Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Neuroscience. 2009 Dec 15;164(3):887-95. doi: 10.1016/j.neuroscience.2009.09.011. Epub 2009 Sep 15.
Gonadal hormones modulate fear acquisition, but less is known about the influence of gonadal hormones on fear extinction. We assessed sex differences and the influence of gonadal hormone fluctuations and exogenous manipulations of estrogen and progesterone on acquisition, extinction learning and extinction recall in a 3 day auditory fear conditioning and extinction protocol. Experiments were conducted on males and naturally cycling female rats. Regarding female rats, significant differences in fear extinction were observed between subgroups of females, depending on their phase of the estrous cycle. Extinction that took place during the proestrus (high estrogen/progesterone) phase was more fully consolidated, as evidenced by low freezing during a recall test. This suggests that estrogen and/or progesterone facilitate extinction. In support of this, injection of both estrogen and progesterone prior to extinction learning in female rats during the metestrus phase of the cycle (low estrogen/progesterone) facilitated extinction consolidation, and blockade of estrogen and progesterone receptors during the proestrus phase impaired extinction consolidation. When comparing male to female rats without consideration of the estrous cycle phase, no significant sex differences were observed. When accounting for cycle phase in females, sex differences were observed only during extinction recall. Female rats that underwent extinction during the metestrus phase showed significantly higher freezing during the recall test relative to males. Collectively, these data suggest that gonadal hormones influence extinction behavior possibly by influencing the function of brain regions involved in the consolidation of fear extinction. Moreover, the elevated fear observed in female relative to male rats during extinction recall suggests that gonadal hormones may in part play a role in the higher prevalence of anxiety disorders in women.
性腺激素调节恐惧的获得，但性腺激素对恐惧消退的影响知之甚少。我们评估了性别差异以及性腺激素波动以及外源性雌激素和孕激素对 3 天听觉恐惧条件反射和消退协议中获得、消退学习和消退回忆的影响。实验在雄性和自然发情周期的雌性大鼠上进行。对于雌性大鼠，根据发情周期的不同阶段，观察到雌性大鼠在恐惧消退方面存在显著差异。发生在发情前期（高雌激素/孕激素）阶段的消退更为完全巩固，这表现为回忆测试期间的低冻结。这表明雌激素和/或孕激素促进了消退。支持这一观点的是，在发情前期（低雌激素/孕激素）周期的发情前期，对雌性大鼠进行消退学习前注射雌激素和孕激素，促进了消退的巩固，而在发情前期阻断雌激素和孕激素受体则损害了消退的巩固。在不考虑发情周期阶段的情况下比较雄性和雌性大鼠时，没有观察到显著的性别差异。当考虑雌性动物的周期阶段时，仅在消退回忆时观察到性别差异。在发情前期进行消退的雌性大鼠在回忆测试期间的冻结显著高于雄性大鼠。总的来说，这些数据表明，性腺激素可能通过影响参与恐惧消退巩固的大脑区域的功能来影响消退行为。此外，在消退回忆期间，雌性大鼠相对于雄性大鼠表现出更高的恐惧，这表明性腺激素可能在一定程度上在女性中更高的焦虑障碍患病率中发挥作用。
