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. 2010 Jul 14;168(3):652-8.
doi: 10.1016/j.neuroscience.2010.04.030. Epub 2010 Apr 22.

The influence of gonadal hormones on conditioned fear extinction in healthy humans

M R Milad  1 , M A Zeidan, A Contero, R K Pitman, A Klibanski, S L Rauch, J M Goldstein
Affiliations

The influence of gonadal hormones on conditioned fear extinction in healthy humans

M R Milad et al. Neuroscience. .

Abstract

Recent rodent studies suggest that gonadal hormones influence extinction of conditioned fear. Here we investigated sex differences in, and the influence of estradiol and progesterone on, fear extinction in healthy humans. Men and women underwent a two-day paradigm in which fear conditioning and extinction learning took place on day 1 and extinction recall was tested on day 2. Visual cues were used as the conditioned stimuli and a mild electric shock was used as the unconditioned stimulus. Skin conductance was recorded throughout the experiment and used to measure conditioned responses (CRs). Blood samples were obtained from all women to measure estradiol and progesterone levels. We found that higher estradiol during extinction learning enhanced subsequent extinction recall but had no effects on fear acquisition or extinction learning itself. Sex differences were only observed during acquisition, with men exhibiting significantly higher CRs. After dividing women into low- and high-estradiol groups, men showed comparable extinction recall to high-estradiol women, and both of these groups showed higher extinction recall than low-estradiol women. Therefore, sex differences in extinction memory emerged only after taking into account women's estradiol levels. Lower estradiol may impair extinction consolidation in women. These findings could have practical applications in the treatment of anxiety disorders through cognitive and behavioral therapies.

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Figures

Figure 1
Figure 1
Fear conditioning and extinction protocol. CS+: conditioned stimulus, CS-: conditioned stimulus never paired with shock (unconditioned stimulus, US). Adapted from Milad et al., 2005.
Figure 2
Figure 2
Conditioned responses (SCRs) of high and low estradiol (HE and LE respectively) females across each session of the experiment. Habituation shows the mean of five trials, Conditioning displays the mean max response, Extinction shows the mean of the last two trials of each subject, Recall shows the mean of the first two trials. All data are shown based on differential response (CS+ minus CS-). Significant differences (p < .05) are indicated by *.
Figure 3
Figure 3
Conditioned responses (SCRs) of high (HP) and low progesterone (LP) women across each session of the experiment. See Figure 2 footnote for details. No significant differences were found.
Figure 4
Figure 4
Conditioned responses (SCRs) of men and all women across each session of the experiment. See Figure 2 footnote for details.
Figure 5
Figure 5
Percent extinction retention for men, women with high estradiol (HE) levels, and women with low estradiol (LE) levels. Significant differences (p < .05) are indicated by *.
See this image and copyright information in PMC

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