Abstract
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.
Highlights
Activity-associated plasticity refers to a form of functional and structural neuroplasticity that is driven by the depolarizing behavior of neurons, and it has been a focal area of research for the past several decades
Recent research has revealed a vast array of immediate early genes (IEGs), epigenetic modifiers, and even new mechanisms for transcriptional and translational regulation associated with neuronal activity (Guzowski et al, 2005; Karpova, 2014; Chen et al, 2015)
Molecular responses to activity-associated plasticity are driven by a layered and complex system
Summary
Activity-associated plasticity refers to a form of functional and structural neuroplasticity that is driven by the depolarizing behavior of neurons, and it has been a focal area of research for the past several decades. Passive bicycling in spinally transected rats led to an upregulation of neural activity-associated proteins, BDNF, and adenylate cyclase 1 (ADCY1) in the somatosensory cortex, and said upregulation was accompanied by an increased tactile response in the denervated limb (Graziano et al, 2013) This indicates that, at least in rats, passive exercise can facilitate cortical plasticity through activity-associated mechanisms, though the degree to which passive exercise alone leverages permanent cortical changes in humans remains unclear. One case report revealed that a person with cervical injury who received bimanual somatosensory stimulation in combination with massed practice (repetitive task oriented training) manifested enhanced sensation, grip force, and performance of task-specific hand skills, such as writing, page turning, lifting of a small object, manipulating checkers etc., which coincided with a reorganization of the cortical map (Hoffman and Field-Fote, 2007) Such cortical rewiring suggests active exercise can initiate a type of synaptic plasticity that is driven by activity-associated mechanisms. While admittedly, such techniques are mostly limited in clinical application, the enhanced targeting of such strategies as well as the ability to selectively initiate changes in specific neural circuits with a high degree of temporal precision will undoubtedly prove a critical resource for uncovering the role of activity-associated plasticity mechanisms at the circuit and cellular level
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