Complex roles of estrogen in emotion: sex matters.

h T e i U t ( a d W omen are more than twice as likely to suffer from fear and anxiety disorders, including generalized anxiety disorder, panic attacks, and posttraumatic stress disorder. One reason for this difference may be that fluctuating ovarian hormone levels in women during their reproductive life span alters emotional processing. For example, the incidence of anxiety symptoms is higher when ovarian hormone levels are low, including during premenstrual, postpartum, and perimenopausal periods. These women can benefit from estrogen treatment, suggesting an anxiolytic effect. Despite these striking sex differences and decades of research investigating the processes involved in controlling emotion, we know surprisingly little regarding the neurobiological mechanisms underlying this disproportionate incidence of fear and anxiety disorders. In the current issue, Zeidan et al. (1) add to the accumulating evidence that estradiol has powerful effects on emotional processing of fearful experiences. The authors found that estradiol facilitates the fear extinction process in both female rats and women, thereby providing a protective function against fear. This finding is in agreement with previous reports showing that estradiol enhances extinction of passive avoidance conditioning in male mice (2) and conditioned taste aversion in both male and female rats (3). The literature on fear learning in general, however, is more controversial. Animal studies have revealed a complex role of estradiol on various aspects of anxiety and fear. For instance, estradiol increased fear in a two-way avoidance task (4), whereas it decreased fear in a contextual fear conditioning paradigm (5). Because fear is often studied in animal models using classical fear-conditioning paradigms, these models involve a learning component that interacts with fear. Estradiol has a well-established procognitive role on the learning aspects of fear; thus, it may, on the one hand, enhance fear by increasing the acquisition or expression of fear conditioning but also reduce fear by accelerating extinction learning. Underscoring this intricate relationship, we have also previously shown differential effects of estradiol: chronic estradiol administration to ovariectomized rats was anxioytic in the open field test yet increased fear potentiated startle (6). A closer examination of within-session extinction during the testing phase of fear potentiated startle revealed that there was increased startle during the initial third of the testing session. However, fear potentiated startle in the estradiol-treated group diminished quickly as testing proceeded. By the end of the session, this group was comparable with the vehicle group, lending support to the idea that estradiol may increase fear initially by enhancing associative learning during fear conditioning yet reduce it later by facilitating fear extinction. In the present issue, Zeidan et al. (1) demonstrate that estrogen acilitates extinction recall when it is administered before or immeiately after extinction learning but not when given after a 4-hour elay, corroborating the notion that estrogen may act by enhanc-