Alcohol and Traumatic Brain Injury; Neuronal and Behavioral Consequences

项目摘要 无论是军人还是平民，创伤性脑损伤都困扰着许多男性和女性。最早的 创伤性脑损伤后的特点是神经炎症和氧化应激，随后是神经行为的改变 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，更高的压力敏感度，快感缺失，冲动控制缺陷，以及 更高的疼痛敏感度。所有这些行为症状都会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 (澳元)诊断。脑外伤后饮酒升级的神经生物学机制不是 为人所知。从医疗负担的角度来看，至关重要的是，我们的实验室和其他实验室已经表明，脑外伤后的酒精 暴露会损害神经行为功能的恢复，加剧胶质细胞增生症，并阻止 神经炎。初步数据显示，谷氨酸能信号和突触超兴奋性在 损伤部位和杏仁基底外侧核，我们认为这是先前观察到的脑损伤后的基础 饮酒升级和获得酒精的动机增加。此外，我们的数据显示，单个 单酰甘油脂肪酶(MAGL)抑制剂JZL184对内源性大麻素的抑制作用 降解，减轻神经炎症，改善脑损伤后的神经行为恢复。此外, JZL184挽救损伤部位过多的谷氨酸能信号和神经元的过度兴奋性，并降低 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 过度兴奋与脑外伤后焦虑样行为和饮酒增加有关。我们预测 药理学(即JZL184)和非药理学(即戒断)治疗干预将 减少脑损伤后酒精饮酒的升级，防止酒精饮用者脑损伤后突触过度兴奋。 建议的研究将使用综合实验方法(行为学、免疫组织化学、生物化学、 电生理学、药理学和化学遗传学)。一个由多个学科组成的调查小组 创伤性脑损伤与酒精炎症反应研究成果记录(Molina)；动物 酒精自我给药、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)；神经元突触的电生理研究 电路(米德尔顿)将指导他们。该项目的总体目标是确定是否要防止 病理性脑损伤后杏仁核突触可塑性阻止脑损伤后饮酒和 改善脑外伤后的转归。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。

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.