Neuroanatomical and behavioral characterization of corticotropin releasing factor-expressing lateral Habenula neurons in mice

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 (LHb ^CRF ) along with their downstream targets. Chemogenetic activation of LHb ^CRF 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 LHb ^CRF neurons. These findings indicate that LHb ^CRF neurons can promote passive defensive responses to immediate danger, with baseline activity potentially influencing the timing of escape.