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名退伍军人和服役人员遭受创伤性脑损伤(TBI) 根据国防部(DOD)的说法。脑外伤的死亡率很高，许多幸存者患有 预期寿命缩短和永久性残疾，包括创伤后应激障碍，这可能 是由于自主神经系统(ANS)功能障碍。ANS功能障碍可以通过心脏减少来量化 心率变异性(HRV)和压力感受器反射敏感性(BRS)与神经功能不佳有关 结果、心律失常和死亡。拟议的研究将评估脑外伤受损的中枢神经回路以 解决了这样的假设，即脑外伤引起的自主神经障碍不仅是一个预后生物标志物，而且是一个 危害退伍军人健康的致病因素。这项提议研究的是杏仁核，这是一个大脑区域， 与恐惧、焦虑和创伤后应激障碍有关，以及与脑外伤后的行为病理学有关，但在 颅脑损伤后ANS功能障碍。杏仁核之所以令人感兴趣，是因为它控制着人类的ANS反应。 和啮齿动物；2)在人类脑损伤和动物模型中受损；3)导致人类的恐惧和焦虑 还有啮齿动物。这一系列因素对退伍军人的健康至关重要。 一种新的旋转脑损伤模型，这种生物工程模拟人类损伤的模型将在男性和 雌性老鼠。这种脑损伤模型导致行为和ANS缺陷，并损害杏仁核。建议数 研究将实施一种多方面的方法来检查脑外伤后的心血管(CV)障碍 通过外科植入的无线电遥测单元监测血压(BP)，心率(HR)，心率变异(HRV)， 在清醒的自由活动的雄性和雌性大鼠中，BRS发生在：1)静止、静息状态；2) 扰乱心血管动态平衡的药理应激源；3)药理和化学遗传学操作 杏仁核；4)恐惧条件反射与杏仁核依赖行为和CV之间的相关性 参数。 目的1将利用HRV和BRS研究脑损伤后杏仁核在自主神经紊乱中的作用。 药理应激源(全身性苯肾上腺素和硝普钠)和杏仁核微量注射。这个 基底外侧核(BLA)和中央杏仁核(CEA)将被伽马氨基丁酸(GABA)激动剂靶向 或拮抗剂，因为GABA能神经元控制杏仁核向行为环路和CV中心的流出。 目标2将评估杏仁核回路的化学遗传操作对心血管控制的影响。兴奋性或抑制性 DREADD(专门由特制药物激活的特制受体)将在杏仁核中表达。心率变异性 在DREADD的药物应激源引起的血压变化后，将在休息时和之后对BRS进行评估 确认杏仁核神经元是脑外伤后ANS功能障碍的潜在治疗靶点的配体或载体。 目标3将量化杏仁核介导的恐惧行为和ANS参数之间的关系 跟随着TBI。杏仁核依赖线索恐惧条件化、消退和恢复期间的行为将 在颅脑损伤后与HRV和BRS同步记录。恐惧条件反射对康复的影响 TBI将通过测量CV参数、体重和全球神经功能进行测试。 该提案将确定ANS功能障碍的神经生理和神经解剖学过程。 作为开发创新治疗战略的新目标的结果是创伤性脑损伤。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 在未来。这里使用的基本方法对退伍军人具有强大的翻译潜力 因为在正常情况下，这些参数可以在人体内进行长时间的非侵入性监测 休息时和紧张时的活动。短期目标将评估与脑外伤相关的ANS功能障碍 简历和情绪障碍，如焦虑或创伤后应激障碍。长期目标将中央电路定义为 为患有脑外伤的退伍军人提供治疗目标，以提高他们的生活质量和长期生存。