Estrogenic regulation of memory consolidation: A look beyond the hippocampus, ovaries, and females
Introduction
Sex differences are currently a hot topic in biomedical research, thanks to recent policies enacted by funding agencies, including the National Institutes of Health, that require consideration of sex as a biological variable in all proposals [1], [2]. The purpose of these policies is clear: they seek to reverse the perennial lack of females in both basic and clinical research to better understand how potential sex differences in brain and behavior may influence human health and response to therapeutic drugs. The relative merits of such policies have been debated of late on both practical and conceptual grounds. On a practical level, examining sex as a biological variable poses certain challenges [3]. Additional time and money are required to include both sexes in research studies, which strains already slim grant budgets in a time of unprecedented funding competition. Forcing researchers without backgrounds in endocrinology and genetics to address sex differences in their studies also raises potential problems for study design and interpretation. Conceptually, it has been argued that considering sex as a biological variable does not make sense for all lines of investigation, in part because this ignores social, cultural, and psychological (i.e., gender) influences on human health [3]. It has further been countered that sex is not a simple binary variable, but rather a complex phenotype involving genetic and hormonal components that are influenced by factors such as age and environment [3]. Despite these arguments, however, ignoring possible sex differences in form and function is simply no longer acceptable, given the potential adverse consequences of doing so. For example, women metabolize the drug zolpidem, the active ingredient in the sleeping pill Ambien, more slowly than men, leading to impairments in tasks such as driving the morning after women take this medication [4], [5]. As such, the Food and Drug Administration reduced the recommended Ambien dosage for women by half in 2013 [5], spurring calls for increased attention to sex-specific responses to therapeutic drugs. Compelling arguments in favor of both the inclusion of females and direct examination of sex differences in biomedical research have been provided by numerous investigators [6], [7], [8], [9], which have served to increase awareness among researchers. In addition, workshops such as that held at American University in April 2017 (“Sex Differences: From Neuroscience to the Clinic and Beyond”), and meetings sponsored by the Organization for the Study of Sex Differences, the Society for Women's Health Research, and the Society for Behavioral Neuroendocrinology, have been important venues for bringing researchers together from a variety of perspectives to discuss sex differences in multiple functional systems. Nevertheless, sex differences have yet to truly penetrate the consciousness of most researchers, precipitating the need for special issues such as this and others (e.g., [10], [11]).
Sex differences in all aspects of human health are interesting and important. However, the sex difference that most piques our laboratory's interest pertains to the relative risk of Alzheimer's disease in men and women. Although age is the single greatest risk factor for Alzheimer's, women are at substantially greater risk of developing Alzheimer's than men, even when accounting for women's longer lifespans [12], [13]. According to recent reports from the Alzheimer's Association, women's estimated lifetime risk of developing Alzheimer's at ages 65, 75, and 85 is approximately twice that of men [14], [15]. One notable aspect of the sex difference in Alzheimer's disease risk is that it appears after menopause. Menopause marks reproductive senescence in women, and is characterized by a loss of menstrual cycling and significant hormonal alterations, including dramatic increases in gonadotropin secretion and decreases in circulating estrogen and progestin levels, that result from ovarian and hypothalamic aging. In particular, the ovarian estrogens produced by reproductively mature women are important trophic factors for neurons in regions of the brain, such as the hippocampus and prefrontal cortex [16], [17], that mediate cognitive functions like learning and memory. As such, the loss of estrogens during menopause is thought to render these neurons more vulnerable to age-related decline and neurodegenerative diseases such as Alzheimer's. Indeed, elderly women with low endogenous estrogen levels experience greater risks of cognitive decline than those with higher estrogen levels [18], [19], [20], [21].
If estrogen loss in post-menopausal women contributes to memory deficits, then estrogen replacement could potentially mitigate this loss. However, the promise of estrogen therapy for reducing and/or reversing memory loss in older women has not borne fruit. For example, treatment with conjugated equine estrogens, with or without an accompanying synthetic progestin, does not maintain or improve cognitive function in post-menopausal women over age 65, and in fact, can be detrimental to cognitive function in this population [22], [23]. Moreover, hormone replacement carries small, but statistically significant, risks of breast cancer, heart disease, and stroke [24]. Despite benefits to colorectal and bone health [24], estrogen therapy is no longer generally recommended for women over age 65, including for purposes of maintaining cognition. Estrogen therapy, particularly that involving the potent estrogen 17β-estradiol (E2), appears to have no adverse effects on cognitive function in perimenopausal women in their 50's [25], [26], [27], suggesting altered responsiveness to estrogen therapy from middle- to old-age. Somewhat similar effects have been reported in rat models of aging, in which long-term ovariectomy lasting throughout middle age diminishes the beneficial effects of E2 on hippocampal synaptic plasticity and hippocampal-dependent memory [28], [29], [30]. As such, determining how estrogens affect brain function and why the brain's responsiveness to estrogens decreases with advanced age are important to understand why women are at greater risk of developing Alzheimer's than men.
To address these questions as they relate to learning and memory, many researchers, including ourselves, have focused on females. This approach makes sense from the perspective of understanding how estrogens work to regulate memory function in the sex most affected by Alzheimer's. Historically, our own rationale has been to first understand how estrogens influence memory in female rodents before examining this issue in males. Other labs have taken the opposite approach by examining hippocampal function in male rodents, and the resulting studies often report similar effects to those in females [31], [32]. In addition, high levels of E2 can be found endogenously in the hippocampus of both male and female rats [33], [34]. Thus, numerous pieces of evidence suggest that E2 not only affects the functioning of cognitive brain regions in males, but also that its effects are generally similar in both sexes. However, recent reports suggest that similar functional effects of E2 in both sexes (e.g., on memory and synaptic plasticity) may be driven by different molecular mechanisms in males and females [35], which could have critical implications for the design of therapeutic interventions for men and women. As discussed below, future work must examine potential sex differences at the cellular and molecular level to determine if distinct sex-specific mechanisms underlie phenotypic differences.
In this vein, our laboratory has spent the past decade identifying molecular mechanisms in the hippocampus through which E2 enhances hippocampal memory consolidation in female mice (for recent reviews, see [36], [37]). We have primarily examined these issues in young adult females to better understand how E2 influences memory formation in an optimally functioning system. We believe that these data from young subjects can then provide the foundation for determining how E2, and its loss at reproductive senescence, may influence age-related memory decline and dementia in aging subjects. Therefore, most of this review discusses data collected in young females, but data from aging females is discussed at appropriate points where available. More recently, we have begun to examine these the molecular mechanisms through which E2 may regulate memory consolidation in young males as well, and have found potentially interesting sex differences that support the notion that E2 may exploit different molecular means in males and females to achieve similar behavioral ends. As such, the bulk of this review will focus on our data from females, with particular emphasis on new directions that illustrate the importance of hippocampally-synthesized E2 and interactions between the hippocampus and prefrontal cortex. The remainder of the review will discuss work from our lab and others describing effects of E2 on hippocampal function in males, and putative roles for sex differences in underlying mechanism. We then conclude with recommendations for future research.
Section snippets
Background
Our laboratory's work on this subject has focused on the hippocampus because this brain region regulates the formation of numerous types of memory (e.g., spatial, contextual, object recognition) that are affected by aging and Alzheimer's disease [38], [39], [40], [41], [42]. The hippocampus is also exquisitely sensitive to levels of E2. For example, acute E2 treatment in young female rodents increases dendritic spine density in the CA1 region, neurogenesis in the dentate gyrus, and various
Interactions between the hippocampus and medial prefrontal cortex
Research on estrogens and cognition has been dominated by a primary focus on the hippocampus. However, accumulating evidence suggests that E2 can influence various forms of learning and memory in other brain regions, such as the prefrontal cortex, striatum, amygdala, and perirhinal cortex (e.g., [106], [107], [108]). As mentioned above, systemic injections of E2 increase dendritic spine density not only in the dorsal hippocampus, but also in the medial prefrontal cortex [54], [55]. Both brain
Role of hippocampally-synthesized estradiol
Estrogens are synthesized in multiple tissues through the body. The primary sources of estrogens in females are the ovaries, however, the brain also makes estrogens. The hippocampus contains all of the enzymes necessary to synthesize estrogens [117], and indeed, the concentration of E2 in the hippocampus of male and female rats is higher than in plasma [33], [34]. Although ovariectomy significantly decreases hippocampal E2 levels, measureable levels remain present, and indeed, levels in
Sex differences in the molecular mechanisms regulating estradiol's effects on memory consolidation
Thus far, this review has focused exclusively on molecular mechanisms underlying estrogenic regulation of memory formation in females because the vast majority of work on this subject has been conducted in this sex. However, E2 also regulates hippocampal function in males, and emerging data suggest interesting sex differences in the molecular mechanisms through which E2 mediates memory consolidation in males and females. In both young males and females, gonadectomy has been reported to impair
Conclusions
This review has highlighted the molecular mechanisms thus far known to be essential for E2 to enhance memory consolidation in females, and presented the intriguing possibility that these mechanisms may be different in males. Much of the literature on sex differences to date has focused on whether a sex difference is present in measureable outcomes, such as memory function, synaptic plasticity, or neuronal morphology. The advent of the new “sex as a biological variable” policy in the United
Conflicts of Interest
None
Acknowledgements
Karyn Frick would like to thank Drs. Colin Saldanha and Terry Davidson, Ms. Bernadette Storey-Laubach, and the Center for Behavioral Neuroscience at American University for organizing the sex differences workshop upon which this review is based and for the invitation to speak at this workshop. During the writing of this manuscript, the authors were supported by National Institutes of Health (R01MH107886), Alzheimer's Association (SAGA-17-419092), and University of Wisconsin-Milwaukee Research
References (141)
- et al.
Endogenous sex hormone levels and risk of cognitive decline in an older biracial cohort
Neurobiol. Aging
(2007) - et al.
Cognitive decline in women in relation to non-protein-bound oestradiol concentrations
Lancet
(2000) - et al.
Endogenous estradiol and testosterone levels are associated with cognitive performance in older women and men
Horm. Behav.
(2002) - et al.
Estradiol replacement extends the window of opportunity for hippocampal function
Neurobiol. Aging
(2014) - et al.
Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: involvement of kinase networks
Brain Res.
(2015) Molecular mechanisms underlying the memory-enhancing effects of estradiol
Horm. Behav.
(2015)- et al.
Assessing rodent hippocampal involvement in the novel object recognition task. A review
Behav. Brain Res.
(2015) - et al.
Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR-dependent mechanism
Neuron
(2012) - et al.
Calcineurin as a potential contributor in estradiol regulation of hippocampal synaptic function
Neuroscience
(2002) - et al.
Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats
Neuroscience
(2008)
The nuclear receptor superfamily: the second decade
Cell
A new approach to understanding the molecular mechanisms through which estrogens affect cognition
Biochim. Biophys. Acta Gen. Subj.
Estradiol and cognitive function: past, present and future
Horm. Behav.
Regulation of object recognition and object placement by ovarian sex steroid hormones
Behav. Brain Res.
Recognition memory tasks in neuroendocrine research
Behav. Brain Res.
Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice
Horm. Behav.
Epigenetic regulation of estrogen-dependent memory
Front. Neuroendocrinol.
Levels of trkA and BDNF mRNA, but not NGF mRNA, fluctuate across the estrous cycle and increase in response to acute hormone replacement
Brain Res.
mTOR signaling: at the crossroads of plasticity, memory and disease
Trends Neurosci.
The neurology of mTOR
Neuron
Rapid effects of the G-protein coupled oestrogen receptor (GPER) on learning and dorsal hippocampus dendritic spines in female mice
Physiol. Behav.
A role for the spine apparatus in LTP and spatial learning
Brain Res.
Dendritic spines: morphological building blocks of memory
Neurobiol. Learn. Mem.
Studying both sexes: a guiding principle for biomedicine
FASEB J.
Evaluating sex as a biological variable in preclinical research: the devil in the details
Biol. Sex Differ.
Sex in context: limitations of animal studies for addressing human sex/gender neurobehavioral health disparities
J. Neurosci.
Gender differences in highway driving performance after administration of sleep medication: a review of the literature
Traffic Inj. Prev.
Considering sex as a biological variable will be valuable for neuroscience research
J. Neurosci.
Sex differences in the brain: the not so inconvenient truth
J. Neurosci.
Sex/gender influences on the nervous system: basic steps toward clinical progress
J. Neurosci. Res.
Why sex matters for neuroscience
Nat. Rev. Neurosci.
Multifaceted origins of sex differences in the brain
Philos. Trans. B R. Soc.
An issue whose time has come
J. Neurosci. Res.
Hormone replacement therapy and incidence of Alzheimer disease in older women
JAMA
Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses
Neurology
2012 Alzheimer's disease facts and figures
Alzheimers Dement.
2015 Alzheimer's disease facts and figures
Alzheimers Dement.
Oestrogen signalling and neuroprotection in cerebral ischaemia
J. Neuroendocrinol.
Stroke neuroprotection: oestrogen and insulin-like growth factor-1 interactions and the role of microglia
J. Neuroendocrinol.
Impact of sex and menopausal status on episodic memory circuitry in early midlife
J. Neurosci.
Conjugated equine estrogens and global cognitive function in postmenopausal women: women's health initiative memory study
JAMA
Effect of estrogen plus progestin on global cognitive function in postmenopausal women. The women's health initiative memory study: a randomized controlled trial
JAMA
Risks and benefits of estrogen plus progestin in healthy postmenopausal women
JAMA
Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS-Cognitive and Affect Study
PLoS Med.
Cognitive effects of estradiol after menopause: a randomized trial of the timing hypothesis
Neurology
Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years
JAMA Int. Med.
Estradiol replacement enhances working memory in milddle-aged rats when initiated immediately after ovariectomy but not after a long-term period of ovarian hormone deprivation
Endocrinology
Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology
Proc. Natl. Acad. Sci. U. S. A.
Posttraining intrahippocampal estradiol injections enhance spatial memory in male rats: interaction with cholinergic systems
Behav. Neurosci.
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