Cre-driven optogenetics in the heterogeneous genetic panorama of the VTA

•Optogenetics has been utilized in the VTA with a focus on targeting entire neurotransmitter populations.•Transgenic Cre-driver lines are crucial for selectivity, but they often target unwanted structures or neurons, and currently used ones are sometimes too broad for the diversity found in the VTA.•We highlight promoters that could be used as an alternative to this neurotransmitter-based strategy, as well as new techniques to generate transgenic lines.

The selectivity of optogenetics commonly relies on genetic promoters to manipulate specific populations of neurons through the use of Cre-driver lines. All studies performed in the ventral tegmental area (VTA) so far have utilized promoters present in groups of cells that release dopamine (DA), GABA, or glutamate. However, neurons that co-release neurotransmitters and variabilities within groups of neurons that release the same neurotransmitter present challenges when evaluating the results. Further complexity is introduced by ectopic expression patterns often occurring in transgenic Cre-drivers. New perspectives could be unfolded by identifying and selecting different types of promoter for driving the Cre recombinase. Here, we discuss some promising candidates and highlight the advantages or disadvantages of different methods for creating novel transgenic lines.