The lateral septum orchestrates state-dependent modulation of associative threat memory dynamics across the ovarian hormone cycle

SUMMARY Cycling ovarian hormones orchestrate neural states that greatly impact brain function and guide behavior. Here, we discover that cued threat memory processes are regulated across the mouse estrous cycle in a state-dependent manner. We show that low hormone states lead to overexpression of threat memory in females. However, high hormone states confer protection against this overexpression via state-dependent recruitment and reengagement of the lateral septum (LS) to the memory ensemble. Chemogenetic manipulations confirmed the LS as necessary and sufficient to suppress female memory overexpression. Single nucleus sequencing revealed a novel LS neuron population, defined by coexpression of neurotensin and somatostatin, selectively recruited to the female memory ensemble during high hormone states. This estradiol-sensitive population exhibits a female bias in projection strength to the nucleus accumbens and displays unique calcium dynamics associated with state-dependent memory suppression. Altogether, we uncover a sexually divergent neural mechanism whereby cycling ovarian hormones modulate memory expression.