Intrinsic properties and environmental factors in the regeneration of adult cerebellar axons

Abstract

The success of axon regeneration in the adult mammalian brain depends on the presence of growth-permissive environmental conditions as well as on specific properties of the affected neurons. To investigate the relative contribution of extrinsic cues and intrinsic determinants to reparative processes we have investigated the regenerative properties of olivocerebellar and Purkinje cell axons. When these axon populations are severed in the cerebellar white matter and confronted with embryonic neural grafts of cerebellar or extracerebellar origin, the former vigorously regenerate into the transplant, whereas the latter invariably fail to do so (Rossi et al., 1995). The same response occurs when dissociated Schwann cells are implanted in the lesion site: Purkinje cell axons fail to regrow, whereas olivocerebellar fibres regenerate for considerable distances. Within the graft, regenerating fibres follow tortuous courses along Schwann cell bundles and sometimes end with poorly developed terminal plexuses. Some of them, however, succeed in crossing the graft and grow further into the host cortex, where they break into fine terminal branches confined to the granular layer. The remarkable regenerative response of olivocerebellar axons revealed by these experiments might be an intrinsic reaction of the affected neurons to axon injury or it might be elicited by growth promoting cues derived from the grafts. To elucidate this point we have undertaken the investigation of cellular changes occurring in adult inferior olivary neurons following the transection of the inferior cerebellar peduncle. Our results show that axotomy induces a series of cellular changes, or reparative and regressive character, which ultimately lead to cell death. Interestingly, however, these modifications are not uniformly distributed throughout the whole inferior olive. (i) Neuronal atrophy and degeneration progress more rapidly in the PO and DAO than in the MAO. (ii) A subpopulation of inferior olivary neurons become reactive for NADPH-diaphorase histochemistry, and their preferential localisation in the MAO suggests that this modification is related to the longer survival of these cells after axotomy. (iii) The developmentally regulated calcitonin gene-related peptide (CGRP) is reexpressed by a subset of neurons in the caudal nuclear compartments. These results further emphasise the conclusion that the dissimilar regenerative response of Purkinje cell and olivocerebellar axons confronted with permissive environmental conditions is due to different intrinsic properties of these neuronal populations. The reexpression of developmentally regulated substances by axotomised inferior olivary neurons suggests that their reparative reaction is triggered by axon injury. However, the pattern of growth of regenerating olivocerebellar axons is strongly conditioned by environmental constraints, which, in the present experimental conditions, do not allow them to reattain denervated Purkinje cells.