Anatomical Plasticity and HPA Axis Dysfunction

描述(申请人提供)：下丘脑-垂体-肾上腺皮质(HPA)轴功能障碍是主要情感性疾病的常见特征。神经内分泌障碍通常表现为皮质醇高分泌和糖皮质激素负反馈抵抗，两者都使个体暴露于过高的应激激素水平及其有害的后遗症。糖皮质激素高分泌的机制目前还不清楚。我们实验室和其他实验室的工作表明，病理性糖皮质激素的升高可能是由于小细胞PVN中的中枢应激整合神经元过度活跃所致，这是HPA轴激活的最终共同途径。在这项研究中，我们使用抑郁症的大鼠慢性应激模型来检验这一新的假设，即以HPA流出持续激活为特征的应激相关疾病是由脑室旁核促垂体区域的生化和/或结构性神经可塑性变化诱导的。这一假设将在三个具体目标上得到检验。第一个目的将验证慢性应激诱导室旁核HPA效应神经元突触后受体表达的功能可塑性的假设。实验将评估慢性应激使受体群体重新配置为有利于兴奋性神经传递而不是抑制作用的预测，测试慢性应激增强兴奋性神经递质对糖皮质激素分泌的作用，并使用基因组学指导的方法提供应激诱导的室旁核神经元受体变化的综合分析。第二个目标将检验这一假设，即慢性应激扰乱控制HPA轴反应的室旁核神经元的糖皮质激素反馈敏感性。这些实验将确定慢性应激是否会降低核糖皮质激素受体信号传递的能力，并在PVN水平上评估应激对反馈效果的影响。第三个目标将检验这一假设，即慢性应激导致微小细胞PVN的形态变化，这预示着兴奋性的增强。这些研究将确定慢性应激是否增强了室旁CRH神经元的兴奋性和抑制性神经递质神经支配，评估应激影响室旁神经元形态的能力，并使用基因组学指导的方法探索应激可塑性的可能分子机制。总体而言，该项目将为情感性疾病状态下丘脑调节神经内分泌功能障碍的机制提供关键的新信息。

DESCRIPTION (provided by applicant): Dysfunction of the hypothalamo-pituitary-adrenocortical (HPA) axis is a common feature of major affective illnesses. Neuroendocrine disturbances are typically manifest as cortisol hypersecretion and glucocorticoid negative feedback resistance, both of which expose individuals to excessive levels of stress hormones and their deleterious sequelae. The mechanism underlying glucocorticoid hypersecretion is currently ill-defined. Work from our laboratories as well as others indicate that pathologically elevated glucocorticoids are likely due to hyperactivity of central stress-integrative neurons in the parvocellular PVN, which represent the final common pathway for HPA axis activation. In this proposal, we use a rat chronic stress model of depression to test the novel hypothesis that stress-related illnesses frequently characterized by sustained activation of HPA outflow result from the induction of biochemical and/or structural neuroplastic changes in hypophysiotropic regions of the paraventricular nucleus. This hypothesis will be tested in three Specific Aims. The first Aim will test the hypothesis that chronic stress induces functional plasticity of post-synaptic receptor expression in the HPA effector neurons in the paraventricular nucleus. Experiments will evaluate the prediction that chronic stress reconfigures receptor populations to favor excitatory neurotransmission over inhibition, test for chronic stress enhancement of excitatory neurotransmitter actions on glucocorticoid secretion, and use a genomics-guided approach to provide an integrated analysis of stress-induced receptor changes in paraventricular nucleus neurons. The second Aim will test the hypothesis that chronic stress disrupts glucocorticoid feedback sensitivity in paraventricular nucleus neurons controlling HPA axis responses. These experiments will determine if chronic stress reduces the capacity for nuclear glucocorticoid receptor signaling, and assess stress effects on feedback efficacy at the level of the PVN. The third Aim will test the hypothesis that chronic stress induces morphological changes in the parvocellular PVN that predict enhanced excitability. These studies will determine whether chronic stress enhances excitatory vs. inhibitory neurotransmitter innervation of paraventricular CRH neurons, assess the ability of stress to affect paraventricular neuronal morphology, and use a genomics-guided approach to probe for possible molecular mechanisms underlying stress plasticity. Overall, this project will provide critical new information on hypothalamic mechanisms mediating neuroendocrine dysfunction in affective disease states.