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

Daniel C Lowes,Emma S Holt,Lisa N Kretsge,Alan J Park,Alexander Z Harris,Armen G Enikolopov,Atheir I Abbas,Linda A Chamberlin,Lyubov Yusufova,Ayesha Firdous,Joshua A Gordon,Zachary H Bretton

doi:10.1038/s41467-021-23906-2

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.

Highlights

Decreased pleasure-seeking forms a core symptom of depression
To screen for the stressinduced neural activity that causes blunted reward-seeking, we recorded local field potentials (LFP)—which reflect local synchronous synaptic activity11,12—across brain areas implicated in depression, including the prefrontal cortex[13,14], NAc4,13, dorsal and ventral hippocampus[13,15], basolateral amygdala[13], and VTA4,13, as mice either explored a familiar environment or underwent 30 mins of acute restraint stress
Recent work has proposed that respiration-driven oscillations originating in the olfactory bulbs and piriform cortex represent the true source of nucleus accumbens (NAc) oscillations[17,18], we found only modest coherence between the NAc LFP and respirations, which was not increased by restraint (Supplementary Fig. 2d, e)

Summary

Introduction

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. 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. Dopamine (DA) transmission between the ventral tegmental area (VTA) and the nucleus accumbens (NAc) lie at the core of reward processing[5,6,7]. Past studies investigating VTA-NAc DA transmission in stress-induced blunted rewardseeking have yielded conflicting results[9,10] These studies relied on indirect measures of reward circuit activity, such as in vitro or baseline in vivo recordings of DA neural firing rates. We record reward circuit activity during both stress and subsequent reward-seeking to directly determine that VTA GABA activity links acute stress and blunted reward-seeking

Methods

Results

Conclusion