Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models

Environmental enrichment induces activity-dependent histone acetylation via a druggable mechanism to promote recovery after spinal cord injury. , An epigenetic mechanism for regenerating axons Functional recovery after spinal cord injury (SCI) is limited by lack of axon regeneration in the mature nervous system. However, recent data showed that increasing neuronal activity promoted axonal regeneration after SCI in rodents. In a new study, Hutson et al. investigated the mechanisms mediating activity-dependent neuronal response in rodent models of spinal cord injury. Increasing neuronal activity using chemical or behavioral approaches promoted recovery through Creb-binding protein (Cbp)–mediated histone acetylation, and using a small-molecule Cbp activator mimicked the effects of increasing neuronal activity. This epigenetic mechanism might be exploited for enhancing repair and functional recovery after SCI. , After a spinal cord injury, axons fail to regenerate in the adult mammalian central nervous system, leading to permanent deficits in sensory and motor functions. Increasing neuronal activity after an injury using electrical stimulation or rehabilitation can enhance neuronal plasticity and result in some degree of recovery; however, the underlying mechanisms remain poorly understood. We found that placing mice in an enriched environment before an injury enhanced the activity of proprioceptive dorsal root ganglion neurons, leading to a lasting increase in their regenerative potential. This effect was dependent on Creb-binding protein (Cbp)–mediated histone acetylation, which increased the expression of genes associated with the regenerative program. Intraperitoneal delivery of a small-molecule activator of Cbp at clinically relevant times promoted regeneration and sprouting of sensory and motor axons, as well as recovery of sensory and motor functions in both the mouse and rat model of spinal cord injury. Our findings showed that the increased regenerative capacity induced by enhancing neuronal activity is mediated by epigenetic reprogramming in rodent models of spinal cord injury. Understanding the mechanisms underlying activity-dependent neuronal plasticity led to the identification of potential molecular targets for improving recovery after spinal cord injury.