Rehabilitation Strategies for Memory Dysfunction After Traumatic Brain Injury

脑外伤后记忆障碍的康复策略

基本信息

批准号：
8708222
负责人：
COLEEN M. ATKINS
金额：
$ 32.47万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708222
关键词：
Acute American Animals Applications Grants Area Atrophic Biochemical Brain Brain Injuries Chronic Cognitive Craniocerebral Trauma Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Responsive DNA-Binding Protein Data Disabled Persons Economic Burden Electrophysiology (science)Exhibits Experimental Models FDA approved Functional disorder Gene Expression Grant Hippocampus (Brain)Human Impairment Knowledge Laboratories Learning Link Liquid substance Long-Term Potentiation MAP2K1 gene Mediating Memory Memory impairment Mitogen-Activated Protein Kinases Modeling Molecular Percussion Performance Pharmaceutical Preparations Pharmacological Treatment Phosphodiesterase Inhibitors Protein Kinase Rehabilitation therapy Research Research Personnel Role Rolipram Short-Term Memory Signal Pathway Slice Stimulus Survivors Synapses Synaptic plasticity Testing Therapeutic Time Training Traumatic Brain Injury Underserved Population United States activating transcription factor base clinically relevant cognitive recovery conditioned fear coping disability improved inhibitor/antagonist injured innovation insight morris water maze novel prevent protein activation public health relevance rehabilitation strategy research study therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): More than 3.17 million Americans are coping with long-term disabilities due to traumatic brain injury (TBI). Since most TBI research focuses on developing acute treatments to prevent or minimize long-term disabilities, chronic TBI survivors represent a large, underserved population. Chronic TBI survivors could significantly benefit from therapies that promote endogenous synaptic plasticity mechanisms. In both experimental models of TBI and in human TBI, previous studies have found that the hippocampus is highly vulnerable to brain injury. Although often not directly mechanically injured by the head injury, in the weeks to months following TBI, the hippocampus undergoes atrophy and exhibits deficits in long-term potentiation (LTP), a persistent increase in synaptic strength that is considered to underlie learning and memory. The overall objective of this grant proposal is to understand the molecular mechanisms that contribute to hippocampal-dependent LTP deficits and learning impairments in the weeks to months after TBI. Given the critical role of the hippocampus in forming declarative memories, we propose that identifying the molecular mechanisms that underlie the deficits in hippocampal LTP after TBI could provide therapeutic targets to improve hippocampal-dependent learning after TBI. To this end, our laboratory has found that activation of extracellular signal-regulated kinase (ERK) and one of its downstream effectors, the transcription factor cAMP-response element binding protein (CREB), is significantly impaired in the hippocampus from 2 weeks to 3 months after TBI. ERK and CREB are required for long-lasting forms of LTP as well as hippocampal-dependent memory formation. Thus, we hypothesize that a pharmacological treatment which stimulates ERK activation in the hippocampus will improve hippocampal- dependent learning deficits at chronic time points after TBI. Indeed, our preliminary data demonstrate that there are deficits in the activation of ERK in TBI animals after a hippocampal learning task and that this can be rescued with a phosphodiesterase inhibitor. Furthermore, when animals at 3 months after TBI receive a phosphodiesterase inhibitor prior to training, hippocampal-dependent learning deficits are ameliorated when assessed using the Morris water maze task and contextual fear conditioning. In Aim 1, we will identify the underlying molecular mechanisms that contribute to the deficits in ERK and CREB activation in the hippocampal after TBI. In Aim 2, we will test the hypothesis that increasing ERK and CREB activation will rescue hippocampal LTP after TBI. In Aim 3, we will determine if increasing ERK and CREB activation improves hippocampal-dependent learning deficits after TBI. This project is highly supported by an established group of investigators who provide expertise in the molecular mechanisms of hippocampal-dependent LTP, learning and memory, and TBI. The proposed studies will provide new insights into the molecular mechanisms of hippocampal-dependent learning impairments after TBI, and develop therapeutic strategies to improve hippocampal-dependent learning for chronic TBI survivors.

描述（由申请人提供）：超过 317 万美国人因创伤性脑损伤 (TBI) 而面临长期残疾。由于大多数 TBI 研究的重点是开发急性治疗方法以预防或尽量减少长期残疾，因此慢性 TBI 幸存者代表了一个庞大的、服务不足的人群。慢性创伤性脑损伤幸存者可以从促进内源性突触可塑性机制的治疗中显着受益。在 TBI 实验模型和人类 TBI 中，先前的研究都发现海马体非常容易受到脑损伤。虽然头部损伤通常不会直接造成机械损伤，但在 TBI 后的数周至数月内，海马体会出现萎缩，并表现出长时程增强 (LTP) 缺陷，突触强度持续增强，被认为是学习和记忆的基础。该拨款提案的总体目标是了解 TBI 后数周至数月内导致海马依赖性 LTP 缺陷和学习障碍的分子机制。鉴于海马在形成陈述性记忆中的关键作用，我们建议确定 TBI 后海马 LTP 缺陷的分子机制，可以为改善 TBI 后海马依赖性学习提供治疗靶点。为此，我们实验室发现海马中细胞外信号调节激酶（ERK）及其下游效应器之一转录因子cAMP反应元件结合蛋白（CREB）的激活在2周至3周期间显着受损。 TBI 后几个月。 ERK 和 CREB 是长期形式的 LTP 以及海马依赖性记忆形成所必需的。因此，我们假设刺激海马 ERK 激活的药物治疗将改善 TBI 后长期时间点的海马依赖性学习缺陷。事实上，我们的初步数据表明，TBI 动物在海马学习任务后 ERK 激活存在缺陷，并且可以通过磷酸二酯酶抑制剂来挽救。此外，当 TBI 后 3 个月的动物在训练前接受磷酸二酯酶抑制剂时，使用莫里斯水迷宫任务和情境恐惧调节进行评估时，海马依赖性学习缺陷得到改善。在目标 1 中，我们将确定导致 TBI 后海马 ERK 和 CREB 激活缺陷的潜在分子机制。在目标 2 中，我们将检验以下假设：增加 ERK 和 CREB 激活将挽救 TBI 后的海马 LTP。在目标 3 中，我们将确定增加 ERK 和 CREB 激活是否可以改善 TBI 后海马依赖性学习缺陷。该项目得到了一组研究人员的大力支持，他们在海马依赖性 LTP、学习和记忆以及 TBI 的分子机制方面提供专业知识。拟议的研究将为 TBI 后海马依赖性学习障碍的分子机制提供新的见解，并制定治疗策略来改善慢性 TBI 幸存者的海马依赖性学习。