When exposed to chronic social stress, animals display behavioral changes that are relevant to depressive-like phenotypes. However, the cascading relationship between incremental stress exposure and neural dysfunctions over time remains incompletely understood. Here we characterize the longitudinal effect of social defeat on goal-directed actions and prefrontal cortical activity in mice, using a head-fixed sucrose preference task and two-photon calcium imaging. Behaviorally, stress-induced loss of reward sensitivity intensifies over days. Motivational anhedonia, the failure to translate positive reinforcements into future actions, requires multiple sessions of stress exposure to become fully established. For neural activity, individual layer 2/3 pyramidal neurons in the Cg1 and M2 subregions of the medial prefrontal cortex have heterogeneous responses to stress. Changes in ensemble activity differ significantly between susceptible and resilient animals after the first defeat session, and continue to diverge following successive stress episodes before reaching persistent abnormal levels. Collectively, these results demonstrate that the cumulative impact of an ethologically relevant stress can be observed at the level of cellular activity of individual prefrontal neurons. The distinct neural responses associated with resilience versus susceptibility raises the hypothesis that the negative impact of social stress is neutralized in resilient animals, in part through an adaptive reorganization of prefrontal cortical activity.Reward-guided behavior is thought to involve the distributed cortical-basal ganglia network including the prefrontal cortex (6). Consistent with the observed deficits in reward processing, the effects of chronic stress on the prefrontal cortex can be detected at many levels, including the morphological, molecular, and cellular (4, 5). For example, in rodents, prolonged stress exposure causes structural atrophy, including dendritic retraction and synapse loss (8,15,16), and disrupts synaptic plasticity and synaptic transmission in the medial prefrontal cortex (17,18). Although it is obvious that the structural and synaptic alterations must compromise prefrontal cortical function, details of stress effects on neural activity in vivo are less clear. There have been several studies of stress effects on cortical activity patterns (19-22), but they provide few details on the effect of escalating stress burden over time.Given the gaps in our current knowledge, the main goal of this study is to determine how social stress influences reward-guided behavior and prefrontal cortical activity over time. To this end, we have designed a self-paced, instrumental sucrose preference task for the head-fixed mouse. Detailed characterization of the lick microstructure and a computational model of the behavior allows us to attribute behavioral alterations more confidently to motivational or appetitive anhedonia. To characterize the concomitant changes in prefrontal cortical activity, we used two-photon calcium imaging ...