Lloyd Brian A, Hake Holly S, Ishiwata Takayuki, Farmer Caroline E, Loetz Esteban C, Fleshner Monika, Bland Sondra T, Greenwood Benjamin N
Department of Psychology, University of Colorado Denver, United States.
Department of Sport and Wellness, Rikkyo University, Saitama, Japan.
Behav Brain Res. 2017 Apr 14;323:56-67. doi: 10.1016/j.bbr.2017.01.033. Epub 2017 Jan 24.
Exercise can enhance learning and memory and produce resistance against stress-related psychiatric disorders such as depression and anxiety. In rats, these beneficial effects of exercise occur regardless of exercise controllability: both voluntary and forced wheel running produce stress-protective effects. The mechanisms underlying these beneficial effects of exercise remain unknown. The mammalian target of rapamycin (mTOR) is a translation regulator important for cell growth, proliferation, and survival. mTOR has been implicated in enhancing learning and memory as well as antidepressant effects. Moreover, mTOR is sensitive to exercise signals such as metabolic factors. The effects of exercise on mTOR signaling, however, remain unknown. The goal of the present study was to test the hypothesis that exercise, regardless of controllability, increases levels of phosphorylated mTOR (p-mTOR) in brain regions important for learning and emotional behavior. Rats were exposed to 6 weeks of either sedentary (locked wheel), voluntary, or forced wheel running conditions. At 6 weeks, rats were sacrificed during peak running and levels of p-mTOR were measured using immunohistochemistry. Overall, both voluntary and forced exercise increased p-mTOR-positive neurons in the medial prefrontal cortex, striatum, hippocampus, hypothalamus, and amygdala compared to locked wheel controls. Exercise, regardless of controllability, also increased numbers of p-mTOR-positive glia in the striatum, hippocampus, and amygdala. For both neurons and glia, the largest increase in p-mTOR positive cells was observed after voluntary running, with forced exercise causing a more modest increase. Interestingly, voluntary exercise preferentially increased p-mTOR in astrocytes (GFAP+), while forced running increased p-mTOR in microglia (CD11+) in the inferior dentate gyrus. Results suggest that mTOR signaling is sensitive to exercise, but subtle differences exist depending on exercise controllability. Increases in mTOR signaling could contribute to the beneficial effects of exercise on cognitive function and mental health.
运动可以增强学习和记忆能力，并对与压力相关的精神障碍如抑郁和焦虑产生抵抗力。在大鼠中，无论运动的可控性如何，运动的这些有益效果都会出现：自愿和强迫性轮转跑步都能产生应激保护作用。运动这些有益效果背后的机制尚不清楚。雷帕霉素的哺乳动物靶点（mTOR）是一种对细胞生长、增殖和存活很重要的翻译调节因子。mTOR与增强学习和记忆以及抗抑郁作用有关。此外，mTOR对运动信号如代谢因子敏感。然而，运动对mTOR信号传导的影响仍然未知。本研究的目的是检验这样一个假设，即无论可控性如何，运动都会增加对学习和情绪行为重要的脑区中磷酸化mTOR（p-mTOR）的水平。将大鼠暴露于6周的久坐（锁定转轮）、自愿或强迫性轮转跑步条件下。在6周时，在跑步高峰期处死大鼠，并使用免疫组织化学法测量p-mTOR的水平。总体而言，与锁定转轮对照组相比，自愿和强迫运动均增加了内侧前额叶皮质、纹状体、海马体、下丘脑和杏仁核中p-mTOR阳性神经元的数量。无论可控性如何，运动还增加了纹状体、海马体和杏仁核中p-mTOR阳性神经胶质细胞的数量。对于神经元和神经胶质细胞，自愿跑步后观察到p-mTOR阳性细胞增加最多，强迫运动导致的增加较为适度。有趣的是，自愿运动优先增加星形胶质细胞（GFAP+）中的p-mTOR，而强迫跑步则增加了齿状回下部小胶质细胞（CD11+）中的p-mTOR。结果表明，mTOR信号传导对运动敏感，但根据运动可控性存在细微差异。mTOR信号传导的增加可能有助于运动对认知功能和心理健康的有益影响。
