Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

C. Neill Epperson

Abstract

Many healthy women with no history of cognitive dysfunction experience subjective executive difficulties during menopause. Indicators of risk for executive function difficulties at menopause are lacking, as is a mechanistic understanding of how loss of estradiol unmasks this vulnerability. We hypothesized that adverse childhood experiences (ACE) increase the risk of executive dysfunction during menopause via alterations in monoaminergic neurotransmission. To test this hypothesis, we evaluated the effect of ACE on subjective and objective measures of executive function as well as executive activation, functional connectivity, and neurochemistry. We used tryptophan depletion (TD) and lisdexamfetamine (LDX) to probe serotonergic and catecholaminergic function, respectively. High ACE women endorsed greater symptoms of executive dysfunction and performed worse on tasks probing sustained attention and working memory. These negative ACE effects were partially mediated by anxiety and depressive symptoms. ACE moderated the impact of TD on DLPFC activation in hypogonadal women such that TD increased activation in high ACE participants but decreased activation in low ACE participants. Importantly, treatment with estradiol attenuated the effects of both ACE and TD. ACE similarly moderated the impact of TD on within-network connectivity. While ACE was associated with lower within-network connectivity regardless of depletion condition, TD increased connectivity in the high ACE group but had no effect on connectivity in the low ACE group. ACE also moderated response to LDX. In the high ACE group, LDX (vs placebo) increased activation in the insula and reduced symptoms related to difficulty with organization and activation for work. In contrast, response to LDX was not significantly different from placebo in the low ACE group.

These results have several clinical and mechanistic implications. First, they highlight that addressing concurrent mood changes is a critical step in treating menopause-induced executive difficulties. Second, this work suggests that early life adversity has latent impacts on serotonergic circuits underlying executive function that are unmasked by loss of estradiol during menopause. Third, they indicate that early adversity may have lasting effects on catecholaminergic neurotransmission and may moderate response to stimulant medications. Together, they emphasize the importance of considering ACE when treating executive difficulties with pharmacologic agents during menopause.

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