Sex differences and metabolic responses to chronic stress

项目摘要 该提案旨在培养一个双学位，DVM-PhD，学生为成功的职业生涯做准备， 临床科学家申请人将获得生物医学科学博士学位，同时获得DVM。 鉴于心血管疾病和代谢紊乱是日益普遍的全球流行病， 这些疾病显著地导致死亡率增加和残疾生存年数增加， 对了解这些疾病的发病机制至关重要。从流行病学的角度来看，慢性压力 心脏代谢风险。已知神经过程会影响对压力的生理反应。然而，在这方面， 研究表明，性激素依赖性的内分泌和代谢生理学变化的具体机制， 慢性压力还没有被很好地理解。因此，本提案中概述的研究旨在确定如何 特定的神经回路影响应激反应，从而影响男性和女性的代谢健康 大鼠具体地说，测试的假设，信号从下边缘皮层（IL）的吻腹外侧 延髓（RVLM）减轻慢性应激后的内分泌应激反应性在性别特异性的方式。的 1）确定IL-RVLM回路的激活是否减轻内分泌 雄性和雌性大鼠对血糖挑战和心理压力的反应。2)确定是否激活 的IL-RVLM电路暴露于慢性应激降低女性的易感性， 反应性将使用光遗传学刺激实现IL-RVLM回路的激活。剧烈的克制将 用作心理应激源以测量应激激素，即糖皮质激素， 葡萄糖、胰高血糖素、血管紧张素II和胰岛素。以葡萄糖耐量试验形式进行的Glycoprotein激发将 代谢应激源。在目标2中，慢性可变压力（CVS）暴露将包括14天的两次- 每天随机的压力源。暴露于CVS后，动物将接受急性束缚和血糖监测。 挑战.除了应激激素、葡萄糖、胰高血糖素、血管紧张素II和胰岛素， 代谢和自主活动的测量，如心率、血压和体温 将在两个目标的急性压力下采取。促肾上腺皮质激素释放激素mRNA将在 下丘脑此外，将以体重和摄食量的形式进行基础代谢测量。 总之，这些研究将为皮层和脑干过程如何整合提供新的见解， 以性别特异性方式影响代谢健康。这将进一步加深我们对压力 导致代谢和心血管疾病。

Project Summary This proposal aims to train a dual-degree, DVM-PhD, student in preparation for a successful career as a clinician-scientist. The applicant will earn a PhD in Biomedical Sciences while simultaneously earning a DVM. Given that cardiovascular disease and metabolic disorders are an increasingly prevalent global epidemic and these disorders significantly contribute to both increased mortality and increased years lived with disability, it is vital to understand the pathogenesis of these disorders. Epidemiologically, chronic stress has a prominent role in cardiometabolic risk. Neural processes are known to influence physiologic responses to stress. However, the specific mechanisms that underlie sex-dependent changes in endocrine and metabolic physiology after chronic stress are not well understood. Therefore, the research outlined in this proposal aims to determine how specific neural circuitry influences stress reactivity and, consequently, metabolic health in male and female rats. Specifically, testing the hypothesis that signaling from the infralimbic cortex (IL) to the rostral ventrolateral medulla (RVLM) mitigates endocrine stress reactivity after chronic stress in a sex-specific manner. The following specific aims will be addressed: 1) determines if activation of the IL-RVLM circuit mitigates endocrine responses to glycemic challenge and psychological stress in male and female rats. 2) Determines if activation of the IL-RVLM circuit following exposure to chronic stress reduces female susceptibility to endocrine hyper- reactivity. Activation of the IL-RVLM circuit will be achieved using optogenetic stimulation. Acute restraint will be used as a psychological stressor to measure activation of stress hormones, namely glucocorticoids, glucose, glucagon, angiotensin II, and insulin. Glycemic challenge in the form of a glucose tolerance test will be used a metabolic stressor. In aim 2, chronic variable stress (CVS) exposure will consist of 14 days of twice- daily randomized stressors. Following exposure to CVS, animals will undergo acute restraint and glycemic challenge. In addition to stress hormones, glucose, glucagon, angiotensin II and insulin, non-invasive measures of metabolism and autonomic activation such as heart rate, blood pressure, and body temperature will be taken during acute stress in both aims. Corticotropin Releasing Hormone mRNA will be quantified in the hypothalamus. Additionally, basal metabolic measures will be taken in the form of bodyweight and food intake. Taken together, these studies will provide novel insight into how cortical and brainstem processes integrate to influence metabolic health in a sex-specific manner. This will further our understanding of how stress contributes to metabolic and cardiovascular diseases.