Sex differences and metabolic responses to chronic stress

性别差异和对慢性压力的代谢反应

• 批准号: 10650346
• 负责人: Carley Dearing
• 金额: $ 4.09万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650346
• 关键词: Acute; Address; Angiotensin II; Animals; Bilateral; Blood Glucose; Blood Pressure; Blood specimen; Body Temperature; Body Weight; Brain Stem; Cannulas; Cardiovascular Diseases; Cause of Death; Chronic; Chronic stress; Code; Corticosterone; Corticotropin-Releasing Hormone; Data; Diabetes Mellitus; Disease; Doctor of Philosophy; Eating; Endocrine; Environment; Epidemic; Epidemiology; Exposure to; Fellowship; Female; Fiber Optics; Future; Glucagon; Glucocorticoids; Glucose; Glucose Intolerance; Glucose tolerance test; Glutamates; Goals; Health; Heart Rate; Homeostasis; Hormones; Hypothalamic structure; Immunohistochemistry; Impairment; Individual; Insulin; Knowledge acquisition; Link; Measures; Mental Depression; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic hormone; Metabolism; Neuroendocrinology; Pathogenesis; Personal Satisfaction; Physiological; Physiology; Positioning Attribute; Predisposition; Prefrontal Cortex; Preparation; Process; Psychological Stress; Quality of life; Randomized; Rattus; Research; Research Personnel; Role; Science; Scientist; Sex Differences; Signal Transduction; Societies; Stress; Students; Synapses; Testing; Time; Training; Viral Packaging; acute stress; biological adaptation to stress; blood glucose regulation; cardiometabolic risk; cardiovascular disorder risk; career; cognitive process; disability; economic impact; frontal lobe; hemodynamics; hypothalamic-pituitary-adrenal axis; insight; knowledge base; male; mortality; neural; neural circuit; neuromechanism; novel; optical fiber; optogenetics; programs; psychologic; psychological stressor; response; restraint; sex; skills; socioeconomics; stress reactivity; stress reduction; stressor; years lived with disability

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.

项目概要 该提案旨在培养一名双学位 DVM-PhD 学生，为作为一名成功的职业生涯做好准备 临床医生科学家。申请人将获得生物医学博士学位，同时获得 DVM。 鉴于心血管疾病和代谢紊乱是一种日益普遍的全球流行病， 这些疾病极大地导致死亡率增加和残疾寿命增加， 了解这些疾病的发病机制至关重要。从流行病学角度来看，慢性压力具有显着的作用 心脏代谢风险。众所周知，神经过程会影响对压力的生理反应。然而， 内分泌和代谢生理学中性别依赖性变化的具体机制 慢性压力尚不清楚。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 老鼠。具体来说，检验以下假设：从边缘下皮层 (IL) 到嘴侧腹外侧的信号传导 髓质（RVLM）以性别特异性方式减轻慢性应激后的内分泌应激反应。这 将解决以下具体目标：1) 确定 IL-RVLM 回路的激活是否会减轻内分泌 雄性和雌性大鼠对血糖挑战和心理压力的反应。 2) 判断是否激活 暴露于慢性压力后 IL-RVLM 回路的变化可降低女性对内分泌亢进的易感性 反应性。 IL-RVLM 电路的激活将通过光遗传学刺激来实现。严重克制会 用作心理压力源来测量应激激素（即糖皮质激素）的激活， 葡萄糖、胰高血糖素、血管紧张素 II 和胰岛素。以葡萄糖耐量测试形式进行的血糖挑战将 用作代谢应激源。在目标 2 中，慢性可变应激 (CVS) 暴露将包括 14 天的两次- 每日随机压力源。接触 CVS 后，动物将经历急性抑制和血糖下降 挑战。除了应激激素、葡萄糖、胰高血糖素、血管紧张素 II 和胰岛素外，无创 新陈代谢和自主激活的测量，例如心率、血压和体温 将在两个目标的严重压力下采取。促肾上腺皮质激素释放激素 mRNA 将在 下丘脑。此外，还将以体重和食物摄入量的形式进行基础代谢测量。 总而言之，这些研究将为皮质和脑干过程如何整合以提供新的见解。 以特定性别的方式影响代谢健康。这将进一步加深我们对压力如何影响的理解 导致代谢和心血管疾病。