Impact of Tryptophan Depletion on Executive System Function during Menopause is Moderated by Childhood Adversity

Abstract

Many healthy women with no history of cognitive dysfunction experience subjective executive difficulties during menopause. Preclinical literature suggests latent effects of early life adversity on serotonin function may play a role in this phenomenon. However, evidence in human participants regarding the mechanisms by which loss of estradiol contributes to this vulnerability is lacking. Here we examined the impact of tryptophan depletion (TD) and adverse childhood experiences (ACE) on brain activation during a working memory task in menopausal women. We hypothesized that an interactive effect between ACE and TD would be observed when women were hypogonadal, and that treatment with estradiol would attenuate this effect. Thirty-three women underwent functional imaging at four time points (123 total scans) in this double-blind, placebo controlled, cross-over study. The effects of TD, ACE, and TD × ACE were evaluated using a voxel-wise, mixed-effects, 2 × 2 ANOVA. In the absence of exogenous estradiol, a TD by ACE interaction was observed on BOLD signal in the right DLPFC such that TD increased activation in high ACE subjects but decreased activation in low ACE subjects. While a similar interaction was observed with placebo treatment, treatment with estradiol attenuated the effects of ACE and TD such that no between or within group differences were observed. Together, these results suggest that early life adversity may have a lasting impact on serotonergic circuits underlying executive function that are unmasked by loss of estradiol during menopause.

Impact of early life adversity and tryptophan depletion on functional connectivity in menopausal women: A double-blind, placebo-controlled crossover study

“…While we hypothesized that TD would selectively impair connectivity in the high ACE group, we found that TD instead selectively improved connectivity in the high ACE group. Though contrary to our hypothesis, this result is consistent with previous findings demonstrating that tryptophan depletion attenuates ACE effects on dorsolateral prefrontal cortex activation during the n-back in menopausal women (Shanmugan et al, 2017a). That TD attenuated the negative effects of ACE on connectivity suggests that serotonergic differences may be contributing to baseline differences in functional connectivity between ACE groups.…”

“…That TD attenuated the negative effects of ACE on connectivity suggests that serotonergic differences may be contributing to baseline differences in functional connectivity between ACE groups. Non-human primate (Shively et al, 2003) and human participant (Shanmugan et al, 2017a) studies have shown that estradiol attenuates the effects of early adversity on serotonin (Shively et al, 2003; Shanmugan et al, 2017a) and DLPFC function (Shanmugan et al, 2017a), suggesting estradiol may similarly attenuate the impact of ACE on connectivity observed in this study. Importantly, many women have contraindications to hormone therapy and results of this study suggest future research aimed at alleviating executive difficulties during menopause should examine serotonergic targets, particularly in the context of significant childhood adversity.…”

“…All participants provided written informed consent. The sample considered here constitutes a superset of participants previously included in a report focusing on the impact of early adversity on prefrontal cortex activation during working memory (Shanmugan et al, 2017a). …”

“…In healthy adults, early trauma has been associated with executive system hyperactivation during working memory (Philip et al, 2016). In healthy menopausal women, estradiol treatment attenuates this ACE-associated executive hyperactivation (Shanmugan et al, 2017a), suggesting the effects of ACE may be magnified when women are hypogonadal.…”

“…In non-human primates, both ovariectomy and social subordination stress are associated with reductions in tryptophan hydroxylase type 2 (TPH2) gene expression (Shively et al, 2003) and 5-HT1A binding potential (Michopoulos et al, 2014). Similarly, lowering central serotonin levels differentially impacts prefrontal cortex activation in menopausal women with high and low levels of early life adversity (Shanmugan et al, 2017a). However, whether ACE and sertononin exhibit a similar interactive effect on functional networks is not known.…”