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） 根据国防部（国防部）的说法。 TBI的死亡率很高，许多冲浪者遭受 降低了预期寿命和持续性残疾，包括创伤后应激障碍（PTSD），可能 由于自主神经系统（ANS）功能障碍。可以通过减少心脏来量化ANS功能障碍 速率变异性（HRV）和压力感受器反射灵敏度（BRS），与神经系统差有关 结果，心律不齐和死亡。拟议的研究将评估TBI受损的中央神经元电路 解决了TBI诱导的功能障碍不仅是预后生物标志物，而且还解决了总体假设 致病元素损害了退伍军人的健康。该建议投资杏仁核，这是一个大脑区域 与恐惧，动画和PTSD以及TBI之后的行为病理有关，但在 TBI后的ANS功能障碍。杏仁核令人感兴趣，因为它：1）控制人类的ANS响应 和啮齿动物； 2）;在人类TBI和动物模型中损坏； 3）有助于人类的恐惧和动画 和啮齿动物。这一因素星座对于退伍军人健康至关重要。 一种新型的旋转TBI模型，该模型被生物工程为模仿人类伤害，将在男性和 雌鼠。该TBI模型诱导行为，ANS定义并损坏了杏仁核。提议 研究将实施一种多方面的方法来检查TBI之后的心血管（CV）灾难 通过手术植入的放射性骨化单元监测血压（BP），心率（HR），HRV， 在以下情况下，BRS将衍生在自由移动的男性和雌性大鼠中：1）不活跃的静止状态； 2） 干扰CV稳态的药理压力源； 3）药理学和化学发生操作 杏仁核； 4）与杏仁核依赖性行为与简历之间的相关性的恐惧调节 参数。 AIM 1将使用HRV和BRS响应于TBI后杏仁核在Dysautonomia中的作用 药理学应激源（全身苯肾上腺素和硝化丙肾）和杏仁核显微注射。这 Bosolatoral（BLA）和中央杏仁核（CEA）将以γ-氨基丁酸（GABA）激动剂为目标 或拮抗剂，因为GABA能神经元将杏仁核的插座控制到行为电路和简历中心。 AIM 2将评估CV控制中杏仁核电路的化学发生操作。兴奋性或抑制性 Dreadds（Designer接收器专门由设计师药物激活）将在杏仁核中表达。 HRV 将在静止状态和BP变化之后评估BRS，这是由于Dreadd的药物应激源而导致的 配体或车辆确认杏仁核神经元是TBI后ANS功能障碍的潜在治疗靶点。 AIM 3将量化杏仁核介导的恐惧行为与ANS参数之间的关系 遵循TBI。杏仁核依赖性提示的恐惧调节，扩展和恢复原状的行为将 在TBI之后，仅使用HRV和BRS记录。恐惧调节对康复的影响 TBI将通过测量CV参数，体重和全局神经功能来测试。 该建议将确定ANS功能障碍基础的神经生理和神经解剖过程 因此，TBI是开发创新治疗策略的新目标。该奖项将提供 在职业发展的稳固基础，期望涵盖一系列相关领域 将来。这里采取的基本方法论方法对退伍军人具有强大的翻译潜力 因为这些参数可以在正常情况下长时间在人类中进行非侵入性监测 休息和压力期间的活动。短期目标将评估与TBI相关的ANS功能障碍，从而有助于 简历和情绪障碍，例如焦虑或PTSD。长期目标将将中央电路定义为 患有TBI的退伍军人的治疗目标，以改善其生活质量和长期生存。