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）。