Characterization of a novel Flpo recombinase line targeting nigral dopamine neurons

项目摘要 靶向黑质多巴胺神经元的新型Flpo重组酶系的鉴定 黑质致密部(SNC)的多巴胺(DA)神经元已被广泛研究 因为它们在帕金森氏病(PD)进展过程中容易选择性地退化。地方检察院 在帕金森病进展过程中，邻近的腹侧被盖区(VTA)的神经元大部分幸免于难； 这一现象仍然鲜为人知。尝试使用分离SNC和VTA功能的研究 现代遗传工具由于缺乏有效分离这两种基因的重组酶系而受到限制。 原子核。最近的研究表明，乙醛脱氢酶1a1(Aldh1a1)在 SNC DA神经元和这个亚群的DA神经元经历了最广泛的变性 散发性帕金森病。此外，最近研究表明，Aldh1a1能够参与GABA的合成。 不依赖于经典的GABA生物合成途径。因此，Aldh1a1+DA神经元代表一种 在解剖学和神经化学上与帕金森病相关的DA神经元群不同。获得基因上的访问 在这个群体中，我们已经在小鼠的Aldh1a1基因座上建立了Flpo重组酶敲入系。使用这个 新的Aldh1a12A-Flpo系与多巴胺转运蛋白Cre系(SLC6a3IRES-Cre)的交叉法 将能够获得Aldh1a1+和Aldh1a1-DA神经元的遗传途径。这项提议旨在 Aldh1a12A-Flpo选择性靶向黑质DA神经元的可行性研究 场和分子表型的多样性。我们还评估了交叉方法的实用性 使用Aldh1a12A-Flpo与Slc6a3IRES-Cre转基因小鼠一起指定VTA DA神经元。

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.