Sex differences and metabolic responses to chronic stress

项目摘要 这项提议旨在培养一名双学位的DVM-博士学生，为成为一名成功的职业生涯做准备 临床医生兼科学家。申请者将获得生物医学博士学位，同时获得DVM学位。 鉴于心血管疾病和代谢紊乱是日益普遍的全球流行病， 这些疾病极大地增加了死亡率，增加了残疾寿命。 对了解这些疾病的发病机制至关重要。在流行病学上，慢性压力具有显著的作用。 心脏新陈代谢风险。众所周知，神经过程会影响对压力的生理反应。然而， 性别依赖性内分泌和代谢生理学改变的具体机制 人们对慢性压力还没有很好的理解。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新陈代谢健康 老鼠。具体地说，测试假设从边缘下皮质(IL)到吻部腹外侧区的信号 延髓(RVLM)以一种性别特异性的方式减轻慢性应激后的内分泌应激反应。这个 将解决以下具体目标：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应激的反应。2)确定是否激活 慢性应激后IL-RVLM回路的改变降低女性内分泌过高的易感性 反应性。IL-RVLM回路的激活将通过光遗传刺激实现。强烈的克制意志 被用作心理应激源来衡量应激激素，即糖皮质激素的激活， 葡萄糖、高血糖素、血管紧张素II和胰岛素。以葡萄糖耐量试验的形式进行血糖挑战将 被用作新陈代谢的压力源。在目标2中，慢性可变压力(CVS)暴露将包括14天的两次- 每天的随机应激源。在暴露于CVS之后，动物将经历急性约束和血糖升高。 挑战。除应激激素、葡萄糖、高血糖素、血管紧张素II和胰岛素外，非侵入性 衡量新陈代谢和自主神经活动的指标，如心率、血压和体温 将在两个目标的急性压力期间采取。促肾上腺皮质激素释放激素mRNA将在 下丘脑。此外，基础代谢措施将采取体重和食物摄入量的形式。 综上所述，这些研究将为皮质和脑干过程如何整合提供新的见解 以性别特有的方式影响新陈代谢健康。这将进一步加深我们对压力的理解 会导致新陈代谢和心血管疾病。

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.