2014 pump priming award recipient
Dr Ilse Pienaar, Imperial College London
Pedunculopontine nucleus (PPN) cholinergic neurons regulate aspects of locomotion and attention. My work recently reported a loss of PPN cholinergic neurons in Parkinson’s Disease (PD) patients compared with controls, implying that afferent and efferent cholinergic innervation to and from the PPN is diminished in PD, potentially contributing to clinical symptoms. Moreover, in the same tissue it was demonstrated that local excitatory neurotransmission within the PPN is decreased. This correlates with others who showed that axial PD symptoms might arise from excessive cholinergic inhibition of the PPN via projections. The PPN has emerged as a target for Deep Brain Stimulation (DBS) for treating PD symptoms.
This award will allow for establishing whether control of PPN cholinergic-specific neurotransmission comprise a potential target for alleviating aspects of Parkinsonism. I will combine genetic rat transgenesis, experimental Parkinsonism, induced via a unihemispheric, intranigral toxin injection, together with a PPN infusion of a viral vector containing mutated receptors, to precisely control PPN cholinergic activity. This approach allows for remote delivery of a drug by which expressed receptors are activated, hence inhibiting cholinergic neuronal activity.
Unlike standard optogenetics, requiring implantation of invasive light-delivering devices, the method allows for a minimally invasive means by which to control PPN cholinergic activity. In addition to behavioural assessment studies when the target neurons are turned on, compared to when turned off, in vivo electrophysiological activity of cholinergic neurons and histological characterisation of SNpc and PPN-containing brain samples collected from the treated rats will be performed.