Estrogen shapes dopamine-dependent cognitive processes: implications for women's health

Abstract

The prefrontal cortex (PFC) is exquisitely sensitive to its neurochemical environment. Minor fluctuations in cortical dopamine (DA) can profoundly alter working memory, a PFC-dependent cognitive function that supports an array of essential human behaviors. Dopamine's action in the PFC follows an inverted U-shaped curve, where an optimal DA level results in maximal function and insufficient or excessive DA impairs PFC function. In animals, 17β-estradiol (the major estrogen in most mammals, referred to henceforth as estradiol) has been shown to enhance DA activity, yet no human study has adequately addressed whether estradiol's impact on cognition occurs by way of modulating specific neurochemical systems. Here we examined the effects of endogenous fluctuations in estradiol on working memory in healthy young women as a function of baseline PFC DA [indexed by catechol-O-methyltransferase (COMT) Val(158)Met genotype and, at a finer scale, COMT enzyme activity]. The results demonstrate that estradiol status impacts working memory function and, crucially, the direction of the effect depends on indices of baseline DA. Moreover, consistent with a DA cortical efficiency hypothesis, functional MRI revealed that inferred optimal DA was associated with reduced PFC activity sustained across task blocks and selectively enhanced PFC activity on trials with the greatest demand for cognitive control. The magnitude of PFC activity during high control trials was predictive of an individual's performance. These findings show that although estrogen, considered in isolation, may have unpredictable effects on cognitive performance, its influence is clarified when considered within a larger neuromodulatory framework. Given the clinical prevalence of dopaminergic drugs, understanding the relationship between estrogen and DA is essential for advancing women's health.

Figure 1.

A, Task protocol: hybrid block/event-related design. Subjects performed blocks of WM trials with loads of 0, 2, and 3. Within load blocks, trial types included targets (an n-back match), lures (a recently seen but nontarget stimulus; e.g., in the 2-back condition, a 1- or 3-back match is a lure), and nontargets (all other nonlure, nontarget trials). Stimuli (uppercase consonants) were presented for 1 s followed by a 1 s delay. Subjects responded to every trial, indicating whether the currently presented letter did or did not match the letter seen n-previously. The 0-back condition consisted of target-detection (the letter X). Null events provide temporal jitter for event-related analyses. B, Theoretical inverted-U model of cortical DA function. Both insufficient and excessive DA-receptor stimulation lead to poor performance on DA-dependent tasks. The val/val allele of the COMT Val¹⁵⁸Met polymorphism is associated with low basal PFC DA (light gray bar), relative to met/met carriers (dark gray bar). Estradiol (solid line) and WM load (dotted line) potentiate DA, which is expected to have beneficial effects for val homozygotes and unfavorable effects for met homozygotes.

Figure 2.

A, Repeated-measures one-way ANOVA shows a significant difference in load accuracy (F_(2,86) = 93.98; p < 0.0005; effect size, η² = 0.69) and response time (F_(1,43) = 401.63, p < 0.0005, η² = 0.90). Post hoc Bonferroni-corrected comparisons showed that all three means for both accuracy and response time were significantly different; subjects performed faster and more accurately on 0-back (accuracy, 78%; response time, 436 ms) compared with 2-back (75.6%, 653 ms) compared with 3-back (71%, 696 ms) trials. Error bars represent SEM. N = 44. B, Similar analyses revealed significant differences in trial type accuracy (F_(1,43) = 81.14; p < 0.0005; effect size, η² = 0.65) and response time (F_(1,43) = 362.78; p < 0.0005; η² = 0.89): nonlure (99%, 644 ms), target (86%, 759 ms), lure (76%, 1019 ms). C, Two-back lure trial performance as a function of genotype [N = 16 (met) 24 (val)] and estradiol status [N = 21 (high) 20, (low)]. met/met + low estradiol (e) subjects (91% ± 2.9% correct; mean ± SEM) performed significantly better than val/val + low estradiol subjects (77% ± 3.7%; p = 0.041, two-tailed t test). D, COMT enzyme activity level by genotype, depicting variance within met/met and val/val genotypes (overlaid on mean values; pale gray bars). Blood samples from three heterozygous val/met samples were analyzed and are included for display only. E, For low estradiol subjects (right), COMT enzyme correlates negatively with 2-back lure accuracy (r = −0.482; p = 0.043). For high estradiol subjects (left), COMT enzyme correlates positively with 3-back lure accuracy (approached significance r = 0.433; p = 0.056).

Figure 3.

Across blocks, sustained PFC activity decreases as PFC DA increases across groups. A, Load-sensitive suprathreshold PFC cluster (right hemisphere shown at family-wise error p value < 0.0001; T = 7.5). Left (L) and right (R) MFG were identified as ROIs (10 contiguous voxels; MNI coordinates of peak locus, left: −45, 32, 30; right: 44, 32, 32; defined at family-wise error p value < 0.00001). N = 44. B, Parameter estimates in bilateral MFG shown together as a function of genotype and estradiol (e) status (lowest vs highest DA groups: val + low estradiol vs met + high estradiol; left MFG, p = 0.021; right MFG, p = 0.019). C, Mean signal in left MFG versus COMT enzymatic activity (N = 37). As COMT activity increased (indicating a probable concomitant decrease in PFC DA), PFC activity became more exaggerated.

Figure 4.

A, B, Target-related (A) and lure-related (B) neural activity as a function of inferred PFC dopamine status (event-related activity on correct trials within 2- and 3-back WM blocks; note that 0-back blocks do not, by necessity, contain lure trials). C, Two-back lure performance versus the magnitude of correct lure-trial activity in right (R) MFG (mean signal within the ROI). D, COMT enzyme versus the magnitude of correct lure-trial activity in right MFG (mean signal). e, Estradiol.