Functional recovery after peripheral nerve injuries is disappointing despite surgical advances in nerve repair. This review summarizes the relatively short window of opportunity for successful nerve regeneration due to the decline in the expression of growth-associated genes and in turn, the decline in regenerative capacity of the injured neurons and the support provided by the denervated Schwann cells, and the atrophy of denervated muscles. Brief, low-frequency electrical stimulation and post-injury exercise regimes ameliorate these deficits in animal models and patients, but the misdirection of regenerating nerve fibers compromises functional recovery and remains an important area of future research.

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.

Regenerative failure remains a significant barrier for functional recovery after central nervous system (CNS) injury. As such, understanding the physiological processes that regulate axon regeneration is a central focus of regenerative medicine. Studying the gene transcription responses to axon injury of regeneration competent neurons, such as those of the peripheral nervous system (PNS), has provided insight into the genes associated with regeneration. Though several individual \"regeneration-associated genes\" (RAGs) have been identified from these studies, the response to injury likely regulates the expression of functionally coordinated and complementary gene groups. For instance, successful regeneration would require the induction of genes that drive the intrinsic growth capacity of neurons, while simultaneously downregulating the genes that convey environmental inhibitory cues. Thus, this view emphasizes the transcriptional regulation of gene \"programs\" that contribute to the overall goal of axonal regeneration. Here, we review the known RAGs, focusing on how their transcriptional regulation can reveal the underlying gene programs that drive a regenerative phenotype. Finally, we will discuss paradigms under which we can determine whether these genes are injury-associated, or indeed necessary for regeneration.

Chronically axotomized motoneurons progressively fail to regenerate their axons. Since axonal regeneration is associated with the increased expression of tubulin, actin and GAP-43, we examined whether the regenerative failure is due to failure of chronically axotomized motoneurons to express and sustain the expression of these regeneration associated genes (RAGs). Chronically axotomized facial motoneurons were subjected to a second axotomy to mimic the clinical surgical procedure of refreshing the proximal nerve stump prior to nerve repair. Expression of α1-tubulin, actin and GAP-43 was analyzed in axotomized motoneurons using in situ hybridization followed by autoradiography and silver grain quantification. The expression of these RAGs by acutely axotomized motoneurons declined over several months. The chronically injured motoneurons responded to a refreshment axotomy with a re-increase in RAG expression. However, this response to a refreshment axotomy of chronically injured facial motoneurons was less than that seen in acutely axotomized facial motoneurons. These data demonstrate that the neuronal RAG expression can be induced by injury-related signals and does not require acute deprivation of target derived factors. The transient expression is consistent with a transient inflammatory response to the injury. We conclude that transient RAG expression in chronically axotomized motoneurons and the weak response of the chronically axotomized motoneurons to a refreshment axotomy provides a plausible explanation for the progressive decline in regenerative capacity of chronically axotomized motoneurons.

Adult peripheral neurons, in contrast to adult central neurons, are capable of regeneration after axonal damage. Much attention has focused on the changes that accompany this regeneration in two places, the distal nerve segment (where phagocytosis of axonal debris, changes in the surface properties of Schwann cells, and induction of growth factors and cytokines occur) and the neuronal cell body (where dramatic changes in cell morphology and gene expression occur). The changes in the axotomized cell body are often referred to as the \"cell body response.\" The focus of the current review is a family of cytokines, the glycoprotein 130 (gp130) cytokines, which produce their actions through a common gp130 signaling receptor and which function as injury signals for axotomized peripheral neurons, triggering changes in gene expression and in neurite outgrowth. These cytokines play important roles in the responses of sympathetic, sensory, and motor neurons to injury. The best studied of these cytokines in this context are leukemia inhibitory factor (LIF) and interleukin (IL)-6, but experiments with conditional gp130 knockout animals suggest that other members of this family, not yet determined, are also involved. The primary gp130 signaling pathway shown to be involved is the activation of Janus kinase (JAK) and the transcription factors Signal Transducers and Activators of Transcription (STAT), though other downstream pathways such as mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) may also play a role. gp130 signaling may involve paracrine, retrograde, and autocrine actions of these cytokines. Recent studies suggest that manipulation of this cytokine system can also stimulate regeneration by injured central neurons.