Salience Signaling and Stimulus Scaling of Ventral Tegmental Area Glutamate Neuron Subtypes.

Ventral tegmental area (VTA) glutamatergic neurons participate in reward, aversion, drug-seeking, and stress. Subsets of these neurons cotransmit glutamate and GABA (VGluT2VGaT neurons), transmit glutamate without GABA (VGluT2VGaT neurons), or cotransmit glutamate and dopamine (VGluT2TH neurons), but whether these molecularly distinct subpopulations show behavior-related differences is not wholly understood. We identified in male and female mice that VGluT2 subpopulations are sensitive to the reward value in unique ways. VGluT2VGaT neurons increased maximum activity with increased sucrose concentration, whereas VGluT2VGaT neurons increased maximum and sustained activity with increased sucrose concentration, and VGluT2TH neurons increased sustained but not maximum activity with increased sucrose concentration. VGluT2 subpopulations also uniquely signaled consumption of sweet/noncaloric (saccharine) and nonsweet/high-calorie rewards (fat). VGluT2VGaT neurons uniquely signaled lower-calorie sucrose over fat, whereas both VGluT2VGaT neurons and VGluT2TH neurons showed a signaling preference for higher-calorie fat over sucrose but in temporally distinct ways. Further experiments suggested that VGluT2VGaT consummatory reward-related activity was related to sweetness, partially modulated by prefeeding, and not dependent on caloric content. Additionally, aversive stimuli increased activity for each VGluT2 subpopulation, but VGluT2VGaT neurons uniquely scaled their magnitude and sustained activity with footshock intensity. Optogenetic activation of VGluT2VGaT neurons during low-intensity footshock enhanced fear-related behavior without inducing place preference or aversion. About half of VGluT2VGaT sucrose-sensitive neurons were transcriptionally activated by footshock. We interpret these data such that VTA glutamatergic subpopulations signal different elements of rewarding and aversive experiences and highlight the unique role of VTA VGluT2VGaT neurons in salience signaling.