Elsevier

Neuroscience

Volume 164, Issue 3, 15 December 2009, Pages 887-895
Neuroscience

Behavioural Neuroscience
Research Paper
Estrous cycle phase and gonadal hormones influence conditioned fear extinction

https://doi.org/10.1016/j.neuroscience.2009.09.011Get rights and content

Abstract

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.

Section snippets

Subjects

A total of 22 male and 150 female Sprague–Dawley rats (approximately 300 g and 8 weeks of age) were housed individually at the Massachusetts General Hospital Center for Comparative Medicine and handled for 5 min/d for 2 days following their arrival. Rats were maintained on a 12 h light/dark cycle and restricted to ∼15 g/d of laboratory rat chow, with free access to water. They were transported to a holding room in our laboratory in the morning and returned to the facility at the end of each

Pro/Met during fear conditioning

Rats that underwent fear conditioning during the proestrus phase (Pro_Cond group) were compared to those that underwent conditioning during the metestrus phase (Met_Cond group). Student's t-test conducted on the acquisition phase and extinction recall phase revealed no significant difference in either phase (t(22)=1.20, P=0.24, t(22)=0.95, P=0.35, for conditioning and extinction recall, respectively). Repeated measures ANOVA conducted on the extinction learning phase revealed a significant main

Discussion

The data gathered in the present study show that naturally cycling gonadal hormones influence fear extinction in that elevated gonadal hormone levels during the proestrus phase appear to facilitate extinction recall. This was further supported by (1) the fact that administration of exogenous estrogen and progesterone prior to extinction learning on day 2 facilitated extinction recall tested on day 3 and (2) the fact that blockade of estrogen and progesterone receptors prior to extinction

Acknowledgments

The work was supported by a grant from the National Institute of Mental Health (K01 MH080346) and a Rapapport Fellowship to M.R.M. The authors would like to thank Dr. David Rubinow and Dr. Gregory J. Quirk for helpful comments on the manuscript.

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