Interaction between stress and sex hormones on fear and extinction memories

恐惧学习和恐惧消退通过促进适应性行为对生存至关重要。这些过程背后的大脑区域富含压力和性激素受体，这表明压力暴露和性激素水平可能会影响恐惧和安全（灭绝）学习的形成。在压力下，大脑专注于威胁性信息，而不是非威胁性信息。事实上，压力暴露促进了对负面信息的记忆巩固。其他研究表明，雌二醇（一种性激素）水平升高的男性和女性在恐惧消退方面的记忆巩固效果更好。重要的是，雌二醇水平升高的男性和女性相对于口服避孕药的女性和雌二醇水平低的女性更具压力反应性（当测量皮质醇时，一种压力激素）。然而，文献综合这些因素在一个全面的方式仍然稀缺。利用内分泌，生理和心理测量，该计划将研究压力暴露和性激素环境对健康成年人的恐惧学习（目标1）和消退学习（目标2）之间的相互作用。我们假设，暴露于社会心理应激源会增加恐惧记忆巩固，但会减少恐惧消退巩固，这些影响将在雌二醇水平升高的男性和女性中更加明显。240名参与者（60名男性，60名服用口服避孕药的女性，60名处于周期早期卵泡期的自然循环女性（低雌二醇水平）和60名处于周期中期的自然循环女性（高雌二醇水平））将接受为期3天的方案;第1天进行恐惧条件反射，第2天进行消退学习，第3天进行消退记忆回忆。对于目标1，80名参与者（20名男性，20名口服避孕药的女性，20名卵泡早期女性，20名月经中期女性）将在恐惧调节之前立即暴露于压力源，而另一组（n=80）将暴露于非压力控制条件。对于目标2，80名新参与者将在消退学习前第2天立即暴露于压力源，并将与目标1相同的对照组进行比较（n=80，无压力暴露）。每天采集唾液样本，检查雌二醇水平和皮质醇水平的变化。皮肤电传导反应、心率、皱眉肌肌电图和恐惧的主观报告将用于量化恐惧水平。该计划将进一步了解压力暴露和性激素调节恐惧和灭绝记忆强度的生理和内分泌机制，以及这如何增加适应不良行为的可能性。这些结果可用于进一步研究这种认知过程的神经基础。总之，该计划有望扩大对恐惧过程中所涉及的机制的理解。

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.