Alcohol and Traumatic Brain Injury; Neuronal and Behavioral Consequences

酒精和创伤性脑损伤；

• 批准号: 10369721
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369721
• 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）困扰着军事和平民的许多男人和女人。早 TBI后期的特征是神经炎症和氧化应激，随后是神经性变化 其中包括睡眠障碍，神经内分泌功能障碍，认知障碍和行为障碍 其中包括更高的焦虑和抑郁，压力敏感性提高，Anhedonia，冲动控制缺陷以及 较高的疼痛敏感性。所有这些行为症状都可以促进人类中升级的饮酒 试图减轻症状的尝试，这最终会增加酒精饮用障碍的可能性 （AUD）诊断。 TBI饮酒后的神经生物学机制不是 已知。从医疗保健负担的角度来看，我们的实验室和其他人表明了TBI酒精后 暴露会损害神经行为功能的恢复，加剧神经胶质病，并防止解决 神经炎症。初步数据显示，在 受伤部位和基底外侧杏仁核，我们认为这是TBI之前观察到的基础 饮酒的升级和增加酒精的动力。此外，我们的数据表明一个 JZL184的伤害后给药，一种单酰甘油脂肪酶（MAGL）抑制剂，可防止内源性大麻素 降解，减轻神经炎症并改善TBI后神经性恢复。此外， JZL184挽救了损伤部位过多的谷氨酸能信号传导和神经元过度刺激性，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检验突触的假设 过度兴奋性与TBI后的焦虑样行为和饮酒有关。我们预测 该药理（即JZL184）和非药理（即禁欲）的治疗干预措施将 减少TBI饮酒后的升级后，并防止饮酒者的TBI突触过度兴奋。 提出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）。一个研究人员的跨学科团队 对TBI研究和对酒精的炎症反应的成就记录（Molina）；动物 酒精自我给药，依赖性和行为药理学的模型（Gilpin）；生化信号传导 酒精依赖机制（爱德华兹）；和神经元突触的电生理研究 电路（Middleton）将进行它们。该项目的总体目标是确定是否防止 杏仁核中TBI突触可塑性可防止TBI饮酒后的升级和 改善了TBI后的结果。研究将得到杰出的科学环境和核心的支持 NIAAA资助的LSUHSC综合酒精研究中心支持的分析设施。