Aerobic exercise promotes beneficial effects in the brain including increased synaptic plasticity and neurogenesis and regulates neuroinflammation and stress response via the hypothalamic-pituitary-adrenal axis. Exercise can have therapeutic effects for numerous brain-related pathologies, including major depressive disorder (MDD). Beneficial effects of aerobic exercise are thought to be mediated through the release of “exerkines” including metabolites, proteins, nucleic acids, and hormones that communicate between the brain and periphery. While the specific mechanisms underlying the positive effects of aerobic exercise on MDD have not been fully elucidated, the evidence suggests that exercise may exert a direct or indirect influence on the brain via small extracellular vesicles which have been shown to transport signaling molecules including “exerkines” between cells and across the blood-brain barrier (BBB). sEVs are released by most cell types, found in numerous biofluids, and capable of crossing the BBB. sEVs have been associated with numerous brain-related functions including neuronal stress response, cell-cell communication, as well as those affected by exercise like synaptic plasticity and neurogenesis. In addition to known exerkines, they are loaded with other modulatory cargo such as microRNA (miRNA), an epigenetic regulator that regulates gene expression levels. How exercise-induced sEVs mediate exercise dependent improvements in MDD is unknown. Here, we perform a thorough survey of the current literature to elucidate the potential role of sEVs in the context of neurobiological changes seen with exercise and depression by summarizing studies on exercise and MDD, exercise and sEVs, and finally, sEVs as they relate to MDD. Moreover, we describe the links between peripheral sEV levels and their potential for infiltration into the brain. While literature suggests that aerobic exercise is protective against the development of mood disorders, there remains a scarcity of data on the therapeutic effects of exercise. Recent studies have shown that aerobic exercise does not appear to influence sEV size, but rather influence their concentration and cargo. These molecules have been independently implicated in numerous neuropsychiatric disorders. Taken together, these studies suggest that concentration of sEVs are increased post exercise, and they may contain specifically packaged protective cargo representing a novel therapeutic for MDD.

The term “neural plasticity” was first used to describe non-pathological changes in neuronal structure. Today, it is generally accepted that the brain is a dynamic system whose morphology and function is influenced by a variety of factors including stress, diet, and exercise. Neural plasticity involves learning and memory, the synthesis of new neurons, the repair of damaged connections, and several other compensatory mechanisms. It is altered in neurodegenerative disorders and following damage to the central or peripheral nervous system. Understanding the mechanisms that regulate neural plasticity in both healthy and diseased states is of significant importance to promote cognition and develop rehabilitation techniques for functional recovery after injury. In this minireview, we will discuss the mechanisms by which environmental factors promote neural plasticity with a focus on exercise- and diet-induced factors. We will highlight the known circulatory factors that are released in response to exercise and discuss how all factors activate pathways that converge in part on the activation of BDNF signaling. We propose to harness the therapeutic potential of exercise by using BDNF as a biomarker to identify novel endogenous factors that promote neural plasticity. We also discuss the importance of combining exercise factors with dietary factors to develop a lifestyle pill for patients afflicted by CNS disorders.

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The brain’s cognitive skills gradually decline with aging. In old animals, damaged proteins accumulate in neurons since autophagy, a catabolic process responsible for organelle and protein degradation, decreases. Physical exercise is a known lifestyle factor that promotes learning and memory formation in the hippocampus. The beneficial effects of exercise are mediated through the induction of the brain derived neurotrophic factor (BDNF). Previous work identified that exercise promotes cognition by inducing autophagy. In this study, we report that voluntary exercise increases autophagic activity in the hippocampus of adult C57BL/6 mice. This increase in autophagy is correlated with enhanced spatial learning and memory formation in the Morris water maze. Inhibition of autophagy in adult exercise mice with chloroquine phosphate (CQ) during the behavioral test showed impaired learning and memory formation, as well as decreased BDNF levels in the hippocampus as compared to the control exercise group. Activation of BDNF signaling in mice treated with CQ did not rescue learning and memory deficits. Hence, our results suggest that BDNF signaling is upstream of autophagy in the hippocampus. The same exercise paradigm did not promote learning and memory formation in middle aged and old male mice. Interestingly, we show that systemic administration of adult exercise plasma into middle-aged mice rejuvenates learning and memory in an autophagy dependent manner. Our results are consistent with autophagy playing central roles in promoting exercise-induced effects on cognition. Among the plasma factors, we identified β-hydroxybutyrate, a liver-derived molecule, as an exercise-induced factor that promotes learning and memory in an autophagy-dependent manner. The results reveal the potential therapeutic benefits of plasma factors released in response to exercise in an autophagy dependent manner.