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 - 30，000名退伍军人和服务人员遭受创伤性脑损伤（TBI） 据美国国防部（DOD）。TBI的死亡率很高，许多幸存者患有 预期寿命缩短和持续残疾，包括创伤后应激障碍（PTSD），这可能 自主神经系统（ANS）功能障碍。ANS功能障碍可以通过减少心脏 心率变异性（HRV）和压力感受器反射敏感性（BRS），这与不良的神经系统 结果心律失常和死亡拟议的研究将评估TBI受损的中枢神经元回路， 解决了TBI诱导的植物神经功能障碍不仅是一种预后生物标志物， 危害退伍军人健康的致病因素这项提议研究了杏仁核，这是一个大脑区域， 与恐惧、焦虑和创伤后应激障碍有关，也与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和动物模型中受损;和3）导致人类的恐惧和焦虑 和啮齿动物。这些因素对退伍军人的健康至关重要。 一种新的旋转TBI模型，它是生物工程模拟人类损伤将采用在男性和 雌性大鼠这种TBI模型诱导行为和ANS缺陷，并损害杏仁核。拟议 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单元监测血压（BP），心率（HR），HRV， 和BRS将在清醒的自由活动的雄性和雌性大鼠中在以下期间得到：1）不活动的静息状态; 2） 药理学应激源，扰乱CV稳态; 3）药理学和化学遗传学操纵 杏仁核依赖行为与CV的相关性 参数 目的1将研究杏仁核在TBI后自主神经功能障碍中的作用， 药理应激（全身性苯肾上腺素和硝普钠）和杏仁核微量注射。的 基底外侧（BLA）和中央杏仁核（CeA）将被γ-氨基丁酸（GABA）激动剂靶向 或拮抗剂，因为GABA能神经元控制杏仁核流出到行为回路和CV中心。 目的2将评估化学遗传操纵杏仁核回路CV控制。兴奋性或抑制性 DREADDs（专门由设计药物激活的设计受体）将在杏仁核中表达。HRV 和BRS将在休息时和由于DREADD的药理学应激源导致的BP变化后进行评价 配体或媒介物来确认杏仁核神经元作为TBI后ANS功能障碍的潜在治疗靶点。 目的3将量化杏仁核介导的恐惧行为与ANS参数之间的关系 TBI之后。在杏仁核依赖的恐惧条件反射、消退和恢复过程中的行为将 与TBI后的HRV和BRS同时记录。恐惧条件反射对术后恢复的影响 将通过测量CV参数、体重和整体神经功能来测试TBI。 这项建议将确定神经生理学和神经解剖学过程的基础ANS功能障碍 作为开发创新治疗策略的新靶点。该奖项将提供 为职业发展打下坚实的基础，期望涵盖一系列相关的研究领域 在未来这里采用的基本方法论方法对退伍军人有强大的转化潜力 因为这些参数可以在人类中非侵入性地监测很长时间 在休息和压力下的活动。短期目标将评估TBI相关的ANS功能障碍， CV和情绪障碍，如焦虑或PTSD。长期目标将把中央电路定义为 治疗目标的退伍军人是从创伤性脑损伤，以改善他们的生活质量和长期生存。