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

成年哺乳动物神经系统的损伤会导致感觉和运动功能的永久性缺陷。这在一定程度上是因为神经元无法启动有效的分子再生反应，导致轴突再生失败。背根神经节(DRG)中的感觉神经元在生理和损伤后的感觉运动功能中起着至关重要的作用，因为它们接收和传递来自环境的感觉信息到脊髓和大脑的运动回路。我们最近发现，在损伤前将小鼠暴露在环境富集物(EE)中可以诱导DRG神经元再生潜力的长期增加。此外，预先接触EE可促进脊髓损伤后感觉轴突的再生和功能改善，当与条件性损伤相结合时，这一点进一步增强。机制实验表明，神经元活性和组蛋白乙酰化的增强可能是观察到的再生表型的原因。在这里，我们将研究EE依赖的感觉轴突再生的增加是否依赖于神经元活性和钙信号的增强，从而导致依赖CREB结合蛋白(CBP)的组蛋白乙酰化和再生基因重新编程。其次，我们将探讨使用CBP的小分子激活剂是否能促进脊髓损伤后轴突的再生和恢复。总之，这项建议将阐明(I)支持这种新的EE依赖的感觉神经元再生启动的条件反射模型的机制，以及(Ii)将测试最近开发的CBP小分子激活剂对脊髓损伤后功能相关的轴突再生的影响。这项研究将是重要的，因为它将为通过使用可供患者使用的再生小分子促进脊髓损伤后的再生和恢复的新的翻译机会奠定基础。

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.