Brainstem Mechanisms of Stress Regulation

描述(申请人提供)：应激相关疾病伴有糖皮质激素和心血管代谢紊乱。特别是，抑郁症患者的糖皮质激素分泌过多与持续的情绪症状和长期的生理功能障碍有关，包括骨质疏松症和内脏肥胖。心率变异性降低与抑郁症患者的负面情绪有关，并导致与这种疾病相关的心血管疾病的高发病率和死亡率。因此，抑郁的生理后果既会导致精神症状，也会导致共病过程。抑郁症的神经和系统效应与大脑中对应激信息的不适当处理有关。目前的建议使用啮齿动物慢性应激模型来解决长期应激后控制生理适应和功能障碍的机制。我们的建议测试了这一新的假设，即不同的脑干神经元作为应激习惯化和敏化的关键整合因子，因此负责适应性和非适应性激素和自主神经反应。目的1确定孤束核(NTS)去甲肾上腺素能神经元是否与慢性应激后HPA轴过度活动和自主神经功能障碍有关。目的2验证神经内分泌和自主神经应激病理是通过前脑应激招募通路不适当地驱动NTS去甲肾上腺素能神经元而介导的假说。目的利用NTS基因敲除技术(慢病毒载体)研究NTS类胰升糖素样肽1(GLP-1)神经元在长期应激适应中的作用。目的4旨在阐明NTS糖皮质激素受体介导的反馈在应激适应和病理调控中的作用。了解NTS在应激适应中的作用将为情感性疾病的潜在回路病理提供新的见解，并为开发治疗干预策略提供新的分子靶点(GLP-1，脑干糖皮质激素受体)。 公共卫生相关性：抑郁症伴随着体内平衡机制的严重破坏，包括糖皮质激素高分泌和心血管功能障碍。重要的是，生理病理参与了情绪症状的产生，这表明抑郁症的全身和神经方面之间存在密切联系。这项建议试图在抑郁症的大鼠慢性应激模型中确定导致糖皮质激素和心血管功能障碍产生的新的神经机制。我们的研究有望提供有关促进应激抵抗和适应的新分子靶点的临床前数据。

DESCRIPTION (provided by applicant): Stress-related diseases are accompanied by glucocorticoid and cardiovascular dyshomeostasis. In particular, glucocorticoid hypersecretion in depression is linked with both ongoing mood symptoms and with long-term physiological dysfunctions, including osteoporosis and visceral obesity. Decreased heart rate variability is associated with negative emotions in depressed patients, and contributes to the high incidence of cardiovascular pathology and mortality associated with the disorder. Thus, physiological consequences of depression contribute to both psychiatric symptoms and co-morbid disease processes. Neural and systemic effects of depression are linked to inappropriate processing of stressful information in the brain. The current proposal uses rodent chronic stress models to address mechanisms that control physiological adaptation and dysfunction following long-term stress. Our proposal tests the novel hypothesis that distinct brainstem neurons act as critical integrators of both stress habituation and sensitization, and are thereby responsible for adaptive as well as maladaptive hormonal and autonomic responses. Aim 1 will determine whether noradrenergic neurons of the nucleus of the solitary tract (NTS) are responsible for driving HPA axis hyperactivity and autonomic dysfunction following chronic stress. Aim 2 tests the hypothesis that neuroendocrine and autonomic stress pathologies are mediated through inappropriate drive of NTS noradrenergic neurons by forebrain stress-recruited pathways. Aim 3 uses a NTS gene knockdown approach (lentiviral vectors) to examine the role of NTS glucagon-like peptide 1(GLP-1) neurons in long-term stress adaptation. Aim 4 is designed to elucidate the role of NTS glucocorticoid receptor-mediated feedback in the control of stress adaptation and pathology. Understanding the role of the NTS in stress adaptation will add new insight into potential circuit pathology in affective disease, and provide novel molecular targets (GLP-1, brainstem glucocorticoid receptors) for development of therapeutic intervention strategies. PUBLIC HEALTH RELEVANCE: Depression is accompanied by major disruption of homeostatic mechanisms, including glucocorticoid hypersecretion and cardiovascular dysfunction. Importantly, physiological pathologies are involved in generation of mood symptoms, indicating a tight linkage between systemic and neural aspects of depression. This proposal seeks to identify novel neural mechanisms responsible for generation of glucocorticoid and cardiovascular dysfunction in a rat chronic stress model of depression. Our studies are expected to provide preclinical data regarding new molecular targets for promoting stress resistance and adaptation.