Elsevier

Physiology & Behavior

Volume 187, 1 April 2018, Pages 57-66
Physiology & Behavior

Estrogenic regulation of memory consolidation: A look beyond the hippocampus, ovaries, and females

https://doi.org/10.1016/j.physbeh.2017.07.028Get rights and content

Highlights

  • Estradiol (E2) rapidly enhances hippocampal memory consolidation in both sexes.

  • Many underlying molecular mechanisms are known in females, but not males.

  • Putative sex differences in these molecular mechanisms are described.

  • Role for the prefrontal cortex in effects of hippocampal E2 infusion is discussed.

  • Involvement of de novo hippocampal E2 synthesis in both sexes is considered.

Abstract

The potent estrogen 17β-estradiol (E2) has long been known to regulate the hippocampus and hippocampal-dependent memories in females, and research from the past decade has begun to shed light on the molecular mechanisms through which E2 mediates memory formation in females. Although E2 can also regulate hippocampal function in males, relatively little is known about how E2 influences memory formation in males, or whether sex differences in underlying mechanisms exist. This review, based on a talk given in April 2017 at the American University symposium entitled, “Sex Differences: From Neuroscience to the Clinic and Beyond”, first provides an overview of the molecular mechanisms in the dorsal hippocampus through which E2 enhances memory consolidation in ovariectomized female mice. Next, newer research is described demonstrating key roles for the prefrontal cortex and de novo hippocampal E2 synthesis to the memory-enhancing effects of E2 in females. The review then discusses the effects of de novo and exogenous E2 on hippocampal memory consolidation in both sexes, and putative sex differences in the underlying molecular mechanisms through which E2 enhances memory formation. The review concludes by discussing the importance and implications of sex differences in the molecular mechanisms underlying E2-induced memory consolidation for human health.

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)

  • D.J. Mangelsdorf et al.

    The nuclear receptor superfamily: the second decade

    Cell

    (1995)
  • K.M. Frick et al.

    A new approach to understanding the molecular mechanisms through which estrogens affect cognition

    Biochim. Biophys. Acta Gen. Subj.

    (2010)
  • V.N. Luine

    Estradiol and cognitive function: past, present and future

    Horm. Behav.

    (2014)
  • J.J. Tuscher et al.

    Regulation of object recognition and object placement by ovarian sex steroid hormones

    Behav. Brain Res.

    (2015)
  • V. Luine

    Recognition memory tasks in neuroendocrine research

    Behav. Brain Res.

    (2015)
  • J.J. Tuscher et al.

    Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice

    Horm. Behav.

    (2016)
  • A.M. Fortress et al.

    Epigenetic regulation of estrogen-dependent memory

    Front. Neuroendocrinol.

    (2014)
  • R.B. Gibbs

    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.

    (1998)
  • C.A. Hoeffer et al.

    mTOR signaling: at the crossroads of plasticity, memory and disease

    Trends Neurosci.

    (2010)
  • J.O. Lipton et al.

    The neurology of mTOR

    Neuron

    (2014)
  • C. Gabor et al.

    Rapid effects of the G-protein coupled oestrogen receptor (GPER) on learning and dorsal hippocampus dendritic spines in female mice

    Physiol. Behav.

    (2015)
  • P. Jedlicka et al.

    A role for the spine apparatus in LTP and spatial learning

    Brain Res.

    (2008)
  • M. Segal

    Dendritic spines: morphological building blocks of memory

    Neurobiol. Learn. Mem.

    (2017)
  • J.A. Clayton

    Studying both sexes: a guiding principle for biomedicine

    FASEB J.

    (2016)
  • C. Tannenbaum et al.

    Evaluating sex as a biological variable in preclinical research: the devil in the details

    Biol. Sex Differ.

    (2016)
  • L. Eliot et al.

    Sex in context: limitations of animal studies for addressing human sex/gender neurobehavioral health disparities

    J. Neurosci.

    (2016)
  • J.C. Verster et al.

    Gender differences in highway driving performance after administration of sleep medication: a review of the literature

    Traffic Inj. Prev.

    (2012)
  • Food and Drug Administration FDA Drug Safety Communication: risk of next-morning impairment after use of insomnia...
  • R.M. Shansky et al.

    Considering sex as a biological variable will be valuable for neuroscience research

    J. Neurosci.

    (2016)
  • M.M. McCarthy et al.

    Sex differences in the brain: the not so inconvenient truth

    J. Neurosci.

    (2012)
  • C.E. Brooks et al.

    Sex/gender influences on the nervous system: basic steps toward clinical progress

    J. Neurosci. Res.

    (2017)
  • L. Cahill

    Why sex matters for neuroscience

    Nat. Rev. Neurosci.

    (2006)
  • M.M. McCarthy

    Multifaceted origins of sex differences in the brain

    Philos. Trans. B R. Soc.

    (2016)
  • L. Cahill

    An issue whose time has come

    J. Neurosci. Res.

    (2017)
  • P.P. Zandi et al.

    Hormone replacement therapy and incidence of Alzheimer disease in older women

    JAMA

    (2002)
  • L.J. Launer et al.

    Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses

    Neurology

    (1999)
  • Alzheimer's Association

    2012 Alzheimer's disease facts and figures

    Alzheimers Dement.

    (2012)
  • Alzheimer's Association

    2015 Alzheimer's disease facts and figures

    Alzheimers Dement.

    (2015)
  • D. Brann et al.

    Oestrogen signalling and neuroprotection in cerebral ischaemia

    J. Neuroendocrinol.

    (2012)
  • F. Sohrabji et al.

    Stroke neuroprotection: oestrogen and insulin-like growth factor-1 interactions and the role of microglia

    J. Neuroendocrinol.

    (2012)
  • E.G. Jacobs et al.

    Impact of sex and menopausal status on episodic memory circuitry in early midlife

    J. Neurosci.

    (2016)
  • M.A. Espeland et al.

    Conjugated equine estrogens and global cognitive function in postmenopausal women: women's health initiative memory study

    JAMA

    (2004)
  • S.R. Rapp et al.

    Effect of estrogen plus progestin on global cognitive function in postmenopausal women. The women's health initiative memory study: a randomized controlled trial

    JAMA

    (2003)
  • J.E. Rossouw et al.

    Risks and benefits of estrogen plus progestin in healthy postmenopausal women

    JAMA

    (2002)
  • C.E. Gleason et al.

    Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS-Cognitive and Affect Study

    PLoS Med.

    (2015)
  • V.W. Henderson et al.

    Cognitive effects of estradiol after menopause: a randomized trial of the timing hypothesis

    Neurology

    (2016)
  • M.A. Espeland et al.

    Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years

    JAMA Int. Med.

    (2013)
  • J.M. Daniel et al.

    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

    (2003)
  • C.C. Smith et al.

    Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • M.G. Packard et al.

    Posttraining intrahippocampal estradiol injections enhance spatial memory in male rats: interaction with cholinergic systems

    Behav. Neurosci.

    (1996)
  • Cited by (45)

    • Estrogens and phytoestrogens in body functions

      2022, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      In women choosing estrogen therapy after menopause, treatment should be tailored to identify the most suitable type, dose and formulation and be weighed against possible increased health risks associated with long-term use (NAMS, 2018). While low-dose estradiol continues to be tested (Kantarci et al., 2016), promising alternative routes to protect women's brain health include simulating the effects of E2 on downstream molecular targets (Frick et al., 2018), new generation selective estrogen receptor modulators (Chaki, 2006) or emerging estrogen prodrugs (Prokai et al., 2015) with the potential to act selectively in the central nervous system without having unwanted proliferative effects in the breast or endometrium (Hampson, 2018). Sex differences have been observed repeatedly in chronic pain in both humans and animals, with females showing a higher incidence (Berkley, 1997; Aloisi, 2003; Riley and Gilbert, 2001; Pieretti et al., 2016; Monroe et al., 2015).

    • Three's Company: Neuroimmune activation, sex, and memory at the tripartite synapse

      2021, Brain, Behavior, and Immunity - Health
      Citation Excerpt :

      As such, sex adds yet another layer of complexity to the function of neurons, astrocytes, and microglia at the tripartite synapse. Estrogens modulate neuronal activity, long-term synaptic plasticity mechanisms, and learning and memory in both males and females (Frick et al., 2018; Hyer et al., 2018; Woolley, 2007). Despite that females have an additional source of ovarian estrogen, the local production of estrogen by aromatase in both sexes plays a more significant role in these mechanisms of neuronal modulation (Lu et al., 2019; Luine et al., 2018; Wang et al., 2018).

    • Coming of age in the frontal cortex: The role of puberty in cortical maturation

      2021, Seminars in Cell and Developmental Biology
      Citation Excerpt :

      In males, circulating androgens also have the potential to activate ERß via aromatization of testosterone to estradiol or the metabolism of dihydrotestosterone to 3-beta-diol, an estrogen receptor agonist [89]. While ERß is classically characterized as a nuclear receptor that mediates transcriptional effects, ERß and the closely related ERα also localize to extra-nuclear sites (e.g. axons, dendrites) and have been shown to exert rapid, non-classical effects on the order of minutes to hours [90]. Recent data in adult female rats demonstrate that PV+ neurons in somatosensory cortex are directly modulated by ovarian hormones.

    View all citing articles on Scopus
    View full text