Behavioral Neuroscience Lab, Journal Club Entry (11/13/07):

THE ROLE OF ESTROGEN RECEPTORS IN FEAR INHIBITION

Review of Toufexis, et al., 2007
By: Evan T. Creed and Ashley T. Westerman
American University, Department of Psychology, Washington, DC, 20016, USA

Gender differences in the prevalence of psychiatric disorders—especially disorders of affect—raise the question of whether neuroendocrine factors are involved in the etiology of such disorders. For example, it has been demonstrated that women are more likely to suffer from anxiety disorders like post-traumatic stress disorder (PTSD) than are men, and while the reasons for the differential rates of PTSD are not entirely understood, researchers speculate that hormones are likely involved (Olff, et al., 2007). In particular, estrogen is believed to play a role in emotional regulation; specifically, recent evidence indicates that estrogen is involved in sex differences that exist in fear and anxiety behaviors (Toufexis, et al., 2007). Estrogen-mediated effects on emotion are likely exerted via interactions with intracellular estrogen receptors α (ERα) and β (ERβ). Namely, activation of ERα increases fear- and anxiety-related behaviors; conversely, activation of ERβ may attenuate fear and anxiety responses (Lund et al., 2005; Toufexis, et al., 2007). Differences in location and concentration of these receptors may partially explain the sexual dimorphism found in emotional disorders.

In a study recently published in The Journal of Neuroscience, Toufexis and colleagues (2007) utilized a discrimination conditioning technique to differentiate between effects of excitatory fear learning and the inhibitory fear attenuation process. This conditioning technique, known as AX+, BX-, begins with a series of trainings with an A stimulus (co-terminating with an X stimulus) which is followed by an electric shock and a B stimulus (also co-terminating with the X stimulus) which is not followed by a shock. By then testing the fear response to the A stimulus, the B stimulus, and a compound AB stimulus, it is possible to determine the level to which the B stimulus, or safety signal, attenuates fear when paired with the A stimulus compared to when subjects are presented with the A stimulus alone. Gonadectomized rats of both sexes were implanted with pellets containing 17β-estradiol (E), a selective agonist for ERα (propyl-pyrazole-triol, or PPT), a selective ERβ agonist (diarylpropionitrile, or DPN), or sham implants.

Interestingly, while both E-implanted and sham implanted males, as well as sham implanted females, had a reduced fear-potentiated startle to the AB compound stimulus when compared to the A stimulus alone, E-implanted females showed no significant reduction in fear-potentiated startle (FPS), suggesting that safety cue generalization did not occur (Toufexis et al., Figure 2). Results indicate that the fear response of animals receiving PPT was greater than that of animals receiving DPN, regardless of gender. This supports the idea that ERα and ERβ act differentially to regulate fear levels. However, groups of both sexes receiving either the ERα agonist or the ERβ agonist alone did not differentiate in response to safety cue. This result is particularly intriguing for the male group, since activation of either ERα or ERβ alone interfered with safety cue generalization, but when both were activated by the 17β-estradiol, or neither were activated by the sham implants, males then reacted to the safety cue with reduced levels of fear response.

Furthermore, Toufexis et al. (2007) performed a simple fear-conditioning test to determine if groups showed differences in the acquisition of a fear response. They found that in both sexes, administration of E, PPT, DPN, or sham implants did not show significant differences on FPS in this task (Toufexis et al., Figure 4). This result suggests that the effect of estrogen on the fear response of females was not due to increased levels of fear; rather, the results indicate a disruption in the ability to generalize safety cues to novel situations that include a fearful or threatening stimulus.

A similar effect of estrogen on fear extinction in women has been previously observed. Specifically, women in the late follicular stage of their menstrual cycle (when estrogen levels are high) experienced decreased fear extinction when compared to women in the early follicular stage of their cycle (when estrogen levels are low) or to men (Milad et al., 2006). From an evolutionary perspective, impairments in fear extinction during the late follicular stage may serve an adaptive function. Increased sensitivity to possible threats during ovulation increases a woman’s chances of survival and consequently increases the likelihood of passing on her genes.

Toufexis et al. (2007) note that elevated estrogen levels (during the late follicular stage, for example) may place women at higher risk of developing stress- and trauma-related pathologies in response to traumatic or highly stressful life events. Olff et al. (2007) highlighted a number of hypotheses that have been advanced by researchers concerning the discrepancy in the prevalence of PTSD in men vs. women. These factors include: the greater exposure of women to interpersonal assault (e.g., rape and sexual abuse); gender-specific cognitive appraisal styles; peritraumatic dissociation; and neuroendocrinological differences in the male and female stress-response systems. The findings of Toufexis et al. (2007) lend credence to the hypothesis that neuroendocrine factors likely play a role in the higher rate of PTSD among women.

The study presented by Toufexis and colleagues (2007) contributes significantly to our understanding of how estrogen might mediate fear response in rats. It achieves this by introducing a methodology that allows researchers to separately test effects upon the excitatory fear learning phase and fear inhibition. Further studies in this area may include cyclic estrogen replacement as described by Gerrits and colleagues (2006). They theorized that constant release of estradiol over the effective period of the pellet implants may result in ER down-regulation and that a cyclic administration, in which subjects are injected once every four days, may be preferable. This approach is reasonable since it better mimics the natural pattern of estrogen activity. The use of cyclic estradiol administration, in conjunction with AX+, BX- fear discrimination learning, may help in determining whether the differentiated effects of estrogen on fear learning and safety cue discrimination reported here by Toufexis et al (2007) are a function of ER down-regulation. A down-regulation of receptors may explain the contradictory findings in prior research on the effects of estrogen on fear noted by Toufexis et al (2007). Finally, to elucidate the role of hormone fluctuations in susceptibility to trauma-related pathologies, it would be interesting to examine prospectively the conditional risk for developing PTSD based on menstrual cycle stage.

References

Gerrits M, Bakker PL, Koch T, Ter Horst GJ (2006) Stress-induced sensitization of the limbic system in ovariectomized rats is partly restored by cyclic 17β-estradiol administration. Eur J Neurosci 23:1747-1756.

Lund TD, Rovis T, Chung WCJ, Handa RJ (2005) Novel actions of estrogen receptor-β on anxiety-related behaviors. Endocrinology 146:797-807.

Milad MR, Goldstein JM, Orr SP, Wedig MM, Klibanski A, Pitman RK, Rauch SL (2006) Fear conditioning and extinction: influence of sex and menstrual cycle in healthy humans. Behav Neurosci 120:1196-1203.

Olff M, Langeland W, Draijer N, Gerson BPR (2007) Gender Differences in Posttraumatic Stress Disorder. Psychol Bull 133:183-204.

Toufexis DJ, Myers K M, Bowser ME, Davis M (2007) Estrogen disrupts the inhibition of fear in female rats, possibly through the antagonistic effects of estrogen receptor α (ERα) and ERβ. J Neurosci 27:9729-9735.