3D mapping of direct VTA-CA2 circuit with potential involvement in Parkinson's disease degeneration.

Parkinson's disease dementia (PDD) is commonly developed in patients at the late stage of Parkinson's disease (PD) with unknown progression mechanisms. From the post-mortem tissues and animal models, the ventral tegmental area (VTA) and the CA2 regions are closely associated with dementia development in PDD. However, the structural connection between the two regions has not been fully traced. In this study, we applied tissue clearing and adeno-associated virus (AAV) tracing to map the neural circuits in a 3D manner. Hence, we have confirmed the direct connection between the regions with two dual AAV tracing systems and traced the VTA-CA2 circuit in 3D reconstruction. With the immunostaining, we have shown that the GABAergic neurons are the potential subtype of the postsynaptic CA2 neurons in the VTA-CA2 circuit. Under the 6-hydroxydopamine (6-OHDA), we have demonstrated the degeneration of the VTA-CA2 circuit from the observation of fragmented axonal projections. Collectively, we have first traced the direct connection of the whole VTA-CA2 circuit in an intact 3D manner and monitored the fragmentation of this target circuit in the 6-OHDA model. This VTA-CA2 circuit can be a target for future studies of the pathological spreading and degeneration mechanism from PD to PDD.