VTA monosynaptic connections by local glutamate and GABA neurons and their distinct roles in behavior

M. Flavia Barbano, Huiling Wang, Shiliang Zhang, Alexey V. Shevelkin, Kevin J. Yu, Christopher T. Richie, Bing Liu, Suyun Hahn, Rong Ye and Marisela Morales ()
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M. Flavia Barbano: National Institutes of Health
Huiling Wang: National Institutes of Health
Shiliang Zhang: National Institutes of Health
Alexey V. Shevelkin: National Institutes of Health
Kevin J. Yu: National Institutes of Health
Christopher T. Richie: National Institutes of Health
Bing Liu: National Institutes of Health
Suyun Hahn: National Institutes of Health
Rong Ye: National Institutes of Health
Marisela Morales: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract The ventral tegmental area (VTA) dopamine neurons have been implicated in diverse behaviors. These VTAdopamine neurons are intermixed with neurons that co-transmit glutamate and GABA (VTAglutamate-GABA), transmit glutamate (VTAglutamate-only) or GABA (VTAGABA-only). In dual recombinase vglut2-Cre/vgat-Flp transgenic mice, we combined quantitative ultrastructural analysis with 3D correlative light and electron microscopy and found that VTAglutamate-only neurons frequently established synapses on VTAdopamine and VTAglutamate-only neurons, and that VTAGABA-only neurons mostly synapsed on VTAdopamine neurons. By selective targeting of VTA subpopulations of neurons, we demonstrated that activation of VTAglutamate-only neurons is rewarding and decreases feeding behavior, while activation of VTAGABA-only neurons is aversive. We found that activation of VTAglutamate-only or VTAGABA-only neurons negatively affected learning to obtain food reward, and impaired cue-induced reinstatement of food-seeking behavior. Collectively, we demonstrated the monosynaptic properties of an unexpected VTA microcircuitry in which distinct neuronal components integrate information related to reward, aversion, and feeding.

Date: 2025
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DOI: 10.1038/s41467-025-63396-0

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