Exercise recovers cholinergic dysfunction through neurotrophin modulation

描述（由申请人提供）：与正常衰老和神经退行性疾病相关的认知和记忆障碍正在成为我们国家最大的健康问题之一。治疗性运动已经成为一种非侵入性技术，可以改善健康和神经系统受损人群的学习、记忆和认知能力。我们提出了一个新的观点，即运动引起的学习和记忆的改善是由两个因素驱动的：首先，脑源性神经营养因子（BDNF）的急剧上升增强了记忆；其次，神经营养因子的持续增加导致基底前脑胆碱能神经元的选择性拯救，这些神经元共同表达巢蛋白，最终产生突触功效的增加。这些增强增强了与活动相关的乙酰胆碱（ACh）在中隔海马体回路中的释放，这就是运动后学习能力延迟改善的原因。这项工作将推动该领域的发展，为一种新的方法提供原理证明

DESCRIPTION (provided by applicant): Cognitive and memory impairments associated with normal aging and neurodegenerative disease are emerging as one of our nation's greatest health concerns. Therapeutic exercise has emerged as a non- invasive technique to improve learning, memory and cognition in both healthy and neurologically compromised populations. We posit a novel position that exercise-induced improvements in learning and memory are driven by two factors: First, acute rises in brain derived neurotrophic factor (BDNF) enhance memory; and second, the protracted increases in neurotrophins lead to a selective rescue of basal forebrain cholinergic neurons that co-express nestin that ultimately produces an increase in synaptic efficacy. These enhancements intensify activity-related acetylcholine (ACh) release within the septohippocampal circuit and this is what produces the delayed improvements in learning after exercise. This work will advance the field by providing proof of principle for a new mechanistic theory for how exercise can lead to improved cognitive functioning based on the modulation of the cholinergic system. In this proposal we will determine whether sustained exercise-induced release of neurotrophins, in particular nerve growth factor (NGF), will rescue a select population of cholinergic forebrain neurons that co-express nestin from a hypotrophic quiescent state produced by thiamine deficiency in a rodent model of amnesia (AIM 1). In addition, we will demonstrate the exercise-facilitated improvements in activity-dependent release of BDNF and ACh are time-dependent and uniquely drive the enhancement of different cognitive processes. Moreover, exercise activation of TrkA or TrkB receptors selectively upregulate critical synaptic proteins involved in the distinct temporal profile of neurochemical release and behavioral improvement (AIM 2). Developing both behavioral and pharmacological therapeutic interventions for cognitive/memory disorders requires a greater understanding of how the pathological brain reacts and adapts differently from the healthy brain. Such critical pre-clinical information is needed to improve the development of therapeutic strategies that are effective for the recovery of cognitive functions.