Alcohol exposure exacerbates inflammation and anxiety-like behavior induced by repeated mild TBI during adolescence

摘要 脑外伤是美国40岁以下人群死亡和残疾的主要原因，患有轻度脑损伤 (MTBI)是中、重度损伤总和的三倍。目前，没有 脑外伤后保存或恢复脑组织和功能的有效疗法。因此，个人可能会 面临终生的赤字。大约五分之一的青少年自我报告有过一次或多次轻度脑外伤 (MTBI)，青少年运动员比非运动同龄人风险更高。此外，青少年 参加团体运动的人更有可能参加饮酒。脑外伤和酒精都是已知的 引起神经炎症，这可能对发育中的青少年大脑特别有害，包括 据报道，在这两种侮辱中的任何一种单独发生后，焦虑的发生率都会更高。而轻度脑损伤(MTBI)是 最常见的是，研究表明，随着时间的推移，重复mTBI(RmTBI)的影响可以积累到 可与中度甚至严重伤害相媲美的损害。此外，研究表明， 脑外伤在发育过程中的炎症效应可能会导致对酒精的过度炎症反应。 在这项研究中，我们建议将青春期雄性和雌性大鼠暴露于一系列四种MTBI中，其中穿插着 酒精暴露的事件来验证这样的假设：虽然rmTBI和青春期的酒精暴露 两者都单独引起神经炎症，这些侮辱的组合将加剧这种影响，并且 这将转化为类似焦虑的行为的增加。最后，我们将用反 炎症性药物利洛酮研究是否可以改善脑损伤后的神经炎症，导致 这些结果的改善。

ABSTRACT TBI is the leading cause of death and disability in people under 40 in the United States, with mild TBI (mTBI) being three times more common than moderate and severe injury combined. Currently, there are no effective therapeutics that will preserve or restore brain tissue and function after TBI. As a result, individuals may face a lifetime of deficits. Approximately one in five adolescents self-report having had one or more mild TBI (mTBI) with adolescent athletes being at a higher risk than non-athletic peers. Additionally, adolescents participating in team sports are more likely to take part in alcohol consumption. Both TBI and alcohol are known to cause neuroinflammation, which can be especially damaging to the developing, adolescent brain, including a higher incidence of anxiety reported following either of these insults independently. While mild TBI (mTBI) is the most common, research has shown that the effects of repeated mTBI (rmTBI) over time can build to a level of damage comparable to moderate or even severe injury. Additionally, studies have suggested that the inflammatory effects of TBI during development can lead to an exaggerated inflammatory response to alcohol. In this study, we propose to expose adolescent male and female rats to a series of four mTBIs interspersed with episodes of alcohol exposure to test the hypothesis that while rmTBI and alcohol exposure during adolescence both independently cause neuroinflammation, the combination of these insults will exacerbate this effect, and that this will translate to increases in anxiety-like behavior. Finally, we will treat these animals with the anti- inflammatory drug licofelone to investigate whether post-TBI neuroinflammation can be ameliorated, leading to an improvement in these outcomes.