Prefrontal Cortical Circuitry Attenuates Cardiovascular Stress Reactivity

前额皮质回路减弱心血管应激反应

基本信息

  • 批准号:
    8969696
  • 负责人:
  • 金额:
    $ 13.09万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-11-17 至 2016-10-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Project Summary This career development award will support my continued training in integrative neuroscience by focusing on the contribution of stress neurobiology to cardiovascular pathophysiology. The funding mechanism also provides a unique opportunity to facilitate the transition to independence. My long-term career goal is to establish an independent academic research program investigating the role of the prefrontal cortex in the generation of abnormal stress responsiveness with an emphasis on cardiovascular health. Determining the mechanisms of cardiovascular stress reactivity is crucial as prolonged or repeated stress represents a prominent risk factor for cardiovascular disease. Additionally, exaggerated physiological reactions to acute stress predict the incidence of cardiovascular disease, as well as cardiac-related morbidity and mortality. However, the specific neural mechanisms that contribute to the cardiovascular consequences of stress are largely unknown. This is an understudied but critical area of research with significant implications for understanding and treating cardiovascular disease, the leading cause of death in the United States. Clinical studies suggest that hypofunctionality of frontal cortical regions affects cardiovascular physiology and our preliminary data demonstrate that genetically-driven decreases in output from the infralimbic prefrontal cortex (IL) exacerbate both cardiovascular and endocrine responses to acute psychological stress in rats. Therefore, the current proposal will explore the mechanisms by which the IL inhibits cardiovascular responsiveness to stress, with the goal of elucidating the neurobiological basis of stress-related disorders such as hypertension and heart disease. The proposed studies will test the overarching hypothesis that IL circuits are necessary for preventing enhanced sympathetic and endocrine responses to stress that promote hypertension, sympathovagal imbalance, and cardiac hypertrophy following chronic stress. Specific Aim 1 will be conducted during the mentored phase and test the hypothesis that decreased glutamate output from the IL is responsible for chronic stress-induced cardiac and vascular pathology. Importantly, all measures related to cardiovascular pathology represent new technical and conceptual training. Lentiviral-mediated gene knockdown will be used to assess the role of IL output in protecting against the sensitization of cardiovascular responses to an unpredictable chronic variable stress regimen. Echocardiography and cardiac histology will be employed to investigate alterations in cardiac function and structure, respectively. Vascular reactivity, inflammatory mediators, and plasma lipids will be assayed to determine the vascular effects of sustained autonomic activation under chronic stress. Training for Specific Aim 2 will occur during the mentored phase and experiments will be completed during the independent phase to test the hypothesis that IL activation is sufficient to restrain cardiovascular output through inhibition of the sympathetic nervous system. To address this hypothesis, optogenetic stimulation of IL projection neurons will be combined with radiotelemetry to measure heart rate, blood pressure, and regional sympathetic nerve activity. Specific Aim 3 will be carried out entirely within the independent phase and test the hypothesis that effects of chronic stress on cardiovascular reactivity can be prevented by stimulating glutamate receptors in downstream pre-sympathetic cardioregulatory regions of the hypothalamus. Optogenetic stimulation of glutamate release at IL terminal sites in the posterior hypothalamus after exposure to CVS combined with glutamate receptor pharmacology will investigate the sufficiency of this circuit for inhibiting the expression of chronic-stress induced sympathovagal imbalance and glucocorticoid hypersecretion. Collectively, these aims examine the cardiovascular consequences of decreased output from prefrontal cortex and determine whether homeostasis can be restored by driving specific neurochemical activation of pre-sympathetic sites in the posterior hypothalamus. The proposed experiments will facilitate advanced training in new technical and conceptual realms, while additional career development activities include technical and grant writing workshops, academic coursework, training events sponsored by the Cardiovascular Center of Excellence, and regular meetings with the career advisory committee. The committee will remain active as mentors through both phases of the award, providing guidance on the transition to an independent position, as well as critiques of initial R01 submissions.
项目简介:本职业发展奖将支持我继续接受综合神经科学方面的培训,重点关注应激神经生物学对心血管病理生理学的贡献。筹资机制还提供了促进向独立过渡的独特机会。我的长期职业目标是建立一个独立的学术研究项目,调查前额叶皮质在异常应激反应产生中的作用,重点是心血管健康。确定心血管应激反应的机制是至关重要的,因为长期或重复的应激是心血管疾病的重要危险因素。此外,对急性应激的夸大生理反应预测心血管疾病的发生率,以及心脏相关的发病率和死亡率。然而,导致应激心血管后果的具体神经机制在很大程度上是未知的。这是一个研究不足但至关重要的研究领域,对理解和治疗心血管疾病具有重要意义,心血管疾病是美国的主要死亡原因。临床研究表明,额叶皮质功能低下影响心血管生理学,我们的初步数据表明,遗传驱动的下缘前额叶皮质(IL)输出减少加剧了大鼠对急性心理应激的心血管和内分泌反应。因此,目前的提案将探索IL抑制心血管应激反应的机制,目的是阐明高血压和心脏病等应激相关疾病的神经生物学基础。拟议中的研究将检验最重要的假设,即IL回路对于防止对应激增强的交感神经和内分泌反应是必要的,这些应激反应会促进慢性应激后的高血压、交感迷走神经失衡和心肌肥大。具体目标1将在指导阶段进行,并测试IL谷氨酸输出减少导致慢性应激诱导的心脏和血管病理的假设。重要的是,所有与心血管病理学相关的措施都代表着新的技术和概念培训。慢病毒介导的基因敲除将被用来评估IL输出在保护心血管反应对不可预测的慢性可变应激方案的敏感化方面的作用。超声心动图和心脏组织学将分别用于研究心脏功能和结构的变化。将对血管反应性、炎症介质和血浆脂类进行检测,以确定慢性应激下持续自主神经激活对血管的影响。针对特定目标2的训练将在指导阶段进行,实验将在独立阶段完成,以验证IL激活足以通过抑制交感神经系统来抑制心血管输出的假设。为了解决这一假设,对IL投射神经元的光遗传刺激将与无线电遥测相结合来测量心率、血压和局部交感神经活动。具体目标3将完全在独立阶段进行,并测试慢性应激对心血管反应性的影响可以通过刺激下丘脑下游交感前心脏调节区的谷氨酸受体来预防的假设。结合谷氨酸受体药理学研究CVS对下丘脑后部IL末端谷氨酸释放的光遗传刺激作用,将探讨该环路是否足以抑制慢性应激诱导的交感迷走神经失衡和糖皮质激素高分泌的表达。总而言之,这些目的是研究前额叶皮质输出减少对心血管的影响,并确定是否可以通过驱动下丘脑后部交感前部位的特定神经化学激活来恢复体内平衡。拟议的实验将促进新的技术和概念领域的高级培训,而其他职业发展活动包括技术和赠款编写讲习班、学术课程、由心血管英才中心赞助的培训活动,以及与职业咨询委员会的定期会议。该委员会将在奖项的两个阶段保持积极的指导作用,为向独立立场的过渡提供指导,以及对最初的R01提交的评论。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Brent Philip Myers其他文献

Brent Philip Myers的其他文献

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{{ truncateString('Brent Philip Myers', 18)}}的其他基金

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
  • 财政年份:
    2019
  • 资助金额:
    $ 13.09万
  • 项目类别:
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:
    10318619
  • 财政年份:
    2019
  • 资助金额:
    $ 13.09万
  • 项目类别:
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:
    10532021
  • 财政年份:
    2019
  • 资助金额:
    $ 13.09万
  • 项目类别:
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:
    10260200
  • 财政年份:
    2019
  • 资助金额:
    $ 13.09万
  • 项目类别:
Prefrontal Cortical Circuitry Attenuates Cardiovascular Stress Reactivity
前额皮质回路减弱心血管应激反应
  • 批准号:
    9377180
  • 财政年份:
    2017
  • 资助金额:
    $ 13.09万
  • 项目类别:
Estrogen Regulation of the Hypothalamic-Pituitary-Adrenal Axis
雌激素对下丘脑-垂体-肾上腺轴的调节
  • 批准号:
    10017956
  • 财政年份:
    2015
  • 资助金额:
    $ 13.09万
  • 项目类别:
Prefrontal Cortical Circuitry Attenuates Cardiovascular Stress Reactivity
前额皮质回路减弱心血管应激反应
  • 批准号:
    8822064
  • 财政年份:
    2014
  • 资助金额:
    $ 13.09万
  • 项目类别:

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