Ventral tegmental area GABA neurons mediate stress-induced anhedonia

Stressful experiences frequently precede depressive episodes[1][1]. Depression results in anhedonia, or disrupted reward-seeking, in most patients[2][2]. In humans[3][3],[4][4] and rodents[5][5],[6][6], stress can disrupt reward-seeking, providing a potential mechanism by which stress can precipitate depression[7][7]-[9][8]. Yet despite decades investigating how stress modulates dopamine neuron transmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc), the underpinnings of the stress-anhedonia transition remain elusive[10][9]-[13][10]. Here we show that during restraint stress, VTA GABA neurons drive low frequency NAc LFP oscillations, rhythmically modulating NAc firing rates. The strength of these stress-induced NAc oscillations predict the degree of impaired reward-seeking upon release from restraint. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and reverses the effect of stress on reward-seeking. By contrast, mimicking these oscillations with rhythmic VTA GABA stimulation in the absence of stress blunts subsequent reward-seeking. These experiments demonstrate that VTA GABA inputs to the NAc are both necessary and sufficient for stress-induced decreases in reward seeking behavior, elucidating a key circuit-level mechanism underlying stress-induced anhedonia. ### Competing Interest Statement AZH is an advisory board member of Genetika+, inc [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-9 [9]: #ref-10 [10]: #ref-13