Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior

Abstract

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.

Of Men and Mice: Modeling the Fragile X Syndrome

“…Despite the unclear status of ERK activation in the cortex, these studies suggest that mGluR1/5 signaling pathways are functioning differently in the cortex and the hippocampus. In line with this notion, a recent study of mTOR activity and exercise demonstrated that the activation status of mTOR is depending on the brain region, the cell type (neuron or glia) and the type of exercise (sedentary, voluntary or forced; Lloyd et al, 2017 ).…”

Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner

“…The prefrontal cortex (mPFC), particularly the infralimbic region, is well known to be involved in fear extinction learning and memory (Do-Monte et al 2015;Giustino and Maren 2015), and it is possible that exercise facilitates prefrontal mechanisms underlying extinction. Plasticity factors such as BDNF (Neeper et al 1995) and mammalian target of rapamycin (Lloyd et al 2017) are increased in the mPFC following at least a few days of wheel running, although whether a few hours of wheel running is enough to up-regulate plasticity factors in the mPFC is unknown. If exercise enhances fear extinction through mPFC mechanisms, one might expect that the infralimbic region of the mPFC would be more active during recall of fear extinction in exercising rats, as the infralimbic region is involved in fear extinction recall (Thompson et al 2010;Chang and Maren 2011) and has been reported to express high levels of immediate early genes in rats with strong fear extinction memory (Knapska and Maren 2009).…”

Physical activity reduces anxiety and regulates brain fatty acid synthesis

“…Phenylalanine, as a tyrosine precursor, is a substrate for tyrosine hydroxylase in the rate-limiting step in catecholamine synthesis [40]. Threonine regulates mTOR signaling [41], which is stimulated in the hippocampus and other brain structures of exercised rodents [42]. Galactose-6-phosphate is in constant equilibrium with fructose-6-phosphate, and the positive correlation between these two compounds was significant in the hippocampi of the running mice (r = 0.82, p < 0.05; data not shown).…”