Hippocampal estrogen levels, receptor types and epigenetics contribute to sex-specific memory-vulnerabilities to concurrent acute stresses [Cut & Run]

It is increasingly recognized that acute traumatic events (e.g., mass shootings, natural disasters) can provoke enduring episodic memory deficits and generalization of trauma cues, and these are more common in women. We investigated mechanisms and sex differences of memory vulnerability to multiple acute concurrent stresses (MACS) in mice, focusing on the sex hormone 17ß-estradiol and its receptors in hippocampus. Surprisingly, high physiological hippocampal estradiol levels, observed in proestrus females and males, were required for MACS-induced episodic memory disruption and sensitization and generalization of stress cues. High estradiol levels were associated with permissive chromatin states in stress-vulnerable mice, while chromatin permissiveness and hippocampal estradiol were low in stress-resilient estrus females. Estrogen receptor (ER)ß activation in resilient estrus females increased chromatin permissiveness and enduring vulnerability to MACS, while ERa mediated milder stress-induced memory disruptions in males. Thus, hippocampal estradiol levels and sex modify chromatin states to enable long-lasting memory vulnerabilities to MACS. Overall design: Cut&Run-seq profiling of H3K27me3 and H3K4me3 in the hippocampus of naive males, females in estrus or females in proestrus. Cut&Run-seq profiling of H3K27me3 and H3K4me3 of females in estrus with MACS, control vehicle or MACS and an ERß agonist, Diarylpropionitrile (DPN).