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

The ventral tegmental area (VTA) dopamine neurons have been implicated in diverse behaviors. These VTA dopamine neurons are intermixed with neurons that co-transmit glutamate and GABA (VTA glutamate-GABA ), transmit glutamate (VTA glutamate-only ) or GABA (VTA GABA-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 VTA glutamate-only neurons frequently established synapses on VTA dopamine and VTA glutamate-only neurons, and that VTA GABA-only neurons mostly synapsed on VTA dopamine neurons. By selective targeting of VTA subpopulations of neurons, we demonstrated that activation of VTA glutamate-only neurons is rewarding and decreases feeding behavior, while activation of VTA GABA-only neurons is aversive. We found that activation of VTA glutamate-only or VTA GABA-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.