Characterization of a novel Flpo recombinase line targeting nigral dopamine neurons

项目总结

Project Summary Characterization of a novel Flpo recombinase line targeting nigral dopamine neurons The dopamine (DA) neurons of the substantia nigra pars compacta (SNc) have been extensively studied because of their selective vulnerability to degeneration during Parkinson's disease (PD) progression. The DA neurons of the closely neighboring ventral tegmental area (VTA) are largely spared during PD progression; a phenomenon that remains poorly understood. Studies attempting to separate SNc and VTA function using modern genetic tools have been limited by the lack of recombinase lines that effectively separate these two nuclei. Recent studies have shown that aldehyde dehydrogenase 1a1 (Aldh1a1) is expressed selectively in SNc DA neurons and this subpopulation of DA neurons undergoes the most extensive degeneration in sporadic PD. Also it has been recently shown that Aldh1a1 is capable of participating in GABA synthesis in a pathway independent of the classic GABA biosynthetic pathway. Thus Aldh1a1+ DA neurons represent an anatomically and neurochemically distinct population of DA neurons relevant to PD. To gain genetic access to this population we have developed a Flpo recombinase knock-in line at the mouse Aldh1a1 locus. Using this novel Aldh1a12A-Flpo line in an intersectional approach with the dopamine transporter Cre line (Slc6a3IRES-Cre) we will be able to gain genetic access to both Aldh1a1+ and Aldh1a1- DA neurons. This proposal is designed to test the feasibility of using Aldh1a12A-Flpo to selectively target SNc DA neurons and to determine their target fields and diversity of molecular phenotypes. We also evaluate the utility of intersectional approaches to specify VTA DA neurons using Aldh1a12A-Flpo with Slc6a3IRES-Cre transgenic mice.