The use of Cre-driver rodent lines for targeting ventral tegmental area (VTA) cell types has generated important and novel insights into how precise neurocircuits regulate physiology and behavior. While this approach generally results in enhanced cellular specificity, an important issue has recently emerged related to the selectivity and penetrance of viral targeting of VTA neurons using several Cre-driver transgenic mouse lines. Here, we highlight several considerations when utilizing these tools to study the function of genetically defined neurocircuits. While VTA dopaminergic neurons have previously been targeted and defined by the expression of single genes important for aspects of dopamine neurotransmission, many VTA and neighboring cells display dynamic gene expression phenotypes that are partially consistent with both classically described dopaminergic and non-dopaminergic neurons. Thus, in addition to varying degrees of selectivity and penetrance, distinct Cre lines likely permit targeting of partially overlapping, but not identical VTA cell populations. This Matters Arising Response paper addresses the Lammel et al. (2015) Matters Arising paper, published concurrently in Neuron.
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