Neuron
Volume 85, Issue 2, 21 January 2015, Pages 429-438
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Matters Arising
Diversity of Transgenic Mouse Models for Selective Targeting of Midbrain Dopamine Neurons

https://doi.org/10.1016/j.neuron.2014.12.036Get rights and content
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Highlights

  • Low dopamine specificity of transgene expression in ventral midbrain of TH-Cre mice

  • DAT-Cre mice exhibit dopamine-specific Cre expression patterns

  • VTA GABA and glutamate neurons bi-directionally modulate lateral habenula cells

Summary

Ventral tegmental area (VTA) dopamine (DA) neurons have been implicated in reward, aversion, salience, cognition, and several neuropsychiatric disorders. Optogenetic approaches involving transgenic Cre-driver mouse lines provide powerful tools for dissecting DA-specific functions. However, the emerging complexity of VTA circuits requires Cre-driver mouse lines that restrict transgene expression to a precisely defined cell population. Because of recent work reporting that VTA DA neurons projecting to the lateral habenula release GABA, but not DA, we performed an extensive anatomical, molecular, and functional characterization of prominent DA transgenic mouse driver lines. We find that transgenes under control of the tyrosine hydroxylase, but not the dopamine transporter, promoter exhibit dramatic non-DA cell-specific expression patterns within and around VTA nuclei. Our results demonstrate how Cre expression in unintentionally targeted cells in transgenic mouse lines can confound the interpretation of supposedly cell-type-specific experiments. This Matters Arising paper is in response to Stamatakis et al. (2013), published in Neuron. See also the Matters Arising Response paper by Stuber et al. (2015), published concurrently with this Matters Arising in Neuron.

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Present address: Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, 142 Life Sciences Addition #3200, Berkeley CA 94720, USA