Interactive effects of estrogen and serotonin on brain activation during working memory and affective processing in menopausal women

Abstract

While cognitive changes and mood instability are frequent symptoms reported by menopausal women, the degree to which the decline in estrogen production is responsible is not yet clear. Several lines of evidence suggest that estrogen may produce its effects on cognition and mood through modulation of serotonergic function. To test this hypothesis, we used the tryptophan depletion (TD) paradigm to lower central serotonin levels and pharmacologically manipulated estrogen levels in healthy menopausal women. We examined the individual and combined effects of estradiol and serotonin on working memory, emotion processing and task-related brain activation. Eight healthy predominantly early postmenopausal women underwent TD or sham depletion followed by functional magnetic resonance imaging (fMRI) both before and after short-term transdermal estradiol 75-150 μg/d administration. There was an estradiol treatment by TD interaction for brain activation during performance on both the N-back Task (working memory) and Emotion Identification Task (affective processing). During the 2-back condition, TD attenuated activation prior to, but not after, estradiol treatment in the right and left dorsal lateral prefrontal and middle frontal/cingulate gyrus. During emotion identification, TD heightened activation in the orbital frontal cortex and bilateral amygdala, and this effect was attenuated by estradiol treatment. These results provide preliminary evidence that serotonergic effects directly mediate the impact of estrogen on brain activation during working memory and affective processing.

FIGURE 1. Change in Free Tryptophan Levels During Active and Sham Depletion

Free plasma tryptophan levels decreased by 64% to 90% from pre to 6 hours pos-ingestion of an amino acid mixture without tryptophan. Free plasma tryptophan levels decreased between 5% and 26% on sham depletion test days.

FIGURE 2. Estradiol Levels Pre and Post Estrogen Treatment

Estradiol levels increased with estrogen administration but did not differ significantly between active and sham depletion test days after estrogen administration.

Figure 3. N-Back Brain Rendering Highlights Regions of Interest

N-back working memory task activation. Bilateral dorsolateral prefrontal cortex (DLPFC) and medal frontal/cingulate gyrus (MF/CG) regions identified by the main effect of working memory load (2 back vs. 0 back) in a whole brain repeated measures ANOVA (p<0.05, corrected). Brain rendering performed with Caret (Van Essen, 2001)

Figure 4

Mean percent signal change for the 2-back minus 0-back contrast calculated from functionally defined dorsolateral prefrontal cortex (DLPFC) and medal frontal/cingulate gyrus (MF/CG) regions of interest.

Figure 5

Mean percent signal change for the Emotion Identification task effect calculated from anatomically defined Amygdala and Orbital Frontal Cortex.