Alcohol and Traumatic Brain Injury; Neuronal and Behavioral Consequences

酒精和创伤性脑损伤；

基本信息

批准号：
9904464
负责人：
NICHOLAS WARREN GILPIN
金额：
$ 32.85万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-10 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904464
关键词：
Abstinence Alcohol consumption Alcohol dependence Alcohols Amygdaloid structure Anhedonia Animal Model Anxiety Astrocytosis Attenuated Behavior Behavioral Behavioral Symptoms Biochemical Biochemistry Brain Injuries CNR1 gene Chronic Brain Injury Collaborations Cytokine Gene Data Dependence Diagnosis Electrophysiology (science)Endocannabinoids Environment Female Foundations Functional disorder Funding Gene Expression Gliosis Goals Guidelines Healthcare Human Immunohistochemistry Impaired cognition Impairment Incidence Individual Inflammatory Inflammatory Response Injections Injury Investigation MAGL inhibitor Measures Mediating Mental Depression Military Personnel Modeling Monoacylglycerol Lipases Motivation National Institute on Alcohol Abuse and Alcoholism Neurologic Neurons Neurosecretory Systems Outcome Oxidative Stress Pain Pathologic Patients Pharmaceutical Preparations Pharmacology Population Publishing Rattus Recording of previous events Records Recovery Research Personnel Resolution Rodent Role Self Administration Signal Transduction Site Sleep disturbances Slice Stress Symptoms Synapses Synaptic plasticity Testing Therapeutic Intervention Tissues Traumatic Brain Injury Western Blotting Woman alcohol effect alcohol exposure alcohol reinforcement alcohol research alcohol response alcohol use disorder anxiety-like behavior approach behavior base behavioral impairment behavioral pharmacology comorbidity designer receptors exclusively activated by designer drugs endogenous cannabinoid system glutamatergic signaling improved injury recovery male men neural circuit neurobehavioral neurobiological mechanism neuroinflammation neuropathology pain sensitivity post intervention prevent protein expression response response to brain injury vapor

项目摘要

Project Summary Traumatic brain injury (TBI) afflicts many men and women in both military and civilian populations. The early post-TBI period is characterized by neuroinflammation and oxidative stress followed by neurobehavioral changes that include sleep disturbances, neuroendocrine dysfunction, cognitive impairments, and behavioral impairments that include higher anxiety and depression, increased stress sensitivity, anhedonia, impulse control deficits, and higher pain sensitivity. All of these behavioral symptoms can promote escalated alcohol drinking in humans in an attempt to mitigate their symptoms, and this can eventually increase the likelihood of an alcohol use disorder (AUD) diagnosis. The neurobiological mechanisms underlying post-TBI escalation of alcohol drinking are not known. Critical from a healthcare burden perspective, our lab and others have shown that post-TBI alcohol exposure impairs recovery of neurobehavioral function, exacerbates gliosis, and prevents resolution of neuroinflammation. Preliminary data show increased glutamatergic signaling and synaptic hyperexcitability at the site of injury and in the basolateral amygdala, which we believe underlies previously observed post-TBI escalation of alcohol drinking and increased motivation to obtain alcohol. Moreover, our data show that a single post-injury administration of JZL184, a monoacylglycerol lipase (MAGL) inhibitor that prevents endocannabinoid degradation, attenuates neuroinflammation and improves neurobehavioral recovery post-TBI. In addition, JZL184 rescues excessive glutamatergic signaling and neuronal hyperexcitability at site of injury, and reduces motivation to obtain alcohol. Proposed studies will use male and female rats to test the hypothesis that synaptic hyperexcitability is associated with post-TBI increases in anxiety-like behavior and alcohol drinking. We predict that pharmacological (i.e., JZL184) and non-pharmacological (i.e., abstinence) therapeutic interventions will reduce post-TBI escalation of alcohol drinking and prevent post-TBI synaptic hyperexcitability in alcohol drinkers. Studies proposed will use an integrated experimental approach (behavior, immunohistochemistry, biochemistry, electrophysiology, pharmacology, and chemogenetics). An interdisciplinary team of investigators with established records of accomplishment on studies of TBI and inflammatory responses to alcohol (Molina); animal models of alcohol self-administration, dependence, and behavioral pharmacology (Gilpin); biochemical signaling mechanisms of alcohol dependence (Edwards); and electrophysiological investigations of neuronal synaptic circuitry (Middleton) will conduct them. The overarching goal of this project is to determine whether preventing pathological post-TBI synaptic plasticity in amygdala prevents post-TBI escalation of alcohol drinking and improves post-TBI outcomes. Studies will be supported by the outstanding scientific environment and Core analytical facilities supported by the NIAAA-funded LSUHSC Comprehensive Alcohol Research Center.

项目概要创伤性脑损伤 (TBI) 困扰着许多军人和平民。早期的 TBI 后时期的特点是神经炎症和氧化应激，随后出现神经行为变化包括睡眠障碍、神经内分泌功能障碍、认知障碍和行为障碍包括更高的焦虑和抑郁、压力敏感性增加、快感缺失、冲动控制缺陷，以及更高的疼痛敏感性。所有这些行为症状都会促进人类饮酒量的增加试图减轻症状，这最终会增加酒精使用障碍的可能性（澳元）诊断。 TBI 后饮酒增加的神经生物学机制并不已知。从医疗保健负担的角度来看，至关重要的是，我们的实验室和其他实验室已经表明，TBI 后的酒精暴露会损害神经行为功能的恢复，加剧神经胶质增生，并阻碍神经行为功能的解决神经炎症。初步数据显示，谷氨酸能信号传导和突触过度兴奋性增加损伤部位和基底外侧杏仁核，我们认为这是之前观察到的 TBI 后观察到的基础饮酒量增加和获取酒精的动机增加。此外，我们的数据表明，单个损伤后给予 JZL184，一种单酰基甘油脂肪酶 (MAGL) 抑制剂，可预防内源性大麻素降解，减轻神经炎症并改善 TBI 后的神经行为恢复。此外， JZL184 可以挽救损伤部位的过度谷氨酸信号传导和神经元过度兴奋，并减少获得酒精的动机。拟议的研究将使用雄性和雌性大鼠来测试突触的假设过度兴奋与 TBI 后焦虑样行为和饮酒的增加有关。我们预测药理学（即 JZL184）和非药理学（即禁欲）治疗干预将减少 TBI 后饮酒量的增加，并防止饮酒者 TBI 后突触过度兴奋。拟议的研究将使用综合实验方法（行为、免疫组织化学、生物化学、电生理学、药理学和化学遗传学）。由跨学科研究人员组成的团队建立了 TBI 和酒精炎症反应研究的成就记录 (Molina)；动物酒精自我管理、依赖性和行为药理学模型（Gilpin）；生化信号传导酒精依赖机制（爱德华兹）；神经元突触和电生理学研究电路（米德尔顿）将指挥它们。该项目的总体目标是确定是否可以预防杏仁核的病理性 TBI 后突触可塑性可防止 TBI 后饮酒和饮酒的升级改善 TBI 后的结果。研究将得到优秀的科学环境和核心的支持分析设施由 NIAAA 资助的 LSUHSC 综合酒精研究中心提供支持。