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The menstrual cycle is a useful means of examining how a particular behavior like sleep or memory varies in relation to reproductive hormones. However, studies have mostly considered only two time points in the menstrual cycle, which limits the ability of isolating effects to a particular hormone (e.g. in the luteal phase, both E2 and progesterone are high). Further, studies have focused mainly on sex steroids, yet, the gonadotropins (FSH and LH) potentially also influence behaviors like sleep and cognition.
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While there is a pronounced increase in sleep spindles in the luteal phase, the mechanism for this increase is unclear, and it remains to be proven whether these spindles share the same circuitry and functionality as sleep spindles outside of the luteal phase.
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Sex steroids may have multiple and sometimes opposing influences on different aspects of memory. It remains to be determined if the positive effects can be selectively harnessed to benefit women.
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Effects of exogenous steroids (in the form of OCs or MHT) on memory are varied and sometimes negative. Only one study investigated sleep dependent memory consolidation, and found no effect of OCs, although encoding was higher in the experimental group than naturally-cycling (control) women, raising the question of whether there is a ceiling effect in women taking OCs. There is also a lack of studies about the effects of OCs on sleep spindles. Overall, studies about OCs are hampered by the heterogeneous mix of compounds and doses used and the potential effects of simultaneous suppression of endogenous sex steroids.
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So far only three studies have examined the effect of sex hormones on sleep-dependent memory consolidation, all of which have been in naps, not nighttime sleep, and probed limited phases of the menstrual cycle. A more systematic analysis tracking fluctuations in sex hormones across the phases of the menstrual cycle and the impact on nighttime sleep is warranted.
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Recent approaches have been successful in enhancing the process of memory reactivation during sleep, including targeted memory reactivation (TMR), which matches a sensory stimulus (e.g., odor or sound cue) with target information (e.g., pairs of words, objects, motor sequences), and then re-presents the cue alone during sleep, and closed-loop auditory stimulation (e.g. 50-ms bursts of pink noise) during the SO down-to-up-state. These methods i) increase SO power; ii) boost phase-locked spindle activity during the SO down-to-up-state; iii) enhance declarative memory performance. However, study outcomes are conflicting, the neural mechanisms underlying these interventions are not yet fully elucidated, potential side effects are still unknown and most importantly, minor variations in experimental design may lead to completely different outcomes (e.g., enhanced, decreased, or unaltered memories).
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Studies have not yet considered whether boosting memory function during sleep should be tailored differently for men and women. Furthermore, it may be more critical in women to initiate memory consolidation ‘protection’/boosting methods at an earlier life stage than men - when the hormone circuitry in the brain is still responsive, due to the critical loss of hormone protection for memory after menopause.
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Limited research in small samples indicates that sleep-dependent memory consolidation varies in association with the hormonal changes of the menstrual cycle in young women, potentially mediated via modulation of electrophysiological events. Further work is needed to confirm these findings. Also, it is unknown whether this menstrual-related variation persists in older, reproductive-age women and whether the decline in E2 (and/or rise in FSH) across the menopausal transition is associated with altered sleep-dependent memory consolidation.
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Further work is needed to investigate potential sex-age and reproductive stage-age interaction effects in sleep-dependent memory consolidation.
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Translational work is needed to determine if sleep-dependent memory consolidation can be improved using sleep interventions at hormone sensitiveftime points (e.g. luteal phase; menopausal transition).
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Work is needed to determine if there are specific vulnerable groups of women in the menopausal transition who should be targeted for intervention (e.g. women with severe hot flashes and insomnia).
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Not only is the menopausal transition a critical time period in reproductive aging in women when sleep and aspects of cognition may be perturbed but it also offers a major advantage in the study of the roles played by hormones in memory consolidation, since it becomes possible to disassociate factors known to be implicated in sleep-dependent memory consolidation: all women experience a change in the hormone environment as they approach menopause but the rate of change in FSH and E2 across the transition and into post-menopause varies between women. Further, there is a mix of ovulatory and non-ovulatory cycles allowing the investigation of the functional importance of monthly cycling in sleep spindles. There is also variability in hormones within ovulatory cycles (in the early menopausal transition), such that luteal phase progesterone levels vary. Thus, differences in rate of change in the reproductive hormone environment allow the opportunity to use longitudinal and cross-sectional designs to study changes and differences in memory function, including sleep-dependent memory consolidation, in relation to sex steroid levels as well as menopausal symptoms like hot flashes.
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More research is needed in basic models to investigate effects of more gradual changes in ovarian hormones, such as occurs across the menopausal transition, on brain function including sleep and cognition, as opposed to ovariectomy, which results in an abrupt loss of hormones. Recently, a rodent model of transitional menopause has been developed (Koebele and Bimonte-Nelson 2016) with first results showing interesting interactions between age and menopausal transition (Koebele et al. 2017), which may be applied to inform future studies in women.
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Understanding the potential interactive mediating role of sex steroids on clearance of the glymphatic system during sleep may provide an overarching mechanism of age-related cognitive decline, as well as an understanding of the increased risk for women to develop Alzheimer’s disease.
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Future longitudinal studies are required to firmly establish the link between E2 and brain volume and whether any increases in volume are associated with preserved memory ability during menopause and later in life. Furthermore, such studies should ascertain the optimal treatment methods (e.g. cyclic vs. continuous schedule, E2 vs combination-MHT, when to administer in relation to menopause onset) in order to fully utilize the potentially neuroprotective effects of E2 on hippocampal integrity.
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