Acute Exercise and Hippocampal Plasticity

描述（由申请人提供）：该拟议培训计划将通过追求旨在确定急性体力活动对介导海马可塑性和学习机制的影响的实验，为申请人提供高质量的专业发展，目标是使用运动作为工具来理解并最终将这些机制应用于其他治疗策略，以增强大脑健康。AMPA型谷氨酸受体（AMPAR）进出突触的运输对于突触可塑性至关重要。了解AMPAR的膜插入介质一直是研究长时程增强（LTP）机制的重点，LTP是学习和记忆的细胞模型。AMPAR的GluR1亚基在膜运输和突触可塑性特异性位点的磷酸化可以在体内通过引起生理唤醒的刺激诱导，在体外通过在急性运动后上调的激素和生长因子诱导。事实上，短期运动训练可以改善海马依赖性学习和记忆，降低LTP的阈值，尽管介导这种效应的机制尚不清楚。与慢性运动相反，人们对急性运动的分子反应知之甚少。传统上，急性运动研究利用基于运动的适应期或多日自愿轮跑协议，使得急性运动效果的解释变得困难。因此，本申请的总体目标，结合精心整合的职业发展活动和具有神经可塑性和运动生理学专业知识的导师，是描述急性运动对海马依赖性学习和记忆、GluR1磷酸化和海马可塑性的其他标志物的影响。将小鼠分成非运动对照组、中等强度运动组或高强度运动组，并暴露于单次急性跑步机运动。运动后，立即对动物进行一次试验记忆任务测试或处死动物进行海马生化和基因表达分析。使用去甲肾上腺素能特异性神经毒素和外源性肾上腺素，将确定中枢和外周儿茶酚胺信号传导的作用以及运动和儿茶酚胺在运动诱导的可塑性中的潜在累加效应。在最后一组实验中，在跑步机运动的急性回合之前，将为动物提供1个月的自主跑步轮，以确定先前的运动训练如何调节对急性运动回合的反应。表征对急性运动的分子反应是理解改善大脑健康和增强神经可塑性的机制的独特和高度信息化的方法。这些机制的识别将比单纯的运动具有更广泛的意义，例如为药物研究提供信息，学校学习计划，治疗创伤后应激障碍，抑郁症和焦虑症，以及了解衰老和疾病中的异常大脑生理学。

DESCRIPTION (provided by applicant): This proposed training plan will provide high-quality professional development for the applicant through the pursuit of experiments designed to determine the impact of acute physical activity on mechanisms that mediate hippocampal plasticity and learning, with the goals of using exercise as a tool to understand and eventually apply these mechanisms to other therapeutic strategies to enhance brain health. Trafficking of AMPA-type glutamate receptors (AMPARs) to and from the synapse is essential for synaptic plasticity. Understanding the mediators of membrane insertion of AMPARs has been a focus of intense investigation in the search for mechanisms mediating long-term potentiation (LTP), a cellular model for learning and memory. Phosphorylation of the GluR1 subunit of the AMPAR at sites specific for membrane trafficking and synaptic plasticity can be induced in vivo by stimuli that cause physiological arousal and in vitro by hormones and growth factors that are upregulated following acute bouts of exercise. Indeed, short-term exercise training can improve hippocampal dependent learning and memory and lower the threshold for LTP, though the mechanisms mediating this effect are unknown. In contrast to chronic exercise, little is known about the molecular response to an acute bout of exercise. Traditionally, acute exercise studies have utilized exercise-based acclimation periods or multiple-day voluntary wheel running protocols, making the interpretation of an acute exercise effect difficult. Therefore, the overall goal of the present application, in combination with carefully integrated career development activities and mentors with expertise in neural plasticity and exercise physiology, is to describe the impact of acute bouts of exercise on hippocampal- dependent learning and memory, GluR1 phosphorylation, and other markers of hippocampal plasticity. Mice will be separated into non-exercise control, moderate-intensity, or high-intensity exercise groups and exposed to a single acute bout of treadmill exercise. Immediately following the exercise, the animals will be tested on a one-trial memory task or sacrificed for hippocampal biochemical and gene expression analysis. Using a noradrenergic specific neurotoxin and exogenous epinephrine, the role of central and peripheral catecholamine signaling and potential additive effects of exercise and catecholamines in exercise-induced plasticity will be determined. In the final set of experiments, animals will be provided access to a voluntary running wheel for 1 month prior to the acute bout of treadmill exercise to determine how prior exercise training modulates the response to an acute bout of exercise. Characterizing the molecular response to acute bouts of exercise is a unique and highly informative approach to understanding mechanisms that improve brain health and enhance neural plasticity. Identification of these mechanisms will have far broader implications than exercise alone, such as informing pharmaceutical research, school based learning programs, treatment of PTSD, depression, and anxiety disorders, and understanding abnormal brain physiology in aging and disease.