31Stressful experiences frequently precede depressive episodes 1 . Depression results in 32 anhedonia, or disrupted reward-seeking, in most patients 2 . In humans 3,4 and rodents 5,6 , 33 stress can disrupt reward-seeking, providing a potential mechanism by which stress can 34 a minority had increased firing rates ( Fig. 2a,b). On average, single unit firing rates 100 became rhythmically entrained to the restraint-induced oscillation (Extended Fig. 2a,b). 101 By contrast, prefrontal cortex single units did not phase-lock to the oscillation recorded in 102 the prefrontal cortex (Extended Fig. 2c), suggesting that the oscillation originates in the 103 NAc and may be volume conducted to other brain regions. Interestingly, while NAc single 104 units with significantly decreased firing rates showed an increase in phase locking, those 105 with significantly increased firing rates did not, suggesting that the stress-induced 106 oscillation reflects a net inhibitory input to the NAc (Fig. 2c,d). Since the magnitude of the 107 oscillation correlates with the degree of impaired reward seeking ( Fig. 1g,h), these results 108 raise the possibility that an inhibitory input to the NAc may mediate stress-induced reward 109 impairments. 110 We hypothesized that since the VTA projects densely to the NAc and provides 111 GABAergic in addition to dopaminergic input, it could be the source of stress-induced 112 oscillations. Consistent with this hypothesis, coherence between VTA and NAc LFPs 113 increased sharply during restraint stress ( Fig. 2e) in the same frequency range as the 114 restraint-induced oscillation. This increase in VTA-NAc coherence was significantly 115 greater than any changes in NAc coherence with the prefrontal cortex, amygdala, or 116 hippocampus (Extended Fig. 2d). Since the VTA and NAc reciprocally communicate, we 117 inferred directionality by examining the lag at which the phase locking of VTA multiunit 118 activity (MUA) to the NAc restraint-induced oscillation peaks 35,36 . In the familiar 119 environment, VTA MUA activity of the future was best phase-locked to the NAc LFP. By 120 contrast, during restraint stress, VTA MUA activity of the past was best phase-locked to 121 the NAc LFP. These results suggest that during restraint stress the predominant 122 directionality of reward circuit activity is from the VTA to the NAc (Fig. 2f). 123 We next examined the role of VTA inputs in driving the restraint-induced NAc 124 oscillation. We infused the GABAA agonist muscimol (0.5 µg/side) or saline control into 125 the VTA while recording NAc LFP activity in restrained mice. Muscimol treatment 126 significantly reduced the restraint-induced oscillation, suggesting that VTA activity is 127 necessary for NAc restraint-induced activity (Fig. 3a). While recent work has proposed 128 that respiration-driven oscillations originating in the olfactory bulbs and piriform cortex 129 represent the true source of NAc oscillations 37,38 , these results and our data showing that 130 the oscillation modulates NAc...