Acute 17β-Estradiol Administration Enhances Fear Extinction Memory and Alters Gut Microbiota in Female Rats

Background Previous studies have shown that fear extinction memory and the gut microbiome are impacted by ovarian hormones. Elevated 17β-estradiol (E2) levels during fear extinction learning have been shown to enhance fear extinction recall 24 hours later. In this study, we concurrently examined the long-term maintenance of this facilitation and the role of the gut microbiome as a potential mediator. Methods Naturally cycling adult female Sprague Dawley rats underwent an auditory-cued fear conditioning/extinction paradigm, during which the estrous cycle was tracked and fecal samples were collected. Habituation and conditioning took place when the rats were in estrus on day 1. On day 2, rats were administered either a sesame oil vehicle ( n = 24) or E2 (15 μg/kg) ( n = 25) before extinction training. Recent recall took place 24 hours after extinction training, and remote recall took place 1 to 2 weeks after extinction training (vehicle n = 13, E2 n = 12). Results E2-treated rats showed significantly lower freezing behavior compared with vehicle-treated rats during recent recall, but not remote recall. Gut bacterial analysis using 16S ribosomal RNA sequencing revealed unique enrichment of estrogen-regulating and anxiety-related bacterial families during remote recall. Conclusions The current data suggest that E2-enhanced fear extinction consolidation may be linked to alterations in gut microbiome composition. These findings may reveal a novel potential target for anxiety and other fear-based psychiatric disorders.