In humans there is a strong effort to understand the effects of estrogen on cognition, but the data have been inconsistent. This study suggests that taking baseline DA into account is crucial for detecting the direction of estrogen’s effect on WM. Specifically, the results establish that estradiol can be beneficial or detrimental to WM and, critically, the direction of the effect depends on COMT genotype and, at a finer scale, COMT enzymatic activity (proxies of baseline PFC DA). At the behavioral level, the effects of estradiol and COMT genotype emerged on trials that require a high demand of cognitive control. Neurally, hormonal and genotypic differences were apparent even in the absence of significant behavioral differences. ‘Suboptimal’ DA subjects showed greater task-related PFC activity across blocks but reduced PFC activity on the high interference lure trials. ‘Optimal’ DA subjects showed the opposite pattern. Conceptually similar results with the same cognitive task were observed in a study of the neural mechanisms of general fluid intelligence (gF) (
Gray et al., 2003), in which low gF subjects (like our suboptimal DA subjects) showed enhanced sustained PFC activity during a WM task but paradoxically reduced activity during high control interference trials. High gF individuals showed the opposite pattern (like our optimal DA subjects).
Our findings are in keeping with work from
Egan et al. (2001), who demonstrated that Met allele load predicts the efficiency of PFC physiology. While all genotypic groups in their sample (val/val, val/met, met/met) showed similar levels of performance on a 2-back WM task, task-related PFC BOLD activity was greatest for val/val subjects, reduced for val/met, and lowest for met/met subjects. In a related pharmacogenomic study,
Mattay et al (2003) found that amphetamine administration improved WM performance and enhanced cortical efficiency for val/val subjects. Met/met subjects, however, became cortically inefficient on drug, presumably because near-optimal basal DA levels were heightened beyond the optimal range. Similarly,
Mehta et al (2000) showed that the indirect catecholamine agonist methylphenidate (Ritalin) improves WM performance and reduces task-related regional cerebral blood flow in the PFC. These beneficial drug effects were most pronounced for subjects with lower baseline WM capacities (a likely behavioral index of DA synthesis capacity) (
Cools et al., 2008). Similar results were found using the D2 receptor agonist bromocriptine (
Gibbs and D’Esposito., 2005;
Cools et al., 2007). Together, these findings contribute to a body of evidence demonstrating that optimal DA levels are associated with greater cortical efficiency (i.e. at a given level of performance, DA optimizes the signal-to-noise ratio of cortical processing, decreasing the extent of task-related PFC activity as measured by BOLD) (
Durstewitz and Seamans, 2002;
Winterer and Weinberger, 2004;
Vijayraghavan et al., 2007). While the relationship between DA, WM and cortical efficiency has been demonstrated in humans using pharmacological manipulation of DA, we observe a strikingly similar relationship when considering the natural hormonal fluctuations that occur over the coarse of a woman’s menstrual cycle each month. Further, we found that estradiol’s ‘DA agonist-like’ effect on behavioral and neural processes depends on COMT Val
158Met genotype and, at an individual level, COMT enzymatic activity—which suggests a dependence on baseline PFC DA.
The importance of ovarian hormones to the neurophysiology underlying prefrontal function was established by
Berman and colleagues (1997). The authors examined the influence of gonadal hormones on regional cerebral blood flow (rCBF) by suppressing endogenous ovarian activity and re-introducing exogenous estradiol and progesterone. Task-evoked prefrontal rCBF patterns were dramatically reduced under hormone-suppression conditions and normalized after hormone replacement. This paradigm provides excellent control for the manipulation of gonadal hormones. Menstrual cycle studies depend on the endogenous fluctuation of sex hormones, and the timing of hormone fluctuation varies between women and between cycles. In the present study, women were tracked for ≥ 4 months to confirm the consistency of their cycle and to infer hormone status at the time of testing (supplemented by direct estradiol measurement from serum samples), but this paradigm is limited in its ability to tease apart the concerted action of multiple sex hormones.
Norepinephrine (NE) also plays a key role in WM mechanisms (
Li and Mei, 1994;
Li et al., 1999;
Ramos et al., 2005) and our results do not rule out the possibility that NE signaling, and modulation thereof, is part of estradiol’s underlying mechanism for modulating PFC function. However, in this study the effects of estradiol were highly dependent on COMT. COMT inactivates catecholamines, including DA and NE, via
o-methylation (
Mannisto and Kaakkola, 1999). Evidence suggests that COMT’s role in metabolizing NE in PFC is minor compared to its role in DA metabolism. Administration of tolcapone, a brain-penetrant COMT inhibitor, enhances extracellular DA in rat medial PFC with little to no change in NE (measured following stimulation of the catecholamine system)(
Tubridge et al., 2004). Furthermore,
Huotari et al (2002) observed that following l-DOPA administration COMT knockout mice show increased accumulation of cortical DA compared to wild-type animals; cortical NE levels did not differ significantly across groups. Together, these data suggest that COMT predominantly impacts PFC DA, with minimal influence over NE signaling.
γ-Aminobutyric acid (GABA), the principle inhibitory neurotransmitter, has also been shown to fluctuate over the menstrual cycle (
Epperson et al., 2002; for a review see:
Cosgrove et al., 2007) and mounting evidence demonstrates that estradiol modulates glutamatergic activity (
McCarthy et al., 2002). Thus, estradiol’s influence on cognition cannot be fully understood without taking other neurochemical systems into account. Moreover, estradiol does not exert its effect in isolation; other gonadal hormones such as progesterone likely modulate PFC function (
Berman et al., 1997). In vitro and in vivo experimental paradigms in animals and carefully designed studies in humans are critical for clarifying the complex relationship between endogenous fluctuations in neuroactive gonadal hormones, neurochemical signaling and cognition (e.g.
Aubele and Kritzer, 2011).
The results of our study are in keeping with work in rodents and non-human primates showing that estradiol enhances DA activity, but a definitive study showing an estradiol-DA link in humans is lacking. Future work is needed to directly assess estradiol’s effect on DA neurotransmission in humans. The only method currently available to assess DA release in vivo in humans combines pharmacological stimulation of the DA system with positron emission tomography (PET), in conjunction with a DA-receptor radioligand such as [
11C]-raclopride(
Cropley et al., 2006;
Laruelle, 2000).
Though to our knowledge no study has compared estradiol levels (e.g.
Bixo et al., 1995) or the pattern of estrogen receptor (ER) expression across specific subregions of PFC in humans, quantitative morphometric studies in nonhuman primates demonstrate estradiol’s influence on synaptic organization within dorsolateral PFC, a region that expresses ERα (
Perlman et al., 2005;
Montague et al., 2008;
Wang et al., 2010). Specifically, when ovariectomized monkeys were treated with estradiol (using a cyclical regimen that mirrors the pre-ovluatory spike in estradiol), striking increases in dendritic spine density were observed in dlPFC layer III pyramidal neurons (
Hao et al., 2006). These physiological changes were accompanied by improved performance on a delayed-response working memory task (e.g.
Rapp et al., 2003). Importantly, the estradiol-dependent effects we observe in humans using fMRI BOLD are also in dlPFC. Thus, the relationship between estradiol, DA and working memory is underscored by the overlapping neural proximity with which these changes are observed.
Another important clue into estradiol’s site of action comes from a series of immunocytochemistry experiments showing ERβ expression in midbrain dopaminergic neurons that project to PFC and constitute the mesocortical DA pathway (
Creutz and Kritzer, 2002). Until recently it was thought that ~30% of cells within the rat mesocortical pathway were dopaminergic (TH-immunoreactive) (
Swanson et al. 1982). However, the data came solely from males and a recent study discovered that females have a significantly greater proportion of dopaminergic cells, around 50%, within this pathway (
Kritzer and Creutz, 2008). Sex differences in mesocortical organization may carry functional consequences for cognitive processes that rely on PFC DA signaling.
Collectively, these data carry direct ramifications for women’s health. The response to DA medications (e.g. Ritalin for attention deficit disorder and l-DOPA for Parkinson’s disease) may differ between men and women, and within women in different endocrine states (
Lukas et al., 1996;
Justice and deWit 1999,
2000;
Evans et al., 2002). A substantial body of evidence from the animal and human literature documents sex differences in neural and behavioral responses to dopaminergic drugs—including pharmacological treatments and drugs of abuse (Carroll et al., 2004;
Becker and Hu, 2008;
Goldstein et al., 2002; Lynch et al., 2002). The present findings suggest that while estrogen, considered in isolation, may have unpredictable effects on cognition, its influence is clarified when considered within a larger neuromodulatory framework. A man and woman’s milieu differ; until we understand how, we cannot fully understand neural processes as they unfold in the healthy state, less still in the diseased state.
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