Risk Factors for Chronic Memory Problems after Traumatic Brain Injury

脑外伤后慢性记忆问题的危险因素

基本信息

批准号：
10554096
负责人：
COLEEN M. ATKINS
金额：
--
依托单位：
MIAMI VA HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554096
关键词：
ARHGEF5 gene Acute Adult Adverse event Animal Model Animals Anxiety Astrocytes Behavior Behavioral Brain Brain Injuries CASP1 gene Cells Childhood Chronic Chronic Phase Chronic stress Cognitive Corticosterone Corticotropin Data Development Exhibits Exposure to Female Flow Cytometry Goals Health Hippocampus IL18 gene Immune Immune system Immunohistochemistry Impaired cognition Impairment Inflammasome Inflammation Inflammatory Inflammatory Response Interleukin Activation Interleukin-1 beta Knockout Mice Learning Life Link Long-Term Potentiation Macrophage Measures Memory Memory impairment Mental Depression Microglia Military Personnel Modeling Molecular Molecular Target Multiprotein Complexes Mus Neurologic Neurons Outcome Pathologic Pathology Pathway interactions Persons Phase Population Post-Concussion Syndrome Predisposing Factor Problem behavior Rattus Recording of previous events Recovery Reporting Risk Risk Factors Series Signal Transduction Sorting Sprague-Dawley Rats Stress Stressful Event Sucrose Synapses Synaptic plasticity TBI Patients TLR4 gene Testing Therapeutic Traumatic Brain Injury Traumatic Brain Injury recovery Veterans adverse childhood events brain tissue cohort conditioned fear cytokine depressive symptoms early childhood early life exposure early life stress experience fluid percussion injury hippocampal atrophy hypothalamic-pituitary-adrenal axis improved inhibitor male maternal separation middle age mild traumatic brain injury military service military veteran neurogenesis neuron loss novel therapeutics persistent symptom preference prevent psychologic pup response restraint stress screening services service member sham surgery targeted treatment water maze young adult

项目摘要

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.

创伤性脑损伤（TBI）是美国现役军人和退伍军人的一个主要健康问题。尽管许多轻度 TBI 患者会在 1-2 周内康复，但中度至重度 TBI 患者以及近乎严重的 TBI 患者 50% 的轻度 TBI 患者会出现持续数月的持续症状。参与 TBI 后持续后遗症的分子机制将有助于最近在一项对美国兵役的研究中发现了治疗小说的发展。成员们早年就经历过不良的童年经历。军事人员和退伍军人的患病率明显高于平民，这是与慢性病相关的关键机制。童年时期的压力导致成年后的神经系统问题是免疫失调。 (ELS) 增强小胶质细胞释放促炎细胞因子以应对随后的炎症该提案的目标是确定开发期间的 ELS 是否限制了之后的恢复轨迹。我们发现，成年期发生的 TBI 通过每天与幼鼠进行短暂的母体分离来模拟 ELS。成年 TBI 之前的 ELS 增加了白细胞介素 1β (IL-1β) 水平和 NLRP3 的表达炎症小体是一种多蛋白复合物，可导致 IL-1β 的裂解和激活。 TBI 之前的 ELS 也会导致海马萎缩、神经元损失和海马依赖性学习相比之下，在未受伤的动物中，单独进行 TBI（无应激或 ELS）不会增加 IL-1β 水平，也不会增加 IL-1β 水平。使用 NLRP3 治疗的海马内是否存在可观察到的学习缺陷或病变。炎性体抑制剂逆转了这些学习缺陷并减少了海马病理学和亲在本提案中，我们将检验 ELS 限制术后恢复的假设。 TBI 通过 NLRP3 炎症小体增加小胶质细胞中的炎症信号传导，从而导致海马病理恶化以及持续学习和记忆缺陷的发展。根据这一假设，提出以下目标： 1) 确定 TBI 之前的 ELS 是否在成年期经历过增加小胶质细胞活化，增强促炎细胞因子表达并激活 NLRP3 炎症体，2) 确定 ELS 和 TBI 是否会导致慢性行为问题，以及这些行为是否会导致慢性行为问题。 NLRP3 炎性体抑制剂可以改善缺陷，并且 3) 确定 ELS 是否恶化 TBI 后海马神经元和突触损失以及是否可以通过 NLRP3 炎性体减少这种损失这些研究将确定幼儿时期的压力是否是该疾病的诱发因素。我们还将测试一种有前景的治疗方法。 TBI，一种 NLRP3 炎性体抑制剂，以确定这是否会减少炎症、预防海马病理学并改善 ELS 和 TBI 后的学习和记忆。