Laboratory of Neurodegenerative Diseases, School of Biomedical Science, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China.
Laboratory of Neurodegenerative Diseases, School of Biomedical Science, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China.
Neurobiol Dis. 2024 Nov;202:106723. doi: 10.1016/j.nbd.2024.106723. Epub 2024 Oct 30.
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.
帕金森病痴呆症（PDD）通常发生在帕金森病（PD）晚期患者中，其进展机制尚不清楚。从尸检组织和动物模型中可以看出，腹侧被盖区（VTA）和 CA2 区与 PDD 痴呆的发展密切相关。然而，这两个区域之间的结构连接尚未完全追踪。在这项研究中，我们应用组织透明化和腺相关病毒（AAV）示踪技术以三维方式绘制神经回路。因此，我们通过两种双 AAV 示踪系统证实了区域之间的直接连接，并在三维重建中追踪了 VTA-CA2 回路。通过免疫染色，我们已经表明 VTA-CA2 回路中的 GABA 能神经元是 CA2 神经元的潜在突触后亚型。在 6-羟基多巴胺（6-OHDA）作用下，我们通过观察碎片化的轴突投射，证明了 VTA-CA2 回路的退化。总的来说，我们首次以完整的三维方式追踪了整个 VTA-CA2 回路的直接连接，并在 6-OHDA 模型中监测了这个目标回路的碎片化。这个 VTA-CA2 回路可能是未来研究 PD 向 PDD 病理扩散和退化机制的一个靶点。
