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TBI患者将在1-2周内恢复，但那些中度至重度TBI以及近 50%的轻度TBI患者会有持续数月的持续症状。了解风险因素 参与TBI后持续性后遗症，潜在的分子机制将促进TBI后持续性后遗症的发生。 开发新的治疗方法。最近一项对美国兵役的研究发现， 成员是预先暴露于早期紧张的生活经历。儿童时期的不良经历报告于 军事人员和退伍军人的水平明显高于平民。一个关键机制将慢性 早期生活中的压力到成年后的神经问题是免疫失调。早期生活压力 (ELS)增强小胶质细胞对随后的炎症反应的促炎细胞因子释放 挑战.本提案的目标是确定开发期间的ELS是否限制了 一种发生在成年期的创伤性脑损伤使用大鼠幼仔每日短暂的母体分离来模拟ELS，我们发现 在成年期TBI之前的ELS增加了白细胞介素-1 β（IL-1β）水平和NLRP 3的表达， 炎性体是导致IL-1β裂解和活化的多蛋白复合物。暴露 TBI前ELS也导致海马萎缩、神经元丢失和海马依赖性学习 赤字相比之下，在未受伤的动物中，没有应激或ELS的单独TBI不会增加IL-1β水平，也不会增加IL-1β水平。 在海马体中是否存在可观察到的学习缺陷或病理。NLRP治疗3 炎性小体抑制剂逆转了这些学习缺陷，并减少了海马病理和促凋亡作用。 炎性细胞因子表达。在本提案中，我们将检验ELS限制恢复的假设， TBI通过增加小胶质细胞中通过NLRP 3炎性体的炎症信号传导，导致TBI的发生。 海马病理学恶化和持续性学习和记忆缺陷的发展。测试 根据这一假设，提出了以下目的：1）确定TBI之前是否在成年期经历ELS 增加小胶质细胞活化，增强促炎细胞因子表达并激活NLRP 3 2）为了确定ELS和TBI是否导致慢性行为问题，以及这些行为问题是否导致慢性行为问题， 可以用NLRP 3炎性体抑制剂改善缺陷，和3）确定ELS是否加重 TBI后海马神经元和突触损失，以及是否可以用NLRP 3炎性体减少 抑制剂.这些研究将确定儿童早期的压力是否是儿童精神分裂症的诱发因素。 TBI后出现持续性神经系统后遗症。我们还将测试一种有前途的治疗方法， TBI，一种NLRP 3炎性体抑制剂，以确定这是否会减少炎症，防止海马 病理学和改善ELS和TBI后的学习和记忆。

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.