Rehabilitation Strategies for Memory Dysfunction After Traumatic Brain Injury

描述（由申请人提供）：超过317万美国人正在应对由于创伤性脑损伤（TBI）造成的长期残疾。由于大多数TBI研究的重点是开发急性治疗方法以预防或最大限度地减少长期残疾，因此慢性TBI幸存者代表了大量服务不足的人群。慢性TBI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TBI和人类TBI的实验模型中，先前的研究已经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，海马会萎缩并表现出长时程增强（LTP）缺陷，这是一种被认为是学习和记忆基础的突触强度的持续增加。这项拨款提案的总体目标是了解TBI后数周至数月内导致脑缺血依赖性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，可以提供治疗靶点，以改善TBI后海马依赖性学习。为此，我们的实验室已经发现，激活的细胞外信号调节激酶（ERK）和它的下游效应器之一，转录因子cAMP反应元件结合蛋白（CREB），是显着受损的海马从2周至3个月后TBI。ERK和CREB是LTP的持久形式以及依赖于大脑的记忆形成所必需的。因此，我们假设刺激海马中ERK激活的药物治疗将改善TBI后慢性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，有赤字的ERK激活TBI动物海马学习任务后，这可以挽救与磷酸二酯酶抑制剂。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，当使用Morris水迷宫任务和上下文恐惧条件反射进行评估时，海马依赖性学习缺陷得到改善。在目标1中，我们将确定潜在的分子机制，有助于在TBI后海马ERK和CREB激活的赤字。在目标2中，我们将测试增加ERK和CREB激活将拯救TBI后海马LTP的假设。在目标3中，我们将确定增加ERK和CREB激活是否改善TBI后的海马依赖性学习缺陷。该项目得到了一个既定的研究小组的高度支持，他们提供了在脑组织依赖性LTP，学习和记忆以及TBI的分子机制方面的专业知识。拟议的研究将提供新的见解TBI后的大脑皮层依赖性学习障碍的分子机制，并制定治疗策略，以改善慢性TBI幸存者的大脑皮层依赖性学习。

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.