BDNF increases homotypic olivocerebellar reinnervation and associated fine motor and cognitive skill.
Résumé
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.