Behavioural analysis of 6-hydroxydopamine rodent models of Parkinson's disease

The aims of this thesis were to characterise further lesion-induced impairments in unilateral rodent models of Parkinson’s disease (PD) on a more cognitive level and to investigate the effects of cell replacement therapies on these tests. Chapter 3.1 deals with the effects of dopamine depletion on a lateralised choice reaction time task in the Skinner box as this apparatus is more widely available than the 9-hole boxes on which initial studies have been based. Unilateral near complete lesions of the nigro-striatal pathway induced a stable side bias that was comparable to the lesion-induced deficits that have been reported in the 9-hole box apparatus. Chapter 3.2 reports on the effects of similar lesions on a more spatial reaction time task and the effects of engraftment of dopamine rich tissue in the denervated striatum. The lesions induced a spatial bias that was only marginally improved by the cell transplantation, clearly showing the limitations of ectopic graft placement. Nevertheless, small but significant improvements on that task could be shown as grafted animals performed with higher accuracy and had reduced movement times compared to the lesion only counterparts. Chapter 3.3 explores the lesion-induced deficit in more detail by implementing an error correction rule on the operant task to enforce a change in the animals’ response strategy. The results of this chapter confirmed earlier findings, that the dopamine depletion produced by the lesion gives rise to a strong near hole bias on the contralateral side which did not recover, even with extensive post lesion testing, i.e. the lesion-induced deficit is most likely to be caused by a misrepresentation of response space, rather than caused by a shift in response strategy. The second strand of this thesis focuses on the development of mouse models of similar dopamine-depleting lesions that are typically used in rat models of PD. In Chapter 3.4 the three most common lesion models are compared to each other on an extensive battery of simple motor tests. The aim was both to characterise the behavioural impact of dopamine depletion in different sites, as well as to identify appropriate hand tests, capable of distinguishing lesions greater than 70% depletion. The differences and similarities between lesions were evaluated and correlations between behavioural performance and nigral cell loss were observed. In Chapter 3.5 I developed parameters which allowed application of the lateral choice reaction time task to mouse models of dopamine depletion. Here I demonstrate the effects of two lesions, either to the medial forebrain bundle or the substantia nigra, on the same task conducted in mice. Lesioned mice of the former group displayed a stronger deficit largely because of the larger dopamine depletion. Subsequently, in Chapter 3.6 I characterise the effects of primary fetal tissue grafts on the previously established model and task. Primary fetal tissue was able to ameliorate some of the lesion-induced deficits on an operant choice reaction time task and a series of simple motor screens. The results of both strands of research in the present thesis have implications for the understanding of the cognitive and motor deficits that are induced by the most commonly used lesion model of PD and for the parameters that can be recovered by cell replacement therapies. The primary fetal tissue will serve as a baseline, against which future stem cell based therapies can be measured