Developing Cognitive Training and Rehabilitation Paradigms for Experimental TBI

描述(申请人提供)：生理性认知功能和创伤性脑损伤(TBI)导致认知功能障碍的神经生物学基础尚不清楚。存在可分离的外显-内隐学习和记忆网络，其中每个网络都可以促进或抑制记忆功能。在脑外伤后，临床文献表明，隐性网络比显性网络相对保留，但显性反馈可能会损害 内隐学习信息的使用。因此，脑外伤后用于促进学习和记忆的康复策略的类型对于优化康复至关重要。在我们的实验性脑外伤啮齿动物模型中，我们采用了这个临床框架，并将空间导航与外显、搜索策略与内隐、学习和记忆联系起来。我们建议，受控皮质撞击(CCI)损伤可以用来模拟脑外伤的内隐和外显学习记忆障碍。在Morris水迷宫(MWM)任务中，大鼠难以掌握任务的空间成分，学习定位平台所需的一般策略的能力降低。颅脑损伤后，重复性非空间环行行为或趋向性占主导地位。然而，我们最近的结果表明，在CCI之前为大鼠提供关于MWM任务的非空间成分的损伤前训练可以降低触觉趋向性，并在2周后测试时改善整体位置学习。事实上，这种内隐的预训练完全消除了在未经训练的CCI和假损伤的大鼠之间进行的空间习得和保持试验中观察到的明显的损伤部位学习缺陷，并且CCI后的内隐记忆基本保持完好。目前，尚无实验性的脑损伤认知康复模型。 这样的模型可以改变我们检查脑外伤后学习和记忆障碍机制的能力，并有助于开发和优化认知训练工具，以便将 诊所。重要的是，我们的新的初步数据表明，损伤后1wk的非空间认知训练导致认知缺陷的大幅减少；并降低了运动能力，证明了我们所提出的模型的可行性。这项高风险/高回报的R21提案探索了MWM中CCI后的内隐学习方法，以改善空间学习、记忆和搜索策略。我们将采用临床上相关的方法，如过度训练、无错误学习和消失线索的方法，建立CCI认知康复模型，以增强MWM的学习和记忆。我们还将评估静态和灵活的内隐学习方法在改进MWM中的新任务条件和促进外显反馈纳入方面的能力。我们还将探索与海马区(HP)损伤、神经发生、可塑性和MWM表现的关系。我们假设，在CCI后，内隐训练范式(COG训练)将提高MWM的成绩，我们可以利用内隐学习方法来促进外显学习和记忆，CCI后COG训练对行为的影响可能部分与HP神经发生和可塑性有关，以及从干预中获得的技能特异性好处。

DESCRIPTION (provided by applicant): The neurobiologic basis of physiologic cognitive function and traumatic brain injury (TBI) induced cognitive dysfunction is not well understood. Dissociable explicit-implicit learning and memory networks exist in which each network can work to either facilitate or inhibit memory function. After TBI, the clinical literature suggests that implicit networks are relatively preserved over explicit networks, but explicit feedback can impair the use of implicitly learned information. Therefore, the types of strategies used in rehabilitatio to promote learning and memory after TBI are critically important in optimizing recovery. In our rodent model of experimental TBI, we have taken this clinical framework and linked spatial navigation to explicit, and search strategy to implicit, learning and memory. We propose that controlled cortical impact (CCI) injury can be used to model implicit and explicit learning and memory deficits of TBI. In the Morris water maze (MWM) task, rats have difficulty mastering the spatial components of task, and a reduced capability to learn the general strategies needed locate the platform. Repetitive non-spatial looping behavior, or thigmotaxis, predominates after TBI. However, our recent results show that providing pre-injury training on the non-spatial components of the MWM task to rats before CCI reduces thigmotaxis and improves overall place learning when tested 2 weeks later. In fact this implicit pre-training completely eliminated the apparent injury place learning deficits typically observed during spatial acquisition and retention trials between untrained CCI and sham injured rats, and implicit memory remains largely intact after CCI. Currently, no experimental cognitive rehabilitation models exist for TBI. Such models could transform our ability to examine mechanisms of learning and memory dysfunction after TBI and help develop and optimize cognitive training tools for translation to the clinic. Importantly, our new preliminary data suggests that 1 wk of non-spatial cognitive training AFTER injury leads to large reductions in cognitive deficits; and reduced thigmotaxis, demonstrating the feasibility of our proposed model. This high-risk/high reward R21 proposal explores post-CCI implicit learning methods in the MWM to improve spatial learning, memory, and search strategy. We will develop a model of cognitive rehabilitation in CCI by adapting clinically relevant approaches like Overtraining, Errorless Learning, and the Method of Vanishing Cues to enhance learning and memory in the MWM. We will also assess static vs. flexible implicit learning methods for their ability to improve carryover to novel task conditions n the MWM and to facilitate incorporation of explicit feedback. We will also explore relationships with hippocampal (HP) damage, neurogenesis, and plasticity and MWM performance. We hypothesize that, after CCI, implicit training paradigms (cog-training) will enhance performance in the MWM, we can exploit implicit learning approaches to facilitate explicit learning and memory, and that post-CCI cog-training effects on behavior may, in part, be related to HP neurogenesis and plasticity as well as the skill specific benefits from the intervention.