Rehabilitation Strategies for Memory Dysfunction After Traumatic Brain Injury

描述（由申请人提供）：超过317万美国人因创伤性脑损伤（TBI）而长期残疾。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，慢性TBI幸存者代表了一个庞大的，服务不足的人群。慢性脑外伤幸存者可以显著受益于促进内源性突触可塑性机制的治疗。在创伤性脑损伤的实验模型和人类创伤性脑损伤中，先前的研究都发现海马体对脑损伤非常脆弱。虽然通常不会直接受到头部损伤的机械损伤，但在脑外伤后的几周到几个月内，海马会经历萎缩，并表现出长期增强（LTP）的缺陷，这是一种持续增加的突触强度，被认为是学习和记忆的基础。这项拨款提案的总体目标是了解脑外伤后数周至数月海马依赖性LTP缺陷和学习障碍的分子机制。鉴于海马体在形成陈述性记忆中的关键作用，我们提出确定脑外伤后海马体LTP缺陷的分子机制可以为改善脑外伤后海马体依赖学习提供治疗靶点。为此，我们的实验室发现，在TBI后2周至3个月，海马细胞外信号调节激酶（ERK）及其下游效应物之一，转录因子camp反应元件结合蛋白（CREB）的激活显著受损。ERK和CREB是长期LTP形式以及海马依赖记忆形成所必需的。因此，我们假设刺激海马ERK激活的药物治疗将改善脑外伤后慢性时间点海马依赖性学习缺陷。事实上，我们的初步数据表明，在海马学习任务后，TBI动物的ERK激活存在缺陷，这可以通过磷酸二酯酶抑制剂来挽救。此外，当脑外伤后3个月的动物在训练前接受磷酸二酯酶抑制剂治疗时，使用莫里斯水迷宫任务和情境恐惧条件反射评估海马依赖学习缺陷时，海马依赖学习缺陷得到改善。在目的1中，我们将确定导致脑外伤后海马ERK和CREB激活缺陷的潜在分子机制。在Aim 2中，我们将验证增加ERK和CREB激活将拯救TBI后海马LTP的假设。在目的3中，我们将确定增加ERK和CREB激活是否能改善脑外伤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，他们在海马依赖的LTP，学习和记忆以及TBI的分子机制方面提供专业知识。本研究将为TBI后海马依赖学习障碍的分子机制提供新的见解，并为慢性TBI幸存者改善海马依赖学习提供治疗策略。

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. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major cause of disability in the United States. There are currently no treatments to improve learning and memory functioning in chronically disabled TBI survivors. This grant will identify the biochemical mechanisms that underlie learning and memory disabilities after TBI and investigate whether an FDA-approved drug can restore learning and memory functioning in the weeks to months after TBI.