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.
Major depression and anxiety are one of the most common mental disorders worldwide. Attempts to alleviate these mental burdens are usually through psycho-therapeutic approaches, but little focus has been placed on lifestyle modifications. Adoption of these modifications, such as physical exercise, improved dietary intake, and proper sleep, have served as a nexus between clinical treatments as well as general health promotion. A multitude of studies points to how physical exercise has positive outcomes on depression and anxiety via the induction of a neurotrophic factor known as brain-derived neurotrophic factor (BDNF). α-ketoglutarate (aKG) was recently identified as a factor that is released into the blood upon exercise. In this study, we investigated whether aKG has prophylactic and antidepressant effects in chronic social defeat stress and chronic variable stress models of depression, as well as unravel the underlying molecular mechanisms. Our work shows that aKG serves as a potential prophylactic treatment for depression in both males and females through the modulation of BDNF in specific brain regions. In males, aKG pretreatment promotes resilience to stress via the PGC1a-BDNF axis within the hippocampus. Moreover, aKG exhibited antidepressant effects in susceptible female mice by modulating BDNF levels. In the hippocampus, aKG increases BDNF levels possibly through the PGC1a-BDNF pathway. In the NAc, aKG decreases BDNF levels possibly through the FNDC5-BDNF pathway.
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