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

脊髓损伤后轴突再生和恢复的环境富集依赖性神经元活动途径

• 批准号: MR/R005311/1
• 负责人: Simone Di Giovanni
• 金额: $ 55.41万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR005311%2F1
• 关键词: Environmental; enrichment; dependent; neuronal; activity

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.

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。这部分是由于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至关重要，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于环境富集（EE）可诱导DRG神经元再生潜力的长期增加。此外，先前暴露于情感表达增强了脊髓损伤后感觉轴突的再生和功能改善，当与条件反射损伤联合使用时，这些功能进一步增强。机制实验表明，神经元活性的增强和组蛋白乙酰化可能是观察到的再生表型的原因。在这里，我们将研究ee依赖性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creb结合蛋白（CBP）依赖性组蛋白乙酰化和再生基因重编程的激活。其次，我们将探讨使用CBP小分子激活剂是否促进脊髓损伤后轴突的再生和恢复。总的来说，该提案将澄清(i)支持这种新的感觉神经元再生启动的ee依赖条件调节模型的机制，（ii）将测试最近开发的CBP小分子激活剂，用于脊髓损伤后与功能相关的轴突再生。这项研究将是重要的，因为它将为一个新的转化机会奠定基础，通过使用可用于患者的再生小分子来促进脊髓损伤后的再生和恢复。

项目成果

Enriched conditioning expands the regenerative ability of sensory neurons after spinal cord injury via neuronal intrinsic redox signaling.

• DOI: 10.1038/s41467-020-20179-z
• 发表时间: 2020-12-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: De Virgiliis F;Hutson TH;Palmisano I;Amachree S;Miao J;Zhou L;Todorova R;Thompson R;Danzi MC;Lemmon VP;Bixby JL;Wittig I;Shah AM;Di Giovanni S
• 通讯作者: Di Giovanni S