TY - JOUR
T1 - Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking in mice
AU - Lowes, Daniel C.
AU - Chamberlin, Linda A.
AU - Kretsge, Lisa N.
AU - Holt, Emma S.
AU - Abbas, Atheir I.
AU - Park, Alan J.
AU - Yusufova, Lyubov
AU - Bretton, Zachary H.
AU - Firdous, Ayesha
AU - Enikolopov, Armen G.
AU - Gordon, Joshua A.
AU - Harris, Alexander Z.
N1 - Funding Information:
This work was supported by a grant from the NIMH to A.Z.H. (K08 MH109735), by a NARSAD grant from the Brain Behavior Research Foundation (A.Z.H.), and by the Hope for Depression Research Foundation (J.A.G., A.Z.H.). The opinions expressed are the authors’ own and do not reflect the view of the National Institute of Mental Health, the National Institutes of Health, the Department of Health and Human Services, or the United States Government.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-23906-2
DO - 10.1038/s41467-021-23906-2
M3 - Article
C2 - 34112787
AN - SCOPUS:85107545470
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3539
ER -