Cardiovascular dysfunction following Traumatic Brain Injury
脑外伤后的心血管功能障碍
基本信息
- 批准号:10365397
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAmygdaloid structureAnimal ModelAnxietyAnxiety DisordersArrhythmiaAutonomic nervous systemAwardBaroreflexBehaviorBehavior ControlBehavioralBiological MarkersBiomedical EngineeringBlood PressureBlood Pressure MonitorsBody WeightBrainBrain ConcussionBrain regionCardiovascular DiseasesCardiovascular PhysiologyCardiovascular systemCessation of lifeChronicCuesDataDepartment of DefenseDevelopmentDiseaseDysautonomiasElementsExposure toExtinction (Psychology)FemaleFoundationsFrightFunctional disorderFutureGABA AgonistsGoalsHealthHeartHeart DiseasesHeart RateHomeostasisHumanImpairmentImplantInjuryKnowledgeLife ExpectancyLigandsLinkMeasuresMediatingMedicalMental HealthMethodologyMicroinjectionsModelingMood DisordersMorbidity - disease rateNatureNervous System PhysiologyNeurological outcomeNeuronsNitroprussideOperative Surgical ProceduresOutcomePathogenicityPathologyPersonsPharmacologyPhenylephrinePost-Traumatic Stress DisordersProcessPrognostic MarkerQuality of lifeRattusRecoveryRegulationRehabilitation therapyRestRodentRoleRotationServicesSiteSolidStressStructureSurvivorsTechnologyTelemetryTestingThallium Myocardial Perfusion Imaging Stress TestTherapeuticTimeTrainingTraumaTraumatic Brain InjuryTraumatic Brain Injury recoveryUnconscious StateVariantVehicle crashVeteransadeno-associated viral vectorantagonistawakecareer developmentcombatconditioned feardesigner receptors exclusively activated by designer drugsdisabilityexpectationfallsfield studygamma-Aminobutyric Acidhealth care service utilizationheart rate variabilityimprovedinjuredinnovationinterestmalemortalityneuronal circuitryneurophysiologynew therapeutic targetnon-invasive monitornovelprematurepressureprognosticationresponseservice memberstressortherapeutic targettranslational potentialtreatment strategy
项目摘要
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)。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher Jon Roberts其他文献
Christopher Jon Roberts的其他文献
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{{ truncateString('Christopher Jon Roberts', 18)}}的其他基金
Cardiovascular dysfunction following Traumatic Brain Injury
脑外伤后的心血管功能障碍
- 批准号:
10617713 - 财政年份:2022
- 资助金额:
-- - 项目类别: