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bioRxiv · 10.1101/2022.03.17.484767

Mesoaccumbal glutamate neurons drive reward via glutamate release, but aversion via dopamine co-release

Warlow, S. M.·Zell, V.·Hunker, A. C.·Zweifel, L.·Hnasko, T. S.
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Abstract

Ventral tegmental area (VTA) projections to the nucleus accumbens medial shell (NAc) drive reward-related motivation. Although dopamine neurons are predominant, a substantial glutamatergic projection is also present, and a subset of these populations can release both dopamine and glutamate. Optogenetic stimulation of VTA glutamate neurons supports self-stimulation, but can also induce place avoidance, even in the same assay. Here, we parsed the selective contribution of glutamate or dopamine co-release from VTA glutamate neurons to reinforcement and avoidance. We expressed Channelrhodopsin (ChR2) in VTA glutamate neurons, in combination with CRISPR/Cas9 to disrupt either the gene encoding vesicular glutamate transporter 2 (VGLUT2) or Tyrosine hydroxylase (Th). Selective disruption of VGLUT2 abolished optogenetic self-stimulation, but left real-time place avoidance intact, while CRISPR/Cas9 deletion of Th preserved optogenetic self-stimulation but abolished place avoidance. Our results demonstrate that glutamate release from VTA glutamate neurons is positively reinforcing, but that dopamine release from these same neurons can induce avoidance behavior.

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Warlow, S. M., Zell, V., Hunker, A. C., Zweifel, L., Hnasko, T. S.. 2022-03-18. Mesoaccumbal glutamate neurons drive reward via glutamate release, but aversion via dopamine co-release. https://doi.org/10.1101/2022.03.17.484767

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