Interrogating stress-relieving neural circuits to alleviate cardiovascular disease

研究缓解压力的神经回路以减轻心血管疾病

基本信息

批准号：
9893161
负责人：
Eric Gerald Krause
金额：
$ 73.34万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-05 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9893161
关键词：
Angiotensin Receptor Angiotensin Type 1a Receptor Angiotensins Attenuated Blood Pressure Brain region Cardiovascular Diseases Cardiovascular system Cause of Death Corticosterone Coupled Development Disease Energy Metabolism Etiology Event Functional disorder Gene Transfer Genes Genetic Heart Rate Human Intervention Laboratory mice Life Link Mediating Modeling Modernization Mus Nervous system structure Neurons Neurosciences Neurosecretory Systems Nodose Ganglion Perception Pharmacology Physiology Population Predisposition Pressoreceptors Psychological Stress Research Stress Structure System Techniques Treatment Efficacy Type 2 Angiotensin II Receptor United States Viral anxiety-like behavior behavioral response blood pressure reduction cardiovascular health experimental study genetic technology improved in vivo indexing insight neural circuit neural patterning novel therapeutics optogenetics preclinical study receptor recombinase-mediated cassette exchange relating to nervous system resilience

项目摘要

Project Summary Stressful life events are linked to the etiology of cardiovascular disease (CVD), which is the leading cause of death in the U.S. The mechanisms by which stress causes pathophysiology contributing to CVD are poorly understood and effective therapeutics that relieve stress and improve cardiovascular health are lacking. A premise of this proposal is that exploration of the neural circuits controlling the perception of stress may provide insight towards mechanisms underlying CVD and interventions aimed at its reversal. Causally-linking patterns of neural activity to stress and the development of CVD in humans is challenging. However, preclinical studies using laboratory mice that implement modern neuroscience and genetic technologies to excite or inhibit specific neural circuits make causally-linking neural activity and indices of stress responsiveness achievable. Using genetically-modified mice, we revealed that the activity of neurons that express genes encoding particular angiotensin receptor subtypes is coupled to cardiovascular, neuroendocrine and behavioral responses to stress. Specifically, we discovered that neurons expressing the angiotensin type-2 (AT2R) and Mas receptor (MasR) densely populate cortical and limbic brain regions controlling the perception of psychological stress and that excitation of these neurons decreases blood pressure, heart rate, circulating levels of corticosterone and anxiety- like behavior. In the periphery, we discovered that the nodose ganglion is densely populated by neurons expressing the angiotensin type 1a receptor (AT1R). These neurons function as primary baroreceptor afferents and excitation of these neurons lowers blood pressure, heart rate and energy expenditure. Collectively, these observations have led to the overall hypothesis that excitation of particular neuronal populations that express the AT1R, AT2R or MasR alters the perception of stress to protect against CVD. Experiments will use the Cre-LoxP system in mice with a cadre of modern neuroscience techniques and classical systems physiology to confirm or refute this hypothesis. Initial experiments utilize Cre-diver mice with virally-mediated gene transfer and in vivo optogenetics to determine whether the excitation or inhibition of neurons that express AT1R, AT2R, or MasR attenuates or exacerbates stress responding. Subsequent experiments use a model of stress-induced pathophysiology to evaluate how the structure and function of neurons that express the AT1R, AT2R or MasR is altered by disease. The final experiments attempt to alleviate stress-induced pathophysiology with optogenetic, genetic or pharmacological manipulations that alter the excitability of neurons that express the AT1R, AT2R or MasR. We anticipate that the proposed research will reveal, at a detailed and mechanistic level, neural circuits that provide stress relief, thereby guiding development of novel therapeutics for CVD.

项目概要生活压力事件与心血管疾病 (CVD) 的病因有关，而心血管疾病是导致心血管疾病的主要原因压力导致 CVD 的病理生理学机制尚不明确目前缺乏缓解压力和改善心血管健康的有效疗法。一个该提议的前提是，探索控制压力感知的神经回路可能会提供深入了解 CVD 的潜在机制以及旨在逆转其的干预措施。因果关系模式神经活动对压力和人类心血管疾病发展的影响具有挑战性。然而，临床前研究使用实施现代神经科学和遗传技术的实验室小鼠来兴奋或抑制特定的神经回路使神经活动和压力反应指数之间存在因果联系。使用在转基因小鼠中，我们发现表达编码特定基因的神经元的活动血管紧张素受体亚型与心血管、神经内分泌和对压力的行为反应有关。具体来说，我们发现表达 2 型血管紧张素 (AT2R) 和 Mas 受体 (MasR) 的神经元密集分布的皮质和边缘大脑区域控制着心理压力的感知这些神经元的兴奋会降低血压、心率、皮质酮的循环水平和焦虑—— 喜欢的行为。在外围，我们发现结状神经节密集地分布着神经元表达血管紧张素 1a 型受体 (AT1R)。这些神经元充当初级压力感受器传入神经元这些神经元的兴奋会降低血压、心率和能量消耗。总的来说，这些观察结果得出了这样一个总体假设：特定神经元群体的兴奋表达 AT1R、AT2R 或 MasR 可以改变压力感知，从而预防 CVD。实验将在具有现代神经科学技术和经典系统骨干的小鼠中使用 Cre-LoxP 系统生理学来证实或反驳这一假设。最初的实验利用带有病毒介导的 Cre-diver 小鼠基因转移和体内光遗传学，以确定是否激发或抑制表达的神经元 AT1R、AT2R 或 MasR 会减弱或加剧应激反应。后续实验使用的模型为应激诱导的病理生理学来评估表达 AT1R 的神经元的结构和功能， AT2R 或 MasR 会因疾病而改变。最终的实验试图减轻压力引起的病理生理学通过光遗传学、遗传或药理学操作改变表达神经元的兴奋性 AT1R、AT2R 或 MasR。我们预计拟议的研究将在详细和机械层面上揭示：缓解压力的神经回路，从而指导CVD新疗法的开发。