Interaction between stress and sex hormones on fear and extinction memories

恐惧学习和恐惧消除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影响恐惧和安全（灭绝）学习的形成。在压力下，大脑会把注意力集中在威胁性信息上，而忽略非威胁性信息。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，在雌二醇（一种性激素）水平升高的男性和女性中，恐惧消退的记忆巩固得更好。重要的是，与服用口服避孕药的女性和雌二醇水平较低的女性相比，雌二醇水平升高的男性和女性更容易产生压力反应（当测量皮质醇时，一种压力激素）。然而，全面整合这些因素的文献仍然很少。本项目将采用内分泌、生理和心理测量方法，研究应激暴露和性激素环境对健康成人恐惧学习（目标1）和消除学习（目标2）的相互作用。我们假设，暴露于社会心理压力源会增加恐惧记忆的巩固，但会减少恐惧消退的巩固，这些影响在雌二醇水平升高的男性和女性中更为明显。240名参与者（60名男性，60名服用口服避孕药的女性，60名处于卵泡期早期（雌二醇水平低）的自然周期女性，以及60名处于周期中期（雌二醇水平高）的自然周期女性）将接受为期3天的试验；第1天是恐惧条件反射，第2天是消退学习，第3天是消退记忆回忆。在第1项试验中，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）将在恐惧条件反射之前立即暴露在压力源中，而另一组（n=80）将暴露在无压力的控制条件下。在第2项实验中，80名新参与者将在第2天立即在消失学习之前暴露于压力源，并与第1项实验的对照组进行比较（n=80，无压力暴露）。每天将采集唾液样本，以检测雌二醇水平和皮质醇水平的变化。皮肤电导反应、心率、瓦楞纸肌电图和恐惧的主观报告将被用来量化恐惧水平。这个项目将进一步加深我们对生理和内分泌机制的理解，通过压力暴露和性激素调节恐惧和消失记忆的强度，以及这是如何增加适应不良行为的可能性的。这些结果可以用来进一步研究这些认知过程背后的神经基础。总之，这个项目有望扩大对恐惧过程中涉及的机制的理解。

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.