Risk Factors for Chronic Memory Problems after Traumatic Brain Injury

创伤性脑损伤(TBI)是美国军人和退伍军人的主要健康问题。 虽然许多轻度脑损伤会在1-2周内恢复，但那些患有中度到重度脑损伤的人以及 50%的轻度脑外伤患者会有持续数月的症状。了解风险因素 参与颅脑损伤后的持续性后遗症及其分子机制将促进 开发新的治疗方法。最近在一项关于美国兵役的研究中发现了一个潜在的因素 成员预先接触到了早期紧张的生活经历。不良童年经历的报告地址为 军事人员和退伍军人的水平明显高于平民。一个关键的连接慢性疾病的机制 早期生活中的应激到成年后的神经问题是免疫失调。暴露在早期生活压力之下 (ELS)促进小胶质细胞释放促炎细胞因子，以应对随后的炎症 挑战。该提案的目标是确定ELS在开发过程中是否限制了以下恢复轨迹 一种发生在成年期的脑外伤。使用小鼠每日短暂的母体分离来建立ELS模型，我们发现 成年期颅脑损伤前ELs升高IL-1β水平及NLRP3的表达 炎症体，这是一种多蛋白复合体，导致IL-1β的裂解和激活。暴露于 脑损伤前的ELS还导致海马区萎缩、神经元丢失和海马区依赖学习。 赤字。相反，在没有应激或ELS的非损伤动物中，单纯的脑创伤并没有增加IL-1的β水平，也没有 在海马体内是否有明显的学习缺陷或病理改变。使用NLRP3进行治疗 炎症体抑制剂逆转了这些学习障碍，并减轻了海马区的病理和促进 炎性细胞因子表达。在这份提案中，我们将检验ELS限制复苏的假设 通过NLRP3炎症体增加小胶质细胞的炎症信号，导致 海马区病理的恶化和持续性学习和记忆障碍的发展。为了测试 在这一假设下，提出了以下目标：1)确定脑外伤前的ELs是否经历了成年期 促进小胶质细胞活化，增强促炎细胞因子表达，激活NLRP3 炎症组，2)确定ELS和TBI是否导致慢性行为问题，以及这些行为是否 缺陷可以用NLRP3炎症体抑制剂来改善，3)确定ELS是否加剧 颅脑损伤后海马神经元和突触的丢失以及NLRP3炎症体是否能减少这种损失 抑制剂。这些研究将确定儿童早期的压力是否是导致 颅脑损伤后持续性神经后遗症的发展。我们还将测试一种有前景的治疗方法 TbI，一种NLRP3炎症体抑制剂，以确定这是否会减少炎症，防止海马区 并能改善ELS和脑外伤后的学习记忆。

Traumatic brain injury (TBI) is a major health problem among US military service members and Veterans. Although many with mild TBI will recover within 1-2 weeks, those with moderate to severe TBI as well as nearly 50% of those with mild TBI will have persistent symptoms lasting for months. Understanding the risk factors involved in the persistent sequelae after TBI and the underlying molecular mechanisms will facilitate the development of novel therapeutics. One potential factor recently identified in a study of US military service members is pre-exposure to early stressful life experiences. Adverse childhood experiences are reported at significantly higher levels among military personnel and Veterans than civilians. A key mechanism linking chronic stress in early life to neurological problems in adulthood is immune dysregulation. Exposure to early life stress (ELS) enhances pro-inflammatory cytokine release by microglia in response to a subsequent inflammatory challenge. The goal of this proposal is to determine if ELS during development limits the recovery trajectory after a TBI that occurs in adulthood. Using brief daily maternal separation in rat pups to model ELS, we have found that ELS prior to TBI in adulthood increased interleukin-1β (IL-1β) levels and expression of the NLRP3 inflammasome, which is a multi-protein complex that results in cleavage and activation of IL-1β. Exposure of ELS prior to TBI also resulted in hippocampal atrophy, neuronal loss, and hippocampal-dependent learning deficits. In contrast, TBI alone without stress or ELS in non-injured animals did not increase IL-1β levels, nor were there observable learning deficits or pathology within the hippocampus. Treatment with an NLRP3 inflammasome inhibitor reversed these learning deficits and reduced hippocampal pathology and pro- inflammatory cytokine expression. In this proposal, we will test the hypothesis that ELS limits the recovery after TBI by increasing inflammatory signaling in microglia through the NLRP3 inflammasome, leading to the worsening of hippocampal pathology and the development of persistent learning and memory deficits. To test this hypothesis, the following aims are proposed: 1) To determine if ELS prior to TBI experienced in adulthood increases microglia activation, potentiates pro-inflammatory cytokine expression and activates the NLRP3 inflammasome, 2) To determine if ELS and TBI result in chronic behavioral problems and if these behavioral deficits can be improved with an NLRP3 inflammasome inhibitor, and 3) To determine if ELS exacerbates hippocampal neuronal and synaptic loss after TBI and if this can be reduced with an NLRP3 inflammasome inhibitor. These studies will determine whether stress in early childhood is a predisposing factor for the development of persistent neurological sequela after TBI. We will also test a promising therapeutic approach for TBI, an NLRP3 inflammasome inhibitor, to determine if this will reduce inflammation, prevent hippocampal pathology and improve learning and memory after ELS and TBI.