A PREFRONTAL-HABENULAR PROJECTION REGULATES SEX-SPECIFIC BEHAVIORAL FLEXIBILITY DURING MOTIVATIONAL CONFLICT

In natural environments, decision-making often involves motivational conflict, where cues signaling potential threat compete with those predicting rewards. Resolving such conflict requires flexible behavioral adjustment based on experience and current context. However, the neural circuits enabling this flexibility remain poorly understood. Here, we investigated the role of the glutamatergic projection from the prelimbic cortex (PL) to the lateral habenula (LHb) in adaptive decision-making under motivational conflict in male and female rats. Animals were trained in a platform-mediated avoidance (PMA) task with two versions: a low-conflict version (threat and reward presented in separate trials) and a high-conflict version (simultaneous presentation of both cues). Rats learned to switch flexibly between avoidance and reward-seeking strategies depending on the cue combination. Optogenetic inhibition of PL→LHb terminals impaired this flexibility in males, leading to persistent reward-seeking despite contextual threat. In contrast, females remained flexible under the same manipulation. This effect was not due to changes in baseline anxiety, locomotion, or reward motivation. Inhibition of the the infralimbic prefrontal projection to the LHb did not affect behavioral flexibility in either sex, indicating pathway specificity. These findings identify a prefrontal–habenular circuit that is critical for context-dependent behavioral flexibility and reveal a sex-specific mechanism that may contribute to differences in vulnerability to affective disorders.