Chronic stress-induced cardiovascular effects are decreased by a cortical-brainstem neural circuit

项目摘要 长期暴露在压力之下是导致全球死亡的主要原因--心血管疾病的危险因素 疾病。尽管慢性应激改变了我们的生理应激反应，但其生物学机制 对心血管疾病的发展负有责任的人仍然不清楚。因此，本提案解决了这一问题 通过确定心血管应激反应的神经基础和 研究减轻慢性应激引起的生理侮辱的预期方法。人体成像 研究表明，前额叶皮质是处理压力相关信息的关键部位。在老鼠体内 前额叶皮质的下缘区(IL)对行为和生理应激反应至关重要。 有趣的是，针对人类和大鼠这一共享皮质区域的脑刺激研究发现 血管降压作用。此外，刺激雄性大鼠的IL神经元可预防心血管缺陷 是由慢性压力引起的。为了确定涉及的生物途径，我们探索了下游的IL 延髓头端腹外侧区(RVLM)的通路和已识别的IL输入。因为RVLM会启动 交感神经-肾上腺髓质应激反应，IL-RVLM通路可能是应激之间的重要联系 评价和共鸣反应。初步研究发现，刺激IL-to-RVLM电路在 新型束缚应激钝化雄性和雌性大鼠的皮质酮释放。进一步，基因表达分析 研究发现，长期的压力暴露会增加两性脑干儿茶酚胺的合成转录。 由于RVLM儿茶酚胺神经元驱动交感神经流出，我们假设IL输入可能减少 交感神经兴奋通过抑制RVLM儿茶酚胺活性，从而减少心血管 慢性压力的后果。(目的1)确定IL-to-RVLM通路在慢性阻塞性肺疾病中的作用 应激，交叉遗传学将用于减少IL-to-RVLM信号和测定儿茶酚胺 慢性应激后合成酶在男性和女性中的表达。利用原位荧光技术 杂交结合免疫标记对儿茶酚胺合成酶基因表达的影响 将阐明慢性应激如何改变雄性和雌性大鼠的神经源性交感活动，以及 慢性应激神经适应中IL-to-RVLM通路的必要性。(目标2)接下来，我们将确定是否 光遗传刺激IL-to-RVLM通路减轻慢性阻塞性肺疾病引起的心血管敏化 压力。通过测量急性应激期间的实时血流动力学和心电图，我们可以评估 刺激IL-to-RVLM信号通路减少交感神经兴奋和心血管高反应性 慢性压力。这些实验的结果将检验负责心血管疾病的神经通路。 压力反应，并确定慢性压力诱导的变化，可能有助于病理和疾病。 此外，这些实验将确定这个回路是否可以代表保护心血管的目标 健康对抗慢性压力的有害后果。

Project Summary Chronic exposure to stress is a risk factor for the leading cause of global mortalities, cardiovascular disease. Although chronic stress alters our physiological stress response, the biological mechanisms responsible for cardiovascular disease development remain unclear. Therefore, this proposal addresses this substantial health problem by determining the neural basis of the cardiovascular stress response and investigating a prospective avenue to alleviate physiological insults caused by chronic stress. Human imaging studies have revealed the prefrontal cortex is a key site for processing stress-related information. Within the rat prefrontal cortex, the infralimbic area (IL) is critical for behavioral and physiological stress reactivity. Interestingly, brain stimulation studies targeting this shared cortical area in humans and rats see a vasodepressor effect. Further, stimulating IL neurons in male rats protects against cardiovascular deficits caused by chronic stress. To determine the biological pathways involved, we explored downstream IL pathways and identified IL inputs to the rostral ventrolateral medulla (RVLM). Because the RVLM initiates the sympatho-adrenomedullary stress response, an IL-to-RVLM circuit may underlie a crucial link between stress appraisal and sympathetic reactivity. Preliminary studies found that stimulating the IL-to-RVLM circuit during novel restraint stress blunts corticosterone release in male and female rats. Further, gene expression analysis revealed chronic stress exposure increases brainstem catecholamine-synthesis transcripts in both sexes. Because RVLM catecholamine neurons drive sympathetic outflow, we hypothesize that IL input may reduce sympathoexcitation by inhibiting RVLM catecholamine activity, thereby reducing the cardiovascular consequences of chronic stress. (Aim 1) To determine the role of the IL-to-RVLM circuit during chronic stress, intersectional genetics will be used to reduce IL-to-RVLM signaling and measure catecholamine synthesis enzyme expression after chronic stress, in males and females. By using fluorescent in situ hybridization coupled with immunolabeling, mRNA expression changes of catecholamine synthesis enzymes would clarify how chronic stress alters neurogenic-driven sympathetic activity in male and female rats and the necessity of the IL-to-RVLM circuit for chronic stress neural adaptations. (Aim 2) Next, we will determine if optogenetically stimulating the IL-to-RVLM circuit alleviates the cardiovascular sensitization caused by chronic stress. By measuring real-time hemodynamics and electrocardiography during acute stress, we can assess if stimulating IL-to-RVLM signaling reduces sympathoexcitation and cardiovascular hyperreactivity caused by chronic stress. Results from these experiments will examine neural pathways responsible for cardiovascular stress responding and identify chronic stress-induced changes that can contribute to pathologies and disease. Moreover, these experiments will determine if this circuit could represent a target to safeguard cardiovascular health against the deleterious consequences of chronic stress.