Estrous cycle stage gates the effect of stress on reward learning

Abstract Stress produces transient physiological responses that lead to long-lasting changes in cue-driven behavior. In particular, a single exposure to stress facilitates reward learning in male rats. Since stress can produce distinct behavioral phenotypes between males and females, it is critical to additionally determine how stress impacts reward learning in females. To address this, female rats were exposed to restraint stress immediately prior to training on an appetitive Pavlovian conditioning task with food rewards. Females were categorized based on their estrous cycle stage on the first day of Pavlovian conditioning. A single exposure to stress enhanced conditioned responding in non-estrus females but suppressed conditioned responding in estrus females. Therefore, a single stress experience produced opposing effects on cue-driven behavior depending upon the estrous cycle stage. In contrast, both estrus and non-estrus rats exposed to repeated prior stress exhibited an increase in conditioned responding relative to animals that underwent a single stress exposure. We further examined if the distal stress experience subsequently impacted extinction and the ability to learn a new cue-reward association. Prior stress did not affect extinction, though estrus and non-estrus rats exposed to repeated prior stress exhibited higher levels of conditioned responding to the novel cue-reward pairing. Taken together, our data demonstrate that the influence of stress on reward learning is impacted acutely by the estrous cycle as well as by one’s prior history with stress. Competing Interest Statement The authors have declared no competing interest. Footnotes Funding: This work was supported by National Institutes of Health grants MH127466 (MJW) and MH133062 (MJW). The work was additionally supported by the National Science Foundation Graduate Research Fellowship Program (MPJ and BIG). Competing Interests: The authors have nothing to disclose. Data Availability Statement: Data will be provided upon request Revised manuscript includes additional analyses and further details in the text