Mapping Functional Connectivity in a Rat Model of Early Stage Parkinson´s Disease with Simultaneous Optogenetic PET/fMRI

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Parkinson´s disease (PD) is the second most common neurodegenerative disorder worldwide. The pathological hallmark is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of small intracyctoplasmatic inclusions known as Lewy Bodies, mainly composed of the presynaptic protein alpha-synuclein (alpha-syn). The progressive degeneration of nigrostriatal neurons results in a profound deficiency of the neurotransmitter dopamine (DA) in the striatum, but clinical symptoms appear at a very late stage when the DA deficit is about 80 %. In contrast, recently published data suggest that dopaminergic dysfunctions occur at a very early time point of the disease before these neurons start to degenerate. The question whether alpha-syn aggregation is a possible mediator of the presynaptic dysfunctions remains still unresolved. The main objective of this research project is to monitor early functional changes of presynaptic neurotransmission in an animal model of early stage PD using simultaneous in vivo PET/BOLD-fMRI. For this purpose methods and protocols to selectively stimulate and record the activity of nigrostriatal neurons in healthy and alpha-syn overexpressing rats under in vivo conditions will be established using the optogenetic approach. The adeno-associated viral (AAV) vector mediated over-expression of alpha-syn provides the opportunity to monitor early functional changes, since neurodegeneration develops progressively over time and reflects early and late stage PD. Optogenetically controlled neuron activation will be achieved by introduction of microbial light-sensitive cation channels, Channelrhodopsin-2 (ChR-2), into nigrostriatal neurons. To achieve combined expression of ChR-2 and human wild type alpha-syn, three different AAV vector constructs will be tested and the best construct will be used for optical stimulations and electrical recordings in brain slices and under in vivo conditions.