Distinct properties of glutamate-dopamine, nonglutamate-dopamine, and glutamate-only ventral tegmental area neurons.

Authors

Emily D Prévost, Lucy A Ward, Daniel Alas, Giulia A Aimale, Sara K Ikenberry, Katie Fox, Melissa Deming, Julianne Pelletier, Annie Ly, Jayson Ball, Zachary P Kilpatrick, Kailyn Price, Abigail M Polter, Fabio Simões de Souza, Suzanne Fulgham, Yoon Seok Kim, Lief E Fenno, Charu Ramakrishnan, Karl Deisseroth, David H Root

Published in

Science signaling. Volume 19. Issue 951. Pages eaee2028. Aug 18, 2026. Epub Aug 18, 2026.

Abstract

Dopamine neurons in the ventral tegmental area (VTA) have roles in motivation, learning, and psychiatric disorders. We found that genetically defined VTA dopamine neuron subtypes had distinct electrophysiological properties, neuronal signaling dynamics in response to reward- and aversion-related stimuli, and roles in somatic optogenetically induced reward dependent on the neurotransmitters they released. Nonglutamate-dopamine neurons increased activity after reward-related stimuli and decreased activity after the omission of an expected reward (negative reward prediction error) and aversion-related stimuli. Glutamate-dopamine and glutamate-only (nonGABAergic and nondopaminergic) neurons were activated by both rewarding and aversive events, but only glutamate-dopamine neurons had sustained cue-induced reward signaling. Recordings of all dopamine neurons without considering glutamate cotransmission showed mixed population responses during prediction error and aversive stimuli that obscured the distinct signaling patterns of its constituent subpopulations. Although the examined cell types largely differ in mediolateral location, cell-type identity better accounted for functional differences than mediolateral location. Glutamate-dopamine neurons were more excitable than nonglutamate-dopamine neurons. Glutamate-dopamine and nonglutamate-dopamine axons had similar but not identical dopamine release dynamics in the nucleus accumbens. Only nonglutamate-dopamine neurons supported somatic optogenetically induced reward and reinforcement. In glutamate-dopamine neurons, the dopamine synthetic enzyme TH contributed to associative learning of aversive or less-beneficial outcomes, whereas the vesicular glutamate transporter VGLUT2 contributed to reward- and exploration-related vigor. Our results suggest that glutamate cotransmission is a distinguishing feature of VTA dopamine neuron signaling patterns and roles in natural reward- or aversion-motivated behavior.

PMID:
42611973
Bibliographic data and abstract were imported from PubMed on 19 Aug 2026.

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