A stress-activated neuronal ensemble in the supramammillary nucleus encodes anxiety but not memory

Anxiety is a prevalent negative emotional state induced by stress; however, the neural mechanism underlying anxiety is still largely unknown. We used acute and chronic stress to induce anxiety and test anxiety-like behavior; immunostaining, multichannel extracellular electrophysiological recording and Ca ²⁺ imaging to evaluate neuronal activity; and virus-based neuronal tracing to label circuits and manipulate circuitry activity. Here, we identified a hypothalamic region, the supramammillary nucleus (SuM), as a key regulator of anxiety. We then characterized a small ensemble of stress-activated neurons (SANs) that are recruited in the encoding of anxiety. These SANs respond specifically to stress, and their activation robustly increases anxiety-like behavior in mice without significantly affecting fear memory. We also found that ventral subiculum (vSub)-SuM projections but not dorsal subiculum (dSub)-SuM projections encode anxiety and that inhibition of these vSub-SuM projections has an antianxiety effect. These results indicate that the reactivation of stress-activated supramammillary engram cells and relevant neural circuits are important neural processes underlying anxiety.