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bioRxiv · 10.1101/2024.06.12.598688

Salience signaling and stimulus scaling of ventral tegmental area glutamate neuron subtypes

McGovern, D. J.·Phillips, A.·Ly, A.·Prevost, E. D.·Ward, L.·Siletti, K.·Kim, Y. S.·Fenno, L.·Ramakrishnan, C.·Deisseroth, K.·Ford, C. P.·Root, D. H.
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Abstract

Ventral tegmental area (VTA) glutamatergic neurons participate in reward, aversion, drug-seeking, and stress. Subsets of VTA VGluT2+ neurons are capable of co-transmitting glutamate and GABA (VGluT2+VGaT+ neurons), transmitting glutamate without GABA (VGluT2+VGaT- neurons), or co-transmitting glutamate and dopamine (VGluT2+TH+ neurons), but whether these molecularly distinct subpopulations show behavior-related differences is not wholly understood. We identified that neuronal activity of each VGluT2+ subpopulation is sensitive to reward value but signaled this in different ways. The phasic maximum activity of VGluT2+VGaT+ neurons increased with sucrose concentration, whereas VGluT2+VGaT- neurons increased maximum and sustained activity with sucrose concentration, and VGluT2+TH+ neurons increased sustained but not maximum activity with sucrose concentration. Additionally, VGluT2+ subpopulations signaled consummatory preferences in different ways. VGluT2+VGaT- neurons and VGluT2+TH+ neurons showed a signaling preference for a behaviorally-preferred fat reward over sucrose, but in temporally-distinct ways. In contrast, VGluT2+VGaT+ neurons uniquely signaled a less behaviorally-preferred sucrose reward compared with fat. Further experiments suggested that VGluT2+VGaT+ consummatory reward-related activity was related to sweetness, partially modulated by hunger state, and not dependent on caloric content or behavioral preference. All VGluT2+ subtypes increased neuronal activity following aversive stimuli 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. 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 the salience of behavioral experiences.

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McGovern, D. J., Phillips, A., Ly, A., Prevost, E. D., Ward, L., Siletti, K., Kim, Y. S., Fenno, L., Ramakrishnan, C., Deisseroth, K., Ford, C. P., Root, D. H.. 2024-06-12. Salience signaling and stimulus scaling of ventral tegmental area glutamate neuron subtypes. https://doi.org/10.1101/2024.06.12.598688

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