ERANET NEURON 1: Establishing an in vivo rodent model to evaluate the behavioural effects of pedunculopontine stimulation in Parkinson’s disease

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The pedunculopontine tegmental nucleus (PPN) is involved in Parkinson's disease (PD): there is progressive loss of cholinergic neurons and PPN metabolic activity is changed by altered inputs from pallidum, subthalamic nucleus and substantia nigra zona reticulata. Most importantly, low frequency deep brain stimulation (DBS) in the PPN has therapeutic benefits. Gait and postural instability improve, and there are suggestions that some cognitive impairments also benefit. This strongly suggests that the PPN has a more significant role in PD than previously thought. This project will explore the role of the PPN in PD: we will create an in vivo rodent model to evaluate the behavioural effects of PPN stimulation in Parkinsonian conditions. There is a pressing need to do this: (i) There is controversy about the location of DBS in relation to PPN. Are the electrodes truly in PPN, and if so, what is the most effective intra-PPN site? (ii) What functions will benefit? We will test motor and cognitive abilities: it is thought that PPN has motor functions, but recent data show that it has a role in learning. Because these structures have been highly conserved through evolution, the rodent PPN and basal ganglia are excellent models for other species. To create a relevant rodent PD model we will make partial bilateral lesions using the novel agent, urotensin II–diphtheria toxin (DIPtx-UII) selective for PPN cholinergic neurons. In the same rats, we will make bilateral lesions of substantia nigra pars compacta dopamine (DA) neurons with 6-hydroxydopamine. We will test motor (gait; locomotion; reaction time) and cognitive performance (learning, memory) inrats that bear lesions, in lesioned rats with PPN electrodes (over which the rats and/or experimenters have control), and appropriate controls. Electrode location in and around PPN will be systematically varied. This will enable us to determine: (i) the effects of PPN DBS on motor and cognitive performance; (ii) whether different electrode locations have differential effects on these, and what neural activity (measured using immediate early gene expression) is changed both by the lesions and by PPN DBS.