神经内分泌系统的靶向靶向的进展一直缺乏。 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在控制与抑郁症相关的神经内分泌变化时。我们假设MPFC中慢性应激诱导的神经塑性（即树突状/轴突回收，突触/末端损失）导致其正常限制对HPA轴的破坏，从 关键的脱节抑制继电器（例如，涉及ABST）到PVH。 AIM 1将评估慢性变化应力暴露后与HPA轴修饰有关的这一新电路的参与，以及这些电路中关键GABA能继电器的免疫毒素消融将测试该途径在慢性应激诱导的内分泌变量中的参与。 AIM 2将利用MPFC/HF神经元中的高分辨率显微镜，数字重建和立体学来评估结构可塑性（树突状，脊柱密度，轴突末端变化），该神经元在慢性可变应力之后，与HPA轴修饰有关的电路特有。 AIM 3将测试MPFC/HF中GC受体的阻滞是否可防止电路特异性神经可塑性，并且在慢性可变应力下，AIM 3将测试AIM 3，进而阻止HPA轴的多动症。预计这些研究将（a）定义抑制性电路中断的基础，涉及在慢性可变应力后撤回HPA限制影响的基础，以及（b）评估边缘皮质神经可塑性与内分泌异常之间的关系之间的关系。希望在本提案中鉴定新的神经解剖靶标和潜在的细胞过程，将为寻找与压力相关的精神病和全身性疾病的更有效治疗提供信息。