Willson Melina L, McElnea Catriona, Mariani Jean, Lohof Ann M, Sherrard Rachel M
Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche (UMR) 7102-Neurobiologie des Processus Adaptatifs (NPA), Centre National de la Recherche Scientifique (CNRS), UMR 7102-NPA, F-75005 Paris, France.
Brain. 2008 Apr;131(Pt 4):1099-112. doi: 10.1093/brain/awn024. Epub 2008 Feb 25.
Recovery of complex neural function after injury to the adult CNS is limited by minimal spontaneous axonal regeneration and/or sprouting from remaining pathways. In contrast, the developing CNS displays spontaneous reorganization following lesion, in which uninjured axons can develop new projections to appropriate target neurons and provide partial recovery of complex behaviours. Similar pathways can be induced in the mature CNS, providing models to optimize post-injury recovery of complex neural functions. After unilateral transection of a developing olivocerebellar path (pedunculotomy), remaining inferior olivary axons topographically reinnervate the denervated hemicerebellum and compensate functional deficits. Brain-derived neurotrophic factor (BDNF) partly recreates such reinnervation in the mature cerebellum. However the function of this incomplete reinnervation and any unwanted behavioural effects of BDNF remain unknown. We measured olivocerebellar reinnervation and tested rotarod and navigation skills in Wistar rats treated with BDNF/vehicle and pedunculotomized on day 3 (Px3; with reinnervation) or 11 (Px11; without spontaneous reinnervation). BDNF treatment did not affect motor or spatial behaviour in normal (control) animals. Px11-BDNF animals equalled controls on the rotarod, outperforming Px11-vehicle animals. Moreover, Px3-BDNF and Px11-BDNF animals achieved spatial learning and memory tasks as well as controls, with Px11-BDNF animals showing better spatial orientation than Px11-vehicle counterparts. BDNF slightly increased olivocerebellar reinnervation in Px3 animals and induced sparse (22% Purkinje cells) yet widespread reinnervation in Px11 animals. As reinnervation correlated with spatial function, these data imply that after injury even a small amount of reinnervation that is homotypic to correct target neurons compensates deficits in appropriate complex motor and spatial skills. As there was no effect in control animals, BDNF effectively induces this axon collateralisation without interfering with normal neuronal circuits.
成年中枢神经系统（CNS）损伤后复杂神经功能的恢复受到限制，原因是轴突自发再生极少和/或剩余神经通路的芽生有限。相比之下，发育中的中枢神经系统在损伤后会自发重组，其中未受损的轴突可以向合适的靶神经元发展出新的投射，并部分恢复复杂行为。类似的通路也可以在成熟的中枢神经系统中诱导产生，从而为优化损伤后复杂神经功能的恢复提供模型。在发育中的橄榄小脑通路进行单侧横断（脑桥切断术）后，剩余的下橄榄核轴突会按拓扑结构重新支配去神经支配的半小脑，并补偿功能缺陷。脑源性神经营养因子（BDNF）在成熟小脑中部分重现了这种重新支配。然而，这种不完全重新支配的功能以及BDNF的任何不良行为影响仍然未知。我们测量了橄榄小脑的重新支配情况，并测试了用BDNF/载体处理且在第3天（Px3；有重新支配）或第11天（Px11；无自发重新支配）进行脑桥切断术的Wistar大鼠的转棒试验和导航技能。BDNF处理对正常（对照）动物的运动或空间行为没有影响。Px11 - BDNF组动物在转棒试验中的表现与对照组相当，优于Px11 - 载体组动物。此外，Px3 - BDNF组和Px11 - BDNF组动物完成空间学习和记忆任务的情况与对照组一样好，Px11 - BDNF组动物的空间定向能力比Px11 - 载体组动物更好。BDNF略微增加了Px3组动物的橄榄小脑重新支配，并在Px11组动物中诱导了稀疏（22%的浦肯野细胞）但广泛的重新支配。由于重新支配与空间功能相关，这些数据表明，损伤后即使是少量与正确靶神经元同型的重新支配也能补偿适当的复杂运动和空间技能的缺陷。由于对照动物没有受到影响，BDNF有效地诱导了这种轴突侧支化，而不会干扰正常的神经回路。
