Activity-Induced Recovery Following Brain Trauma

描述(由申请人提供)：创伤性脑损伤(TBI)通过损害认知功能而降低生活质量。我们假设，脑外伤后认知能力的降低是支持突触可塑性的分子机制功能障碍的结果。这损害了细胞处理、传输和存储信息的能力，从而最终影响到学习和记忆等高阶功能。脑源性神经营养因子(BDNF)在所有这些事件中起着关键作用，因此，我们提出了一种生理手段，通过使用BDNF作为中央机制来调节大脑对二次损伤的补偿能力。受我们最初的发现，即体育活动在完整的大脑中诱导BDNF的鼓舞，我们建议可以利用运动来促进脑外伤后的功能恢复。因此，这项建议的中心目标是将运动与神经营养因子联系起来，并优化运动诱导的内源性BDNF的表达，以促进脑损伤后的功能恢复。新的证据表明，神经活动驱动的营养相互作用介导了不同的过程，如神经元的弹性和突触功能，这可能是中枢神经系统康复和学习/记忆的基础。我们范式的一个重要而新颖的方面结合了这一发现，即除了帮助神经元存活外，BDNF在突触可塑性方面发挥着重要作用。鉴于我们的主要目标是应用运动来改善脑外伤的状况，我们研究的设计考虑了能量危机期--创伤损伤大脑的急性期--可能会如何干扰运动。这些研究的积极结果将为脑外伤患者开辟一条新的治疗路线，上调内源性神经营养素。大多数脑外伤的干预程序都集中在向大脑中添加外源性物质，从而忽视了大脑固有的可塑性能力。鉴于大多数临床试验都没有对结果产生积极的影响，我们认为是时候重新考虑诱导功能恢复的概念了。因此，我们建议的独特方面是评估作为神经元可塑性调节器的经验，可用于促进脑外伤后的功能恢复。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) curtails quality of life by compromising cognitive function. We hypothesize that reduced cognitive capacity following TBI is the result of dysfunction in the molecular mechanisms that support synaptic plasticity. This compromises the capacity of cells to process, transmit, and store information, thereby ultimately affecting higher order functions such as learning and memory. Brain-derived neurotrophic factor (BDNF) has a critical action in all of these events - thus, we propose a physiological means to modulate the capacity of the brain to compensate for secondary insults, by using BDNF as a central mechanism. Encouraged by our original findings that physical activity induces BDNF in the intact brain, we propose that exercise can be employed to improve functional recovery after TBI. It is, therefore, a central goal of this proposal to link exercise with neurotrophins and optimize the exercise-induced expression of endogenous BDNF that can boost functional recovery following brain trauma. Emerging evidence suggests that trophic interactions driven by neural activity mediate diverse processes, such as neuronal resilience and synaptic function, that may underlie CNS healing and learning/memory. An important and novel aspect of our paradigm incorporates the finding that, in addition to helping neuronal survival, BDNF plays a significant role in synaptic plasticity. Given that our main objective is to apply exercise to benefit the TBI condition, the design of our studies takes into consideration how the period of energy crisis, characterizing the acute phase of the traumatically injured brain, may interfere with exercise. A positive outcome of these studies would open a new line of therapeutic treatments for TBI patients that upregulates endogenous neurotrophins. Most intervention procedures for TBI have focused on adding exogenous substances into the brain, thereby ignoring the intrinsic capacity of the brain for plasticity. Given that the majority of clinical trials have not resulted in a positive effect on outcome, we feel it is time to re-think the concept of inducing recovery of function. Therefore, the unique aspect of our proposal is to evaluate experience as a modulator of neuronal plasticity that can be used to enhance functional recovery following TBI.