Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking in mice

Daniel C. Lowes, Linda A. Chamberlin, Lisa N. Kretsge, Emma S. Holt, Atheir I. Abbas, Alan J. Park, Lyubov Yusufova, Zachary H. Bretton, Ayesha Firdous, Armen G. Enikolopov, Joshua A. Gordon and Alexander Z. Harris ()
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Daniel C. Lowes: College of Physicians and Surgeons
Linda A. Chamberlin: College of Physicians and Surgeons
Lisa N. Kretsge: College of Physicians and Surgeons
Emma S. Holt: College of Physicians and Surgeons
Atheir I. Abbas: Oregon Health & Science University
Alan J. Park: College of Physicians and Surgeons
Lyubov Yusufova: College of Physicians and Surgeons
Zachary H. Bretton: College of Physicians and Surgeons
Ayesha Firdous: College of Physicians and Surgeons
Armen G. Enikolopov: Columbia University Medical Center
Joshua A. Gordon: National Institute of Mental Health
Alexander Z. Harris: College of Physicians and Surgeons

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Decreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.

Date: 2021
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DOI: 10.1038/s41467-021-23906-2

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