Flerlage, W. J.; Gouty, S. C.; Thomas, E. H.; Simmons, S. C.; Tsuda, M. C.; Rujan, O.; Iyer, L.; Petrus, E. S.; Cox, B. M.; Wu, T. J.; Nugent, F. S.

The lateral habenula (LHb), which plays a critical role in value-based decision-making and in stress responses, is linked to drug addiction and mood disorders. Prior research from our lab demonstrated the LHb's responsiveness to corticotropin-releasing factor (CRF), yet the origin of CRF inputs to this region remained elusive. Here, we mapped CRF projections to the LHb, revealing several contributing brain regions and a subpopulation of CRF-expressing LHb neurons (LHbCRF) along with their downstream targets. Chemogenetic activation of LHbCRF neurons did not affect conditioned place preference or anxiety-related behaviors in mice of either sex. However, it enhanced passive action-locking responses to a simulated aerial threat in both male and female mice as well as induced subtle sex-specific differences in escape latency which aligned with our observation of higher basal spontaneous activity in male LHbCRF neurons. These findings indicate that LHbCRF neurons can promote passive defensive responses to immediate danger, with baseline activity potentially influencing the timing of escape.