The induction and inhibition of post-lesional transcommissural climbing fibre reinnervation in the neonatal and adult rat cerebellum using brain-derived neurotrophic factor: anatomical and functional implications

Dixon, Kirsty Jane (2006) The induction and inhibition of post-lesional transcommissural climbing fibre reinnervation in the neonatal and adult rat cerebellum using brain-derived neurotrophic factor: anatomical and functional implications. PhD thesis, James Cook University.

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In the adult mammalian central nervous system, reinnervation and recovery from trauma is limited. During development however, post-lesion plasticity generates alternate paths providing models to investigate factors that promote reinnervation to appropriate targets.

Following unilateral transection of the neonatal rat olivocerebellar pathway, axons from the remaining inferior olive reinnervate the denervated hemicerebellum and develop topographically organised normal climbing fibre arbors on Purkinje cells. However, the capacity to recreate this accurate target reinnervation in a mature system remains unknown. This thesis will identify whether one factor, Brain-derived neurotrophic factor (BDNF) is involved in reinnervation during the neonatal period and whether it induces similar reinnervation in the mature system. If BDNF does induce reinnervation in the mature system, this thesis will identify any return of lost function.

In rats lesioned on postnatal days 3 (P3), P15, P20 or P30 and treated with an intracerebellar injection of brain-derived neurotrophic factor (BDNF) or a BDNF blockade 24 hours following surgery, the morphology and organisation of transcommissural olivocerebellar reinnervation was examined using neuronal tracers and immunohistochemistry. The behavioural sequela of these rats was also investigated using vestibulo-spinal reflexes, simple locomotion, complex locomotion and gait synchronisation tests. Additionally, in neonatal rats (P3) with a unilateral lesion and treated with an intraolivary injection of BDNF, the survival of the axotomised inferior olivary complex and associated ipsilateral olivocerebellar pathway was examined using histochemical dyes and neuronal tracers.

In neonatal animals (P3), intracerebellar application of a BDNF blockade prevents olivocerebellar reinnervation of target Purkinje cells in the treatment area, while addition of BDNF in the mature system induces transcommissural olivocerebellar axonal growth into the denervated hemicerebellum. The distribution of BDNF-induced reinnervating climbing fibres was not confined to the injection sites, but extended throughout the denervated hemivermis and, less densely, up to 3.5 mm into the hemisphere. Transcommissural reinnervating axons were organised into parasagittal microzones that were almost symmetrical to those in the right hemicerebellum.

Reinnervating climbing fibre arbors were predominantly normal, but in the P30-lesioned group 10 % branched within the molecular layer forming a smaller secondary arbor, and in the P15-lesion group, the reinnervating arbors extended their terminals almost to the pial surface and were larger than control arbors (p<0.02). Behavioural testing revealed that BDNF and extensive exercise induce olivocerebellar reinnervation and that this reinnervation provides functional recovery, although this is delayed in the vehicletreatment group. Additionally, the behavioural testing revealed that functional recovery is dependent on the age of the animal, whereby animals lesioned prior to acquiring task specific skills were developmentally disadvantaged. Lastly, during the neonatal period intraolivary BDNF transiently prevented degeneration of the axotomised inferior olivary complex, however it was unsuccessful in inducing transcommissural axonal growth of the ipsilateral olivocerebellar pathway into the denervated hemisphere.

For the first time, data from this PhD suggests that BDNF is involved in transcommissural reinnervation of denervated areas during the neonatal period and show that BDNF promotes topographically organised morphologically correct reinnervation in the mature rat cerebellum. Additionally, this reinnervation in the mature system provides functional recovery similar to sham-operated control animals. BDNF administered intraolivary however does not maintain the persistence of axotomised olivary neurons or induce transcommissural axonal growth of the ipsilateral olivocerebellar pathway. Data from this study can one day be used to contribute to a repair mechanism for traumatic brain injury, minimising long-term disabilities and ongoing costs to society.

Item ID: 2058
Item Type: Thesis (PhD)
Keywords: rats, reinnervation, climbing fibre, neurotrophins, brain-derived neurotrophic factor, BDNF, traumatic brain injury, pathways, Purkinje cells
Date Deposited: 14 Jan 2009 05:17
FoR Codes: 06 BIOLOGICAL SCIENCES > 0606 Physiology > 060601 Animal Physiology - Biophysics @ 0%
17 PSYCHOLOGY AND COGNITIVE SCIENCES > 1702 Cognitive Science > 170205 Neurocognitive Patterns and Neural Networks @ 0%
06 BIOLOGICAL SCIENCES > 0608 Zoology > 060805 Animal Neurobiology @ 0%
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