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

基本信息

批准号：
9886272
负责人：
JASON J RADLEY
金额：
$ 50.47万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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/9886272
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

项目摘要

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.

项目概要对压力的反应是由边缘前脑结构网络调节的，而这些结构的功能障碍慢性病后的神经系统被广泛认为与应激相关的发病机制有关精神疾病。迄今为止，几乎没有关于慢性压力的中心效应器的信息。诱导内分泌和行为改变，也没有任何尝试挽救正常功能长期压力后。该领域的工作表明内侧前额叶皮层提供自上而下的抑制作用下丘脑室旁核中下丘脑-垂体-肾上腺 (HPA) 效应神经元的控制 (PVH) 在急性应激期间，通过涉及纹状体床核中 GABA 能神经元的突触通路终端 (BST)。然而，目前还没有关于神经回路机制的信息。随后暴露于新的挑战（即敏化）时，HPA 反应过度的发生。此外，我们的初步数据表明，BST 在协调内分泌和内分泌方面发挥着更广泛的作用。各种挑战期间的行为应对反应（例如，悬尾、强迫游泳、冲击探针防御性掩埋测试），通过涉及 PVH 和导水管周围灰色区域（PAG）的可分离通路。因此，我们本提案的目标是操纵这些电路元件来阐明其机制慢性压力诱导的 HPA 敏化并转向被动行为反应挑战。这些研究将结合光遗传学和神经生理学，以建立我们现有的优势操纵大鼠假定的应激调节网络的解剖学和行为方法。在目标 1 中，我们将询问从 BST 到 PVH 和 PAG 的不同途径在调节适应不良的 HPA 和慢性可变压力暴露后的行为变化。目标 2 将检查是否减少前额叶对 BST 和/或 PAG 下行通路的控制是慢性应激诱发的原因适应不良的 HPA 和行为改变。这项工作将推动我们思考不同的特征如何压力反应是协调的，并且可以更清楚地了解调节性大脑的功能障碍是如何发生的回路可能会导致多个系统的慢性压力相关功能障碍，这在精神病学中很常见抑郁症等疾病。