Abstract
Neural injury in mammals often leads to persistent functional deficits as spontaneous repair in the peripheral nervous system (PNS) is often incomplete, while endogenous repair mechanisms in the central nervous system (CNS) are negligible. Peripheral axotomy elicits growth-associated gene programs in sensory and motor neurons that can support reinnervation of peripheral targets given sufficient levels of debris clearance and proximity to nerve targets. In contrast, while damaged CNS circuitry can undergo a limited amount of sprouting and reorganization, this innate plasticity does not re-establish the original connectivity. The utility of novel CNS circuitry will depend on effective connectivity and appropriate training to strengthen these circuits. One method of enhancing novel circuit connectivity is through the use of electrical stimulation, which supports axon growth in both central and peripheral neurons. This review will focus on the effects of CNS and PNS electrical stimulation in activating axon growth-associated gene programs and supporting the recovery of motor and sensory circuits. Electrical stimulation-mediated neuroplasticity represents a therapeutically viable approach to support neural repair and recovery. Development of appropriate clinical strategies employing electrical stimulation will depend upon determining the underlying mechanisms of activity-dependent axon regeneration and the heterogeneity of neuronal subtype responses to stimulation.
Highlights
Following injury to the adult mammalian central nervous system (CNS), neural circuits are permanently disrupted as severed axons fail to undergo spontaneous regeneration
Direct low-frequency electrical stimulation of the intact rodent sciatic nerves at 20 Hz for 1 h induces a significant upregulation in the expression of growth associated protein-43 (GAP-43), the neurotrophin BDNF and its high-affinity receptor trkB, as well as increased phosphorylation of the transcription factor cAMP response element binding protein (CREB) in dorsal root ganglia (DRG) neurons (English et al, 2007; Senger et al, 2018, 2019)
The limited effectiveness of electrical conditioning extends to the CNS as well, as regeneration of the central axon of dorsal column projecting sensory neurons after a spinal cord injury is less robust in rats conditioned
Summary
Following injury to the adult mammalian central nervous system (CNS), neural circuits are permanently disrupted as severed axons fail to undergo spontaneous regeneration. In much the same manner that electrical stimulation of the cortex activates pro-regenerative molecular pathways, electrical stimulation of peripheral nerves has been shown to induce identified RAG expression in both sensory and motor neurons.
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