Estrogen modulates inhibition of return in healthy human females

Abstract

Estrogen has a key role in explaining gender differences in dopaminergic functioning. To date, previous studies on estrogen have focused on inhibitory output control, such as the intentional suppression of overt pre-potent actions, but whether input control is also modulated is an open question. For the first time, this study compared the ability to perform a cued target-detection task that measured inhibition of return (IOR), a reflexive inhibitory mechanism that delays attention from returning to a previously attended location, in young women (n = 21) across the three phases of their menstrual cycle (salivary estradiol and progesterone concentrations were assessed) and in young men (n = 21). Women showed more pronounced IOR effect in their follicular phase, which is associated with both higher estradiol levels and higher dopamine turnover rates, than in their luteal or menstruation phase. This increase in women's IOR in their follicular phase was also greater than the effect found for men at any of the three phases. Our results are consistent with the idea that estrogen promotes IOR. Given that the mechanism underlying IOR biases the cognitive system towards the intake of novel information, our findings suggest that when the estrogen level is high, women are biased towards cognitive flexibility rather than cognitive stability. We conclude that gender differences in inhibitory input control are variable and state-dependent but not structural.

Introduction

The gonadal steroid hormone estrogen does not only have a reproductive function, but also seems to modulate cognition. Several studies investigating cognitive performance during the menstrual cycle have shown that estrogen affects cognitive functions such as learning and working memory in both animal (Warren & Juraska, 1997) and human females (Gasbarri et al., 2008, Hampson, 1990a, Hampson, 1990b, Maki et al., 2002). Consistent with this notion, studies assessing menopause or ovariectomy have revealed cognitive impairments in memory functions as consequence of the decline of the level of estrogen (Sherwin, 2002, Sherwin, 2005).

Growing evidence suggests that estrogen affects cognition through its neuromodular effect on the cholinergic (Norbury et al., 2007), the serotoninergic (Bethea, Lu, Gundlah, & Streicher, 2002), and the GABA system (Amin et al., 2006). However, the dopaminergic system seems to be particularly strongly affected by estrogen. After estrogen enters the brain, it is converted to cathecol estrogen, which is suspected to inhibit the catechol O-methyltransferase (Ball, Knuppen, Haupt, & Breuer, 1972), an enzyme responsible for the degradation of dopamine (DA). Moreover, the DA content of striatal tissue in mice is higher in females than in males (McDermott, Liu, & Dluzen, 1994) and DA turnover rates are higher during diestrus (rising estrogen level) than in estrus (low estrogen level) in rats (Fernandez-Ruiz, Hernandez, de Miguel, & Ramos, 1991). As pointed out by Czoty et al. (2009), receptor autoradiography studies have demonstrated that D2 receptor densities can increase in the presence of natural elevations in estrogen during the estrous cycle and after exogenous estrogen administration (Bazzett and Becker, 1994, Becker, 1999, Di Paolo et al., 1988, Pazos et al., 1985; see Di Paolo, 1994). Consistent with this picture, other studies have pointed out that the follicular phase is related to enhancement in DA release associated by high levels of estrogen in rodents (Becker et al., 2001, Dazzi et al., 2007, Di Paolo et al., 1986; for review see Becker, 1999) and in monkeys (Czoty et al., 2009).

Previous studies on estrogen have focused on inhibitory output control, such as the intentional suppression of overt pre-potent actions. For example, a recent study by Colzato, Hertsig, van den Wildenberg, and Hommel (2010) showed that gender differences in inhibiting prepotent responses are restricted to the phase in women's menstrual cycle in which the estrogen level is particularly high—the follicular phase (FP)—while women do not differ from men in their luteal (LP) and menstrual phase (MP). In the present study, we investigated whether input control processes, specifically attentional selection, may also be affected. To examine this, we took advantage of the perhaps most reliable inhibitory phenomenon in human attention, the so-called inhibition of return (IOR) effect (Posner & Cohen, 1984), a reflexive inhibitory mechanism that delays attention from returning to a previously attended location. It is observed if people attend sequential displays or scan complex visual scenes (Klein, 1988) or other circumstances under which they move their attentional focus from one location or object to another location or object. Once a given location has been inspected and attention has moved to another location, the time needed to return to that previous location is increased—presumably to enhance the efficiency of attentional scanning by biasing attention away from irrelevant, old information and towards novel information (Klein, 1988).

Given the natural high level of estrogen in the FP is associated with increases in D2 receptor densities, there are a number of reasons suggesting that estrogen might impact IOR. For example, IOR is (a) eliminated after long-term intake of cocaine, which reduces D2 receptors densities (Colzato & Hommel, 2009), (b) reduced in Parkinson's patients, who suffer from a loss of nigrostriatal DA cells (Filoteo et al., 1997, Yamaguchi and Kobayashi, 1998), and (c) more pronounced in carriers of the 9-repeat allele of the DAT1 gene, associated with higher striatal DA levels than the 10-repeat allele (Colzato, Pratt, & Hommel, 2010). These studies converge onto the proposed crucial role of dopamine as the neurobiological mechanism underlying IOR (Poliakoff et al., 2003), and this transmitter is primarily targeted by estrogen.

The aim of the present study was twofold. The first goal was to determine whether estrogen can impact IOR. To test this, we compared the performance of young women in an IOR paradigm across different phases of their menstrual cycle. All three phases were considered: the FP, which is associated with the highest level of estrogen, the LP, and the MP. Given that estrogen is associated with higher DA turnover rates, if estrogen affects the DA functioning in driving inhibitory input control, we would expect more pronounced IOR in the FP (i.e., with the highest level of estrogen) than in the LP and MP.

The second goal of the study was to investigate whether women differ from men in inhibitory input control performance. As shown by Colzato, Hertsig, et al. (2010), it is possible that gender differences are restricted to a particular phase of the women's menstrual cycle, so we have conducted separate comparisons for the three phases of the cycle. Because estrogen modulates striatal DA activity in females, but not in males (McDermott et al., 1994), if estrogen affects the DA functioning in driving inhibitory control then we would expect gender differences to be most pronounced for women in their FP (which is associated with an elevated level of estrogen).