Estrogen-mediated effects on depression and memory formation in females

Abstract

Women are twice as likely to suffer from depression as men. It has been proposed that the ovarian hormones estrogen and progesterone contribute to the higher incidence of this potentially debilitating disorder. Depression can also be accompanied by a loss of cognitive performance. Here we review estrogen-mediated effects on depression and memory formation in females. We propose that changes in levels of estrogen are associated with sex differences in learning as well as changes in affect prior to menses, immediately after pregnancy and during perimenopause and the menopausal transition. Finally, we discuss the animal model of depression known as 'learned helplessness' and describe research from our laboratory demonstrating that exposure to an acute stressful experience compromises a female's later ability to acquire certain types of new memories. This response to stressful experience is opposite to that observed in males and is dependent on the presence of estrogen, and more specifically-changing levels of estrogen. This observation indicates that females and males can use different hormonal and neural mechanisms to respond to the same emotional event and underscore the importance of studying the unique and changing biology of females, especially when considering treatment strategies for depression and stress-related illness.

Fig. 1

Effects of stress on learning in males versus females. Figure depicts the percent conditioned responses across 300 trials of delay (A) and trace (B) classical eyeblink conditioning in the rat. Unstressed females in proestrus conditioned more than unstressed males. Exposure to an acute stressor of restraint and brief intermittent tail-shocks facilitated classical conditioning in males 24 h later, whereas in females exposure to the same stressor during diestrus impaired conditioning 24 h later during proestrus.

Fig. 2

Contribution of ovarian hormones to the stress-induced impairment of learning. (A) Females exposed to sham surgery were impaired in their ability to acquire the classically conditioned eyeblink response 24 h after exposure to the stressor. Removal of ovarian hormones (OVX) prevented the stress-induced impairment of classical eyeblink conditioning in females. (B) Effect of estrogen receptor antagonist on the stress-induced impairment of learning in females. Stressed females receiving the vehicle (VEH) were impaired relative to unstressed controls injected with VEH. After receiving injections of the estrogen antagonist, tamoxifen (TAM), females were not impaired by stressor exposure.

Fig. 3

Stages of estrus influence learning. Percentage conditioned eyeblink responses for female rats in different stages of their cycle: proestrus, estrus and diestrus. Rats in each stage were exposed to a stressor of intermittent tailshock and trained 24 h later. Female rats in proestrus, when estrogen levels are relatively high, emitted more conditioned responses in 300 trials than females in other stages.

Fig. 4

Relationships between estrogen and learning. Two hypotheses regarding the relationship between levels of estrogen and performance are diagrammed. (A) A linear relationship between estrogen and performance would suggest that elevated levels of estrogen (proestrus) are associated with enhanced performance whereas reduced levels of estrogen (diestrus and estrus) are associated with poor performance. (B) An inverted U relationship would suggest that when estrogen levels are very low and very high, performance is poor, and when estrogen levels are moderate, performance is optimal. Stressor exposure that impairs conditioning in female rats enhances the release of estrogen (Shors et al., 1999) consistent with an inverted-U shaped relationship.

Fig. 5

Contribution of adrenal hormones to the stress effects on learning. (A) Males exposed to sham surgery emitted more conditioned responses 24 h after stressor exposure than unstressed males. ADX prevented the stress-induced facilitation in males. (B) Females exposed to sham surgery exhibited the stress-induced impairment of conditioning. ADX did not prevent the impairment of conditioning in females 24 h following stressor exposure.