Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | eaaw2064 |
| Journal | Science Translational Medicine |
| Volume | 11 |
| Issue number | 487 |
| DOIs | |
| State | Published - Apr 10 2019 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models. / Hutson, Thomas H.; Kathe, Claudia; Palmisano, Ilaria; Bartholdi, Kay; Hervera, Arnau; De Virgiliis, Francesco; McLachlan, Eilidh; Zhou, Luming; Kong, Guiping; Barraud, Quentin; Danzi, Matt C.; Medrano-Fernandez, Alejandro; Lopez-Atalaya, Jose P.; Boutillier, Anne L.; Sinha, Sarmistha H.; Singh, Akash K.; Chaturbedy, Piyush; Moon, Lawrence D.F.; Kundu, Tapas K.; Bixby, John; Lemmon, Vance; Barco, Angel; Courtine, Gregoire; Giovanni, Simone Di.
In: Science Translational Medicine, Vol. 11, No. 487, eaaw2064, 10.04.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models
AU - Hutson, Thomas H.
AU - Kathe, Claudia
AU - Palmisano, Ilaria
AU - Bartholdi, Kay
AU - Hervera, Arnau
AU - De Virgiliis, Francesco
AU - McLachlan, Eilidh
AU - Zhou, Luming
AU - Kong, Guiping
AU - Barraud, Quentin
AU - Danzi, Matt C.
AU - Medrano-Fernandez, Alejandro
AU - Lopez-Atalaya, Jose P.
AU - Boutillier, Anne L.
AU - Sinha, Sarmistha H.
AU - Singh, Akash K.
AU - Chaturbedy, Piyush
AU - Moon, Lawrence D.F.
AU - Kundu, Tapas K.
AU - Bixby, John
AU - Lemmon, Vance
AU - Barco, Angel
AU - Courtine, Gregoire
AU - Giovanni, Simone Di
PY - 2019/4/10
Y1 - 2019/4/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064175124&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064175124&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aaw2064
DO - 10.1126/scitranslmed.aaw2064
M3 - Article
C2 - 30971452
AN - SCOPUS:85064175124
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 487
M1 - eaaw2064
ER -