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.