Distinct ventral tegmental area neuronal ensembles are indispensable for reward-driven approach and stress-driven avoidance behaviors

Ioannis Koutlas, Lefkothea Patrikiou, Stef E. Starre, Diaz Danko, Inge G. Wolterink-Donselaar, Mieneke C. M. Luijendijk, Roger A. H. Adan and Frank J. Meye ()
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Ioannis Koutlas: Utrecht University
Lefkothea Patrikiou: Utrecht University
Stef E. Starre: Utrecht University
Diaz Danko: Utrecht University
Inge G. Wolterink-Donselaar: Utrecht University
Mieneke C. M. Luijendijk: Utrecht University
Roger A. H. Adan: Utrecht University
Frank J. Meye: Utrecht University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Assigning valence to stimuli for adaptive behavior is an essential function, involving the ventral tegmental area (VTA). VTA cell types are often defined through neurotransmitters (NT). However, valence function in VTA does not parse along NT-boundaries as, within each NT-class, certain neurons are excited by reward and others by stressors. Here we identify, in male mice, the co-activated VTA neuronal ensembles for reward and stress, and determine their role in adaptive behaviors. We show that stimuli of opposite valence (opioid vs acute social stress) recruit two distinct VTA neuronal ensembles. These two ensembles continue to be preferentially engaged by congruent valence stimuli. Stimulation of VTA stress- or reward ensembles is aversive/reinforcing, respectively. Strikingly, external valence stimuli fully require activity of these small discrete VTA ensembles for conferring approach/avoidance outcomes. Overall, our study identifies distinct VTA ensembles for positive and negative valence coding and shows their indispensability for adaptive behavior.

Date: 2025
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DOI: 10.1038/s41467-025-58384-3

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