Neural Stimulation and Molecular Mechanisms of Plasticity and Regeneration: A Review

Neural stimulation modulates the depolarization of neurons, thereby triggering activity-associated mechanisms of neuronal plasticity. Activity-associated mechanisms in turn play a major role in post-mitotic structure and function of adult neurons. Our understanding of the interactions between neuronal behavior, patterns of neural activity, and the surrounding environment is evolving at a rapid pace. Brain derived neurotrophic factor is a critical mediator of activity-associated plasticity, while multiple immediate early genes mediate plasticity of neurons following bouts of neural activity. New research has uncovered genetic mechanisms that govern the expression of DNA following changes in neural activity patterns, including RNAPII pause-release and activity-associated double stranded breaks. Discovery of novel mechanisms governing activity-associated plasticity of neurons hints at a layered and complex molecular control of neuronal response to depolarization. Importantly, patterns of depolarization in neurons are shown to be important mediators of genetic expression patterns and molecular responses. More research is needed to fully uncover the molecular response of different types of neurons-to-activity patterns; however, known responses might be leveraged to facilitate recovery after neural damage. Physical rehabilitation through passive or active exercise modulates neurotrophic factor expression in the brain and spinal cord and can initiate cortical plasticity commensurate with functional recovery. Rehabilitation likely relies on activity-associated mechanisms; however, it may be limited in its application. Electrical and magnetic stimulation direct specific activity patterns not accessible through passive or active exercise and work synergistically to improve standing, walking, and forelimb use after injury. Here, we review emerging concepts in the molecular mechanisms of activity-derived plasticity in order to highlight opportunities that could add value to therapeutic protocols for promoting recovery of function after trauma, disease, or age-related functional decline.