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Sex differences in the neurobiology of fear conditioning and extinction: a preliminary fMRI study of shared sex differences with stress-arousal circuitry

Kelimer Lebron-Milad1*, Brandon Abbs2, Mohammed R Milad1, Clas Linnman13, Ansgar Rougemount-Bücking14, Mohammed A Zeidan1, Daphne J Holt1 and Jill M Goldstein12

Author Affiliations

1 Department of Psychiatry, Harvard Medical School & Massachusetts General Hospital, 149 13th St, Charlestown, MA, 02129, USA

2 Departments of Psychiatry and Medicine, Harvard Medical School, Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, 75 Francis St., Boston, MA, 02120, USA

3 P.A.I.N. Group, Department of Anesthesia, Children´s Hospital, Boston, MA, USA

4 Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 7 rue Saint-Martin, 1003, Lausanne, Switzerland

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Biology of Mood & Anxiety Disorders 2012, 2:7  doi:10.1186/2045-5380-2-7

Published: 16 April 2012



The amygdala, hippocampus, medial prefrontal cortex (mPFC) and brain-stem subregions are implicated in fear conditioning and extinction, and are brain regions known to be sexually dimorphic. We used functional magnetic resonance imaging (fMRI) to investigate sex differences in brain activity in these regions during fear conditioning and extinction.


Subjects were 12 healthy men comparable to 12 healthy women who underwent a 2-day experiment in a 3 T MR scanner. Fear conditioning and extinction learning occurred on day 1 and extinction recall occurred on day 2. The conditioned stimuli were visual cues and the unconditioned stimulus was a mild electric shock. Skin conductance responses (SCR) were recorded throughout the experiment as an index of the conditioned response. fMRI data (blood-oxygen-level-dependent [BOLD] signal changes) were analyzed using SPM8.


Findings showed no significant sex differences in SCR during any experimental phases. However, during fear conditioning, there were significantly greater BOLD-signal changes in the right amygdala, right rostral anterior cingulate (rACC) and dorsal anterior cingulate cortex (dACC) in women compared with men. In contrast, men showed significantly greater signal changes in bilateral rACC during extinction recall.


These results indicate sex differences in brain activation within the fear circuitry of healthy subjects despite similar peripheral autonomic responses. Furthermore, we found that regions where sex differences were previously reported in response to stress, also exhibited sex differences during fear conditioning and extinction.

Sex differences; Fear extinction; Fear conditioning; fMRI; Stress response circuitry