Anxiety and Working Memory Function in Women: Exploring the Role of Dopamine and Ovarian Hormones

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PROJECT ABSTRACT Anxiety is the 6th leading cause of disability worldwide and is two times more prevalent in females than males. Importantly, anxiety is associated with reduced prefrontal cortex (PFC) function in areas critical for cognitive processes such as working memory. Although preclinical models have proposed complex interactive effects of anxiety and estradiol on working memory through modulations of prefrontal dopamine (DA), no research to date has examined the translational significance of these models in human females. To address this gap, this project aims to examine DA and estradiol’s effects on the relationship between worry, a core cognitive feature of anxiety, and neural oscillatory activity (i.e., theta-gamma coupling; TGC) indexing working memory function in females. The specific aims are to (1) establish the relationship between worry and TGC; (2) examine the role of basal DA in the relationship between worry and TGC; and (3) to examine the role of estradiol in the relationship between worry and TGC. Based on theoretical and empirical work demonstrating that worry reduces performance by placing an additional “load” on the cognitive system, I expect that worry will be related to reduced TGC, particularly under more difficult task conditions that place a high load on PFC function. To address Aim 2, the role of basal DA will be examined, given its critical role in working memory function. Specifically, DA demonstrates an inverted-U association with working memory function such that moderate levels of DA promote optimal working memory function whereas too much or too little DA is impairing. As such, I expect that higher worry will be associated with lower TGC in individuals with lower circulating DA (i.e., Val allele carriers of the catechol-o-methyltransferase genotype). Finally, higher estradiol levels have been shown to facilitate working memory-related PFC functioning in humans. I, therefore, predict that the association between higher worry and lower TGC will be larger when estradiol levels are low compared to when they are high in females across the menstrual cycle. This will be the first study of its kind to examine these aims and will significantly advance the research by examining a neurobiologically plausible mechanism through which anxiety impairs working memory function in females. Knowledge generated from this project will ultimately advance theoretical models of anxiety and the unique mechanisms involved in the expression and impact of anxiety in females for the improvement of women’s health.