THE ROLE OF THE PROGESTERONE TO ESTRADIOL RATIO IN FEAR EXTINCTION IN MICE AND HUMANS

Sex differences in fear-based disorders have been previously reported. However, the influence of the menstrual/estrous cycle and related hormonal fluctuations remains unclear. The literature suggests that estradiol and progesterone influence fear learning, but their specific effects are inconsistent across studies. This study focuses on the impact of menstrual/estrous cycle phases and sex hormone fluctuations on fear acquisition and within-session extinction in both humans and mice. Our human sample includes men, women in the different menstrual cycle phases, and oral contraceptive users. Participants underwent a fear acquisition and delayed extinction paradigm, with fear responses assessed through skin conductance responses and fear-potentiated startle. Hormone levels were quantified using liquid chromatography-mass spectrometry (LC-MS) analysis of saliva samples. In parallel, we conducted an experiment in male and female mice across the estrous cycle, where hormone levels were quantified via LC-MS in blood samples. Results showed that higher estradiol levels in humans were associated with enhanced within-session extinction. Machine learning analyses revealed that a higher progesterone-to-estradiol ratio predicted better extinction in both humans and mice, suggesting an interacting hormonal effect. Additionally, systemic co-administration of progesterone and estradiol in male and female mice prior to fear extinction training enhanced extinction learning. These findings emphasize the importance of considering hormonal fluctuations in fear extinction across species and may have broader implications for memory and neural processes influenced by sex steroids. Ultimately, this research provides new insights into how hormonal dynamics contribute to sex differences in fear-based disorders.