Feature-specific threat coding in lateral septum guides defensive action

The ability to rapidly detect and evaluate potential threats is essential for survival and requires the integration of sensory information, with internal state and prior experience. The lateral septum (LS), an inhibitory structure in the limbic forebrain, is thought to integrate these higher-order ‘cognitive’ signals to regulate defensive responses. However, the cellular, circuit, and computational mechanisms fundamental to this process remain unknown. Here, we focus on the LS population expressing the type 2 CRH receptor (LS ^Crhr2 ), a neuronal subset shown to be critical for state-dependent behavioral changes and threat responsivity. We use a combination of single-cell calcium imaging, molecular sequencing, and circuit dissection to reveal the spatial and functional organization of the cell-types involved, the computations they perform, and the information relayed by their upstream activators. We determined that LS ^Crhr2 population activity is required for cue-driven defensive actions by rapidly and dynamically encoding threat representations that predict behavioral outcomes. We find that these threat representations are formed through the convergence of various signals differentially represented among distinct LS ^Crhr2 subclasses, which are defined by their molecular features, spatial location, and input architecture. Most importantly, their responses reflect specific afferents from the hippocampus and hypothalamus that preferentially impart cue- and action-related signals, respectively. These findings establish a multifeatured organizational principle that underlies how LS mediates motivated behaviors in response to environmental challenges.