Alcohol and Traumatic Brain Injury; Neuronal and Behavioral Consequences

酒精和创伤性脑损伤；

• 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
• 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

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.

项目摘要 创伤性脑损伤（TBI）困扰着许多军人和平民。早期 创伤后时期的特征是神经炎症和氧化应激，随后是神经行为变化 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，快感缺乏，冲动控制缺陷， 更高的疼痛敏感性。所有这些行为症状都可以促进人类饮酒的升级， 试图减轻他们的症状，这最终会增加酒精使用障碍的可能性 (AUD)诊断.脑外伤后饮酒升级的神经生物学机制并不 知道的从医疗负担的角度来看，我们的实验室和其他实验室已经表明，TBI后的酒精 暴露损害神经行为功能的恢复，加重神经胶质增生，并阻止神经功能恢复。 神经炎症初步数据显示，在100 - 200 ℃时， 我们认为这是以前观察到的脑外伤后的基础 饮酒量的增加和获得酒精的动机增加。此外，我们的数据显示， 损伤后给予JZL 184，一种防止内源性大麻素的单酰基甘油脂酶（MAGL）抑制剂 在TBI后，它可以促进神经降解，减弱神经炎症并改善神经行为恢复。此外，本发明还提供了一种方法， JZL 184拯救损伤部位的过度的神经元能信号传导和神经元过度兴奋，并降低 获得酒精的动机。拟议中的研究将使用雄性和雌性大鼠来验证突触 过度兴奋与TBI后焦虑样行为和饮酒的增加有关。我们预测 药理学上（即，JZL 184）和非药理学（即，禁欲）治疗干预措施将 减少TBI后饮酒的升级并预防饮酒者中的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）。一个跨学科的研究团队， 建立TBI和酒精炎症反应研究成果记录（Molina）;动物 酒精自我管理，依赖和行为药理学模型（吉尔平）;生化信号 酒精依赖的机制（爱德华兹）;和神经元突触的电生理学研究 电路（米德尔顿）将进行他们。该项目的首要目标是确定是否预防 杏仁核中的病理性TBI后突触可塑性防止了TBI后饮酒的升级， 改善TBI后的结果。研究将得到杰出的科学环境和核心的支持 由NIAAA资助的LSUHSC综合酒精研究中心支持的分析设施。