Willson, Melina L. (2007) The function of spontaneous and BDNF-induced repair of the rat olivocerebellar system. PhD thesis, James Cook University.

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Abstract

Research on improving recovery of neural function after adult brain injury has focused on axonal regeneration, i.e. the concept of recapitulating developmental axonal growth in the central nervous system (CNS). Although studies that increase axonal regeneration give rise to some functional improvement, it rarely ameliorates complex neural actions. Some attention has been directed to the type of reinnervation that takes place in the neonatal CNS, in which neurons surviving after injury spontaneously develop new axons to replace the damaged path and re-form its specific pattern with correct afferent-target connections. Such reinnervation is partly recreated in the maturing CNS by injection of growth factors e.g. brain-derived neurotrophic factor (BDNF). The aim of this project was to examine in vivo the structure and function of spontaneous and BDNF-associated alternate reinnervation.

We used the rat olivocerebellar projection to characterise the anatomy, physiology and complex (cognitive) neural function of spontaneous and BDNF-associated post-lesion olivocerebellar reinnervation. In the adult, the olivocerebellar path has a well-defined topography where axons enter the cerebellum via the contralateral inferior cerebellar peduncle and terminate as climbing fibres (CFs) onto Purkinje cells (PCs) to regulate motor and spatial functions. Our model involves unilateral axonal transection of this path (pedunculotomy; Px), either at postnatal day (P) 3 to induce spontaneous reinnervation, or P11 when reinnervation only occurs after injection of BDNF.

First, we examined whether spontaneous olivocerebellar reinnervation compensated complex functions such as spatial learning. As reinnervation is partial in the region which mediates spatial cognition, its capacity to mediate navigation was unknown. We tested rats with (Px3) and without (Px11) reinnervation in simple locomotion and spatial (water maze) tasks. Px3 animals performed the spatial task as well as controls despite learning more erratically while Px11 animals did not learn the task. The amount of reinnervation directly correlated with spatial ability, suggesting that even partial reinnervation was associated with functional benefit in a complex task.

Next, we assessed the effect of increasing olivocerebellar reinnervation by BDNF on its associated functions. BDNF/vehicle-treated animals were tested on simple/complex motor and spatial tasks and the amount and distribution of reinnervation were analysed. BDNF did not affect basic motor skills, however on the rotarod BDNF-treated Px11 animals were similar to normal and Px3 groups. They also exhibited better spatial abilities than vehicle-treated Px11 animals. BDNF treatment increased the amount and distribution of reinnervation in both Px3 and Px11 animals. This suggests that neurotrophin-induced reinnervation facilitated appropriate complex (i.e. cognitive) actions.

Finally, as reinnervating synapses do not always induce appropriate target responses, we examined the synaptic function of BDNF-associated olivocerebellar reinnervation to assess any correlation between CF reinnervation and improved behaviour. CF currents (amplitude, paired-pulse depression [PPD], fatigue) were recorded from adult PCs and the structural CF-PC interactions measured. In synapses forming ~6days post Px3, BDNF was associated with impaired CF-PC interaction (smaller synaptic amplitude, greater PPD smaller CFs). Whereas BDNF-induced reinnervation (i.e.Px11) had increased PPD without affecting anatomical attributes. As PPD aids CF-PC transmission at low in vivo frequencies, these synaptic changes are unlikely to affect cerebellar function. Therefore, spontaneous and BDNF-associated reinnervation form functional synapses with associated functional recovery.

Item ID:	2099
Item Type:	Thesis (PhD)
Keywords:	spontaneous repair, BDNF induced repair, rats, olivocerebellar system, brain injury recovery, axonal regeneration, brain-derived neurotrophic factors, climbing fibres, Purjinki cells, spatial learning, reinnervation, neurons
Date Deposited:	25 Feb 2009 22:56
FoR Codes:	06 BIOLOGICAL SCIENCES > 0608 Zoology > 060805 Animal Neurobiology @ 0%
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