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 co-transmit glutamate and GABA (VGluT2+VGaT+ neurons), transmit glutamate without GABA (VGluT2+VGaT- neurons), or co-transmit 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 reward value in unique ways. VGluT2+VGaT+ neurons increased activity magnitude with increased sucrose concentration, whereas VGluT2+VGaT- neurons increased magnitude 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 signaled consumption of sweet/non-caloric (saccharine) and non-sweet/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 pre-feeding, 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 enhancing salience. Ventral tegmental area glutamate neurons play a role in reward and aversion-based motivated behaviors. We identify that genetically-distinct ventral tegmental area glutamatergic subpopulations show differences in their signaling of consummatory rewards and aversive experiences. While all glutamatergic subpopulations signaled rewarding and aversive experiences, glutamatergic subtypes differed in their phasic magnitude and sustained activity profiles in response to the value of consummatory rewards, comparisons between multiple present rewards, and the value of aversive stimuli. VGluT2+VGaT+ neurons showed unique profiles related to both rewarding and aversive events. Based on these results we hypothesize that VTA VGluT2+VGaT+ neurons have a role in signaling the general salience of positive and negatively valenced behavioral experiences.