Rehabilitation Strategies for Memory Dysfunction After Traumatic Brain Injury

脑外伤后记忆障碍的康复策略

• 批准号: 8522319
• 负责人: COLEEN M. ATKINS
• 金额: $ 31.65万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/8522319
• 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

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(申请人提供)：超过317万美国人正在应对由于创伤性脑损伤(TBI)而导致的长期残疾。由于大多数脑外伤研究的重点是开发急性治疗，以预防或尽量减少长期残疾，因此，慢性脑损伤幸存者是一个庞大的、未得到充分服务的人群。慢性脑外伤幸存者可以从促进内源性突触可塑性机制的治疗中显著受益。无论是在脑损伤的实验模型中，还是在人类的脑损伤模型中，先前的研究都发现海马体非常容易受到脑损伤的影响。尽管通常不是直接受到头部损伤的机械损伤，但在脑损伤后的几周到几个月里，海马体经历了萎缩，并表现出长时程增强(LTP)的缺陷，LTP是突触强度的持续增加，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损伤后几周到几个月内导致海马区依赖LTP缺陷和学习障碍的分子机制。鉴于海马区在形成陈述性记忆中的关键作用，我们认为，确定脑损伤后海马LTP缺陷的分子机制可以为改善脑损伤后海马依赖学习提供治疗靶点。为此，我们的实验室发现，脑创伤后2周至3个月的海马区，细胞外信号调节蛋白(ERK)及其下游效应因子之一的转录因子cAMP反应元件结合蛋白(CREB)的激活明显受损。ERK和CREB是长时程增强和海马区依赖记忆形成所必需的。因此，我们假设，刺激海马区ERK激活的药物治疗将改善脑损伤后慢性时间点的海马区依赖学习障碍。事实上，我们的初步数据表明，在完成海马区学习任务后，脑外伤动物体内ERK的激活存在缺陷，这可以用磷酸二酯酶抑制剂来挽救。此外，当脑损伤后3个月的动物在训练前接受磷酸二酯酶抑制剂时，使用Morris水迷宫任务和情景恐惧条件反射进行评估时，海马区依赖的学习缺陷得到改善。在目标1中，我们将确定导致脑创伤后海马区ERK和CREB激活缺陷的潜在分子机制。在目标2中，我们将验证这样的假设，即增加ERK和CREB的激活将挽救脑损伤后的海马LTP。在目标3中，我们将确定增加ERK和CREB的激活是否改善脑损伤后海马依赖的学习障碍。该项目得到了一组成熟的研究人员的高度支持，他们提供了海马依赖的LTP、学习和记忆以及脑外伤的分子机制方面的专业知识。这些研究将为脑外伤后海马依赖学习障碍的分子机制提供新的见解，并开发治疗策略来改善慢性脑损伤幸存者的海马依赖学习。 公共卫生相关性：在美国，创伤性脑损伤(TBI)是导致残疾的主要原因。目前还没有治疗方法来改善长期残疾的脑外伤幸存者的学习和记忆功能。这笔赠款将确定脑损伤后学习和记忆障碍的生化机制，并调查FDA批准的药物是否可以在脑损伤后几周到几个月内恢复学习和记忆功能。