Activity-Induced Recovery Following Brain Trauma

描述（由申请人提供）：创伤性脑损伤（TBI）通过损害认知功能来降低生活质量。我们假设脑外伤后认知能力下降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，从而最终影响了学习和记忆等高阶功能。脑源性神经营养因子（BDNF）在所有这些事件中都起着关键作用，因此，我们提出了一种生理手段，通过使用BDNF作为中心机制来调节大脑补偿继发性损伤的能力。我们最初的研究结果表明，体育活动可以诱导完整大脑中的BDNF，因此我们提出运动可以改善脑外伤后的功能恢复。因此，本研究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，从而促进脑外伤后的功能恢复。新出现的证据表明，由神经活动驱动的营养相互作用介导了多种过程，如神经元弹性和突触功能，这可能是中枢神经系统愈合和学习/记忆的基础。我们的范式的一个重要和新颖的方面包括发现，除了帮助神经元存活外，BDNF在突触可塑性中起着重要作用。鉴于我们的主要目标是应用运动来改善TBI状况，我们研究的设计考虑了能量危机时期（创伤性脑损伤急性期的特征）如何干扰运动。这些研究的积极结果将为上调内源性神经营养因子的TBI患者开辟一条新的治疗途径。大多数TBI的干预程序都侧重于向大脑中添加外源性物质，从而忽略了大脑的内在可塑性。鉴于大多数临床试验并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经验作为神经元可塑性的调节剂，可用于增强TBI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.