Summary 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 both insufficient or excessive DA impairs PFC function. In animals, 17-β 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, in healthy young women, we examined the effects of endogenous fluctuations in estradiol on working memory as a function of baseline PFC DA (indexed by COMT Val158Met 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 ‘optimal DA’ was associated with 1) reduced PFC activity sustained across task blocks 2) selectively enhanced PFC activity on trials with the greatest demand for cognitive control and 3) the magnitude of PFC activity during high control trials was predictive of an individual’s performance. These findings show that while 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.

Dopaminergic drugs affect a variety of cognitive processes, but the direction and extent of effects vary across individuals and tasks.Paradoxical effects are observed, by which the same drug causes cognitive enhancing as well as adverse effects. Here, we demonstrate that individual differences in impulsive personality account for the contrasting effects of dopaminergic drugs on working memory and associated frontostriatal activity. We observed that the dopamine D 2 receptor agonist bromocriptine improved the flexible updating (switching) of relevant information in working memory in high-impulsive subjects, but not in low-impulsive subjects. These behavioral effects in high-impulsive subjects accompanied dissociable effects on frontostriatal activity. Bromocriptine modulated the striatum during switching but not during distraction from relevant information in working memory. Conversely, the lateral frontal cortex was modulated by bromocriptine during distraction but not during switching. The present results provide a key link between dopamine D 2 receptor function, impulsivity, and frontostriatal activity during component processes of working memory.Key words: dopamine; working memory; prefrontal cortex; basal ganglia; fMRI; impulsivity IntroductionThe mesocorticolimbic dopamine (DA) system is implicated in working memory (Brozoski et al., 1979;Sawaguchi and Goldman-Rakic, 1991). However, the effects of dopaminergic drugs are complex and depend on task demands and associated neural systems . Recent work suggests that DA may have opposite effects depending on the neural site of modulation [prefrontal cortex (PFC) vs striatum] (Crofts et al., 2001;Frank et al., 2001;Gruber et al., 2006). DA in the PFC is thought to stabilize representations by reducing susceptibility to distraction (Durstewitz et al., 2000;Seamans and Yang, 2004). Conversely, DA in the striatum may rapidly update representations in a task-relevant manner (Frank et al., 2001;Gruber et al., 2006). In the current study, we aimed to test the hypothesis that DA modulates the striatum and frontal cortex during the flexible updating and stable maintenance of representations, respectively, by examining the effects of the D 2 receptor agonist bromocriptine with functional magnetic resonance imaging (fMRI). Dopaminergic drug effects vary not only across task demands but also across individuals . Paradoxical effects are observed, by which drugs improve performance in individuals with suboptimal DA and poor performance but impair performance in individuals with already optimized DA and good performance (Kimberg et al., 1997;Arnsten, 1998;Mattay et al., 2003;Phillips et al., 2004). Here, we demonstrate that dopaminergic drug effects can also be predicted from trait impulsivity. We observed differential effects of bromocriptine in highand low-impulsive subjects, who were preselected based on selfreport trait impulsivity. The rationale for impulsivity-based subject selection was threefold. First, impulsivity is the primary trait thought to mediate vulnerability ...

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Objective Few have characterized cognitive changes with age as a function of menopausal stage relative to men, or sex differences in components of memory in early midlife. The study aim was to investigate variation in memory function in early midlife as a function of sex, sex steroid hormones, and reproductive status. Methods 212 men and women ages 45–55 were selected for this cross-sectional study from a prenatal cohort of pregnancies whose mothers were originally recruited in 1959–1966. They underwent clinical and cognitive testing and hormonal assessments of menopausal status. Multivariate general linear models for multiple memory outcomes were used to test hypotheses controlling for potential confounders. Episodic memory, executive function, semantic processing and estimated verbal IQ were assessed. Associative and episodic verbal memory were assessed using Face-Name Associative Memory Exam (FNAME) and Selective Reminding Test (SRT), given increased sensitivity to detecting early cognitive decline. Impacts of sex and reproductive stage on performance were tested. Results Women outperformed men on all memory measures including FNAME (β = −0.30, p < 0.0001) and SRT (β = −0.29, p <0.0001). Further, premenopausal and perimenopausal women outperformed postmenopausal women on FNAME (Initial Learning, β= 0.32, p= 0.01) and SRT (Recall, β= 2.39, p= 0.02). Across all women, higher estradiol was associated with better SRT performance (Recall, β = 1.96, p= 0.01) and marginally associated with FNAME (Initial Learning, β = .19, p=.06). Conclusion This study demonstrated that, in early midlife, women outperformed age-matched men across all memory measures, but sex differences were attenuated for postmenopausal women. Initial learning and memory retrieval were particularly vulnerable, while memory consolidation and storage were preserved. Findings underscore the significance of the decline in ovarian estradiol production in midlife and its role in shaping memory function.