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

• 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
• 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

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(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。治疗性锻炼已经成为一种非侵入性的技术，可以改善健康人群和神经受损人群的学习、记忆和认知能力。我们假设了一个新的观点，运动诱导的学习和记忆的改善是由两个因素驱动的：第一，脑源性神经营养因子(BDNF)的急剧上升增强记忆；第二，神经营养因子的长期增加导致选择性地拯救共同表达巢蛋白的基底前脑胆碱能神经元，最终产生突触效率的增加。这些增强增强了隔区-海马区回路中与活动相关的乙酰胆碱(ACh)的释放，这就是运动后学习能力延迟改善的原因。这项工作将通过为新的 以胆碱能系统调节为基础的运动如何改善认知功能的机械理论。在这项建议中，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，是否将在健忘症啮齿动物模型(AIM 1)中从硫胺素缺乏所产生的营养不良的静止状态中拯救部分共同表达巢蛋白的胆碱能前脑神经元(AIM 1)。此外，我们将展示运动促进的BDNF和ACh活动依赖性释放的改善是时间依赖的，并独特地驱动不同认知过程的增强。此外，运动激活TrkA或TrkB受体选择性地上调关键突触蛋白，这些突触蛋白参与神经化学释放和行为改善的不同时间分布(AIM 2)。开发认知/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性大脑如何做出不同于健康大脑的反应和适应。这些关键的临床前信息对于改善治疗策略的发展是必要的，这些治疗策略对认知功能的恢复是有效的。