Anatomical Plasticity and HPA Axis Dysfunction

解剖可塑性和 HPA 轴功能障碍

• 批准号: 7609008
• 负责人: James P Herman
• 金额: $ 35.58万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-08 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609008
• 关键词: Adrenal Cortex Hormones; Adrenergic Agents; Affect; Affective; Amygdaloid structure; Biochemical; Biology; Cells; Chronic stress; Collaborations; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Data; Dendrites; Disease; Feedback; Functional disorder; GABA-A Receptor; Gene Expression; Genes; Genomics; Glucocorticoid Receptor; Glucocorticoids; Glutamate Receptor; Glutamates; Growth; Hippocampus (Brain); Hormones; Hydrocortisone; Hyperactive behavior; Hypothalamic structure; In Situ Hybridization; Individual; Injection of therapeutic agent; Label; Laboratories; Medial; Mediating; Messenger RNA; Microinjections; Microscopic; Modeling; Molecular; Mood Disorders; Morphology; Neuroglia; Neurons; Neurosecretory Systems; Neurotransmitter Receptor; Neurotransmitters; Nuclear; Nuclear Translocation; Pathway interactions; Pattern; Pituitary Gland; Population; Proteins; Rattus; Receptor Signaling; Regulation; Research Personnel; Resistance; Signal Transduction; Stress; Synaptic Receptors; Testing; Therapeutic; Up-Regulation; Work; adrenergic; alpha-adrenergic receptor; base; biocytin; biological adaptation to stress; combat; depression; design; excitatory neuron; gamma-Aminobutyric Acid; nerve supply; neuronal cell body; neurotransmission; novel; paraventricular nucleus; parvocellular; programs; receptor; receptor binding; receptor expression; research study; response; theories; transmission process

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.

描述（由申请人提供）：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。神经内分泌紊乱通常表现为皮质醇分泌过多和糖皮质激素负反馈抵抗，这两者都使个体暴露于过量的应激激素及其有害的后遗症。糖皮质激素分泌过多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，病理性升高的糖皮质激素可能是由于小细胞PVN中的中枢应激整合神经元的过度活跃，这代表了HPA轴激活的最终共同途径。在这个建议中，我们使用大鼠慢性应激抑郁症模型来测试新的假设，即应激相关疾病的特点是持续激活HPA流出导致诱导的生化和/或结构性神经可塑性变化的室旁核的垂体区域。这一假设将在三个具体目标中得到检验。第一个目的是检验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。实验将评估预测，慢性应激重构受体群体，有利于兴奋性神经递质抑制，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，以提供一个综合分析室旁核神经元应激诱导的受体变化。第二个目标将测试的假设，慢性应激破坏室旁核神经元控制HPA轴反应的糖皮质激素反馈敏感性。这些实验将确定慢性应激是否降低核糖皮质激素受体信号传导的能力，并评估应激对PVN水平反馈功效的影响。第三个目标将测试的假设，慢性应激诱导的小细胞PVN预测增强兴奋性的形态学变化。这些研究将确定慢性应激是否增强室旁CRH神经元的兴奋性与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来探测潜在的应激可塑性分子机制。总的来说，这个项目将提供关键的新信息下丘脑机制介导的情感疾病状态的神经内分泌功能障碍。