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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1

Illustration of the experimental fear conditioning and extinction protocol used in our experiment. Adapted from Zeidan et al., 2011. Note that the CS- (represented in a third color of light (yellow) is not shown in this figure for simplicity.

Figure 2

Differences between men and women in psychophysiological and BOLD measures during fear acquisition. A. Skin conductance responses (SCR) averaged across the first 4 conditioning trials for the conditioned stimulus that was reinforced, i.e. paired with the shock (CS+) and for the conditioned stimulus not paired with the shock (CS-). B. BOLD activation to the CS + vs. CS- contrasting Females vs. Males during fear conditioning is shown. C. Mean beta weights extracted from the dorsal anterior cingulate cortex (dACC), rostral anterior cingulate (rACC), and amygdala are shown, to illustrate the direction of activation within group. The threshold display for the maps in B is p < 0.01, uncorrected. M = males; F = females.

Figure 3

Differences between men and women in psychophysiological and BOLD measures during extinction memory recall. A. Skin conductance responses (SCR) averaged across the first 4 extinction recall trials for the extinguished stimulus (CS + E) compared to the unextinguished stimulus (CS + U). B. BOLD activation to the CS + E vs. CS + U contrasting Females vs. Males during extinction recall are shown. C. Mean beta weights extracted from the left and right rostral ACC and insula are shown, to illustrate the direction of activation within group. The threshold for the maps in B is p < 0.01, uncorrected. M = males; F = females.