Interrogating stress-relieving neural circuits to alleviate cardiovascular disease

项目摘要 应激性生活事件与心血管疾病(CVD)的病因有关，心血管疾病是 美国的死亡压力导致心血管疾病的病理生理学机制很差 了解和有效的治疗方法，以缓解压力和改善心血管健康是缺乏的。一个 这一建议的前提是探索控制压力感知的神经回路可能会提供 洞察心血管疾病的潜在机制和旨在扭转其趋势的干预措施。因果关系模式 人类对应激和心血管疾病的神经活动的研究是具有挑战性的。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刺激或抑制特定的 神经回路使神经活动和应激反应指数之间的因果联系成为可能。vbl.使用 转基因小鼠，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、神经内分泌和行为应激反应有关。 具体地说，我们发现表达血管紧张素2型(AT2R)和Mas受体(MASR)的神经元 大脑皮质和边缘区域密集分布，控制着对心理压力的感知 这些神经元的兴奋可以降低血压、心率、循环中的皮质酮水平和焦虑-- 就像行为一样。在周围，我们发现结状神经节内有密集的神经元。 表达血管紧张素1a型受体(AT1R)。这些神经元起初级压力感受器传入的作用。 这些神经元的兴奋可以降低血压、心率和能量消耗。总而言之，这些 观察结果导致了一个总体假设，即对特定神经元群体的兴奋 表达AT1R、AT2R或MASR可以改变人们对压力的感知，从而预防心血管疾病。实验将会 在拥有大量现代神经科学技术和经典系统的小鼠身上使用Cre-loxP系统 生理学证实或驳斥这一假说的生理学利用Cre-diver小鼠进行病毒介导的初步实验 基因转移和体内光遗传学确定神经元是兴奋还是抑制表达 AT1R、AT2R或MASR可减弱或加剧应激反应。随后的实验使用了一个模型 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。最后的实验试图减轻应激诱导的病理生理学 通过光遗传、遗传或药物操作改变神经元的兴奋性，表达 AT1R、AT2R或MASR。我们预计，拟议的研究将在详细和机械的层面上揭示， 神经回路提供压力缓解，从而指导心血管疾病新疗法的发展。

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.