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

酒精暴露会加剧青春期期间反复轻度 TBI 引起的炎症和焦虑样行为

• 批准号: 10605755
• 负责人: Sydney M Vita
• 金额: $ 6.72万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605755
• 关键词: ARHGEF5 gene; Address; Adolescence; Adolescent; Adult; Affect; Alcohol consumption; Alcohols; Animal Model; Animals; Anti-Inflammatory Agents; Anxiety; Anxiety Disorders; Area; Astrocytes; Automobile Driving; Behavioral; Brain; Cause of Death; Clinical; Complex; Development; Environment; Enzymes; Event; Exposure to; Face; Female; Financial cost; Funding; General Population; Growth and Development function; Health; Hippocampus (Brain); Human; Immunohistochemistry; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Knowledge; Lead; Link; Lipoxygenase; Lipoxygenase Inhibitors; Male Adolescents; Measures; Mentors; Microglia; Modeling; Motion; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Neurons; Oral; Outcome; Outcome Measure; Patient Self-Report; Performance; Persons; Pharmaceutical Preparations; Physiology; Population; Pre-Clinical Model; Predisposition; Prostaglandin-Endoperoxide Synthase; Public Health; Rattus; Recording of previous events; Reporting; Research; Role; Series; Sex Differences; Signal Transduction; Site; Sports; Testing; Time; Translating; Traumatic Brain Injury; United States; Western Blotting; Wistar Rats; Work; adolescent alcohol exposure; alcohol exposure; alcohol research; alcohol response; anxiety-like behavior; axon injury; base; brain tissue; chemokine; clinically relevant; comorbidity; cytokine; designer receptors exclusively activated by designer drugs; disability; high risk; improved outcome; inflammatory marker; male; mild traumatic brain injury; neuroinflammation; novel therapeutics; peer; preservation; severe injury; therapeutically effective; tool

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.

抽象的 TBI 是美国 40 岁以下人群死亡和残疾的主要原因，轻度 TBI (mTBI) 的发生率是中度和重度损伤总和的三倍。目前，没有 有效的治疗方法可以在 TBI 后保留或恢复脑组织和功能。结果，个人可能 面临一生的赤字。大约五分之一的青少年自我报告患有一次或多次轻度 TBI （mTBI），青少年运动员比非运动同龄人面临更高的风险。此外，青少年 参加团队运动的人更有可能参加饮酒。 TBI 和酒精都是已知的 引起神经炎症，这对发育中的青少年大脑尤其有害，包括 在这些侮辱中的任何一种独立后，报告的焦虑发生率更高。虽然轻度 TBI (mTBI) 是 最常见的是，研究表明，随着时间的推移，重复 mTBI (rmTBI) 的影响可能会达到以下水平： 伤害相当于中度甚至重度伤害。此外，研究表明， 发育过程中 TBI 的炎症作用可能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穿插有 酒精暴露事件来检验以下假设：青少年时期 rmTBI 和酒精暴露 两者都独立地引起神经炎症，这些损伤的结合会加剧这种影响，并且 这将转化为焦虑样行为的增加。最后，我们将用抗病毒药物治疗这些动物 炎症药物 licofelone 研究是否可以改善 TBI 后的神经炎症，从而导致 这些结果的改善。