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 (VGluT2⁺VGaT⁺ neurons), transmit glutamate without GABA (VGluT2⁺VGaT^- neurons), or cotransmit glutamate and dopamine (VGluT2⁺TH⁺ 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. VGluT2⁺VGaT⁺ neurons increased maximum activity with increased sucrose concentration, whereas VGluT2⁺VGaT^- neurons increased maximum and sustained activity with increased sucrose concentration, and VGluT2⁺TH⁺ 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). VGluT2⁺VGaT⁺ neurons uniquely signaled lower-calorie sucrose over fat, whereas both VGluT2⁺VGaT^- neurons and VGluT2⁺TH⁺ neurons showed a signaling preference for higher-calorie fat over sucrose but in temporally distinct ways. Further experiments suggested that VGluT2⁺VGaT⁺ 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 VGluT2⁺VGaT⁺ neurons uniquely scaled their magnitude and sustained activity with footshock intensity. Optogenetic activation of VGluT2⁺VGaT⁺ neurons during low-intensity footshock enhanced fear-related behavior without inducing place preference or aversion. About half of VGluT2⁺VGaT⁺ 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 VGluT2⁺VGaT⁺ neurons in salience signaling.