Environmental enrichment-dependent neuronal activity pathways for axonal regeneration and recovery after spinal cord injury

Injury to the adult mammalian nervous system leads to permanent deficits in sensory and motor function. This is partly due the inability of neurons to initiate an effective molecular regenerative response, resulting in failed axon regeneration. Sensory neurons in the dorsal root ganglia (DRG) are vital for physiological and post-injury sensorimotor function as they receive and convey sensory information from the environment to motor circuits in the spinal cord and brain. We have recently found that exposing mice to environmental enrichment (EE) prior to an injury induces a long-lasting increase in the regenerative potential of DRG neurons. Moreover, prior exposure to EE augmented sensory axon regeneration and functional improvements after spinal cord injury, which were further enhanced when combined with a conditioning injury. Mechanistic experiments suggest that an enhancement in neuronal activity and histone acetylation may be responsible for the observed regenerative phenotype. Here we will investigate whether an EE-dependent increase in sensory axon regeneration depends upon enhancing neuronal activity and calcium signalling, leading to activation of CREB-binding protein (CBP)-dependent histone acetylation and regenerative gene reprogramming. Secondly, we will explore whether the use of a small molecule activator of CBP promotes axonal regeneration and recovery after spinal cord injury. Overall this proposal will clarify (i) the mechanisms supporting this novel EE-dependent conditioning model for regenerative priming of sensory neurons and (ii) will test a recently developed small molecular activator of CBP for functionally relevant axon regeneration after spinal injury.
This research will be important as it will set the groundwork for a novel translational opportunity to promote regeneration and recovery after spinal injury by using a regenerative small molecule amenable for use in patients.

Injury to the adult mammalian nervous system leads to permanent deficits in sensory and motor function. This is partly due the inability of neurons to initiate an effective molecular regenerative response, resulting in failed axon regeneration. Sensory neurons in the dorsal root ganglia (DRG) are essential for sensorimotor function as they receive and convey sensory information from the environment to motor circuits in the spinal cord and brain. We have recently found that exposing mice to environmental enrichment (EE) prior to an injury induces a long-lasting increase in the regenerative potential of DRG neurons, including when combined with a conditioning lesion, priming them for robust axon regeneration in both the peripheral and central nervous system after injury. Therefore, we propose EE as a novel "injury free" paradigm priming sensory neurons for axon regeneration. Mechanistically, our recent combined RNAseq and proteomics studies suggest that EE may enhance neuronal activity and creb binding protein (CBP)-dependent histone acetylation leading to gene expression for a long-lasting enhanced axonal regenerative ability. Here, we will investigate (1) whether EE-dependent proprioceptive input from muscle spindles is required for EE-dependent modulation of neuronal activity and DRG sensory growth by studying EGR KO mice that have an impaired muscle spindle feedback signalling. (2) Second, we will explore whether EE-dependent neuronal activity is required for EE-dependent DRG outgrowth (DREADD based approaches), CBP and histone acetylation. Lastly, 83) we will ask whether a small molecule activator of CBP will enhance axonal regeneration and (neurophysiological and sensorimotor recovery after SCI mimicking the effects of EE and EE in combination with a conditioning lesion. In summary, this proposal aims to provide both mechanistic and translational advancements for the understanding and treatment of experimental and clinical SCI.

The prevalence for spinal cord injury is estimated to be approximately of 500,000 worldwide, affecting mainly young adults. There is no cure for spinal cord injury, and it is one of the most common acute neurological diseases with chronic sequelae that affect young adults in the western world, leading to long-term disability, suffering and very high social costs. It is a truly devastating condition which usually occurs in the 2rd to 3th decades of life and leads to locomotion impairment, pain, cardiac, respiratory, urinary and sexual dysfunction among other symptoms. To date, there is no effective treatment to improve disability in spinal cord patients, who rely only on long-term, time consuming and physically as well as psychologically demanding rehabilitation plans. This disability has a major impact on the quality of life of those with spinal cord injury and their close families and carers.


The economic benefit to the healthcare system of the UK in limiting the disability in spinal cord injury patients is clearly substantial. The cost of loss of employment cost of chronic care facilities and treatment of chronic disease associated problems associated with spinal cord injury is a serious burden on the health system worldwide. Indeed, although we do not envisage that a therapy derived from our research will be available in the clinic within the time span of this research programme, we are hopeful that it will contribute to set the groundwork for targeted clinical trials in the near future.

The research that we have proposed is based on truly novel results that have been obtained by the detailed study of the impact of environmental enrichment upon neuronal signaling, gene regulation, axonal regeneration and functional recovery in clinically relevant experimental models of spinal cord injury. Particular emphasis is in fact placed on what could underlie regenerative failure that does allow lifting the overall disability burden of spinal cord injury. We have identified a specif critical pathway that we intend to modulate pharmacologically with a small molecular compound that activates the histone acetyltransferase protein CBP/p300. If successful, we believe that there could be a relatively short time span before this and similar compounds could be tested in clinical spinal cord injury.

Provided that activation of CBP/p300 with a small molecule will lead to axonal regeneration and functional recovery in the mouse after spinal cord hemisection, further studies should be performed in mice and rats including in contusion models of spinal cord injury, that more closely resembles clinically spinal cord injury. However, the contusion model does not allow studying with accuracy spinal axonal regeneration and is therefore not a first choice for our studies. In case of success in terms of neurological recovery also in spinal contusion models ideally in both mice and rats, safety clinical trials in humans may be initiated including in patients affected by spinal cord injury.