BBA - General Subjects (v.1800, #10)

Special issue on estrogen actions in the brain by Gemma Casadesus; Jan-Åke Gustafsson (1029).

Modulation of synaptic plasticity by brain estrogen in the hippocampus by Hideo Mukai; Tetsuya Kimoto; Yasushi Hojo; Suguru Kawato; Gen Murakami; Shimpei Higo; Yusuke Hatanaka; Mari Ogiue-Ikeda (1030-1044).
The hippocampus is a center for learning and memory as well as a target of Alzheimer's disease in aged humans. Synaptic modulation by estrogen is essential to understand the molecular mechanisms of estrogen replacement therapy. Because the local synthesis of estrogen occurs in the hippocampus of both sexes, in addition to the estrogen supply from the gonads, its functions are attracting much attention.Hippocampal estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly. Slow actions of 17β-estradiol (17β-E2) occur via classical nuclear receptors (ERα or ERβ), while rapid E2 actions occur via synapse-localized ERα or ERβ. Elevation or decrease of the E2 concentration changes rapidly the density and morphology of spines in CA1–CA3 neurons. ERα, but not ERβ, drives this enhancement/suppression of spinogenesis. Kinase networks are involved downstream of ERα. The long-term depression but not the long-term potentiation is modulated rapidly by changes of E2 level.Determination of the E2 concentration in the hippocampus is enabled by mass-spectrometry in combination with derivatization methods. The E2 level in the hippocampus is as high as approx. 8 nM for the male and 0.5–2 nM for the female, which is much higher than that in circulation. Therefore, hippocampus-derived E2 plays a major role in modulation of synaptic plasticity.Many hippocampal slice experiments measure the restorative effects of E2 by supplementation of E2 to E2-depleted slices. Accordingly, isolated slice experiments can be used as in vitro models of in vivo estrogen replacement therapy for ovariectomized female animals with depleted circulating estrogen.
Keywords: Estradiol; Estrogen; Androgen; Neurosteroid; Synaptic plasticity; Estrogen receptor; Hippocampus; Spine; LTD; LTP;

A new approach to understanding the molecular mechanisms through which estrogens affect cognition by Karyn M. Frick; Stephanie M. Fernandez; Lauren L. Harburger (1045-1055).
Traditional approaches to the study of hormones and cognition have been primarily observational or correlational in nature. Because this work does not permit causal relationships to be identified, very little is known about the specific molecules and cellular events through which hormones affect cognitive function. In this review, we propose a new approach to study hormones and memory, where the systematic blocking of cellular events can reveal which such events are necessary for hormones to influence memory consolidation. The discussion will focus on the modulation of the hippocampus and hippocampal memory by estrogens, given the extensive literature on this subject, and will illustrate how the application of this approach is beginning to reveal important new information about the molecular mechanisms through which estrogens modulate memory consolidation. The clinical relevance of this work will also be discussed.
Keywords: Estradiol; Hippocampus; Memory; Object recognition; Cell signaling; Gene expression; ERK; Estrogen receptor; Selective estrogen receptor modulator; ER knockout; Progesterone;

Estrogens modulate the morphology and function of the hippocampus. Recent studies have focused on the effects of different types of estrogens on neuroplasticity in the hippocampus and cognition. There are three main forms of estrogens found in mammals: estradiol, estrone, and estriol. The vast majority of studies have used estradiol to investigate the effects of estrogens on the brain.This review focuses on the effects of different estrogens on adult hippocampal neurogenesis, synaptic plasticity in the hippocampus, and cognition in female rats.Different forms of estrogens modulate neuroplasticity and cognition in complex and intriguing ways. Specifically, estrogens upregulate adult hippocampal neurogenesis (via cell proliferation) and synaptic protein levels in the hippocampus in a time- and dose-dependent manner. Low levels of estradiol facilitate spatial working memory and contextual fear conditioning while high levels of estradiol impair spatial working, spatial reference memory and contextual fear conditioning. In addition, estrone impairs contextual fear conditioning.Advances in our knowledge of how estrogens exert their effects on the brain may ultimately lead to refinements in targeted therapies for cognitive impairments at all stages of life. However caution should be taken in interpreting current research and in conducting future studies as estrogens likely work differently in males than in females.
Keywords: 17β-estradiol; 17α-estradiol; Estrone; Hippocampus-dependent learning and memory; Hippocampal neurogenesis; Estrogen receptors; Synaptic plasticity; Cognition;

In addition to its primary role in reproduction estrogen impacts brain areas important for cognition, including the hippocampus and prefrontal cortex. It has been hypothesized that decline in estrogen levels in women following menopause is associated with, or can exacerbate, age-related cognitive decline. However, clinical evidence to support a role for estrogen in preventing cognitive decline in women as they age is equivocal. The critical period hypothesis of estrogen effects on cognition, which proposes that estrogen administration has to be initiated within a critical time period following the loss of ovarian function in order for it to exert positive effects on the central nervous system, is offered as one explanation for inconsistencies across studies.This review details results from basic research using rodent models investigating the effects of estrogen on cognition in the aging female. Emphasis is placed on work investigating effects of timing of initiation of estrogen administration on its subsequent efficacy.Results of basic research provide support for the critical period hypothesis. Furthermore, results of work in rodent models suggest mechanisms by which the response to estrogen is altered if treatment is initiated following long-term ovarian hormone deprivation.Understanding if and under what conditions hormone administration following the loss of ovarian function positively affects the brain and behavior could have important implications with regard to female cognitive aging. Results of basic research can contribute to this understanding and provide insight into the complex mechanisms by which estrogen affects cognition.
Keywords: Estrogen; Estradiol; Cognition; Learning and memory; Aging; Menopause;

Menopause is associated with sharp declines in concentrations of circulating estrogens. This change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive aging.Focused review of published results of randomized clinical trials of estrogen-containing hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on cognition across the menopause transition, and observational research on the association of hormone therapy and Alzheimer's disease risk.Clinical trial evidence supports conclusions that estrogen therapy does not improve dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone exposures are less well studied. There is no strong indication of short-term cognitive benefit of hormone use after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after surgical menopause; limited clinical trial data imply short-term benefit of prompt initiation at the time of oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or cognitive aging much later in life is unanswered by available data. Observational results raise the possibility of long-term cognitive benefit, but bias is a concern in interpreting these findings.Estrogen-containing hormone therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term cognitive effects of estrogen exposures closer to the age of menopause.
Keywords: Aging; Alzheimer's disease; Cognition; Dementia; Estrogen; Hormone therapy;

Studies of the mechanisms by which estrogens influence brain function and behavior have advanced from the explication of individual hormone receptors, neural circuitry and individual gene expression. Now, we can report patterns of estrogen receptor subtype contributions to patterns of behavior. Moreover, new work demonstrates important contributions of nuclear receptor coactivator expression in the central nervous system. In this paper, our current state of knowledge is reviewed.
Keywords: Estrogen receptor; Hypothalamus; Preoptic area; Lordosis; Aggression; Progestin receptor; Sexual differentiation; Steroid receptor coactivator-1 (SRC-1);

A plethora of evidence supports a beneficial role of estrogen in the brain. However, while these effects are hypothesized to be driven via the two main forms of estrogen receptors (ERα and ERβ), the mechanism through which these receptors mediate estrogen's effects on cognition and plasticity remain unclear. Estrogen receptors are heterogeneously expressed in many cognition sensitive regions of the brain, have the ability to dimerize and heterodimerize, and are localized to both neurons and glia. In addition, while many of the known actions of estrogen through their receptor are mediated via the classical genomic regulatory mechanism of gene transcription, rapid non-genomic action of estrogens are also gaining relevance. These complex events make the mechanistic understanding of estrogen effects challenging. The development of transgenic estrogen receptor knockout mouse models has provided some much needed insight on the role of these receptors in mediating estrogen effects on cognition and synaptic plasticity. This review provides an overview of estrogen receptors in the brain and an update of knowledge gained from transgenic knockout models on cognition and synaptic plasticity.
Keywords: Estrogen; Cognition; Synaptic plasticity; Estrogen receptor (ERα and ERβ) ER knockout model; CNS;

Diversity of mechanisms involved in aromatase regulation and estrogen action in the brain by Thierry D. Charlier; Charlotte A. Cornil; Gregory F. Ball; Jacques Balthazart (1094-1105).
The mechanisms through which estrogens modulate neuronal physiology, brain morphology, and behavior in recent years have proven to be far more complex than previously thought. For example, a second nuclear estrogen receptor has been identified, a new family of coregulatory proteins regulating steroid-dependent gene transcriptions was discovered and, finally, it has become clear that estrogens have surprisingly rapid effects based on their actions on cell membranes, which in turn result in the modulation of intracellular signaling cascades.This paper presents a selective review of new findings in this area related to work in our laboratories, focusing on the role of estrogens in the activation of male sexual behavior. Two separate topics are considered. We first discuss functions of the steroid receptor coactivator-1 (SRC-1) that has emerged as a key limiting factor for behavioral effects of estradiol. Knocking-down its expression by antisense oligonucleotides drastically inhibits male-typical sexual behaviors. Secondly, we describe rapid regulations of brain estradiol production by calcium-dependent phosphorylations of the aromatase enzyme, themselves under the control of neurotransmitter activity.These rapid changes in estrogen bioavailability have clear behavioral consequences. Increases or decreases in estradiol concentrations respectively obtained by an acute injection of estradiol itself or of an aromatase inhibitor lead within 15–30 min to parallel changes in sexual behavior frequencies.These new controls of estrogen action offer a vast array of possibilities for discrete local controls of estrogen action. They also represent a formidable challenge for neuroendocrinologists trying to obtain an integrated view of brain function in relation to behavior.
Keywords: Aromatase; Non-genomic action of steroids; Steroid receptor coregulator; Preoptic area; Male sexual behavior; Estrogen receptor;

Actions of estrogens on glial cells: Implications for neuroprotection by María-Angeles Arevalo; María Santos-Galindo; María-José Bellini; Iñigo Azcoitia; Luis M. Garcia-Segura (1106-1112).
Glial cells are directly or indirectly affected by estradiol and by different estrogenic compounds, such as selective estrogen receptor modulators. Acting on oligodendrocytes, astrocytes and microglia, estrogens regulate remyelination, edema formation, extracellular glutamate levels and the inflammatory response after brain injury. In addition, estradiol induces the expression and release of growth factors by glial cells that promote neuronal survival. Therefore, glial cells are important players in the neuroprotective and reparative mechanisms of estrogenic compounds.
Keywords: Astroglia; Estradiol; Microglia; Myelin; Oligodendroglia; Selective estrogen receptor modulator;

Mitochondrial mechanisms of estrogen neuroprotection by James W. Simpkins; Kun Don Yi; Shao-Hua Yang; James A. Dykens (1113-1120).
Mitochondria have become a primary focus in our search not only for the mechanism(s) of neuronal death but also for neuroprotective drugs and therapies that can delay or prevent Alzheimer's disease and other chronic neurodegenerative conditions. This is because mitochrondria play a central role in regulating viability and death of neurons, and mitochondrial dysfunction has been shown to contribute to neuronal death seen in neurodegenerative diseases. In this article, we review the evidence for the role of mitochondria in cell death and neurodegeneration and provide evidence that estrogens have multiple effects on mitochondria that enhance or preserve mitochondrial function during pathologic circumstances such as excitotoxicity, oxidative stress, and others. As such, estrogens and novel non-hormonal analogs have come to figure prominently in our efforts to protect neurons against both acute brain injury and chronic neurodegeneration.
Keywords: Estrogen; Estradiol; Non-feminizing estrogens; Mitochondria; Neuroprotection; Estrogen receptor; Alzheimer's disease;

Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence by Jia Yao; Ryan T. Hamilton; Enrique Cadenas; Roberta Diaz Brinton (1121-1126).
We have previously demonstrated that mitochondrial bioenergetic deficits precede Alzheimer's pathology in the female triple transgenic Alzheimer's (3xTgAD) mouse model. Herein, we sought to determine the impact of reproductive senescence on mitochondrial function in the normal non-transgenic (nonTg) and 3xTgAD female mouse model of AD.Both nonTg and 3xTgAD female mice at 3, 6, 9, and 12 months of age were sacrificed and mitochondrial bioenergetic profile as well as oxidative stress markers were analyzed.In both nonTg and 3xTgAD mice, reproductive senescence paralleled a significant decline in PDH, and Complex IV cytochrome c oxidase activity and mitochondrial respiration. During the reproductive senescence transition, both nonTg and 3xTgAD mice exhibited greater individual variability in bioenergetic parameters suggestive of divergent bioenergetic phenotypes. Following transition through reproductive senescence, enzymes required for long-chain fatty acid (HADHA) and ketone body (SCOT) metabolism were significantly increased and variability in cytochrome c oxidase (Complex IV) collapsed to cluster at a ∼ 40% decline in both the nonTg and 3xTgAD brain which was indicative of alternative fuel generation with concomitant decline in ATP generation.These data indicate that reproductive senescence in the normal nonTg female brain parallels the shift to ketogenic/fatty acid substrate phenotype with concomitant decline in mitochondrial function and exacerbation of bioenergetic deficits in the 3xTgAD brain.These findings provide a plausible mechanism for increased life-time risk of AD in postmenopausal women and suggest an optimal window of opportunity to prevent or delay decline in bioenergetics during reproductive senescence.
Keywords: Mitochondria; Bioenergetics; Reproductive senescence; Alzheimer's disease; Estrogen;

Role of estrogen receptors in pro-oxidative and anti-oxidative actions of estrogens: A perspective by Sukhdeep Kumar; Kusum Lata; Srirupa Mukhopadhyay; Tapan K. Mukherjee (1127-1135).
Estrogens are steroid hormones responsible for the primary and secondary sexual characteristics in females. While pre-menopausal women use estrogens as the main constituents of contraceptive pills, post-menopausal women use the same for Hormone Replacement Therapy. Estrogens produce reactive oxygen species by increasing mitochondrial activity and redox cycling of estrogen metabolites. The phenolic hydroxyl group present at the C3 position of the A ring of estrogens can get oxidized either by accepting an electron or by losing a proton. Thus, estrogens might act as pro-oxidant in some settings, resulting in complicated non-communicable diseases, namely, cancer and cardiovascular disorders. However, in some other settings the phenolic hydroxyl group of estrogens may be responsible for the anti-oxidative beneficial functions and thus protect against cardiovascular and neurodegenerative diseases.To date, no single review article has mentioned the implication of estrogen receptors in both the pro-oxidative and anti-oxidative actions of estrogens.The controversial role of estrogens as pro-oxidant or anti-oxidant is largely dependent on cell types, ratio of different types of estrogen receptors present in a particular cell and context specificity of the estrogen hormone responses. Both pro-oxidant and anti-oxidant effects of estrogens might involve different estrogen receptors that can have either genomic or non-genomic action to manifest further hormonal response.This review highlights the role of estrogen receptors in the pro-oxidative and anti-oxidative actions of estrogens with special emphasis on neuronal cells.
Keywords: Estrogens; Estrogen receptors; Estrogen receptor related receptors; Pro-oxidative action; Anti-oxidative action;

There is an increased risk for depressive symptoms and affective disorders in individuals who experience drastic drops or fluctuations of gonadal hormones. Moreover, clinical studies indicate that estrogens have the potential to be effective in treating depression.Possible underlying mechanisms for the antidepressant activity of estrogens are reviewed and discussed.Estrogens exert their antidepressant activity via a multimodal mechanism of action by regulating several pathways and functions associated with antidepressive effects. Estrogens increase serotonergic activity by regulating the synthesis and degradation of serotonin, as well as spontaneous firing of the serotonergic neurons in the raphe nuclei. Both pre- and postsynaptic serotonin receptors are shown to be regulated by estrogens. In addition, estrogens are neurotrophic and promote neuroplasticity and neurogenesis. Similar effects are also observed after treatment with current antidepressant therapies. However in stark contrast to current therapies which must be administered chronically to produce an effect, the responses to estrogens are often observed after a single dose. Many of these estrogenic effects, including antidepressant and anxiolytic responses in behavioral models in rodents, appear to be mediated via the estrogen receptor β subtype.The rapid onset of action combined with the multifactorial mechanism of action of estrogens indicates that estrogen treatment could complement currently available therapies for depression. Considering safety aspects, selective estrogen receptor β agonists would probably be the optimal estrogenic therapy.
Keywords: Estrogen; Estradiol; Depression; Affective disorders; Serotonin;

Sex steroids can positively affect the brain and from this it would follow that high levels of sex steroids could be associated with better cognitive function in older men and women.This Healthy Ageing Study sample comprised of 521 older participants (51% women) without dementia at baseline, with an age range from 64 to 94 years. Testosterone and sex hormone binding globulin were measured using the automated Immulite 2000 and analyzed in association with baseline memory, global cognitive function and decline (assessed using the Mini-Mental Status Examination or MMSE) and controlling for potential confounds such as age, education, vascular disease, smoking, diabetes, thyroid function, and body mass index.In healthy older men and women, optimal levels of testosterone were associated with better MMSE scores at baseline. Follow-up analyses indicated that in men, low testosterone levels (OR = .94, 95% CI = .88 to 1.00) were a risk factor for a sharp cognitive decline after 2 years, perhaps indicative of dementia. Associations were independent of covariates and baseline MMSE. Conversely, women at risk for a sharp drop in cognitive function showed some evidence for higher calculated free testosterone levels at baseline.Results replicate earlier cross-sectional findings that high levels of sex steroids are not associated with better cognitive function in older people. In men, age accelerated endocrinological change could be associated with dementia pathology.These data do not support increasing testosterone levels to prevent cognitive decline in men and women over 65 years of age.
Keywords: Estrogen; Testosterone; Sex hormone binding globulin; Thyroid hormones; Cognition;