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

皮质脑干神经回路可减少慢性压力引起的心血管影响

• 批准号: 10389523
• 负责人: Sebastian Andres Pace
• 金额: $ 3.53万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389523
• 关键词: Address; Affect; Area; Automobile Driving; Behavioral; Biological; Blood Pressure; Brain; Brain Stem; Cardiac; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Catecholamines; Cause of Death; Cell Nucleus; Chronic; Chronic stress; Cognitive; Corticosterone; Coupled; Data; Development; Devices; Disease; Electrocardiogram; Endocrine; Enterobacteria phage P1 Cre recombinase; Enzymes; Exposure to; Female; Fiber Optics; Fluorescent in Situ Hybridization; Functional disorder; Gene Expression Profiling; Genetic; Glutamates; Health; Heart Rate; Human; Implant; In Situ Hybridization; Investigation; Life; Light; Link; Measures; Medial; Metabolic Diseases; Methyltransferase; Microinjections; Modernization; Neural Pathways; Neurons; Output; Pathology; Pathway interactions; Personal Satisfaction; Physiological; Prefrontal Cortex; Process; Proteins; Rattus; Risk Factors; Rodent; Role; Signal Transduction; Site; Societies; Stimulus; Stress; Synapses; Synaptic Transmission; Testing; Tetanus Toxin; Time; Toxin; Transcript; Tyrosine 3-Monooxygenase; Vascular Diseases; Ventricular Remodeling; Viral; acute stress; base; biological adaptation to stress; cardiovascular disorder risk; cardiovascular effects; cardiovascular health; cell type; experimental study; glutamatergic signaling; hemodynamics; human imaging; imaging study; mRNA Expression; male; mortality; neural circuit; neuroadaptation; novel; optogenetics; prevent; prospective; relating to nervous system; response; restraint stress; retrograde transport; sex; stress reactivity; stressor

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.

项目摘要 长期暴露于压力是全球死亡率的主要原因，心血管疾病， 疾病虽然慢性压力改变了我们的生理应激反应， 导致心血管疾病发展的原因尚不清楚。因此，本提案针对这一点 通过确定心血管应激反应的神经基础， 研究缓解慢性压力引起的生理损伤的潜在途径。人体成像 研究表明，前额叶皮层是处理压力相关信息的关键部位。在大鼠体内 前额皮质，边缘下区（IL）对于行为和生理应激反应是关键的。 有趣的是，针对人类和大鼠这一共同皮层区域的脑刺激研究发现， 血管降压作用此外，刺激雄性大鼠中的IL神经元可防止心血管缺陷 是由慢性压力引起的为了确定所涉及的生物学途径，我们探索了IL-10的下游， 通路和确定的IL输入头端腹外侧延髓（RVLM）。因为RVLM启动了 交感-肾上腺髓质应激反应，IL-RVLM回路可能是应激之间的关键联系 评价和同情反应。初步研究发现，刺激IL-至-RVLM回路， 新的束缚应激减弱雄性和雌性大鼠的皮质酮释放。此外，基因表达分析 显示慢性应激暴露增加脑干儿茶酚胺合成转录在两种性别。 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。(Aim 1）确定IL-至-RVLM回路在慢性脑缺血期间的作用。 应激时，交叉遗传学将用于减少IL-至-RVLM信号传导并测量儿茶酚胺 合成酶表达后，慢性应激，在男性和女性。通过使用荧光原位 杂交结合免疫标记，儿茶酚胺合成酶mRNA表达变化 将阐明慢性应激如何改变雄性和雌性大鼠的神经原性驱动的交感神经活动， IL到RVLM回路对慢性应激神经适应的必要性。(Aim 2）接下来，我们将确定是否 光遗传学刺激IL-至-RVLM回路可消除慢性炎症引起的心血管敏化。 应力通过测量急性应激时的实时血流动力学和心电图，我们可以评估 刺激IL-至-RVLM的信号传导减少了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查负责心血管疾病的神经通路。 压力反应和识别慢性压力引起的变化，可以有助于病理和疾病。 此外，这些实验将确定该回路是否可以代表保护心血管系统的目标。 健康对抗慢性压力的有害后果。