Interaction between stress and sex hormones on fear and extinction memories

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Fear learning and fear extinction are essential to survival by promoting adaptive behaviors. The brain regions underlying these processes are rich in stress and sex hormones receptors, suggesting that stress exposition and sex hormone levels could influence the formation of fear and safety (extinction) learning. Under stress, the brain focuses on threatening information to the detriment of non-threatening information. In fact, stress exposure promotes memory consolidation for negative information. Other studies have shown better memory consolidation of fear extinction in men and women with elevated estradiol levels (a sex hormone). Importantly, men and women with elevated estradiol levels are more stress reactive (when measuring cortisol, a stress hormone) relative to women taking oral contraceptives and women with low estradiol levels. Yet, the literature integrating these factors in a comprehensive manner remains scarce. Using endocrine, physiological, and psychological measures, this program will study the interaction between stress exposure and sex hormone milieu on fear learning (Aim 1) and extinction learning (Aim 2) in healthy adults. We hypothesize that exposure to a psychosocial stressor will increase fear memory consolidation, but will decrease fear extinction consolidation, and these effects will be more pronounced in men and women with elevated estradiol levels. 240 participants (60 men, 60 women taking oral contraceptives, 60 naturally-cycling women in the early follicular phase of their cycle (low estradiol levels), and 60 naturally-cycling women at mid-cycle (high estradiol levels)) will undergo a 3-day protocol; fear conditioning on Day 1, extinction learning on Day 2, and extinction memory recall on Day 3. For Aim 1, 80 participants (20 men, 20 women on oral contraceptives, 20 early follicular women, 20 mid-cycle women) will be exposed to a stressor immediately before fear conditioning whereas another group (n=80) will be exposed to a non-stressful control condition. For Aim 2, 80 new participants will be exposed to a stressor on Day 2 immediately before extinction learning and will be compared to the same control group than Aim 1 (n=80, no stress exposition). Saliva samples will be taken on each day to examine estradiol levels and variation in cortisol levels. Skin conductance responses, heart rate, corrugator electromyography, and subjective reports of fear will be used to quantify fear levels. This program will further our understanding of the physiological and endocrine mechanisms by which stress exposure and sex hormones modulate the strength of fear and extinction memories and how this could increase the likelihood of maladaptive behaviors. These results could then be used to further investigate the neural bases underlying such cognitive processes. In sum, this program promises to expand understanding of the mechanisms involved in fear processes.