Hedrick Tristan, Danskin Bethanny, Larsen Rylan S, Ollerenshaw Doug, Groblewski Peter, Valley Matthew, Olsen Shawn, Waters Jack
Northwestern University, 303 E Chicago Ave, Chicago IL 60611, United States of America.
Allen Institute for Brain Science, 551 N 34th St, Seattle WA 98103, United States of America.
PLoS One. 2016 May 31;11(5):e0156596. doi: 10.1371/journal.pone.0156596. eCollection 2016.
The study of cholinergic signaling in the mammalian CNS has been greatly facilitated by the advent of mouse lines that permit the expression of reporter proteins, such as opsins, in cholinergic neurons. However, the expression of opsins could potentially perturb the physiology of opsin-expressing cholinergic neurons or mouse behavior. Indeed, the published literature includes examples of cellular and behavioral perturbations in preparations designed to drive expression of opsins in cholinergic neurons. Here we investigate expression of opsins, cellular physiology of cholinergic neurons and behavior in two mouse lines, in which channelrhodopsin-2 (ChR2) and archaerhodopsin (Arch) are expressed in cholinergic neurons using the Cre-lox system. The two mouse lines were generated by crossing ChAT-Cre mice with Cre-dependent reporter lines Ai32(ChR2-YFP) and Ai35(Arch-GFP). In most mice from these crosses, we observed expression of ChR2 and Arch in only cholinergic neurons in the basal forebrain and in other putative cholinergic neurons in the forebrain. In small numbers of mice, off-target expression occurred, in which fluorescence did not appear limited to cholinergic neurons. Whole-cell recordings from fluorescently-labeled basal forebrain neurons revealed that both proteins were functional, driving depolarization (ChR2) or hyperpolarization (Arch) upon illumination, with little effect on passive membrane properties, spiking pattern or spike waveform. Finally, performance on a behavioral discrimination task was comparable to that of wild-type mice. Our results indicate that ChAT-Cre x reporter line crosses provide a simple, effective resource for driving indicator and opsin expression in cholinergic neurons with few adverse consequences and are therefore an valuable resource for studying the cholinergic system.
允许在胆碱能神经元中表达报告蛋白(如视蛋白)的小鼠品系的出现,极大地促进了对哺乳动物中枢神经系统中胆碱能信号传导的研究。然而,视蛋白的表达可能会干扰表达视蛋白的胆碱能神经元的生理学或小鼠行为。事实上,已发表的文献中有一些例子,展示了在旨在驱动胆碱能神经元中视蛋白表达的实验准备中出现的细胞和行为扰动。在这里,我们研究了两种小鼠品系中视蛋白的表达、胆碱能神经元的细胞生理学和行为,在这两种小鼠品系中,使用Cre-lox系统在胆碱能神经元中表达了通道视紫红质-2(ChR2)和古紫质(Arch)。这两种小鼠品系是通过将ChAT-Cre小鼠与依赖Cre的报告品系Ai32(ChR2-YFP)和Ai35(Arch-GFP)杂交产生的。在这些杂交产生的大多数小鼠中,我们仅在前脑基底的胆碱能神经元和前脑其他假定的胆碱能神经元中观察到ChR2和Arch的表达。在少数小鼠中,出现了非靶向表达,荧光并不局限于胆碱能神经元。对荧光标记的前脑基底神经元进行的全细胞记录显示,这两种蛋白都具有功能,光照时可驱动去极化(ChR2)或超极化(Arch),对被动膜特性、放电模式或动作电位波形影响很小。最后,在行为辨别任务中的表现与野生型小鼠相当。我们的结果表明,ChAT-Cre×报告品系杂交为在胆碱能神经元中驱动指示剂和视蛋白表达提供了一种简单、有效的资源,不良后果很少,因此是研究胆碱能系统的宝贵资源。