Exercise recovers cholinergic dysfunction through neurotrophin modulation

运动通过神经营养素调节恢复胆碱能功能障碍

基本信息

批准号：
8846694
负责人：
Lisa M Savage
金额：
$ 18.72万
依托单位：
STATE UNIVERSITY OF NY,BINGHAMTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8846694
关键词：
Acetylcholine Acute Adult Amnesia Amnestic Disorder Behavioral Brain Brain Injuries Brain-Derived Neurotrophic Factor Cells Choline O-Acetyltransferase Cholinergic Fibers Cognition Cognitive Coupled Data Disease Exercise Exposure to Figs - dietary Functional disorder Growth Factor Health Hippocampus (Brain)Impaired cognition Lead Learning Literature Medial Mediating Memory Memory Disorders Memory impairment Modeling Nature Nerve Growth Factors Neurites Neurodegenerative Disorders Neuromodulator Neurons Neurotrophic Tyrosine Kinase Receptor Type 1 Performance Phenotype Phosphorylation Population Positioning Attribute Prosencephalon Proteins Pyrithiamine Rattus Receptor Protein-Tyrosine Kinases Recovery Rodent Model Role Running Shapes Short-Term Memory Signal Transduction Synapses Synapsins System Techniques Testing Therapeutic Intervention Therapeutic exercise Thiamine Deficiency Time Wernicke-Korsakoff Syndrome Work acetylcholine transporter basal forebrain basal forebrain cholinergic neurons base cholinergic cholinergic neuron cognitive enhancement cognitive function cognitive performance cognitive process density frontal lobe improved in vivo insight memory retention nestin protein neuroadaptation neurochemistry neurogenesis neuronal cell body neurotransmission neurotrophic factor normal aging novel pre-clinical presynaptic receptor restoration septohippocampal theories therapeutic development

项目摘要

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.

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国最大的健康问题之一。治疗性运动已成为一种非侵入性技术，可改善健康人群和神经受损人群的学习、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）的急剧增加增强记忆力；其次，神经营养素的持续增加导致了对共表达巢蛋白的基底前脑胆碱能神经元的选择性拯救，最终提高了突触功效。这些增强增强了隔海马回路内与活动相关的乙酰胆碱（ACh）的释放，这就是运动后学习延迟改善的原因。这项工作将通过为新的方法提供原理证明来推动该领域的发展关于运动如何基于胆碱能系统的调节改善认知功能的机制理论。在本提案中，我们将确定持续运动诱导的神经营养因子（特别是神经生长因子（NGF））的释放是否能够拯救啮齿类动物中由硫胺素缺乏引起的营养不足的静止状态，共同表达巢蛋白的胆碱能前脑神经元群体健忘症模型（AIM 1）。此外，我们将证明运动促进的 BDNF 和 ACh 的活动依赖性释放的改善是时间依赖性的，并且独特地驱动不同认知过程的增强。此外，TrkA 或 TrkB 受体的运动激活选择性上调关键突触蛋白，这些蛋白参与神经化学物质释放和行为改善的不同时间特征 (AIM 2)。开发针对认知/记忆障碍的行为和药物治疗干预措施需要更好地了解病理大脑如何与健康大脑不同地反应和适应。需要此类关键的临床前信息来改进有效恢复认知功能的治疗策略的开发。