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

项目摘要 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 慢性疾病后的神经系统被广泛地牵涉到应激相关的发病机制中 精神疾病。到目前为止，几乎没有关于慢性应激的中央影响因素的信息- 诱导内分泌和行为改变，也没有任何试图挽救正常功能 在长期的压力下。现场工作表明，内侧前额叶皮质提供自上而下的抑制 下丘脑室旁核对下丘脑-垂体-肾上腺效应神经元的控制 (PVH)在急性应激时，通过纹状体床核GABA能神经元参与的双突触通路 终末(BST)。然而，目前还没有关于神经回路机制的信息。 HPA在随后暴露于新的挑战(即敏化)时过度反应的成因。 此外，我们的初步数据表明，BST在协调内分泌和 在各种挑战(例如，尾部悬挂、强迫游泳、电击探头)期间的行为应对反应 通过涉及PVH和导水管周围灰质区(PAG)的可分离通路。 因此，我们在这项提议中的目标是操纵这些电路元件来阐明 慢性应激诱导的HPA敏感化和向被动行为反应的转变 挑战。这些研究将结合光遗传学和神经生理学，以增强我们在 通过解剖学和行为学方法操纵大鼠可能存在的应力调节网络。在目标1中，我们 将询问从BST到PVH和PAG在调节不适应的HPA和 慢性可变压力暴露后的行为变化。目标2将检查是否减少了 前额叶对BST和/或PAG下行通路的控制是慢性应激诱导的原因 适应不良的HPA和行为改变。这项工作将推动我们思考如何不同的功能 应激反应是协调的，这将为调节性大脑功能障碍提供更清晰的图景 回路可能会导致慢性应激相关的多系统功能障碍，这在精神病学中很常见 抑郁症等疾病。

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.