Cortical-Medullary Circuitry Preventing the Cardiovascular Consequences of Chronic Stress

皮质-髓质回路预防慢性压力的心血管后果

• 批准号: 10532302
• 负责人: Brent Philip Myers
• 金额: $ 36.4万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-16 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532302
• 关键词: Acute; Address; Animals; Biological; Biological Process; Blood Pressure; Blood Vessels; Brain Stem; Brain region; Cardiac; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Catecholamines; Cause of Death; Cells; Chronic; Chronic stress; Cognition; Cognitive; Corticosterone; Corticotropin; Data; Disease; Electrocardiogram; Endocrine; Endothelium; Enterobacteria phage P1 Cre recombinase; Epidemiology; Epinephrine; Exposure to; Female; Fiber Optics; Functional disorder; Gene Expression; Genes; Glutamates; Goals; Heart Diseases; Heart Hypertrophy; Heart Rate; Hormones; Hypertrophy; Incidence; Injections; Life Stress; Light; Link; Measures; Medial; Mediating; Mediator; Mood Disorders; Morbidity - disease rate; Myography; Neurons; Neurosecretory Systems; Norepinephrine; Output; Pathologic; Pathology; Pathway interactions; Physiological; Plasma; Population; Predisposition; Prefrontal Cortex; Presynaptic Terminals; Psychological Stress; Psychosocial Stress; Rattus; Rodent; Role; Severities; Signal Pathway; Signal Transduction; Site; Stress; Synapses; Telemetry; Testing; Tetanus Toxin; United States; Vascular Diseases; Vascular Endothelium; Viral; acute stress; biological adaptation to stress; burden of illness; cardiovascular effects; cardiovascular health; combinatorial; experience; experimental study; glutamatergic signaling; heart function; heart rate variability; hemodynamics; hypothalamic-pituitary-adrenal axis; in vivo; knock-down; mRNA Expression; male; mortality; nano-string; neural circuit; neuromechanism; novel; optical fiber; optogenetics; pressure; prevent; response; restraint; retrograde transport; stress disorder; stress reactivity; therapeutic target; ultrasound; vector

Summary Cardiovascular disease is the leading cause of death worldwide. Prolonged psychosocial stress is a significant predictor of disease incidence and severity. However, the specific neural mechanisms that contribute to the cardiovascular consequences of stress are largely unknown. Therefore, the current proposal will explore how the cortical circuits responsible for cognitive appraisal of stress inhibit physiological stress responses. Recent studies in rats identified a population of cells in the infralimbic (IL) region of the medial prefrontal cortex that reduce endocrine and autonomic responses to chronic stress. Further, knockdown of glutamate release from IL neurons leads to vascular dysfunction after chronic stress. While the activity of excitatory IL projection neurons is critical for preventing the deleterious effects of chronic stress, the pathways used by these cells to limit reactivity of autonomic and endocrine effectors remain to be determined. Preliminary data indicate that the IL projects to catecholaminergic (epinephrine/norepinephrine producing) neurons in the ventrolateral medulla (VLM), the primary site of sympathetic activation. These excitatory IL projections also target inhibitory GABAergic and glycinergic neurons within the VLM, leading to the hypothesis that IL glutamatergic signaling to the VLM limits cardiovascular and endocrine stress reactivity and the consequences of chronic stress on vascular stiffness and cardiac hypertrophy. This hypothesis will be tested by optogenetic activation of IL synapses in the VLM during stress exposure in male and female rats. This approach will be employed in animals that have been previously exposed to chronic variable stress or remained as unstressed controls. Cardiovascular telemetry will be used to measure heart rate, blood pressure, and sympathetic activity. A separate aim will examine neuroendocrine stress responses of the hypothalamic- pituitary-adrenal axis. To determine how IL inputs to the VLM impact pathological responses to chronic stress, a combinatorial viral approach will be used to retrogradely silence the IL-VLM circuit with Cre-dependent tetanus toxin. Vascular stiffness, cardiac hypertrophy, and endothelial function will be assessed in male and female rats exposed to chronic stress. This circuit silencing approach will also be used to examine the importance of IL signaling for preventing chronic stress effects on the expression of cellular signaling genes in the VLM. Collectively, these experiments will determine specific circuit and cellular pathways linking cognitive appraisal and physiological stress responses. Further, this connection represents a critical biological process that could be harnessed to intervene in the cardiovascular consequences of chronic stress.

总结 心血管疾病是全世界死亡的主要原因。长期的心理压力是一种 疾病发生率和严重程度的重要预测因子。然而，特定的神经机制， 导致压力的心血管后果在很大程度上是未知的。因此，目前的建议 将探讨负责压力认知评估的皮层回路如何抑制生理压力 应答最近在大鼠中的研究确定了在内侧核的边缘下（IL）区域的细胞群， 减少内分泌和自主神经对慢性压力的反应。此外，击倒 IL神经元的谷氨酸释放导致慢性应激后血管功能障碍。的活力 兴奋性IL投射神经元对于防止慢性应激的有害作用是至关重要的， 由这些细胞用来限制自主和内分泌效应物的反应性仍有待确定。 初步数据表明，IL投射到儿茶酚胺能（产生肾上腺素/去甲肾上腺素） 延髓腹外侧（VLM）的神经元，交感神经激活的主要部位。这些兴奋性白细胞介素 投射还靶向VLM内的抑制性GABA能和甘氨酸能神经元，导致以下假设： VLM的IL-12介导信号限制了心血管和内分泌应激反应， 慢性应激对血管僵硬和心脏肥大的影响。这一假设将得到检验 通过雄性和雌性大鼠在应激暴露期间VLM中IL突触的光遗传学激活。这 方法将用于先前暴露于慢性可变应激或 保持为非应激对照。心血管遥测将用于测量心率、血压， 和交感神经活动。一个单独的目标将检查下丘脑的神经内分泌应激反应- 垂体肾上腺轴为了确定VLM的IL输入如何影响慢性应激的病理反应， 将使用组合病毒方法逆行沉默具有Cre依赖性的IL-VLM回路。 破伤风毒素将在雄性和雌性中评估血管僵硬度、心脏肥大和内皮功能， 雌性大鼠暴露于慢性应激。这种电路消音方法也将用于检查 IL信号传导对于预防慢性应激对细胞信号传导基因表达的影响的重要性 的VLM。总的来说，这些实验将确定特定的电路和细胞通路连接认知 评估和生理应激反应。此外，这种连接代表了一个关键的生物过程， 可以用来干预慢性压力对心血管的影响。