Neural Circuit Basis of Maladaptive Endocrine and Behavioral Responses Following Chronic Stress

慢性压力后内分泌适应不良和行为反应的神经回路基础

• 批准号: 10063831
• 负责人: JASON J RADLEY
• 金额: $ 43.47万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-05 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063831
• 关键词: Accounting; Acute; Address; Adrenal Glands; Affect; Anatomy; Animals; Area; Axon; Behavior; Behavior Therapy; Behavioral; Brain; Chronic; Chronic stress; Data; Development; Disease; Electrophysiology (science); Elements; Endocrine; Event; Exposure to; Functional disorder; Future; Glutamates; Goals; Human; Hypothalamic structure; Impairment; Intervention; Knowledge; Lead; Medial; Mediating; Mental Depression; Mental disorders; Mood Disorders; Nervous system structure; Neuronal Dysfunction; Neurons; Outcome; Output; Pathogenesis; Pathway interactions; Pattern; Pituitary Gland; Pituitary-Adrenal System; Play; Predisposition; Prefrontal Cortex; Prosencephalon; Rattus; Recording of previous events; Research; Response to stimulus physiology; Rodent; Role; Shock; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Swimming; System; Systemic disease; Tail Suspension; Testing; Thinking; Validation; Work; acute stress; base; behavioral response; biological adaptation to stress; coping; experience; experimental study; midbrain central gray substance; neural circuit; neuronal circuitry; neurophysiology; novel; optogenetics; paraventricular nucleus; relating to nervous system; response; virtual

Project Summary Responses to stress are regulated by a network of limbic forebrain structures, whereas dysfunction in these neural systems following chronic conditions has been widely implicated in the pathogenesis of stress-related psychiatric illness. To date, there is virtually no information accounting for central effectors of chronic stress- induced endocrine and behavioral modifications, nor has there been any attempt to rescue normal function after chronic stress. Work in the field implicates the medial prefrontal cortex in providing top-down inhibitory control over hypothalamo-pituitary-adrenal (HPA) effector neurons in the paraventricular hypothalamic nucleus (PVH) during acute stress, via a disynaptic pathway involving GABAergic neurons in the bed nuclei of the stria terminalis (BST). However, no information is currently available regarding the neural circuit mechanisms in the genesis of exaggerated HPA responses upon subsequent exposure to novel challenges (i.e., sensitization). Additionally, our preliminary data suggest that BST plays a broader role in coordinating both endocrine and behavioral coping responses during a variety of challenges (e.g., tail suspension, forced swim, shock probe defensive burying tests), via dissociable pathways involving the PVH and periaqueductal gray area (PAG). Therefore, our objective in this proposal is to manipulate these circuit elements to elucidate the mechanisms of chronic stress-induced HPA sensitization and shift toward passive behavioral responses to subsequent challenges. These studies will combine optogenetics and neurophysiology to build on our existing strengths in anatomical and behavioral approaches to manipulate putative stress modulatory networks in rats. In Aim 1, we will interrogate the divergent pathways from BST to PVH and PAG in mediating the maladaptive HPA and behavioral changes following chronic variable stress exposure. Aim 2 will examine whether diminished prefrontal control over descending pathways to BST and/ or PAG account for chronic stress-induced maladaptive HPA and behavioral alterations. This work will advance our thinking of how different features of stress responses are coordinated, and will provide a clearer picture of how dysfunction in modulatory brain circuits may lead to chronic stress-related dysfunction of multiple systems as is common in psychiatric illnesses such as depression.

项目摘要 对压力的反应受边缘前脑结构网络的调节，而这些功能障碍 慢性条件下的神经系统已广泛与应力相关的发病机理。 精神病。迄今 诱导内分泌和行为修饰，也没有尝试挽救正常功能 慢性应激之后。该领域的工作暗示内侧前额叶皮层提供自上而下的抑制 控制下丘脑下丘脑下丘脑核中下丘脑 - 垂体 - 肾上腺（HPA）效应神经元 （PVH）在急性应激期间，通过涉及肌室床核中GABA能神经元的无突触途径 终端（BST）。但是，目前尚无有关神经回路机制的信息 随后暴露于新的挑战（即致敏）时，夸张的HPA反应的起源是。 此外，我们的初步数据表明，BST在协调内分泌和 在各种挑战期间的行为应对反应（例如，尾悬架，强迫游泳，冲击探测器 防御性埋葬测试），通过涉及PVH和灰灰色区域（PAG）的可分离途径。 因此，我们在此提案中的目标是操纵这些电路元素，以阐明 慢性应激引起的HPA敏感性，并向被动行为反应转向随后 挑战。这些研究将结合光遗传学和神经生理学，以我们现有的优势在 解剖学和行为方法来操纵大鼠推定的应力调节网络。在AIM 1中，我们 将询问从BST到PVH的不同途径，并介导适应不良的HPA和PAG 慢性变化应力暴露后的行为变化。 AIM 2将检查是否减少 对慢性应激诱导的BST和/或PAG的下降途径的前额叶控制 适应不良的HPA和行为改变。这项工作将推动我们思考的思考 压力反应是协调的，将为调节大脑中的功能障碍如何提供更清晰的了解 电路可能导致多个系统的长期与压力相关的功能障碍，这在精神病学中很常见 抑郁等疾病。