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：
8316294
负责人：
COLEEN M. ATKINS
金额：
$ 32.8万
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/8316294
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. 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.

描述（由申请人提供）：超过317万美国人由于脑损伤（TBI）而应对长期残疾。由于大多数TBI研究都致力于开发急性治疗以预防或最大程度地减少长期残疾，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TBI幸存者可以从促进内源性突触可塑性机制的疗法中显着受益。在TBI和人类TBI的实验模型中，先前的研究发现海马高度容易受到脑损伤的影响。尽管通常不会直接受到头部损伤的机械伤害，但在TBI后的几周到几个月中，海马经历了萎缩并表现出长期增强（LTP）的缺陷，突触强度的持续增加，这被认为是学习和记忆的基础。该赠款提案的总体目标是了解在TBI之后的几周到几个月内导致海马依赖性LTP缺陷和学习障碍的分子机制。鉴于海马在形成声明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提供治疗靶标，以改善TBI后海马依赖性学习。为此，我们的实验室发现，细胞外信号调节激酶（ERK）的激活及其下游效应子之一，转录因子CAMP响应元件结合蛋白（CREB）在TBI后2周至3个月中显着受损。 ERK和CREB是LTP的长期形式以及海马依赖性记忆形成所必需的。因此，我们假设刺激海马中ERK激活的药理学治疗将改善TBI后慢性时间点的海马依赖性学习缺陷。确实，我们的初步数据表明，海马学习任务后TBI动物的ERK激活存在缺陷，并且可以使用磷酸二酯酶抑制剂来挽救这一点。此外，当TBI在训练之前接受磷酸二酯酶抑制剂3个月后，当使用Morris Water Maze Task和上下文恐惧调节评估时，将海马依赖性学习缺陷得到改善。在AIM 1中，我们将确定有助于TBI后海马的ERK和CREB激活缺陷的潜在分子机制。在AIM 2中，我们将测试以下假设：增加ERK和CREB激活将在TBI之后挽救海马LTP。在AIM 3中，我们将确定增加ERK和CREB激活是否会改善TBI后海马依赖性学习缺陷。该项目得到了一组既定的研究人员的支持，他们在海马依赖性LTP，学习和记忆以及TBI方面提供了专业知识。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，以改善慢性TBI幸存者的海马依赖性学习。公共卫生相关性：创伤性脑损伤（TBI）是美国残疾的主要原因。目前尚无治疗方法可以改善长期残障的TBI幸存者的学习和记忆功能。该赠款将确定在TBI之后学习和记忆障碍基础的生化机制，并研究FDA批准的药物是否可以在TBI之后的几周到几个月内恢复学习和记忆的功能。