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The Journal of Neuroscience, September 5, 2007, 27(36):9729-9735; doi:10.1523/JNEUROSCI.2529-07.2007

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Behavioral/Systems/Cognitive
Estrogen Disrupts the Inhibition of Fear in Female Rats, Possibly through the Antagonistic Effects of Estrogen Receptor {alpha} (ER{alpha}) and ERß

Donna J. Toufexis, Karyn M. Myers, Michael E. Bowser, and Michael Davis

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, and The Center for Behavioral Neuroscience, Atlanta, Georgia 30329

Correspondence should be addressed to Donna J. Toufexis, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, and The Center for Behavioral Neuroscience, 954 Gatewood Drive NE, Atlanta, GA 30329. Email: dtoufex{at}emory.edu

The ambiguous role of estrogen in emotional learning may result from opposing actions of estrogen receptor {alpha} (ER{alpha}) and ERß. Using a fear-conditioning paradigm called the AX+, BX– discrimination, in which cue A comes to elicit fear and cue B becomes a safety signal, we examined the effect of 17ß-estradiol (E) and selective ER{alpha} and ERß agonists on excitatory and inhibitory fear learning. Gonadectomized (GDX) male and female rats implanted with E or selective ER{alpha} or ERß agonists were trained on the AX+, BX– discrimination and tested periodically to A, B, and AB. GDX sham-implanted male and female rats and GDX E-implanted males, but not GDX E-implanted females, exhibited less fear to AB than to A, suggesting that estrogen interferes with generalization of safety signals in female rats. ER{alpha} and ERß agonists disrupted discrimination learning in both sexes. ER{alpha}-implanted groups had higher fear responses to all cues than did ERß-implanted groups, suggesting that these two receptors have opposing effects in aversive discrimination learning. In contrast, neither E nor ER{alpha} and ERß agonists affected single-cue fear conditioning in either sex. These data suggest that E does not enhance fear in emotional learning but acts to disrupt the inhibition of fear in females only.

Key words: emotion; hormone; learning and memory; limbic; memory formation; sex difference


Received Oct. 2, 2006; revised July 11, 2007; accepted July 11, 2007.

Correspondence should be addressed to Donna J. Toufexis, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, and The Center for Behavioral Neuroscience, 954 Gatewood Drive NE, Atlanta, GA 30329. Email: dtoufex{at}emory.edu




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