Cardiovascular dysfunction following Traumatic Brain Injury

脑外伤后的心血管功能障碍

• 批准号: 10365397
• 负责人: Christopher Jon Roberts
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365397
• 关键词: Address; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Arrhythmia; Autonomic nervous system; Award; Baroreflex; Behavior; Behavior Control; Behavioral; Biological Markers; Biomedical Engineering; Blood Pressure; Blood Pressure Monitors; Body Weight; Brain; Brain Concussion; Brain region; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cessation of life; Chronic; Cues; Data; Department of Defense; Development; Disease; Dysautonomias; Elements; Exposure to; Extinction (Psychology); Female; Foundations; Fright; Functional disorder; Future; GABA Agonists; Goals; Health; Heart; Heart Diseases; Heart Rate; Homeostasis; Human; Impairment; Implant; Injury; Knowledge; Life Expectancy; Ligands; Link; Measures; Mediating; Medical; Mental Health; Methodology; Microinjections; Modeling; Mood Disorders; Morbidity - disease rate; Nature; Nervous System Physiology; Neurological outcome; Neurons; Nitroprusside; Operative Surgical Procedures; Outcome; Pathogenicity; Pathology; Persons; Pharmacology; Phenylephrine; Post-Traumatic Stress Disorders; Process; Prognostic Marker; Quality of life; Rattus; Recovery; Regulation; Rehabilitation therapy; Rest; Rodent; Role; Rotation; Services; Site; Solid; Stress; Structure; Survivors; Technology; Telemetry; Testing; Thallium Myocardial Perfusion Imaging Stress Test; Therapeutic; Time; Training; Trauma; Traumatic Brain Injury; Traumatic Brain Injury recovery; Unconscious State; Variant; Vehicle crash; Veterans; adeno-associated viral vector; antagonist; awake; career development; combat; conditioned fear; designer receptors exclusively activated by designer drugs; disability; expectation; falls; field study; gamma-Aminobutyric Acid; health care service utilization; heart rate variability; improved; injured; innovation; interest; male; mortality; neuronal circuitry; neurophysiology; new therapeutic target; non-invasive monitor; novel; premature; pressure; prognostication; response; service member; stressor; therapeutic target; translational potential; treatment strategy

Every year more than 15,000 – 30,000 Veterans and service members suffer a traumatic brain injury (TBI) according to the Department of Defense (DOD). Mortality from TBI is high and many survivors suffer from reduced life expectancy and persistent disability, including post-traumatic stress disorder (PTSD), which might be due to autonomic nervous system (ANS) dysfunction. ANS dysfunction can be quantified by reduced heart rate variability (HRV) and baroreceptor reflex sensitivity (BRS), which are associated with poor neurological outcomes, arrhythmias, and death. The proposed studies will assess TBI-impaired central neuronal circuitry to address the overall hypothesis that TBI-induced dysautonomia is not only a prognostic biomarker, but also a pathogenic element compromising Veteran's health. This proposal investigates the amygdala, a brain region that is related to fear, anxiety and PTSD, as well as in behavioral pathology following TBI, but is under-studied in the ANS dysfunction following TBI. The amygdala is of interest because it: 1) controls ANS responses in humans and rodents; 2); is damaged in human TBI and animal models; and 3) contributes to fear and anxiety in humans and rodents. This constellation of factors is critical for Veterans health. A novel, rotational TBI model, that is bioengineered to mimic human injury will be employed in male and female rats. This TBI model induces behavioral and ANS deficits, and damages the amygdala. The proposed studies will implement a multi-faceted approach to examine cardiovascular (CV) disturbances following TBI by monitoring blood pressure (BP) via surgically implanted radiotelemetry units from which heart rate (HR) , HRV, and BRS will be derived in awake freely moving male and female rats during: 1) inactive, resting states; 2) pharmacological stressors that disturb CV homeostasis; 3) pharmacological and chemogenetic manipulation of the amygdala; and 4) fear conditioning with correlation between amygdala-dependent behaviors and CV parameters. Aim 1 will examine the role of the amygdala in dysautonomia after TBI using HRV and BRS in response to pharmacological stressors (systemic phenylephrine and nitroprusside) and amygdala microinjections. The basolateral (BLA) and central amygdala (CeA) will be targeted with gamma-aminobutyric acid (GABA) agonists or antagonists because GABAergic neurons control amygdala outflow to behavioral circuits and CV centers. Aim 2 will assess chemogenetic manipulation of amygdala circuits on CV control. Excitatory or inhibitory DREADDs (designer receptors exclusively activated by designer drugs) will be expressed in the amygdala. HRV and BRS will be evaluated at rest and following BP changes due to pharmacological stressors with DREADD ligand or vehicle to confirm amygdala neurons as a potential therapeutic target for ANS dysfunction after TBI. Aim 3 will quantify the relationship between amygdala mediated fear behaviors and ANS parameters following TBI. Behaviors during amygdala-dependent cued fear conditioning, extinction and reinstatement will be recorded simultaneously with HRV and BRS following TBI. The impact of fear conditioning on recovery after TBI will be tested by measuring CV parameters, body weight, and global neurological function. This proposal will identify neurophysiological and neuroanatomical processes underlying ANS dysfunction consequent to TBI as novel targets for development of innovative treatment strategies. This award will provide a solid foundation for career development with the expectation of encompassing a range of related fields of study in the future. The basic methodological approach employed here has powerful translational potential to Veterans because these parameters can be monitored non-invasively in humans over long periods of time during normal activities at rest and during stress. The short-term goal will assess TBI related ANS dysfunction contributing to CV and mood disorders, such as anxiety or PTSD. The long-term goal will define the central circuitry as a therapeutic target for Veterans that are suffering from TBI to improve their quality of life and long-term survival.

每年有超过 15,000 至 30,000 名退伍军人和现役军人遭受创伤性脑损伤 (TBI) 据国防部 (DOD) 称。 TBI 死亡率很高，许多幸存者患有以下疾病 预期寿命缩短和持续残疾，包括创伤后应激障碍（PTSD），这可能 是由于自主神经系统（ANS）功能障碍造成的。 ANS 功能障碍可以通过心脏下降来量化 速率变异性（HRV）和压力感受器反射敏感性（BRS），这与神经功能不良有关 结果、心律失常和死亡。拟议的研究将评估 TBI 损伤的中枢神经元回路，以 解决了总体假设，即 TBI 引起的自主神经功能障碍不仅是一种预后生物标志物，而且也是一种 危害退伍军人健康的致病因素。该提案研究了杏仁核，这是一个大脑区域， 与恐惧、焦虑和创伤后应激障碍 (PTSD) 以及创伤性脑损伤 (TBI) 后的行为病理学有关，但在 TBI 后 ANS 功能障碍。杏仁核之所以令人感兴趣，是因为它：1）控制人类的 ANS 反应 和啮齿动物； 2）；在人类 TBI 和动物模型中受到损害； 3）导致人类恐惧和焦虑 和啮齿动物。这一系列因素对于退伍军人的健康至关重要。 一种新颖的旋转 TBI 模型，经过生物工程设计以模拟人体损伤，将用于男性和女性 雌性老鼠。这种 TBI 模型会诱发行为和 ANS 缺陷，并损害杏仁核。拟议的 研究将采用多方面的方法来检查 TBI 后的心血管 (CV) 紊乱 通过手术植入的无线电遥测装置监测血压 (BP)，其中心率 (HR)、HRV、 BRS 来源于清醒、自由活动的雄性和雌性大鼠，其处于以下状态： 1) 不活动、休息状态； 2） 扰乱心血管稳态的药物应激源； 3) 药理学和化学遗传学操作 杏仁核； 4）恐惧调节与杏仁核依赖性行为和CV之间的相关性 参数。 目标 1 将使用 HRV 和 BRS 来检查杏仁核在 TBI 后自主神经功能障碍中的作用，以响应 药理学应激源（全身去氧肾上腺素和硝普钠）和杏仁核微注射。这 γ-氨基丁酸（GABA）激动剂将靶向基底外侧（BLA）和中央杏仁核（CeA） 或拮抗剂，因为 GABA 能神经元控制杏仁核向行为回路和心血管中心的流出。 目标 2 将评估杏仁核回路对 CV 控制的化学遗传学操作。兴奋性或抑制性 DREADD（仅由设计药物激活的设计受体）将在杏仁核中表达。心率变异性 BRS 将在静息时以及由于 DREADD 药物应激源引起的血压变化后进行评估 配体或载体确认杏仁核神经元作为 TBI 后 ANS 功能障碍的潜在治疗靶点。 目标 3 将量化杏仁核介导的恐惧行为与 ANS 参数之间的关系 TBI 后。杏仁核依赖性提示恐惧调节、消除和恢复期间的行为将 TBI 后与 HRV 和 BRS 同时记录。恐惧调节对术后恢复的影响 TBI 将通过测量 CV 参数、体重和整体神经功能进行测试。 该提案将确定 ANS 功能障碍背后的神经生理学和神经解剖学过程 TBI 作为开发创新治疗策略的新目标。该奖项将提供 为职业发展奠定坚实的基础，期望涵盖一系列相关的研究领域 将来。这里采用的基本方法对退伍军人来说具有强大的转化潜力 因为这些参数可以在正常情况下长时间对人体进行非侵入性监测 休息时和压力期间的活动。短期目标将评估 TBI 相关的 ANS 功能障碍，导致 心血管和情绪障碍，例如焦虑或创伤后应激障碍。长期目标将把中央电路定义为 患有 TBI 的退伍军人的治疗目标，以改善他们的生活质量和长期生存。