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Endocrine Reviews 20 (3): 279-307
Copyright © 1999 by The Endocrine Society

Estrogen Actions in the Central Nervous System1

Bruce S. McEwen and Stephen E. Alves

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, Rockefeller University, New York, New York 10021


    Abstract
 Top
 Abstract
 I. Introduction
 II. Mechanisms of Estrogen...
 III. Areas of the...
 IV. Effects of Estrogens...
 V. Estrogens, Neuroprotection,...
 VI. Conclusions
 References
 

I. Introduction
II. Mechanisms of Estrogen Action
A. "Genomic" and "nongenomic" mechanisms
B. Steroid hormone actions on gene expression
C. Subtypes of estrogen receptors
D. Steroid hormone actions on putative receptors on membranes
E. Rapid actions of steroids on neuronal excitability
F. Steroid hormone actions via second messengers
G. Neuroprotective effects of estrogens
H. Summary
III. Areas of the Brain Affected Outside of the Hypothalamus
A. Studies of hypothalamic and extrahypothalamic actions of estrogens
B. Estrogens and the cholinergic system
C. Estrogens and the serotonergic system
D. Catecholaminergic neurons
E. Spinal cord
F. Hippocampus
G. Glial cells, endothelial cells, and the blood-brain barrier
H. Summary
IV. Effects of Estrogens on Learning and Memory
V. Estrogens, Neuroprotection, and Alzheimer’s Disease
VI. Conclusions


    I. Introduction
 Top
 Abstract
 I. Introduction
 II. Mechanisms of Estrogen...
 III. Areas of the...
 IV. Effects of Estrogens...
 V. Estrogens, Neuroprotection,...
 VI. Conclusions
 References
 
GONADAL hormones affect the nervous system in ways that extend beyond their essential actions of regulating gonadotropin and PRL secretion and modulating sexual behavior. For example, estrogens and androgens have been reported to influence verbal fluency, performance on spatial tasks, verbal memory tests, and fine motor skills (1, 2, 3, 4); and they affect the coordination of movement in animals (5) and symptoms of Parkinson’s disease and tardive dyskinesia in human subjects (6). Estrogens are also linked to symptoms of depression and treatment of depressive illness (7, 8, 9, 10).

Many estrogen effects differ qualitatively or quantitatively between the sexes, suggesting that they may be subject to sexual differentiation during pre- or early postnatal development. In addition, circulating hormone levels may contribute differentially in adult males and females. Sex differences in brain function also include gender differences in the incidence of psychopathologies such as depressive illness, which is more common in women, substance abuse and antisocial behavior, which are more common in men, as well as pain sensitivity (see Ref. 11 for review).

The diversity of these effects implies that regions of the brain are involved outside of the hypothalamus, which has been the traditional site for the study of ovarian steroid receptors and their role in the control of reproductive function. For example, the hormonal influences on memory processes appear to involve actions on brain structures such as hippocampus and basal forebrain, while the effects on normal and abnormal motor activity undoubtedly involve brain structures such as the caudate-putamen, nucleus accumbens, and substantia nigra and ventral tegmental, A9 and A10, respectively, and dopaminergic nuclei of the midbrain; and those on mood involve, at least in part, the serotonergic system of the midbrain raphe nuclei. Indeed, mapping of intracellular receptors, which modulate genomic actions, has revealed the presence of estrogen and/or progestin receptors in regions such as the olfactory lobe, amygdala, hippocampus, cortex, locus ceruleus, dorsal raphe, midbrain central gray, and cerebellum. Although the density of such receptors is sometimes lower and more diffuse in many of these brain areas compared with hypothalamus and amygdala, the existence of prominent estrogen and progestin effects requires a careful examination of the role of the cells that do express intracellular receptors in these brain regions, as well as a consideration of possible alternative mechanisms of steroid action, involving membrane receptors. There are also indications that steroid receptor expression is developmentally regulated and transient in some brain regions.

This article will review the neural actions of estrogens in the central nervous system (CNS), focusing on brain structures outside of the hypothalamus and on neurally mediated processes other than reproductive behavior and reproductive neuroendocrine events. We do this, however, in the context of what is known about estrogen actions in the hypothalamus. In this summary of the recent scientific literature, we place particular emphasis on estrogen and progestin effects in the hippocampal formation, as well as basal forebrain of the rat, because these brain structures are prominent in learning and memory and also are sites of neural degeneration in dementing illnesses such as Alzheimer’s disease. We will also discuss ovarian steroid influences in the midbrain and brainstem monoaminergic systems, and spinal cord, in view of their widespread involvement with brain functions that subserve affective state and movement, as well as analgesia and nociception. First, however, we will summarize the cellular mechanisms of estrogen action in neural tissue.


    II. Mechanisms of Estrogen Action
 Top
 Abstract
 I. Introduction
 II. Mechanisms of Estrogen...
 III. Areas of the...
 IV. Effects of Estrogens...
 V. Estrogens, Neuroprotection,...
 VI. Conclusions
 References
 
A. "Genomic" and "nongenomic" mechanisms
It has been customary to distinguish between steroid hormone actions that are delayed in onset and prolonged in duration and are called "genomic" effects and other steroid hormone actions that are rapid in onset and short in duration and are called "nongenomic" (12). This is because the discovery of intracellular steroid hormone receptors in the early 1960s created, for a number of decades, a single-minded focus on the long lasting effects of steroids on cell function, even though rapid actions of steroids were known since the 1930s from anesthetic effects of progesterone (13).

While rapid and delayed effects of steroids are clearly distinguishable from each other at their extremes in terms of mechanism, there is a gray area of uncertainty for actions that have onset times of minutes, as to whether "genomic" or "nongenomic" mechanisms apply. Genomic actions of glucocorticoids on lymphocytes were reported with onset latencies of 20 min (12). Thus, changes in neural activity recorded in vivo after systemic administration of steroids could have onset latencies of minutes, leading to uncertainty as to whether the lag was due to a delay in steroid reaching the tissue or to an intrinsic delay in the mechanism of action (14).

Still further uncertainty about mechanism of action was provided by demonstrations of rapid, but apparently genomic, actions of steroids affecting neuronal excitability and promoting or suppressing long-term potentiation (15, 16, 17, 18, 19). On the other hand, at least several steroid actions on membranes involve either a demonstrated coupling to G proteins or an effect that resulted in the generation of a second messenger (20), raising the possibility that a membrane steroid receptor may regulate gene expression indirectly via a second messenger-regulated DNA-binding protein such as a member of the cAMP response element-binding protein (CREB) family (21).

Even more in contradiction to the simple stereotype, it has become apparent that some important steroid actions require the coparticipation of certain neurotransmitters, involving hormone actions on cells that do not appear to have the genomic steroid receptors inside of them; rather, the effects may be transmitted via other steroid-sensitive neurons. An important example is the GnRH system of the hypothalamus. The activity of GnRH neurons is regulated by the ovarian steroids; yet, in vivo, these cells have not been found to concentrate estrogen (22) or express the classical ER{alpha}, ERß, or PR, in any species studied (23, 24, 25). However, distinct populations of adjacent cells, immunoreactive to neurotensin (23), galanin (26), {gamma}-aminobutyric acid (GABA), or glutamate (24), have been shown to express ER{alpha} and/or PR protein. Furthermore, it is known that GnRH release is regulated by hypothalamic amino acid transmitter systems (27, 28). Collectively, these findings point to an indirect, transsynaptic regulation of GnRH neurons by estrogen and progesterone in vivo, although it should be pointed out that GT1–7 cells, immortalized mouse GnRH neurons, do express seemingly functional ER{alpha} (29). A similar, possibly transsynaptic regulation by estrogen of synapse formation occurs in hippocampus, as will be discussed below in Section III.F. The finding of estrogen induction of synapses in hippocampus and also hypothalamus has challenged the notion of a morphologically stable adult brain by showing that steroids alter structures of the adult brain, including remodeling of synapses, changes in dendritic structure, and neurogenesis, as will be reviewed below in Section III.F.

B. Steroid hormone actions on gene expression
The identification and mapping of cells expressing the genomic steroid receptors by binding, immunocytochemistry, and in situ hybridization have provided the target sites for investigation of hormonal control of gene expression. Nevertheless, it is only a starting point, because the qualitative nature of hormonal regulation of gene expression cannot be predicted with any certainty from one brain region to another. For example, vasopressin is an important neuropeptide system that is subject to gonadal hormone regulation, and vasopressin mRNA levels are induced by androgens in the bed nucleus of the stria terminalis (30) and are suppressed by glucocorticoids in the paraventricular nuclei (31). CRH gene expression is suppressed by glucocorticoids in paraventricular nuclei, but induced in placenta (32, 33); in addition, there are brain areas that contain both glucocorticoid receptors and CRH in which there is no apparent glucocorticoid regulation of CRH gene expression (32).

Sexual differentiation involves more than sex differences in structure and wiring of the brain. There are also sex differences in gene expression, in which the male and female brain respond differently to the same hormone (34). For example, estradiol has a double role—as an ovarian steroid in females and as the product of the aromatization of testosterone in males. Therefore, it is not surprising that estradiol can produce somewhat different effects on the male and female brain, e.g., inducing prodynorphin mRNA in the anterioventral periventricular nucleus of female, but not male, rats (35). Moreover, some of these sex differences are known to be reversed by the hormonal conditions during early life that reverse the sex differences in sexual behavior. For example, in anterioventral periventricular nucleus, male rats express more preproenkephalin mRNA than females, whereas the reverse is true for prodynorphin mRNA; females that are androgen sterilized at birth show male patterns of neuropeptide gene expression (35). Alternatively, some genes appear to be similarly regulated by estradiol in both sexes, such as the hypothalamic oxytocin receptor (36), the serotonin 2A receptor (37), and the {alpha}-form of the estrogen receptor (ER{alpha}) in some brain regions (38, 39).

C. Subtypes of ERs
The discovery and cloning of the ß-isoform of the estrogen receptor (ERß) (40, 41, 42) radically changed our view of estrogen action and provided, among other things, a basis for understanding how the knockout of ER{alpha} (ERKO) (43, 44) could result in a viable organism and a continued responsiveness of at least some tissues to estrogens. Before the full recognition of ERß, a mapping study was carried out in the ERKO brain using [125I]estrogen, and estrogen induction of progestin receptor (PR) was also mapped by in situ hybridization of the mRNA (45). A low level of residual estrogen binding was found in the medial preoptic nucleus, arcuate nucleus, bed nucleus of the stria terminalis, and amygdala, and a significant estrogen-induced up-regulation of PR mRNA was found in the medial preoptic nucleus (45). Subsequent attempts to map ERß have confirmed that residual estrogen binding and action in ERKO mice might be due to ERß, and these studies have also provided some novel sites for ERß as well as some overlap with ER{alpha} (46, 47, 48). As for PR regulation and the functionality of residual ER (particularly ERß) in ERKO mice, a recent immunocytochemical study has shown estrogen induction of PR immunoreactivity in several hypothalamic nuclei and in amygdala (49).

A recent study by Krege and colleagues (50) has reported the generation of mice lacking functional ERß. Interestingly, ERß knockout females and males appear to develop normally, exhibit normal sexual behavior, and are reproductively competent, although females do exhibit reduced fertility (i.e., fewer and smaller litters), apparently due to decreased ovarian efficiency. This is in sharp contrast to {alpha}ERKO mice, which are sterile and do not display normal sexual behavior (51, 52, 53, 54). Thus, it appears that ER{alpha}, more so than ERß, is necessary for the estrogen-mediated regulation of reproductive physiology, including the behavioral components.

Distributions of ER{alpha} and ERß in the body differ quite markedly, with moderate to high expression of ER{alpha} in pituitary, kidney, epididymis, and adrenal, moderate to high expression of ERß in prostate, lung, and bladder, and overlapping high expression in brain, ovary, testis, and uterus (48, 55, 56). It is now known that at least several isoforms of ERß are expressed (57, 58, 59, 60). The best characterized of these variants has been termed ERß2, vs. the originally identified ERß1, and this isoform appears to have a lower affinity for estrogens (61), presumably due to an 18-amino acid insertion in the ligand-binding domain (58). The ERß2 variant was found at levels equal to ERß1 in ovary, prostate, pituitary, and muscle; in brain, expression was found in cortex, hypothalamus, and hippocampus, although at lower levels than ERß1 (57). Despite diminished ligand binding, ERß2 can bind at the ERE, and it apparently acts as a negative regulator of estrogen action, as it was found to suppress ER{alpha} and ß1-mediated transcriptional activation in a dose-dependent manner (58). Moreover, both ERß1 and ER{alpha} are reported to interact with the estrogen-dependent coactivator, SRC-1, whereas ERß2 does not do so and requires 100- to 1000-fold higher 17ß-estradiol concentrations to activate a promotor containing the estrogen response element (ERE) (62). Human ERß isoforms 2–5, with alterations in the ligand-binding domain, have also been identified, and they can form homo- and heterodimers with ERß1 and ER{alpha} (42, 59). Another variant, termed ERßcx, has a truncated C terminus, but has 26 additional amino acids due to alternative splicing (60). This form appears to specifically inhibit ER{alpha}-induced transcription; however, ERßcx has not yet been found in brain (60). The genomic effects of estradiol via intracellular ER are depicted in the top panel of Fig. 1Go.



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Figure 1. Schematic diagram of intracellular estrogen action via ER{alpha} and ERß, as well as possible cell surface effects of putative membrane ERs that produce neuroprotection (top) or affect intracellular signaling (bottom) via the cAMP and MAP kinase pathways. Top panel, Estradiol exerts its effects intracellularly via two principal receptor types, ER{alpha} and ERß, and these are characterized by a distinct specificity for 17{alpha}-estradiol over 17ß-estradiol. Estrogens also exert neuroprotective effects in part via a mechanism in which 17{alpha}-estradiol has equal or greater potency compared with 17ß-estradiol. Bottom panel, Estradiol acts either via cell surface receptors or an intracellular ER to activate two different second messenger pathways, one involving the MAP kinase cascade and the other involving cAMP. Both pathways result in activation of gene transcription via at least three possible response elements: CRE, SRE, and AP-1. Note that in the case of intracellular second messengers there is some uncertainty concerning the involvement of ER{alpha} and ERß in the signaling process vs. the role of other, as yet uncharacterized, receptors (see text). AC, Adenylate cyclase; CREB-P, phosphorylated form of CREB; ras, ras oncogene; MAPK, mitogen-activated protein kinase; MAPKK, mitogen-activated protein kinase kinase; fos-jun, fos-jun heterodimer.

 
In brain, the distribution of ER{alpha} is fairly well established, but there is less certainty and more controversy surrounding the localization of functional ERß. The original autoradiographic maps of [3H]estradiol uptake and retention in brain (63, 64) reflect binding to all forms of the ER, particularly the ER{alpha} and the ERß1 isoform, which have similar affinities for 17ß-estradiol (55). In situ hybridization data suggest widespread distribution of ERß mRNA throughout much of the brain (46, 47) while results from immunocytochemical studies (see below) tend to indicate a more restricted localization of detectable protein, raising questions about the specificity of the in situ hybridization procedure, on the one hand, and the efficacy of the antibodies used for immunocytochemistry, on the other.

The initial commercially available polyclonal antiserum to ERß (no. 310, Affinity BioReagents, Inc.), raised against a short fragment of the C terminus of the receptor, has produced a consistent pattern of strong cell nuclear label in the medial amygdala, paraventricular nucleus (PVN), and preoptic area, and striking cytoplasmic/fiber label in cells of the lateral septum (65, 66, 67). Detection of cell nuclear ERß labeling in the supraoptic nucleus (SON) may be dependent upon the use of acrolein in the fixation procedure (65, 67). If the C terminus antiserum is preabsorbed with the synthetic peptide in a 1:1 (wt/vol) ratio, labeling is completely absent in these brain regions (65, 66, 67). However, in other brain regions such as hippocampus and cortex, immunolabeling is not as consistent, and such labeling is not always obliterated by preabsorption of the antiserum (S. E. Alves and B. S. McEwen, unpublished results). This is particularly true for the N terminus antiserum (no. 311, Affinity BioReagents, Inc., Golden, CO), which produces both cytoplasmic and nuclear labeling. Factors such as fixative (acrolein vs. paraformaldehyde), gonadal state of the animal (gonadectomized vs. intact), or stage of the estrous cycle, appear to affect ERß protein detection in the brain. Thus, caution must be taken in the interpretation of ERß immunoreactivity in brain regions other than the hypothalamus and amygdala using these antibodies.

Moreover, reports of the neurochemical phenotypes of ERß-containing cells in some brain regions, particularly the PVN and SON, have been somewhat conflicting. While all studies thus far have identified subpopulations of oxytocin neurons in the PVN and/or SON to contain ERß (46, 66, 67, 68), differences have been reported in the specific cell populations, as well as for other peptide systems. For example, two studies measuring either ERß mRNA (8) or protein (7) have reported colocalization with vasopressin, particularly in the SON; another study has reported that colocalization between ERß mRNA and vasopressin was only seen in scattered cells of the parvocellular PVN (46). This later study also reported that more than half of the CRH neurons of the caudal parvicellular PVN contain ERß mRNA. In contrast, Alves and co-workers (67) observed only few scattered parvicellular CRH-positive neurons to contain ERß protein, using the C terminus antiserum.

Several viable explanations for discrepancies between message and protein data exist. Considering the existence of receptor variants, one possible explanation is that a form of ERß, not recognized by the short C terminus antiserum, is expressed in these cells, which would result in an underestimation of ERß-expressing cells when using this antiserum. Alternatively, perhaps not all ERß mRNA is translated into functional protein or it is translated in a transient manner that differs between cell types and developmental stages. On the other hand, it is also possible that the discrepancies in the results of different laboratories are due to false-positives with the existing probes to ERß.

However, if the reported CNS distribution of ERß mRNA is found to reflect the expression of some functional ERß protein in those brain regions, this would certainly help to explain numerous estrogen actions in brain regions with little or no ER{alpha}. This includes areas such as the olfactory bulbs, cerebellum, and cerebral cortex, in which ERß mRNA has been abundantly detected (48). It is hoped that future investigations into the seemingly complex detection and expression of ERß will provide a clearer picture of the distribution and phenotype of cells that contain functional ERß.

As noted above, ER{alpha} and ERß1 are similar not only in affinity for a number of estrogens and estrogen antagonists (55), but also in their ability to regulate genes in which the ERE is the primary site of interaction (69) (see top panel of Fig. 1Go). The major differences between ER{alpha} and ERß1 concern their ability to regulate transcription via the AP-1 response element. For interactions of ER{alpha} with AP-1, 17ß-estradiol, as well as a number of antiestrogens, activated transcription; however, for ERß1 interacting with AP-1, 17ß-estradiol failed to activate transcription but antiestrogens activated transcription (69). As mentioned above, ER{alpha} and ERß1 can form heterodimers when expressed in the same cells, thus giving rise to additional possible variants of gene regulation (42). Thus far, the endogenous colocalization of ER{alpha} and ERß has been reported recently in the hypothalamic preoptic area, bed nucleus of the stria terminalis, and medial amygdaloid nucleus (68).

The agonist effects of estrogen antagonists bring to mind earlier studies in which estrogen antagonists produced estrogen-like effects on some neurochemical endpoints and antagonistic effects on others. The antagonistic effects for CI-628, a tamoxifen-like estrogen antagonist, were seen in terms of PR induction and lordosis behavior (70, 71) (see Fig. 2Go), whereas the agonist-like effects of CI-628 were seen for choline acetyltransferase regulation and monoamine oxidase A regulation, but not for the regulation of glucose-6-phosphate dehydrogenase in pituitary and uterus (72) (see Fig. 3Go). The molecular mechanisms underlying the differences in these antiestrogen effects remain to be explored, and they may reflect the operation in some of the cases of a response element other than the ERE and perhaps even the operation of heterodimers of ER{alpha} and ß, but the diverse effects of CI-628 indicate that the nonsteroidal antiestrogens do not have uniform agonist-like or antagonist-like effects in the brain. This is an important consideration for the therapeutic use of estrogen antagonists of this type.



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Figure 2. Effect of the estrogen antagonist, CI-628 (nitromiphene citrate; {alpha}-[4-pyrrolidin-oethoxyl] phenyl-4-methoxy-{alpha}-nitrostilbene), on the induction of cytosol PRs in the hypothalamic/preoptic region of ovariectomized female rats by estradiol (E2) or estradiol benzoate (EB). Treatment protocols are referred to as follows: 1 DAY: 5 µg E2 and 2 mg CI-628 at 0 h, killed at 24 h; 2 DAYS: 2 µg EB at 0 h and CI-628 at 0 h and 24 h, killed at 48 h; 3 DAYS: 15 µg EB and 2 mg CI-628 at 0, 24, 48 h, sacrificed at 72 h. Cytosolic receptors were assayed using 3H-labeled R 5020, a synthetic progestin. Black bar indicates increase above control levels. It can be seen that estrogen treatment increased PR binding and that CI-628 at least partially antagonized the effects of estrogen treatment under all conditions. In the lower right panel, a Scatchard analysis of PR binding of rats treated with 2 µg EB at 0 h vs. 2 µg EB at 0 h plus two injections of 2 mg CI-628 at 0 h and 24 h, killed at 48 h (2 DAYS protocol). [Reprinted with permission from E. Roy et al.: Endocrinology 104:1333–1336, 1979 (70 ). © The Endocrine Society.]

 


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Figure 3. Effect of the estrogen antagonist, CI-628, on estradiol benzoate (EB)-dependent enzyme changes in uterus, pituitary, and brain. Ovariectomized rats were injected for 5 days with sesame oil vehicle, CI-628 (18 mg/kg), or EB (140 µg/kg) either alone or in combination. Enzyme activities are reported as mean ± SEM for choline acetyltransferase (CAT) in preoptic area, type A monoamine oxidase (MAO) in amygdala, glucose-6-phosphate dehydrogenase (G6PDH) in pituitary and uterus. Details of the assay may be found in the original publication (72 ). Differences among groups were tested by Newman-Keuls procedures: *, Different from OVX, P < 0.05; **, P < 0.01; different from EB + CI, P < 0.05. For uterus, all groups were significantly different from one another. [Reproduced with permission from V. Luine and B. S. McEwen: Endocrinology 100:903–910, 1977 (72 ). © The Endocrine Society.] It can be seen that CI-628 exerted agonist-like effects on CAT and MAO activity, whereas it antagonized estrogen induction of G6PDH activity in pituitary and uterus.

 
D. Steroid hormone actions on putative receptors on membranes
Membrane ERs have been reported on pituitary, uterine, ovarian granulosa cell, and liver cell membranes, but they have been characterized only partially and have not yet been shown to be linked to signal transduction mechanisms (73, 74, 75, 76, 77, 78, 79, 80). For membrane fractions from pituitary and ovarian granulosa cells, the specificity of the binding sites shows equal potency of 17{alpha}- and 17ß-estradiol, estriol, and estrone; for liver and uterine cells, there is a preference for 17ß- over 17{alpha}-estradiol (73, 75, 76, 79, 80). However, for GH3/B6 pituitary cells, a 17ß-estradiol binding site was identified using an estrogen-BSA conjugate; but, in contrast to the other reports suggesting a novel membrane ER (cited above), monoclonal antibodies to the intracellular ER{alpha}, H226, and H222, as well as the polyclonal antiserum, ER21, each recognizing a unique epitope on ER{alpha}, labeled sites on these cells in or near the cell surface (77, 81). A more recent report used transient transfection of both ER{alpha} and ERß cDNA into Chinese hamster ovarian cells and demonstrated both types of ER expressed in both cell membrane and nuclear fractions; the binding affinities for estradiol were similar in both membrane nuclear fractions, and, in membranes, estradiol activated G{alpha}q and G{alpha}s proteins in the membrane and rapidly simulated, respectively, inositol phosphate production and adenylate cyclase activity (82).

These limited findings can be viewed in relation to data about other membrane steroid receptors. The best understood membrane receptor for a steroid is the GABA-A receptor. Anesthetic effects of progesterone derivatives (13) led, after many years, to the recognition of a unique membrane recognition site on many subunit combinations of the GABA-A-benzodiazepine receptor system (83, 84). A-ring-reduced metabolites of progesterone and deoxycorticosterone are among the most active steroids affecting the GABA-A receptor system, and such metabolites are produced in the body, including the brain, from the parent steroid. The effects of these steroid metabolites include not only anesthetic effects but also antiepileptic, sedative-hypnotic, and anxiolytic actions (83). The efficacy of these metabolites in normal physiology is suggested by experiments on progesterone facilitation of lordosis in the hamster, in which it was found that local application of GABA-A-active derivatives of progesterone to the midbrain ventral tegmental area (VTA) of the estrogen-primed hamster was able to facilitate lordosis (85, 86, 87). Moreover, while GABA-A receptor-active pregnane steroids, applied to the ventral tegmental area, facilitate lordosis behavior, inhibitors of 5{alpha}-reductase, the first step in A-ring reduction, prevented systemically applied progesterone from facilitating lordosis (20).

Other membrane receptors for steroid hormones are not so well characterized (20). One exception is the membrane-binding site for 1{alpha},25-dihydroxyvitamin D3 in basal-lateral membranes of chick intestinal epithelium, which demonstrates pharmacological specificity for a receptor modulating nongenomic transport of calcium (88). Another example is a membrane steroid receptor site for corticosterone in the newt, Taricha granulosa. Using both autoradiography and binding assays on isolated membrane fractions, the corticosterone site has been shown to be coupled to a G protein and to have the characteristics expected of a site involved in the rapid inhibition of sexual behavior (89). However, it has been difficult to obtain satisfactory binding data for putative steroid receptors on rat brain membranes. Approaches using progesterone linked to 125I-labeled BSA have met with some success in labeling putative progestin sites on brain membranes (90). However, the majority of the evidence to date is based on functional studies using electrophysiology or other endpoints, and some of this will be summarized below as it applies to the coupling to second messenger systems.

E. Rapid actions of steroids on neuronal excitability
Estrogens and other steroids affect neuronal excitability, and one of the challenges in studying estrogen actions on neurons is to identify whether genomic or nongenomic mechanisms are involved. For the induction of the so-called MINK potassium channel by estrogens (91), a genomic mechanism is clearly implicated. On the other hand, estradiol has been reported to rapidly excite neurons in cerebellum, cerebral cortex, and the CA1 pyramidal neurons of hippocampus (see below) by a mechanism that seems not to involve intracellular ERs, which do not appear to be found in the responding neurons. However, as discussed above in Section II.C, the presence of ERß mRNA in these brain areas leaves open the possibility of some functional ERß receptor. Nevertheless, the rapidity of many of these effects makes a genomic mechanism unlikely.

For example, direct application of 17ß-estradiol rapidly decreases the spontaneous firing of neurons in medial preoptic area (92) and rapidly increases the firing rate of pituitary cells (93). 17ß-Estradiol also increases excitatory postsynaptic potentials in the hippocampus, apparently by increasing currents mediated by kainate receptors in hippocampal neurons (94, 95, 96), and 17ß-estradiol increases responses to applied glutamate in the cerebellum (97, 98). 17ß-Estradiol also causes rapid hyperpolarization of neurons in medial amygdala (99, 100), and it suppresses µ-opioid and GABA-B receptor-based hyperpolarization of hypothalamic arcuate neurons in the guinea pig (101). Furthermore, 17ß-estradiol directly potentiates potassium-stimulated dopamine release in the rat nucleus accumbens (102). These effects are very rapid, occurring within seconds; moreover, in one instance, the estrogen antagonist, tamoxifen, was shown not to mimic or block estrogen actions on the kainate currents (96). Furthermore, mice lacking ER{alpha} show the same estrogen effect on the kainate current, providing further evidence that a separate type of ER may be involved (103). However, there is no extensive data with estrogen antagonists on many of these rapid estrogen effects, and thus they remain relatively uncharacterized pharmacologically.

Other steroid effects occur rapidly, albeit within minutes and not seconds, and yet they are blocked by antagonists of intracellular steroid receptors; yet, in most cases, specific gene products are not yet identified. This is true for the actions of adrenal steroids through type I receptors to disinhibit CA1 pyramidal neurons from serotonin 1A (5-HT1A) receptor-mediated inhibition and to suppress via type II receptors’ noradrenaline-mediated facilitation of CA1 excitability (104) (see Ref. 105 for review). A similar story has been described for adrenal steroid effects on the induction of long-term potentiation (LTP) and its relative, primed burst potentiation (PBP) (see Ref. 106 for review).

F. Steroid hormone actions via second messengers
Estrogens and other steroids affect the activity of second messenger systems and may do so via genomic as well as nongenomic mechanisms. Three categories of second messengers will be considered from the standpoint of evidence for receptor mechanisms involved, both genomic and nongenomic. Because these second messenger pathways interact with each other, the phenomenology described below is not mutually exclusive. Moreover, the phenomena described below may be related to the membrane-binding sites described above and/or to the estrogen effects on excitability described in the previous section.

1. cAMP regulation. The finding that progesterone stimulates accumulation of cAMP in frog oocytes and stimulates phosphoinositol turnover in sperm (107, 108, 109, 110) raised the possibility that membrane actions of certain steroids on certain target cells might regulate second messenger formation. The identification of membrane receptors for corticosterone in Taricha granulosa that are coupled to G-proteins further strengthens this possibility (89).

Addition of estrogen to MCF-7 or uterine cells in culture evoked an increase in cAMP levels; and, although 17{alpha}-estradiol and other nonestrogenic steroids were without effect, a number of estrogen antagonists mimicked the estradiol effect, and protein and RNA synthesis blockade failed to prevent the effect (111). In some brain regions, estrogen treatment increases phosphorylation of CREB via a cAMP-dependent mechanism (112, 113). Estrogen-induced depolarization of hypothalamic neurons involves cAMP and also attenuates potassium conductance (99, 100); in pituitary, estradiol was reported to inhibit GTPase activity, although this effect was also produced by testosterone and progesterone (114). The so-far limited evidence for estrogenic regulation of cAMP levels, which in many cases lack definitive structure-activity studies or the use of antagonists, is nevertheless consistent with an alternative or indirect pathway for gene regulation by which steroid-driven second-messenger responses, possibly via a novel receptor mechanism, regulate gene expression via DNA-binding proteins such as the phosphorylate form of CREB (PCREB) (21). The effects of estrogens involving a second messenger system are schematically summarized in the bottom panel of Fig. 1Go, although it must be pointed out that there are many unknowns about the nature of the intracellular sites for these effects and the receptors that may be involved.

2. Mitogen-activated protein (MAP) kinase regulation. In addition to protein kinase A and cAMP, the MAP kinase system has been implicated in estrogen action. In human mammary cancer MCF-7 cells, 17ß-estradiol was reported to induce immediate and transient activation of the Src/p21ras/Erk pathway via a mechanism that is blocked by the pure estrogen antagonist ICI 182780 and which, therefore, appears to involve an intracellular ER (115, 116, 117). In a follow-up study, progesterone activation of this pathway was shown to occur by an association of the PR with an N-terminal region of ER{alpha} and not with c-Src directly (116).

In neuroblastoma SK-N-SH cells and in cortical explants, 17ß-estradiol was reported to activate the MAP kinase and phosphorylate and activate two of them, ERK-1 and ERK-2 (118). In contrast to MCF-7 cells, the response in SK-N-SH neuroblastoma cells and cortical explants was not blocked by ICI 182780 or by tamoxifen (118), indicating that a classical ER may not be involved. Further support for this in SK-N-SH cells came from the finding that 17ß-estradiol conjugated to BSA activates a reporter gene driven by the mouse c-fos protooncogene, which responds to MAP kinase activation, but does not activate transcription mediated by a promotor containing the ER response element, ERE (118). A possible sequence of signaling events is summarized in the bottom panel of Fig. 1Go. Estrogen-dependent activation of MAP kinases, ERK-1 and ERK-2, has also been studied in embryonic cerebral cortical explants grown in culture (119, 120). The activation of ERK was blocked by the MEK-1 inhibitor, PD98059, but not by ER antagonist ICI 182780, again suggesting that a conventional ER may not be involved (119).

3. Calcium homeostasis. Calcium ions also constitute an important player in second messenger pathways, and the effect of estrogen on calcium channels and calcium release from intracellular stores has also emerged as a possible cellular mechanism of estrogen action that is relevant to excitability and neuronal vulnerability to damage. There appear to be at least three distinct pathways for estrogen action on calcium homeostasis that have been documented in different cell systems, each involving a different type of membrane ER, and at least one pathway for affecting calcium homeostasis via a genomic mechanism.

In the first of the nongenomic pathways, 17ß-estradiol activates a G-protein-coupled receptor in rat neostriatal neurons and, within seconds, suppresses currents mediated by L-type calcium channels (121). 17{alpha}-Estradiol is considerably less potent than 17ß-estradiol, as are other steroids, and the estrogen antagonist, tamoxifen, mimicked estrogen action and did not block them (121), thus further supporting a unique ER on the cell surface. Interestingly, these estrogen effects were sex specific, occurring more robustly in neurons from female rats (121). A similar effect of 17ß-estradiol to inhibit currents mediated by L-type calcium channels was reported in aortic smooth muscle, providing a basis for the well known effects of estradiol to regulate vascular tone (122).

In a second nongenomic pathway, as shown for liver and uterine endometrial cell membranes, estradiol binds stereospecifically (17ß >> 17{alpha}), and these sites may be responsible for estrogenic stimulation of calcium influx into these cells (74, 75, 76, 78, 79). In contrast, via a third pathway, in chicken ovarian granulosa cells, 17ß- and 17{alpha}-estradiol facilitated release of intracellular calcium stores equipotently in a concentration range of 10-10 to 10-6 M (80). Estriol and estrone were also effective in the same range, but progestins and androgens were ineffective; moreover, estrogen actions were not blocked by tamoxifen or by RNA and protein synthesis inhibitors (80), thus defining an estrogen membrane site of broader specificity than that seen in liver or endometrial cells or striatal neurons.

There are, however, reported estrogen effects on calcium currents that are more consistent with an intracellular, genomic action of estradiol. In a study on GH3 pituitary cells, 17ß-estradiol treatment increased low voltage-activated calcium currents over 24 h by a mechanism requiring protein synthesis (123). Moreover, in a hippocampal slice study, in vivo treatment with estradiol increased in vitro both the sustained and transient calcium currents, while in vivo progesterone acutely amplified the estrogen effects over 4 h; in contrast, potassium currents were not altered by these same treatments (124). These results appear to be more consistent with the genomic actions of estradiol that are related to synaptogenesis and will be discussed below.

G. Neuroprotective effects of estrogens
Estrogens exert protective effects on neuronal cells in culture that may be mediated, at least in part, by their ability to alter free radical production and/or free radical action on cells. However, as was also the case for the second messenger systems, the evidence for involvement of intracellular ERs vs. novel membrane receptors is controversial, although tending to point to a nontraditional receptor mechanism. The distinction between neuroprotective effects of estrogens mediated by intracellular receptors and those mediated by putative receptors located in other parts of the cell are summarized in the top panel of Fig. 1Go and is based on the different estrogen structure-activity profile, as will be described below.

The first neuroprotective actions of estradiol were described in relation to the effects of serum deprivation on neuronal survival in cell culture (125, 126, 127, 128, 129). In one of these studies (127), picomolar levels of 17ß-estradiol enhanced fetal rat hypothalamic neuronal survival in a serum-free medium in the presence or absence of glial cells by a mechanism that was blocked by tamoxifen and that, presumably, involves intracellular ERs. A similar example will be given at the end of this section regarding estrogenic neuroprotection from glutamate toxicity (130).

In serum-free medium, embryonic cortical neurons were shown to survive better in the presence of nanomolar concentrations of 17ß-estradiol; in fact, 17ß-estradiol facilitated neurite outgrowth by a process that was blocked by AP5, an N-methyl-D-aspartate (NMDA) receptor antagonist, but not by ICI 182,780, an ER antagonist, suggesting a possible nongenomic mechanism (131).

In another series of studies (128, 129), neuroblastoma SK-N-SH cells were protected by concentrations of both 17ß- and 17{alpha}-estradiol in serum-free media. In the first of these studies (128), 17ß-estradiol concentrations of 2 µM enhanced total live cell number for up to 48 h without increasing thymidine incorporation, indicating an effect on cell survival and not cell division. In the second study in this series (129), 17ß- and 17{alpha}-estradiol in the range of 0.2–2 nM protected SK-N-SH cells in culture, and a 10-fold molar excess of tamoxifen antagonized only one-third of the neuroprotective effect. Taken together, the absence of stereoselectivity of 17ß- vs. 17{alpha}-estradiol and the weak antagonism by tamoxifen argue against involvement of the classical intracellular ERs in neuroprotection of SK-N-SH cells.

The other situation in which neuroprotection by estrogenic steroids has been described is in relation to oxidative damage, and, once again, the weight of evidence is against a role for the classical intracellular ERs. Before discussing estrogen effects on cell survival, we note a chemical study carried out in the absence of living cells or cellular extracts, in which the addition of 200 nM 17ß-, 17{alpha}-estradiol, or estriol each reduced the generation of free radicals, whereas other steroids were ineffective (132). This suggests that features of the estrogen A ring, involving the 3 hydroxyl group, have the ability to interfere with free radical production in the absence of proteins or other cellular materials.

There have been a number of studies investigating a neuroprotective role of estrogen from free radical damage in cells in culture. In the first of these, exposing cloned mouse HT22 hippocampal cells to amyloid-ß, hydrogen peroxide or glutamate resulted in oxidative damage and cell loss that was reduced by preincubating cells for 20 h with 10 µM 17ß-estradiol or 200 uM vitamin E, but not by 10 µM progesterone, aldosterone, corticosterone, or cholesterol; 17ß-estradiol at a concentration of 0.1 µM was not effective in these studies (133). A follow-up structure-activity study by the same group revealed a broad spectrum of estrogen specificity, with 17ß- and 17{alpha}-estradiol as well as estriol and estrone all being effective and pointing to the C3 {alpha}-hydroxyl group on the steroid A ring as being important as well as implying that intracellular ERs are not involved (134).

Dissociated embryonic hippocampal neurons were also sensitive to estrogen-mediated protection against amyloid-ß toxicity, glucose deprivation, glutamate treatment, or FeSO4 toxicity; in this study, the effective steroid concentration range was 100 nM to 10 µM, and estriol and progesterone were also effective, whereas corticosterone enhanced neurotoxicity across this concentration range (135).

In contrast to these studies using high, supraphysiological concentrations of estrogens, another recent investigation showed that as little as 0.2–2 nM estradiol, either 17ß or 17{alpha}, protected SK-N-SH cells against ß-amyloid toxicity (136). This raises the question of how different investigators have found such different concentrations of estrogens to be effective (136). These discrepancies in effective concentration ranges of estrogens are difficult to understand. However, one possible clue points to the concentration of natural reducing agents in the culture medium, i.e., a recent report showed that the addition of glutathione to HT22 cells in culture, which lack functional ER, reduced the dose range of estrogen neuroprotection by 400-fold (137).

In contradistinction to all of the above mentioned neuroprotection studies, a report on glutamate toxicity in primary cortical neurons in culture suggests involvement of an intracellular ER; 24-h pretreatment with 15–50 nM 17ß-estradiol reduced glutamate-induced toxicity, measured by lactate dehydrogenase release, an effect that was blocked by the estrogen antagonist, tamoxifen. Thus, this finding suggests that there are situations in which estrogen neuroprotection may involve the activation of intracellular ER (130).

In a related study, the toxicity of gp120 for hippocampal cells in culture is inhibited over 72 h by 17ß-estradiol at concentrations of 1 nM or above (138). Since gp120 exerts its effects via excitatory amino acids and calcium ions, culminating in free radical-induced damage (138), it is noteworthy that estradiol reduces the free radical accumulation induced by gp120 (R. Sapolsky, personal communication). However, there are no experiments with this system to indicate whether a conventional ER mechanism or a novel type of receptor is involved.

Finally, there is another mechanism potentially involved in neuroprotective estrogen effects, namely, the regulation of the Bcl-2 family of genes (139). Some members of this family, such as Bcl-2 and Bcl-XL, suppress programmed cell death, whereas others such as Bax.Bad and Bid act as positive regulators of apoptosis (see Ref. 139). In arcuate nucleus neurons of female rats, estrogen treatment up-regulated expression of Bcl-2 immunoreactivity (139). Estrogen up-regulation of Bcl-XL was also reported both in vivo and in vitro in hippocampal and cortical cells (140). Thus, estradiol may also increase gene expression that inhibits programmed cell death, although the mechanism by which estrogen regulates Bcl expression is not known at this time; intracellular ER{alpha} and/or ERß may very well be involved in such genomic regulation, as both receptors are found in these brain regions.

H. Summary
Estrogen actions on brain cells occur through at least two types of intracellular receptors as well as other mechanisms for which receptor sites are not yet clearly identified. Indeed, for a number of processes, there are conflicting reports, based upon structure-activity studies with different estrogens and the actions of estrogen antagonists, as to whether intracellular receptors are involved. For estrogen actions on some aspects of calcium homeostasis, activation of certain second messenger systems, and some features of neuroprotection, a novel receptor mechanism may exist in which stereospecificity for 17ß- over 17{alpha}-estradiol is replaced by a broader specificity for the 3-hydroxyl group on the A ring.


    III. Areas of the Brain Affected Outside of the Hypothalamus
 Top
 Abstract
 I. Introduction
 II. Mechanisms of Estrogen...
 III. Areas of the...
 IV. Effects of Estrogens...
 V. Estrogens, Neuroprotection,...
 VI. Conclusions
 References
 
A. Studies of hypothalamic and extrahypothalamic actions of estrogens
Until recently, the hypothalamus has been the focus of much of the attention regarding neural effects of gonadal hormones. Ovarian hormone actions on neurons of the ventromedial hypothalamus, which are important for the regulation of sexual behavior in female rats, include regulation of neuropeptide gene expression (141) and second messenger systems (142) and induction of oxytocin receptors, PR, and the regulation of cyclic synaptogenesis (36, 143, 144, 145). There are also developmentally programmed sex differences involving both neuronal wiring as well as programming of responses to hormonal activation of gene expression (144, 146). All of these actions occur in neurons that express high levels of ER{alpha} and PR, in contrast to the hippocampus, midbrain raphe, basal forebrain, brainstem, and spinal cord, in which ER{alpha} and PR, if detected at all, appear to be relatively scarce and are found in many cases in interneurons or scattered principal neurons. As noted in Section II.C, the extrahypothalamic distribution of ERß protein is still unclear, but the presence of ERß mRNA in brain regions such as the cerebellum, hippocampus, cerebral cortex, and olfactory bulbs (47, 48) suggests that ERß must be regarded as a potential mediator of estrogen action in those brain areas.

This is a very important consideration, since gonadal hormones, and, in particular, estrogens, have many effects on the nervous system that extend beyond their very important actions in hormonal regulation of reproductive function. Moreover, many of these estrogen effects differ qualitatively or quantitatively between the sexes, suggesting that they may be influenced by the process of sexual differentiation during early pre- or postnatal development and/or by different levels of circulating sex hormones. In considering these nonreproductive actions of estrogens, we must also consider other brain regions outside of the hypothalamus. However, this does not mean that the hypothalamus is concerned only with reproduction, nor does it mean that the extrahypothalamic brain regions are not contributing to reproductive functions. Indeed, the hypothalamus is concerned with many aspects of autonomic and neuroendocrine control, and extrahypothalamic systems such as serotonin and the catecholamines play important supporting roles in reproductive endocrinology. Nevertheless, in addition to reproduction there is much more to brain function that is influenced by estrogens and by sex differences, and this is the primary focus of the following discussion.

Sex differences in brain function also include gender differences in the incidence of psychopathologies such as depressive illness, which is more common in women, and substance abuse and antisocial behaviors, which are more common in men, as well as pain sensitivity (11). Sex differences and estrogen effects upon the serotonergic, cholinergic, dopaminergic, and noradrenergic systems all may contribute to many aspects of brain function that are affected by ovarian hormones, including affective state (7), movement disorders (6), and cognitive function (2, 147). Furthermore, the discovery of estrogen-induced synapse formation in hippocampus and hypothalamus, which are described below, are relevant to postmenopausal changes in brain function, including decline of short-term verbal memory (147), as well as to the occurrence of dementia, which becomes more prevalent in women after the menopause as well as in men as they age (148). Recent epidemiological studies have suggested a possible protective role for postmenopausal estrogen therapy against Alzheimer’s disease (149, 150). Furthermore, estrogen treatment trials have shown some benefit to demented woman as far as global cognitive function and mood (151, 152) as well as to normal women (3, 4, 153) as far as verbal memory. A recent study also suggests a positive role for estrogen therapy on cognitive function in multiple sclerosis (154). Moreover, estrogen and progestin-induced regulation of synapse formation and excitability may play a role in catamenial epilepsy, which varies in frequency during the menstrual cycle (155). The presence or absence of hormones also contributes to aging of the brain, e.g., loss of hippocampal neurons as a result of elevated glucocorticoid activity (156, 157); and consequences of estrogen loss in females may include loss of synaptic connections in hippocampus (158) or decline in basal forebrain cholinergic function in the absence of circulating estrogens (159). An additional aspect of estrogen action is the regulation of neurogenesis in the dentate gyrus, which continues to produce new neurons in adult life. A recent report indicates that female rats have a higher rate of neurogenesis than males and that neurogenesis varies during the estrous cycle with a peak on the day of proestrus (160).

Sex differences in brain structures and mechanisms are programmed early in life by gonadal hormones and are permanent for the life of the individual. Sex differences occur in brain regions other than the hypothalamus, such as hippocampus, and they appear to be involved in aspects of cognitive function and other processes that go beyond the reproductive process itself. In this review, we refer to "sex differences" and the process of "sexual differentiation" but not to "sexual dimorphism," which is a term that refers to nonoverlapping differences in phenotype between the sexes. This is because true "sexual dimorphisms" are very rare, and the more common pattern of sex differences involves overlapping, but significantly different, distributions of phenotypic traits.

Understanding the cellular and molecular basis of sex differences and of sex differences in the actions of gonadal hormones is vitally important for assessing how pharmaceutical agents differentially affect the brains of males and females (161), as well as in understanding other male-female differences relevant to health and disease, such as the higher incidence of depression in women and of substance abuse in males (7). There are also sex differences in the severity of brain damage resulting from transient ischemia (162) and sex differences in the response of the brain to lesions (163) and to severe, chronic stress (164, 165).

The diversity of these effects implies that regions of the brain are involved outside of the hypothalamus. Indeed, as we have noted in Section II.C above, mapping of intracellular receptors, which modulate genomic actions, has revealed the presence of ER and/or PR expression in regions such as the olfactory lobe, hippocampus, cortex, locus ceruleus, midbrain raphe nuclei, and midbrain central gray and cerebellum. Although the density of ER{alpha} is often lower and more diffuse in many of these brain areas compared with hypothalamus and amygdala, the existence of prominent estrogen and progestin effects in many of these brain areas requires a careful examination of the role of the cells that express intracellular receptors in these brain regions. We have noted in Section II above that the localization and expression of ERß is an important consideration, along with a consideration of possible alternative mechanisms of steroid action. We now consider a number of the extrahypothalamic brain regions that are sensitive to estrogens and progestins.

B. Estrogens and the cholinergic system
The basal forebrain contains cholinergic neurons that project to cerebral cortex and hippocampus, where they play an important role in cognitive function. Studies of estrogen effects on the expression of cholinergic enzymes were among the first that pointed to nonreproductive actions of gonadal steroids (166). Experiments with ovariectomy and estrogen replacement therapy revealed an induction of choline acetyltransferase (ChAT), the rate-limiting enzyme for acetylcholine formation, within 6–24 h in basal forebrain of female rats. In addition, estrogen treatment increased ChAT activity in projection areas of the basal forebrain 10 days after hormone injection, suggesting that estrogen-induced ChAT was transported from cell bodies to nerve endings in the cerebral cortex and hippocampus (166). 17ß-Estradiol treatment also induced acetylcholinesterase, as well as ChAT activity, implying that a general trophic effect on the cholinergic neurons might occur (166). The estrogen induction of ChAT was mimicked by the estrogen antagonist, CI-628 (see Fig. 3Go), suggesting that a different type of interaction with the genome is involved than the traditional one involving an ER operating via the ERE (see Section II.C) (72).

A recent investigation of long-term (5–28 wk) ovariectomy and long-term estrogen replacement in rats revealed a decline in high-affinity choline uptake and in ChAT activity in frontal cortex and hippocampus that was at least partially prevented by estrogen treatment (167). Estrogen treatment also increased the acetylcholine released by potassium depolarization (168). Estrous cycle variations in ChAT mRNA levels were also reported in the basal forebrain cholinergic system (168). Along with these effects, long-term ovariectomy caused a decline in learned performance of active avoidance behavior that was prevented by estrogen replacement therapy (167).

One possible candidate as a regulator of the cholinergic system of the basal forebrain is nerve growth factor (NGF), which is produced by the hippocampus and transported retrogradely to basal forebrain neurons to produce trophic effects. Although the effects of estrogen treatment on NGF levels in hippocampus remain to be investigated, ER{alpha} have been reported to colocalize with low-affinity NGF receptors in cholinergic neurons of the basal forebrain of the newborn rat (169). Moreover, estrogen replacement in both young and aged female rats increases both trkA (NGF receptor) mRNA and ChAT mRNA expression in basal forebrain (170).

The basal forebrain of male rats failed to show the same response to estrogen treatment as females, and postnatal estrogen treatment of females or blockade of aromatization in males failed to change this sex difference (166, 171), indicating that the sexual differentiation of the cholinergic system either occurs earlier in development or does not involve the aromatization of testoserone to estradiol. Additional studies revealed that the basal forebrain cholinergic system differs between male and female rats, with females having smaller and more densely packed cholinergic neurons compared with untreated males (172). Moreover, application of T3 to newborn male and female rats, creating transient hyperthyroidism during the first week of postnatal life, revealed further indications of sexual differentiation of the basal forebrain cholinergic system in which male rats responded to the treatment while females did not (172). For example, treatment with T3 increased cholinergic cell density and induced increased ChAT activity and muscarinic receptor binding in the septum/diagonal band region of males. Females did not respond to T3 in most respects, except in medial septum where they showed the opposite effect to males, namely, an increased cholinergic cell body area (172). This finding suggests that there is an interaction between the prenatal effects of testosterone in the development of the cholinergic system of the basal forebrain (173) and the postnatal effects of T3 (172).

On the other hand, in another study of sex differences in the cholinergic system, female rats showed larger effects than males to the cholinergic lesions produced in hippocampus by the specific cholinergic neurotoxin, AF64A, and females were particularly sensitive when the toxin was administered into the lateral ventricles on the day of proestrus (174). A recent clinical study of estrogen replacement in relation to Alzheimer’s disease revealed that the beneficial effects of tacrine, a cholinergic-enhancing drug, were evident in women on estrogen replacement therapy and not in women who did not receive estrogen replacement therapy (175).

Taken together, these results point to a sexually differentiated organization of the basal forebrain cholinergic system in the rat, involving a prenatally programmed difference in the neuroanatomical organization as well as sex differences in response to estradiol as far as cholinergic enzyme induction in adult life and the effects of T3 treatment within the first week of postnatal life. These differences may underlie, at least in part, the sex differences in spatial learning that are discussed below.

C. Estrogens and the serotonergic system
Serotonin neurons of the midbrain/brainstem raphe nuclei are among the earliest neuronal phenotype to become differentiated during CNS development, and serotonin is believed to act as a regulatory/developmental agent (176, 177). The more rostral nuclei (primarily the dorsal and medial raphe) form ascending projections, densely innervating such forebrain regions as the hypothalamus, hippocampus, and cortex. Thus, the serotonergic system is involved in the regulation of such diverse functions as reproduction, mood, sleep, and cognition. While serotonergic activity is regulated by the ovarian steroids, the mechanisms by which such regulation occurs are not fully understood. Here, we will briefly review findings that suggest involvement of both presynaptic and postsynaptic actions.

A sex difference in the serotonin system of the rat brain is established by the end of the second postnatal week (178). Female rats demonstrate higher serotonin levels and/or synthesis measured in whole brain (179), forebrain (180), raphe (181), frontal cortex (182), hypothalamus (181, 182, 183), and hippocampus (182, 184) compared with the male rat brain. A similar sex difference in rat brain serotonin turnover, an indication of serotonergic activity, has also been reported (180, 185). Furthermore, brain serotonin levels and activity are altered during periods of physiological ovarian hormone fluctuation, including the estrous cycle, pregnancy, or the postpartum period (186, 187, 188, 189, 190) in the rodent. In addition, estrogen and/or progesterone treatment of ovariectomized rats has been shown to positively affect the serotonergic system of the female rat brain (51, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202).

In addition to reporting significant increases in hippocampal serotonin levels and synthesis rate in females, Haleem and colleagues (184) found that female rats are much more responsive to the 5-HT1A receptor-mediated inhibition of serotonin synthesis. That is, after the administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin, female rats exhibited a decrease in hippocampal serotonin synthesis that was twice that seen in males. This may be partly explained by the finding that estrogen treatment increases the efficiency of the 5-HT1A receptor to inhibit cAMP formation in isolated membrane fractions in the hippocampus (203).

With regard to the estrogen sensitivity of serotonergic neurons, the direct or indirect nature of hormone action is only now beginning to emerge at the level of the raphe nuclei. Estrogen-concentrating cells, determined by autoradiography, have been previously reported in the raphe nucleus in the male and female lizard, Anolis carolinensis, but it was not determined whether the cells were serotonergic (204). More recently, in rhesus macaques, Bethea (205) demonstrated the presence of estrogen-inducible PR in a majority of serotonin neurons, as well as in nonserotonin cells, in the dorsal and ventral (medial) raphe of intact and spayed estrogen- and progesterone-treated macaques. Because progesterone treatment of estrogen-primed macaques increases PRL release via a serotonergic mechanism (206, 207), the finding of PR in serotonin neurons provides a direct means by which the ovarian steroids can regulate serotonergic function. In addition, Bethea’s group has demonstrated that ovarian hormones increase the expression of tryptophan hydroxylase (TPH), the key enzyme in serotonin biosynthesis, and suppress expression of the serotonin transporter (SERT) in the macaque raphe nuclei (208, 209). For a recent review, see (210). While TPH mRNA levels do not appear to be regulated by estrogen or progesterone in the rat dorsal raphe (S. Alves and B. McEwen, unpublished results), SERT mRNA has been reported to be increased by estrogen in the dorsal raphe of this rodent species (211). It is not presently known whether this difference in SERT regulation between the macaque and the rat is due to difference(s) in species and/or length of hormone treatment.

Curiously, the rat does not show localization of ER{alpha} or PR in serotonergic neurons (38) in spite of the ample evidence for ovarian hormone regulation of serotonergic function in the rat brain. However, a number of ER{alpha} and/or PR immunoreactive neurons are found within the female and male rat dorsal raphe, adjacent to the serotonin cells (Fig. 4Go), suggesting transsynaptic regulation; females were found to have significantly more PR-containing cells, but no sex difference in the number of ER-labeled cells was observed (38). Recent data indicate that a subpopulation of these steroid target cells demonstrate immunoreactivity to the excitatory amino acids, glutamate and aspartate (212). ERß mRNA has been reported within the dorsal raphe of the rat (47), although ERß protein has not yet been detected (38) (see Section II.C for discussion of possible explanations for this type of discrepancy). Yet there are estrogen effects in the rat serotonin system that may eventually be explained by the presence of functional ERß.



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Figure 4. Map of ER- and PR-containing neurons in the rat midbrain dorsal raphe region and surrounding periaqueductal gray (PAG). Each dot represents approximately two immunoreactive cells. A, Nuclear {alpha} ERs (ER{alpha}) in gonadectomized (GDX) rats. B, Nuclear PRs in GDX rats treated with estradiol benzoate for several days. The brain levels depicted are measured in distances from Bregma (B). Note the higher density of cells containing ER{alpha} immunoreactivity at the more rostral levels of the dorsal raphe nucleus (DRN) but the higher concentration of PR-immunoreactive cells specifically within the lateral wings (LW) of the DRN, depicted at level B - 8.30. In contrast to most other regions of the DRN examined, this population of neurons maintains rather abundant PR immunoreactivity without E priming. AQ, Cerebral aqueduct; ELi, caudal linear raphe nucleus; V4, fourth ventricle. [Reproduced with permission from S. Alves et al.: J Comp Neurol 391:322–334, 1998 (38 ). © Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.]

 
Estrogen and progesterone treatment alters the expression of several genes within the rat dorsal raphe nucleus that are involved in serotonergic transmission: the postsynaptic 5-HT2A receptor (37, 213) and the presynaptic SERT (211) and vesicular monoamine transporter (VMAT2) (214). These data suggest that ovarian steroids are likely to modulate serotonergic transmission at the dorsal raphe by regulating both nonserotonergic and serotonergic cells. Interestingly, recent findings indicate that the former two genes appear to be similarly regulated by estrogen in females and males (37, 215), which is in agreement with the lack of a gender difference in the number of ER{alpha}-containing cells within this nucleus. Ovarian steroid regulation of VMAT2 has been reported only in females, and in this study it was demonstrated that progesterone, either alone or in combination with estrogen treatment, decreased VMAT2 mRNA to a similar extent. It would be interesting to investigate whether such regulation occurs in males, considering the gender difference in PR immunoreactive cells within the dorsal raphe (38).

Thus far, the only conclusion to be drawn is that ovarian hormones may work indirectly in the rat brain through adjacent neurons that express ER{alpha} and/or PR, and perhaps both directly and indirectly in the macaque raphe nuclei, to influence serotonergic function at the midbrain level. However, as noted, the demonstration of functional ERß in the dorsal raphe could change this interpretation, particularly for the rat. Moreover, the rat may be unusual, in that preliminary evidence from the mouse suggests that ER{alpha} or PR immunoreactivity occurs in some TPH-labeled neurons, and abundantly in non-TPH cells in the dorsal raphe, suggesting direct steroid regulation of at least a subpopulation of serotonin cells in this rodent species (212). It should be mentioned that while estrogen-induced PR have been identified in serotonin neurons in the macaque (as described above), ER{alpha}s have not been detected in the macaque raphe (C. L. Bethea, personal communication), once again raising the issue of a problem in antigen detection and/or rather that ERß may be the functional ER in this species. Recent evidence from the ERKO mouse indicates abundant estrogen binding in the dorsal raphe (216), strengthening the idea that ERß may play an important role in this brain region.

Thus, by a multiplicity of pre- and postsynaptic mechanisms, ovarian steroids affect serotonergic function in a sexually dimorphic fashion, and these actions are relevant to the actions of estrogens on mood and cognition. High doses of estrogens were reported to have antidepressant effects in human subjects (217), and estrogen treatment influences the response to antidepressant drugs in animal models (8) and in clinical studies (10). Moreover, estrogen treatment of ovariectomized rats led to less struggling or immobility, and more time swimming, in the forced swim test, a measure of anxiety; and estrogen treatment reduced the number of cells expressing the immediate early gene, c-fos, during the forced swim test (218). Both of these results are consistent with an antianxiety effect of estrogens in the rat and human. Indeed, results from a recent clinical trial of fluoxetine (Prozac, Eli Lilly, Indianapolis, IN) indicated that women receiving estrogens as well as Prozac were the most responsive (10). However, in view of the small sample size in that study, this is a finding that needs to be replicated in a larger study.

D. Catecholaminergic neurons
1. Noradrenergic system. In addition to the cholinergic and serotonergic systems, catecholaminergic systems respond to estrogens, i.e., brainstem catecholaminergic neurons (A6 and to a lesser extent A5 and A7) contain small numbers of ER (219), and estrogen treatment after gonadectomy exerts complex, time-dependent effects on the level of tyrosine hydroxylase mRNA (220). Moreover, recent studies of rats (221) and sheep (222) indicate that A1 and A2 noradrenergic neurons specifically express the ER{alpha} and show cyclical and estrogen-dependent patterns of immediate early gene expression (223, 224). In the rat locus ceruleus, galanin is coexpressed in many noradrenergic neurons, and estrogen treatment increased the expression of galanin mRNA, leading to the speculation that estrogen treatment might reduce noradrenergic tone in the absence of separate effects on tyrosine hydroxylase expression by enhancing the cosecretion of galanin, which reduces noradrenaline release (225).

2. Dopaminergic systems. Incertohypothalamic dopamine neurons are distributed in the rostral, periventricular, caudal, and dorsomedial regions of the hypothalamus and represent an internal source of dopamine innervation for the hypothalamus and preoptic region (226). The incertohypothalamic dopamine neurons express sex differences in neuron number and function (227). Estrogen and PRL have heterogeneous effects on dopamine turnover, increasing it in dorsomedial nucleus and decreasing it in rostral periventricular, medial preoptic, and preoptico-suprachiasmatic nuclei (228).

In the midbrain dopaminergic projections to the corpus striatum and nucleus accumbens, there are sexually dimorphic actions of estrogens and progestins, involving both pro- and antidopaminergic effects that depend on the dose and time course of estrogen administration and are manifested in both the nigrostriatal and mesolimbic dopaminergic systems (229, 230). Estrogen facilitates amphetamine- or apomorphine-stimulated dopamine release and locomotor activity in rats unilaterally lesioned by 6-hydroxydopamine (231, 232, 233), and this activity is responsive to natural fluctuations in estradiol and generally increased during late proestrus and early estrus (232, 233, 234). Spontaneous sensorimotor activity is also influenced by estrogens, e.g., in a "tight-rope" walking task (235). Coordination of locomotor activity may also involve estrogen actions in other brain regions, such as cerebellum, where membrane actions of the steroid are suspected on the basis of rapidity of effects and absence of known intracellular receptors (1, 98). In spite of their rapidity, these effects must still be considered in terms of the presence of ERß mRNA in cerebellum and cerebral cortex (48) even though functional ERß protein has not yet been demonstrated (see Section II.C).

In striatum, ovariectomy decreases, and administration of estradiol potentiates, the depolarization-induced release of dopamine as well as rotational behavior in a sexually dimorphic pattern (236, 237, 238, 239, 240). Male rats show smaller responses to estrogen than females, and castration of males does not affect the amphetamine stimulation of rotational behavior or striatal dopamine release (234, 241, 242).

In females, no classical ER have been identified in striatum (63, 64, 243); nevertheless, intrastriatal application of estradiol rapidly causes rotational behavior (244) and enhances sensorimotor performance (235). Estrogen directly potentiates potassium-stimulated dopamine release from rat nucleus accumbens (102), and estrogen pretreatment increases the firing rate of neostriatal neurons in response to dopamine (245), possibly via changes in D1 or D2 receptor coupling (246). A variety of estrogen effects on dopamine receptor binding have been reported (see Refs. 229, 230 for reviews).

Estrogen actions in the striatum that do not involve the classical ER have been proposed on the basis of four types of evidence: 1) the lack of intracellular ER in striatum; 2) the rapidity of estrogen effects; 3) the pharmacological profile of estrogen action, particularly the ineffectiveness of diethylstilbestrol; and 4) the ability of estradiol conjugated to BSA to mimic effects of free estradiol (247). One possible explanation, already described above, are the actions of estradiol to reduce L-type calcium channel activity in striatal neurons via a G-protein-coupled receptor (121).

The dopamine system shows declining function in the aging brain (248), and clinical observations indicate antidopaminergic effects of moderate to high doses of estrogens. Relatively high levels of estrogens, including oral contraceptives and estrogen replacement therapy, exacerbate symptoms of Parkinson’s disease (6, 249, 250), pointing to antidopaminergic actions that are opposite to the actions of physiological levels of estradiol. A similar antagonistic effect of chronic or high-dose estrogen was found in male and female rats for drug-induced motor activity (251, 252).

E. Spinal cord
The spinal cord contains limited numbers of cells demonstrating intracellular ER, and there is also evidence for antinociceptive and analgesic actions of estrogens, with a large sex difference that may be mediated at the spinal level or at other levels of the neuraxis (for discussion see Refs. 253, 254). However, the information is rather limited regarding possible genomic or nongenomic mechanisms, and functional studies do not coincide with the information about ER localization.

ER{alpha}s have been colocalized by immunocytochemistry with enkephalin in many neurons in the medullary and spinal dorsal horn, particularly in the superficial laminae where they could be involved in modulating sensory and nociceptive processing (253, 254). A moderate concentration of labeled cells expressing ERß mRNA has been reported in lamina II of the spinal cord, whereas scattered cells expressing ER{alpha} mRNA were found in laminae I and II, the medial portion of laminae VI and VII, and in lamina X near the central canal (47).

Pain sensitivity differs strikingly between men and women and in women in different reproductive hormone states (see below and Refs. 253, 254). Sex differences in analgesia have been reported in mice along with sex-specific effects of estrogens. In particular, nonopioid analgesia produced by swim stress was different between male and female Swiss-Webster mice and became equalized by ovariectomy; estrogen replacement of ovariectomized females reversed the effect, but estrogen treatment of intact or castrated males had no effect, indicating an insensitivity of this system to estrogens in the male mouse (254). In a follow-up study, quantitative trait locus (QTL) mapping was carried out and led to the identification of a female-specific QTL on chromosome 8 (255). This female-specific mechanism, which is sensitive to estrogen modulation, is consistent with a gene that is turned off by testosterone exposure during sexual differentiation (256). Because it involves nonopioid analgesia, this form of estrogen-sensitive analgesia is unlikely to be related to the enkephalin/estrogen colocalization described above or to NMDA-receptor mediated analgesia to which mice are also insensitive; rather, a novel form of nonopioid, non-NMDA analgesia is indicated (254, 255). The role of ERß mRNA expression in spinal cord and its relationship to functional ERß receptors in this structure remain to be established.

F. Hippocampus
1. Cyclic synaptogenesis on hippocampal neurons. While synapses are formed and eliminated during development, synaptogenesis was, until recently, believed to be more limited in the adult nervous system. Estrogens regulate synapse density in the adult rat hypothalamic ventromedial nucleus that differs between males and females (145, 257, 258). This discovery led to the finding that the ovarian cycle regulates cyclic synaptogenesis on excitatory spines in hippocampal CA1 pyramidal neurons in female but not in male rats (259, 260). Synaptogenesis is cyclic, and fluctuations in synapse density occur throughout the estrous cycle of the female rat (158). The increase in synapses on dendritic spines after estrogen treatment is shown in Fig. 5Go, along with the decrease in spine synapse density that occurs between the days of proestrus and estrus in cycling female rats. Male rats show much less estrogen-induced synapse formation unless they are treated at birth with an aromatase inhibitor (260). This suggests that the developmentally regulated expression of ERs and aromatase activity in hippocampus (261, 262) is involved in programming the response of the adult hippocampus.



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Figure 5. Depiction of ovarian steroid regulation of the density of excitatory spine synapses in the CA1 region of the female rat hippocampus. Estimated density of synapses on dendritic spines in the stratum radiatum of the CA1 region of the hippocampus, in panel A, of an ovariectomized (OVX) rat treated with oil (O) or estradiol (E) or, in panel B, of intact rats in the proestrus or estrus phase of the estrous cycle. Values represent mean ± SEM obtained using the Disector method. Note that in each case, higher estradiol levels are correlated with a greater density of synapses. Data were analyzed with unpaired, two-tailed t tests, n = 4 in each case. *, P < 0.025. [Reproduced with permission from C. Woolley and B. S. McEwen: J Neurosci 12:2549–2554, 1992 (158 ).]

 
Cyclic synaptic turnover in the hippocampus and hypothalamus during the estrous cycle of a female rat shows a high degree of specificity. For example, in hypothalamus, neurons of the ventromedial nucleus show cyclic synaptogenesis directed by ovarian steroids. In CA1 pyramidal neurons of the hippocampus, estrogen-induced synaptogenesis occurs on dendritic spines and not on shafts, and there are no estrogen effects on dendritic length or branching; moreover, as far as one can tell, such synaptic plasticity is extremely specific and does not occur on CA3 pyramidal neurons or dentate gyrus granule neurons (263). The discreteness and specificity of this synapse formation imply that molecular markers may be very specific or subtle and that the mechanism may involve changes in a limited number of cellular events, including transcription of discrete structural genes and posttranscriptional events such as translation of mRNAs for structural proteins. Moreover, local regulation, as via afferent input or interneurons, may be very important.

One of the surprises of the synaptogenesis story is that estrogen induction of synapses is blocked by NMDA receptor antagonist treatment, indicating that excitatory amino acids and NMDA receptors are involved in synapse formation (264, 265). Progesterone secreted at the time of ovulation appears to be responsible for down-regulation of estrogen-induced synapses in the CA1 region (266), and the cellular location of PRs, as well as of the ERs, is a prime question.

2. Localization of intracellular ERs. The presence of the classical ER{alpha} and the recently discovered ERß complicates the story of estrogen action. ER{alpha}s have been identified by immunocytochemistry in scattered GABA-ergic interneurons in the rat hippocampus (39), and this distribution of ER is in agreement with autoradiography of [3H]estradiol uptake (267), so that one does not need to postulate the existence of another high-affinity intracellular ER. The localization of ER{alpha} is summarized for the hippocampus and adjacent cerebral cortex in Fig. 6Go. ERß expression has been claimed in pyramidal neurons by immunostaining and also mRNA expression (46, 47, 65), although, as mentioned previously, our laboratory has not seen consistent ERß immunostaining in hippocampus (N. Weiland, S. E. Alves, V. Lopez, and K. Bulloch, unpublished). Clearly, more studies are needed on this issue. There are a number of plant estrogens, genestein and daidzein, with approximately 20-fold higher affinities for ERß than ER{alpha}, which makes them useful to discriminate between the two receptor types (55, 268), and these may be useful in further studies on the role of ERß in the hippocampus.



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Figure 6. Map of ER{alpha} immunoreactivity in the hippocampus and cortex of the rat brain. [Drawings are modified from L. W. Swanson, Brain Maps: Computer Graphic Files (version 1.0), and represent coronal sections from three different levels of brain measured from bregma.] Each dot represents one ER{alpha}-immunoreactive cell (total number is mean from male and female rats, which do not differ significantly from each other). Note the ER{alpha} immunoreactivity cells are interneurons, not pyramidal neurons, in agreement with previous autoradiographic studies (see text). DGlb, Lateral blade of the dentate gyrus; ENT, entorhinal cortex; fc, fasciola cinerea; fi, fimbria; hf, hilar fissure; mo, molecular layer of the dentate gyrus; PAR, parietal cortex; po, polymorph layer (hilus) of the dentate; RSP, retrosplenial cortex; sg, stratum granulosum; so, stratum oriens; sp, stratum pyramidale; sr, stratum radiatum; SUB, subiculum; v3, third ventricle; vip, velum interpositum; vl, lateral ventricle. [Reproduced with permission from N. G. Weiland et al.: J Comp Neurol 388:603–612, 1997 (39 ). © Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.]

 
3. Role of the NMDA receptors. Antagonists of NMDA receptors blocked estrogen-induced synaptogenesis on dendritic spines in ovariectomized female rats (264, 265). Because estrogen treatment increases the density of NMDA receptors in the CA1 region of hippocampus (265, 269, 270), it is possible that activation of NMDA receptors by glutamate is the primary action that induces new excitatory synapses to develop. Spines are occupied by asymmetric, excitatory synapses, and they are sites of Ca++ ion accumulation and thus ideal sites for NMDA receptors (271). NMDA receptors are expressed in large amounts in CA1 pyramidal neurons and can be imaged by conventional immunocytochemistry as well as by confocal imaging (270), in which individual dendrites and spines can be studied for colocalization with other markers (272, 273). NMDA receptor mRNA can also be measured by in situ hybridization, and four different forms show different regional patterns and developmental regulation (274).

NMDA receptors are implicated in other morphogenetic processes in the adult brain such as suppressing neurogenesis in the dentate gyrus (275), and they are also involved in the developing nervous system as facilitators of neuronal migration (276, 277). However, there is a noteworthy paradox, in that NMDA receptors are implicated during visual system development in the reduction of synaptic contact in the developing retinal axon arbors (278), and NMDA receptor blockade results in rapid acquisition of dendritic spines by visual thalamic neurons (279). It appears likely that hippocampus and visual system neurons respond in opposite ways to NMDA receptors, since a recent report on embryonic hippocampal neurons in culture (see Section III.F.5 below) indicates that NMDA receptor blockade prevents estrogen-induced synaptogenesis (280).

4. Genomic vs. nongenomic actions of estrogens on synapse formation. The paradoxical estrogen effects on hippocampal pyramidal neurons that do not appear to have intracellular ER{alpha} or show uptake and cell nuclear retention of [3H]estradiol might be explainable if there were cell surface ERs. Rapid estrogen effects on CA1 pyramidal neurons of the hippocampus have been described by in vitro electrophysiological studies on slices from this brain region, and these appear to involve non-NMDA excitatory amino acid receptors (94, 95) that are very likely to be AMPA ({alpha}-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (96). One approach to rule in or out nongenomic actions of estrogen would be to study ERKO mice lacking intracellular ER{alpha} (43), and a recent study with mice lacking ER{alpha} has shown that estrogen actions on kainate-stimulated ionic currents are still present (103). An ER double knockout would be even better, provided there are only two intracellular ER genes.

Another approach to discriminate between classical intracellular ER and membrane ER is to use antiestrogens that bind to the intracellular ER but which mimic, rather than block, the rapid membrane effects, such as was the case for estrogen effects on calcium currents in neurons from the corpus striatum (121). Antiestrogens also have another use, namely, to discriminate between the response elements that the ER uses to activate transcription. As noted above, the major differences between ER{alpha} and ERß1 concern their ability to regulate transcription via the AP-1 response element. For interactions of ER{alpha} with AP-1, 17ß-estradiol as well as a number of antiestrogens activated transcription; however, for ERß1 interacting with AP-1, 17ß-estradiol failed to activate transcription but antiestrogens activated transcription (69).

Estrogen antagonists have been very useful in testing alternatives to conventional genomic actions of estrogen on hippocampal synapse formation by providing pharmacological evidence in favor of a particular pathway of hormone action and against other possible mechanisms (281). The antiestrogen, CI-628, has previously been shown to enter the brain and block estrogen induction PR (see Fig. 3Go). The same dose of CI-628 that blocked PR induction was also able to block spine synapse induction by estrogen in the hippocampus, and CI-628 did not have any agonist-like activity of its own (281) (see Fig. 7Go). An agonist-like action of CI-628 would have been expected had it exerted its action nongenomically via calcium channels, as has been shown for striatal neurons (121). An agonist-like action might also have occurred via ER{alpha} or -ß, or a heterodimer, acting via another response element than the ERE (see Section II.C). The fact that CI-628 blocked, rather than mimicked, estrogen action is inconsistent with any known nongenomic effect and is similar to the estrogen induction of PRs that is believed to involve an ERE (282). Moreover, it is consistent with an action of estrogen via the intracellular ER{alpha}s that are known to exist in hippocampal interneurons, although, again, it should be pointed out that ERß could also mediate actions via an ERE and that the presence of some functional ERß in hippocampus is still a distinct possibility given the presence of ERß mRNA in this brain region (see Section II.C).



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Figure 7. Effect of the estrogen antagonist, CI-628, on estrogen induction of increased dendritic spine density on CA1 pyramidal neurons. CI-628 (10 mg/kg) was given at 0, 24, and 48 h, and estradiol benzoate (EB, 10 µg/kg) was given at 24 and 48 h to ovariectomized female rats, which were then killed at 72 h. The single-section Golgi procedure was carried out to stain dendrites of CA1 pyramidal neurons for visualization of dendritic spines. Data are expressed as the number of spines/10 µm length on secondary dendrites that were greater than 10 µm in length and located 150–200 µm away from the cell body. Six CA1 neurons fulfilling the criteria described in the original publication (281 ) were analyzed for each rat brain. The number of rats per group was six for the CI628 + EB group and five for each of the other treatments. The error bars show the SEM; this is based on the mean and variance calculated across animals, with data for the six neurons of each animal in a treatment compiled into a single average. Statistical analysis of data revealed that there was an overall treatment effect, P < 0.0001, by one-way ANOVA. A Tukey post hoc comparison revealed a clear E induction of spines, in which ovx + E was different from each of the other groups (P < 0.001). Moreover, CI-628 partially blocked the E effect, in that ovx + E + CI-628 was significantly elevated compared with OVX (P < 0.01) and significantly less that ovx + E (P < 0.001). There was no agonist effect of CI-628 by itself on spine density (P = 0.92). [Reproduced with permission from B. S. McEwen et al.: Endocrinology 140:1044–1047, 1999 (281 ). © The Endocrine Society.]

 
5. Synapse formation in cultured hippocampal neurons. Recent studies on hippocampal neurons in culture have revealed that estrogen induces spines on dendrites of dissociated hippocampal neurons in culture by a process that is blocked by an NMDA receptor blocker and not by an AMPA/kainate receptor blocker (283). In a subsequent study, estrogen treatment was found to increase expression of PCREB and CREB, and a specific antisense to CREB prevented both the formation of dendritic spines and the elevation in PCREB (284).

ER{alpha}s have been located on glutamic acid carboxylase (GAD)-immunoreactive cells in vitro that constitute approximately 20% of neurons in the culture (39), and this is consistent with in vivo data summarized above. 17ß-Estradiol treatment of cultured cells caused GAD content and the number of neurons expressing GAD to decrease, and mimicking this decrease with an inhibitor of GABA synthesis, mercaptopropionic acid, caused an up-regulation of dendritic spine density, simulating the effects of 17ß-estradiol (285). Figure 8Go summarizes the hypothesized interaction between these GABA interneurons and the pyramidal neurons upon which the synapses are induced by estrogen treatment. Both cell culture data and in vivo studies summarized above are consistent with this model.



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Figure 8. This model of synaptogenesis in the hippocampus emphasizes the role of NMDA receptors and the key role of inhibitory GABA interneurons. ER{alpha} is present in interneurons, and its presence coincides with the distribution of ER-binding sites from in vivo [3H]estradiol autoradiography. According to the best evidence to date, based upon immunocytochemistry of hippocampus and cell culture studies, estrogens suppress GABA function transiently and lead to disinhibition of a large number of innervated CA1 neurons resulting in up-regulation of NMDA receptors and synapse formation. Blocking NMDA receptors prevents estrogen-induced synapse formation.

 
An additional factor in the formation of dendritic spines in the in vitro cell culture model is the neurotrophin, brain-derived neurotropic factor (BDNF), which is expressed in GABA interneurons in hippocampal cell cultures (286). In addition to down-regulating GABA in these interneurons, estrogen treatment also reduced BDNF by 60% within 24 h (286). Since exogenous BDNF blocked estrogen induction of dendritic spines and BDNF depletion with an antisense or blockade with BDNF antibodies both mimicked estrogen in inducing spine density, the authors suggest that BDNF is an important player in the regulation of GABA inhibition, which in turn blocks activity-dependent regulation of dendritic spines in hippocampal neurons (286). It is interesting to note that neurotrophins such as BDNF and NT-3 also increase the function of inhibitory and excitatory synapses in hippocampal cell cultures, and BDNF causes an increase in axonal branching and length of GABA-ergic interneurons (287).

6. Developmentally regulated sex differences in the hippocampus. The hippocampus is one of a number of extrahypothalamic brain structures that shows subtle sex differences. For example, there are sex differences in the density of apical dendritic excrescences and branching of dendrites of CA3 pyramidal neurons. Treatment with T3 during the first week of postnatal life enhanced these differences (288). Excrescences on the proximal region of apical dendrites receive input from mossy fiber synapses from granule neurons of the dentate gyrus. Therefore, the greater density of excrescences in males is consistent with a report that male rats have a greater number of mossy fiber synapses than females (289). Other studies have pointed to sex differences in hippocampal morphology that are dependent on the rearing environment (290).

The dentate gyrus of mice and rats also shows sex differences. In mice, there are strain-dependent sex differences: in strains with large numbers of granule neurons, males have more neurons than females, while in strains with fewer granule neurons, the sexes do not differ from each other in neuron number (291). Male rats have a larger and more asymmetric dentate gyrus than females, and neonatal testosterone treatment caused the genetically female dentate gyrus to appear male like (292). Neonatal testosterone treatment in female rats also improved spatial learning ability in a Morris water maze (292).

How do these sex differences come about during development? Like the cerebral cortex, the rat hippocampus expresses ER{alpha} transiently during perinatal development (261, 293). The presence of these receptors in hippocampus coincides with the transient expression of the aromatizing enzyme system that converts testosterone to estradiol (294); as a result, ER{alpha} in male rats would be exposed to locally generated estradiol, and this could lead to sexual differentiation of hippocampal structure and function. Consistent with this scenario are data showing that, while neonatal castration of male rats produced female-like learning curves in a Morris water maze, the administration of estradiol to newborn female rats produced a male-like learning curve (295).

It should be noted that the cell culture model described above for studying estrogen-induced synaptogenesis in vitro lies right on the interface between developmental actions of estrogens and the activational effects in mature neurons. That is, the cell cultures are generated from late fetal brain tissue before the stage of sexual differentiation has been completed; however, the fact that the hippocampal cell cultures are allowed to mature in vitro, differentiate into excitatory and inhibitory neurons, and form synaptic connections makes them more like the mature nervous system. It is interesting to consider whether application of gonadal steroids during the differentiation and formation of synaptic connection might mimic aspects of the sexual differentiation of hippocampal circuits and functions described above and might lead, for example, to a permanent "male-like" inability of the cultures to show synapse induction in response to estradiol.

7. Comparison with other forms of structural plasticity. The hippocampus also undergoes two other forms of plasticity, in which circulating hormones and excitatory amino acids acting via NMDA receptors are involved. One of these is the ongoing neurogenesis in the adult rat dentate gyrus, which continues for at least 1 yr after birth and can be increased either by adrenalectomy or by treatment with an NMDA receptor antagonist (275). Although the male dentate gyrus is larger than that of the female (296), there are data for the prairie vole (297) and rat (298) indicating that estrogens increase neurogenesis of granule neurons in the female. Thus, it remains to be established for males and females what the balance is between neurogenesis and programmed cell death to account for sex differences in overall neuron number between the sexes.

Dentate gyrus granule neurons innervate the CA3 region of Ammon’s horn, and stress causes apical dendrites of CA3 pyramidal neurons to undergo atrophy by a process that is dependent in part on circulating adrenal steroids and in part on excitatory amino acids acting via NMDA receptors (299). Stress-induced dendritic atrophy is also reversible (A. M. Magarinos and B. S. McEwen, unpublished), but severe and prolonged social stress (in vervet monkeys) and cold-swim stress (in rats) causes CA3 pyramidal neuron loss in males that is not evident in females (164, 165). Thus, there is the possibility that intrinsic sex differences in hippocampal morphology or in response to hormones or excitatory amino acids may have a protective role in the female.

A recent study indicates that female rats are also resistant to the stress-induced atrophy of CA3 pyramidal neurons in hippocampus (300). In addition to the larger dentate gyrus of the male (296), male CA3 neurons have more excrescences for mossy fiber contacts, while female CA3 apical dendrites are more extensively branched (288). However, it is not clear how these differences might contribute to the sex differences in the effects of stress.

8. The functional significance of synaptogenesis in the hippocampus. The functional significance of synaptogenesis in the hippocampal CA1 region has been shown in electrophysiological studies indicating that estrogen treatment of ovariectomized rats produces a delayed facilitation of synaptic transmission in CA1 neurons that is NMDA mediated (95) and leads to an enhancement of voltage-gated Ca++ currents (94, 95). This approach has now been taken to a new level by Woolley, who has used biocytin injection and immunostaining after recording from CA1 pyramidal neurons to visualize estrogen induction of spines; she found that spine density correlates negatively with input resistance and that input/output curves show an increased slope under conditions in which NMDA receptor-mediated currents predominate, whereas there is no increased slope where AMPA receptor currents predominate (265). Moreover, in intact female rats, there is a peak of LTP sensitivity on the afternoon of proestrus in female rats at exactly the time when excitatory synapse density has reached its peak (301).

Proestrus is also the time of the estrous cycle when seizure thresholds in dorsal hippocampus are the lowest (302). Because activation of NMDA receptors in hippocampus is enhanced via AMPA receptors in some cases but not in others (303), it remains to be seen how plastic the AMPA receptor system is to ovarian steroid manipulations or whether the estrogen-induced synapses are so-called "silent" synapses or ones in which AMPA receptors are induced by LTP. Blockade of AMPA receptors with 6-nitro-7-sulfamobenzo(f) quinoxaline-2,3-dione during estrogen treatment failed to block synaptogenesis (264), which suggests that AMPA receptors do not play a major role in the operation of the estrogen-induced synapses.

G. Glial cells, endothelial cells, and the blood-brain barrier
A separate category of estrogen actions concern the glial cells of the brain and the endothelial cells, thus blood-brain barrier, since both cell types affect the entry of vital substances such as glucose into the brain. Glial cells are affected by estrogens in vivo and in vitro (304, 305). In addition, estrogens regulate specific genes such as Apolipoprotein E within astrocytes and microglia (306, 307). Apolipoprotein E is a lipophilic protein involved in cholesterol transport, and its absence has recently been linked to a deficit in synaptic sprouting in the hippocampus (307). Estrogen treatment also regulates morphology of astrocytes in hypothalamus (308) and hippocampus (309, 310, 311, 312), and these changes may reflect a role of glial cells in normal synaptic plasticity as well as lesion-induced plasticity.

Gonadal steroids, including estrogen, regulate the expression of glial fibrillary acidic protein (GFAP). In the arcuate nucleus, estrogen elevation at proestrus transiently increased expression GFAP mRNA in female mice (313). However, removal of gonadal steroids increases GFAP expression in hippocampus (314), and this mirrors the cyclicity of astroglial morphology in the CA1 region of hippocampus, with increases of astrocytic volume on diestrus when estrogen levels are low and decreases of astrocytic volume on proestrus when estrogen levels are elevated (312). It is noteworthy that levels of GFAP mRNA and protein increase throughout the brain as it ages, regardless of gender or species (313, 315), and thus the effect of gonadal steroids in both sexes opposes the effect of aging. Schipper (316) has recently reviewed the relationship between astrocytes and brain aging.

Astroglia play a role in synaptic retraction during the ovulatory cycle in the adult hypothalamic arcuate nucleus. During the preovulatory and ovulatory phases of the female rat estrous cycle, there is a transient disconnection of inhibitory synaptic inputs to arcuate nucleus neurons (317). This remodeling is mimicked by estrogen, blocked by progesterone, and begins with the onset of puberty in female rats; moreover, neonatal testosterone during the sensitive period for sexual differentiation of the brain alters the pattern of synaptic contacts in the arcuate nucleus (317). Astroglia regulate this process of synaptic remodeling by controlling the amount of neuronal membrane available for synaptic contacts and by releasing soluble factors, such as insulin-like growth factor I (IGF-I) (317, 318). The decline in synaptic inputs to arcuate neurons between the morning of proestrus and the morning of estrus was blocked by an IGF-I receptor antagonist (318). Moreover, there seems to be a reciprocal interaction between IGF-I and estrogen, and one speculation is that estrogens may act in arcuate nucleus neurons to regulate the production of a factor, possibly GABA, that, in turn, regulates the expression of IGF-I by astroglia (tanycytes) in the arcuate nucleus region (Refs. 317, 318 ; M. Garcia-Segura, personal communication).

The mechanisms of estrogen action on glial cell function remain unclear. Central glial cells have been reported to express ER{alpha} (304, 305), although receptor protein is not usually detectable in vivo within glia at the light microscopy level (B. S. McEwen, N. Weiland, S. E. Alves, and K. Bulloch, unpublished results). The widespread distribution of ERß mRNA within the CNS may eventually be shown to include expression within astrocytes, oligodendrocytes, and/or microglia.

Glial cells and vascular epithelium also play another role in the adult brain, namely, in relation to glucose uptake and energy metabolism. Ovarian steroids also play a role in the ability of the female brain to utilize glucose as its primary energy source. While ovariectomized rats show a significantly decreased capacity for glucose utilization, estrogen treatment increases this capacity by 20–39% (319, 320). In studies on postmenopausal women with or without estrogen replacement therapy, there were significant enhancing effects of estrogen on verbal and figural memory tests as well as enhancements of cerebral blood flow during the memory tasks (321). One potential mechanism for these effects may be the reported estrogen induction of increased glucose transporter-1 in the endothelial cells of the blood-brain barrier (322). Moreover, one study has reported immunoreactivity for ER{alpha} in cerebrovascular endothelia (304). It has been suggested that decreased capacity to remove glucose from the blood may be a factor that contributes to the cascade of events in Alzheimer’s disease (323, 324, 325), and, indeed, glucose supplementation is beneficial to cognitive function in the aging brain (326, 327).

H. Summary
Estrogens have effects on many brain regions involved in a host of nonreproductive brain functions. Whereas actions of estradiol on hippocampal synaptogenesis appear to be attributable to intracellular ER{alpha} or -ß, actions of estrogens in the striatum and accumbens on dopaminergic activity appear to be mediated by membrane actions that are not characterized as yet in terms of receptors. Estrogen actions on noradrenergic, serotonergic, and hypothalamic dopaminergic systems, on the other hand, are likely to be mediated by known intracellular ER either within these cells and/or in adjacent neurons. The spinal cord also has intracellular ER, but the reported effects on nociception and analgesia do not directly relate to those receptor sites in enkephalin-expressing spinal neurons. Moreover, endothelial cells and at least some glial cells express ER and must be considered as targets for estrogen action that affect glucose uptake and mechanisms that support the replenishment of cell membranes and possibly also synaptogenesis and other forms of structural plasticity. Finally, as will be seen in the next section, estrogen effects on memory have been reported in animal models and in studies on humans. The memories affected are ones in which the hippocampus plays a role along with the basal forebrain cholinergic system.


    IV. Effects of Estrogens on Learning and Memory
 Top
 Abstract
 I. Introduction
 II. Mechanisms of Estrogen...
 III. Areas of the...
 IV. Effects of Estrogens...
 V. Estrogens, Neuroprotection,...
 VI. Conclusions
 References
 
In addition to reducing seizure thresholds and enhancing LTP in hippocampus, estrogen treatment is reported to exert effects on memory, particularly those types of memory in which the hippocampus plays a role. Four types of effects have been reported. First, estrogen treatment of ovariectomized rats has been reported to improve acquisition, as well as choice accuracy, on a radial maze task as well as in a reinforced T-maze alternation task (328, 329, 330). Second, sustained estrogen treatment is reported to improve performance in a working memory task (331) as well as in the radial arm maze (329, 332). Third, estrogen treatment is reported to promote a shift in the strategy that female rats use to solve an appetitive two-choice discrimination, with estrogen increasing the probability of using a response as opposed to a spatial strategy (333). Fourth, aging female rats that have low estrogen plasma levels in the "estropause" are reported to perform significantly more poorly in a Morris water maze than female rats with high estrogen levels (334). The effects of sustained estrogen replacement in rats are reminiscent of the effects of estrogen treatment in women whose ovarian function has been eliminated by surgical menopause or by a GnRH antagonist used to shrink the size of fibroids before surgery (3, 4, 153).

In contrast to the effects of sustained estrogen treatment on memory processes, it should also be noted that, in the natural estrous cycle of the female rat, it has been difficult to detect cyclicity of performance in spatial tasks, with either no effect reported (335), or differences reported in motivational or attentional parameters (336), or an impairment reported in performance on proestrus (337). In female mice, the background strain showed impairment of a spatial memory task by estrogen treatment, whereas the ERKO genotype was unresponsive to estrogen (338). These authors suggest that ER{alpha} activation is responsible for inhibition of spatial discrimination in female mice (338).

In human subjects, there is also some evidence that estrogen treatment has a negative effect on performance of spatial tasks in women while enhancing verbal performance (2, 3, 339). The inhibitory effects of estrogen on spatial memory, while estrogen also appears to have positive effects on declarative memory, may indicate that spatial memory is affected differently from declarative memory. Yet there are additional dimensions to this growing story.

There is evidence for acute actions of estrogen on hippocampal-dependent memory, particularly in relation to the cholinergic system. Posttraining, intrahippocampal injections of estrogen, immediately after training but not 2 h later, enhanced memory in a Morris water maze measured 24 h later, and these effects could be blocked by peripheral administration of the cholinergic antagonist, scopolamine (340, 341). A similar, rapid effect on this memory task was found using systemic estrogen treatment (342). In addition, estrogen treatment of ovariectomized rats also improved performance of a reinforced T-maze alternation task and counteracted the amnestic effects of scopolamine administration systemically or into the hippocampus (343). Moreover, estrogen replacement of ovariectomized rats attenuated the effects of scopolamine and lorezepam to cause deficits in acquisition of a passive avoidance memory task (344), another memory task in which there is a hippocampal involvement (345). Although it is tempting to attribute the cholinergic involvement in these results as effects on "memory," another point of view is that the basal forebrain cholinergic system is concerned primarily with selective attention (346). As far as potential relevance of the cholinergic system to attentional and memory processes in humans, it should be noted again that the beneficial effects of tacrine, a cholinergic-enhancing drug, were evident in women on estrogen replacement therapy but not in women who did not receive hormone replacement (175).

Taken together, estrogens exert complex and time-dependent effects on spatial and declarative memory in animals and humans. The basal forebrain cholinergic system and hippocampus are two brain systems that appear to be involved in both attentional and memory effects of estrogens. At the same time, the inhibition of spatial memory task performance under some experimental conditions in animal models and in human subjects raises questions about the relationship of spatial memory to other forms of memory. The complexity of the estrogen effects on memory suggest that other estrogen-sensitive brain systems, in addition to the cholinergic system and the hippocampus, are also involved.


    V. Estrogens, Neuroprotection, and Alzheimer’s Disease
 Top
 Abstract
 I. Introduction
 II. Mechanisms of Estrogen...
 III. Areas of the...
 IV. Effects of Estrogens...
 V. Estrogens, Neuroprotection,...
 VI. Conclusions
 References
 
We have seen that estrogens affect multiple brain regions and do so via multiple mechanisms that have different consequences for cell function and survival. The decline of ovarian activity after surgical and natural menopause appears to affect a number of brain functions, including mood and certain types of memory, as discussed above. However, these effects appear to be largely reversible and distinguishable from the long-term degenerative changes associated with Alzheimer’s disease, and, for that reason, we consider this topic separately.

It stands to reason that the loss of ovarian hormones may increase the vulnerability of brain cells to damage and degeneration. Indeed, there are recent and somewhat controversial findings that estrogen treatment of postmenopausal women may have a protective effect on the brain toward Alzheimer’s disease. These findings and the concerns raised by them will be reviewed below followed by a discussion of possible mechanisms.

Regarding the evidence for a link between estrogens and Alzheimer’s disease, some, but not all, recent retrospective and prospective epidemiological studies have suggested a possible protective role for postmenopausal estrogen therapy toward Alzheimer’s disease (148, 149, 150, 347, 348, 349, 350). There have also been several prospective studies showing that hormone replacement therapy benefits normal cognitive function in postmenopausal women (351, 352). However, not all studies of this kind have revealed significant effects (353), and justified caution has recently been expressed against any firm conclusions until large, placebo-controlled studies are carried out (350).

A number of estrogen treatment trials have indicated some benefit to demented women as far as improving measures of global cognitive function and mood (151, 152, 354, 355) and also improvements of verbal memory performance in nondemented women (3, 4, 153). However, all of the published trials to date have been quite small in size, short in duration, unrandomized, and uncontrolled, which has prompted caution against overenthusiasm until more data are collected (350).

In spite of the reservations, it is appropriate to ask the following question: By what mechanisms might estrogen exert neuroprotective and cognitive or mood-enhancing effects? Based upon the information covered in the preceding sections of this review article, one can envision two principal pathways: 1) maintaining neural functions and 2) protection against damage.

First, as far as maintaining neural functions, estrogens, as we have seen, regulate neural functions in a wide range of brain structures, including cholinergic and monoaminergic systems that ramify and affect many brain regions, including the hippocampus. As estrogen levels decline over the menopause, these systems and the cognitive and other behavioral processes that depend upon them also decline in their functional capacities; but they are, at least in principle, subject to reversal by estrogen replacement therapy unless irreversible degenerative changes take place.

Second, regarding degeneration and neuroprotection, the absence of estrogens may increase vulnerability of brain cells to insults and to the effects of other age-related changes in neural function. We have seen above that the A ring of the estrogen molecule appears to have special properties with respect to the formation of free radicals and special protective effects on cells in culture that are deprived of serum or exposed to free radical generators (see above). In vivo studies of estrogen-mediated neuroprotection have reported successful reduction of lesion size by Silastic implants of 17ß-estradiol in male rats subjected to middle cerebral artery occlusion (356). In another study, a single injection of 17ß-estradiol reduced damage to hilar neurons in the hippocampal dentate gyrus of female rats caused by kainic acid treatment (357).

In addition to these interactions of estrogens with neuronal survival in cell culture and in vivo, there is another mechanism that points to a unique action of estrogens in relation to Alzheimer’s disease, namely, the regulation of the secreted form of the amyloid precursor protein and suppression of the toxic ß-amyloid protein (358, 359). This effect has been demonstrated in both fibroblasts and neural cell lines but is thus far without a mechanistic explanation as far as involvement of intracellular ER or some of the nongenomic estrogen actions described above. It should be noted that the ß-amyloid protein produces its toxic effects via the generation of free radicals (360), whereas the secreted form of the ß-amyloid precursor protein is actually neuroprotective against the toxic ß-amyloid protein (361). Recent data from in vivo studies of estrogen action in relation to neuroprotection from ischemia caused by middle cerebral artery occlusion indicate that the increased expression of ß-amyloid precursor protein caused by the ischemia is reduced by a single dose of 17ß-estradiol 2 h before the ischemic episode (362).

Another aspect of brain aging is how the presence or absence of hormones also contributes to aging of the brain, e.g., loss of hippocampal neurons as a result of elevated glucocorticoid activity (156, 157) and consequences of estrogen loss in females, which may include loss of synaptic connections in hippocampus (158) or decline in basal forebrain cholinergic function in the absence of circulating estrogens (159). In addition to the loss of circulating hormones and degeneration of the neural systems that are maintained by them, there are also sex differences in the severity of brain damage resulting from transient ischemia (162) and sex differences in the response of the brain to lesions (163) and to severe, chronic stress (164, 165).


    VI. Conclusions
 Top
 Abstract
 I. Introduction
 II. Mechanisms of Estrogen...
 III. Areas of the...
 IV. Effects of Estrogens...
 V. Estrogens, Neuroprotection,...
 VI. Conclusions
 References
 
Estrogens have numerous effects on the brain throughout the lifespan, beginning during gestation and continuing on into senescence, and they do so via multiple mechanisms in which both genomic and cell surface receptors appear to be involved. For genomic effects, both the ER{alpha} and ERß genes are expressed in brain tissue, and mapping studies continue to reveal new ER-containing cells in regions of the nervous system not previously thought to be estrogen targets. For cell surface actions, receptors are not well characterized, but many actions are reported, ranging from second messenger systems to effects on neuronal excitability and ion channels, as well as calcium ion homeostasis. In addition, estrogens are reported to have neuroprotective effects against free radical-induced damage and to do so, at least in part, via a nongenomic mechanism.

In addition to affecting the hypothalamus and other brain areas related to reproduction, ovarian steroids have widespread effects throughout the brain: on catecholaminergic neurons and serotonergic pathways and the basal forebrain cholinergic system, as well as the hippocampus, spinal cord, nigrostriatal and mesolimbic systems, in addition to glial cells and the blood-brain barrier. Regulation of the serotonergic system appears to be linked to the presence of estrogen and progestin-sensitive neurons in the midbrain raphe, whereas the ovarian steroid effects on cholinergic function involve induction of ChAT and acetylcholinesterase according to a pattern that differs between the sexes. Because of the widespread influences of these various neuronal systems, ovarian steroids have measurable effects on mood and affect as well as on cognition, with implications for dementia. One of the most surprising estrogen effects is the regulation of synapse turnover in the CA1 region of the hippocampus during the 4- to 5-day estrous cycle of the female rat. Formation of new excitatory synapses is induced by estrogen and involves NMDA receptors, whereas down-regulation of these synapses involves intracellular PRs. There are developmentally programmed sex differences in hippocampal structure that may help to explain differences in the strategies which male and female rats use to solve spatial navigation problems. Collectively, the multiple sites and mechanisms of estrogen action in brain underlie a variety of important effects on cognitive and other brain functions as well as possible protection in Alzheimer’s disease.

Therefore, estrogens are now increasingly recognized as multipurpose messengers to many regions of the brain, and they influence many processes and many brain regions throughout the entire lifespan. Estrogen actions on the brain, originally believed to act via a single type of intracellular receptor, are now known to take place through the products of at least two distinct genes for intracellular ER, as well as via a host of actions on the cell surface that are mediated by as yet uncharacterized receptor sites. Because of these widespread and diverse actions throughout the nervous system, it is not so surprising that estrogen actions now include effects on cognitive function, coordination of movement, pain, and affective state, among other processes, and that estrogen withdrawal after natural or surgical menopause can lead to a host of changes in brain function and behavior. The putative neuroprotective effects of estrogens are among the most puzzling and novel, and rapid progress in this area offers some hope for preventing or retarding Alzheimer’s disease, although this aspect must be treated somewhat tentatively until more data are in hand.


    Footnotes
 
Address reprint requests to: Bruce S. McEwen, Ph.D., Laboratory of Neuroendocrinology, Rockefeller University, 1230 York Avenue, New York, New York 10021 USA.

1 Work in the authors’ laboratory on this topic is supported by NIH Grants NS-07080 (to B.Mc.) and by NRSA Fellowship F32 NS-10047 (to S.E.A.) as well as NIH Grant NS-30105 to Dr. Nancy Weiland, a laboratory colleague who has made important contributions to this ongoing story that are covered in this review. Back


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 V. Estrogens, Neuroprotection,...
 VI. Conclusions
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EndocrinologyHome page
C. A. Christian and S. M. Moenter
Critical Roles for Fast Synaptic Transmission in Mediating Estradiol Negative and Positive Feedback in the Neural Control of Ovulation
Endocrinology, November 1, 2008; 149(11): 5500 - 5508.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
D. Della Seta, F. Farabollini, F. Dessi-Fulgheri, and L. Fusani
Environmental-Like Exposure to Low Levels of Estrogen Affects Sexual Behavior and Physiology of Female Rats
Endocrinology, November 1, 2008; 149(11): 5592 - 5598.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
N. Romano, K. Lee, I. M. Abraham, C. L. Jasoni, and A. E. Herbison
Nonclassical Estrogen Modulation of Presynaptic GABA Terminals Modulates Calcium Dynamics in Gonadotropin-Releasing Hormone Neurons
Endocrinology, November 1, 2008; 149(11): 5335 - 5344.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
D. P. Srivastava, K. M. Woolfrey, K. A. Jones, C. Y. Shum, L. L. Lash, G. T. Swanson, and P. Penzes
Rapid enhancement of two-step wiring plasticity by estrogen and NMDA receptor activity
PNAS, September 23, 2008; 105(38): 14650 - 14655.
[Abstract] [Full Text] [PDF]


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Menopause IntHome page
N. Kalleinen, P. Polo-Kantola, S.-L. Himanen, P. Alhola, A. Joutsen, A. S Urrila, and O. Polo
Sleep and the menopause - do postmenopausal women experience worse sleep than premenopausal women?
Menopause Int, September 1, 2008; 14(3): 97 - 104.
[Abstract] [Full Text] [PDF]


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Menopause IntHome page
B. N Frey, C. Lord, and C. N Soares
Depression during menopausal transition: a review of treatment strategies and pathophysiological correlates
Menopause Int, September 1, 2008; 14(3): 123 - 128.
[Abstract] [Full Text] [PDF]


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Phil Trans R Soc BHome page
G. F Ball and J. Balthazart
Individual variation and the endocrine regulation of behaviour and physiology in birds: a cellular/molecular perspective
Phil Trans R Soc B, May 12, 2008; 363(1497): 1699 - 1710.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
D. Mitsushima, K. Takase, T. Funabashi, and F. Kimura
Gonadal Steroid Hormones Maintain the Stress-Induced Acetylcholine Release in the Hippocampus: Simultaneous Measurements of the Extracellular Acetylcholine and Serum Corticosterone Levels in the Same Subjects
Endocrinology, February 1, 2008; 149(2): 802 - 811.
[Abstract] [Full Text] [PDF]


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Nucleic Acids ResHome page
V. Bourdeau, J. Deschenes, D. Laperriere, M. Aid, J. H. White, and S. Mader
Mechanisms of primary and secondary estrogen target gene regulation in breast cancer cells
Nucleic Acids Res., January 17, 2008; 36(1): 76 - 93.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
J. M. Wang, L. Liu, and R. D. Brinton
Estradiol-17 -Induced Human Neural Progenitor Cell Proliferation Is Mediated by an Estrogen Receptor -Phosphorylated Extracellularly Regulated Kinase Pathway
Endocrinology, January 1, 2008; 149(1): 208 - 218.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Cell Physiol.Home page
E. Chang, M. E. O'Donnell, and A. I. Barakat
Shear stress and 17{beta}-estradiol modulate cerebral microvascular endothelial Na-K-Cl cotransporter and Na/H exchanger protein levels
Am J Physiol Cell Physiol, January 1, 2008; 294(1): C363 - C371.
[Abstract] [Full Text] [PDF]


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Reproductive SciencesHome page
E. B. Gold, B. Lasley, S. L. Crawford, D. McConnell, H. Joffe, and G. A. Greendale
Relation of Daily Urinary Hormone Patterns to Vasomotor Symptoms in a Racially/Ethnically Diverse Sample of Midlife Women: Study of Women's Health Across the Nation
Reproductive Sciences, December 1, 2007; 14(8): 786 - 797.
[Abstract] [PDF]


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J. Biol. Chem.Home page
J. Cheng, D. V. Yu, J.-H. Zhou, and D. J. Shapiro
Tamoxifen Induction of CCAAT Enhancer-binding Protein {alpha} Is Required for Tamoxifen-induced Apoptosis
J. Biol. Chem., October 19, 2007; 282(42): 30535 - 30543.
[Abstract] [Full Text] [PDF]


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Biol Res NursHome page
G.C. Lasiuk and K.M. Hegadoren
The Effects of Estradiol on Central Serotonergic Systems and Its Relationship to Mood in Women
Biol Res Nurs, October 1, 2007; 9(2): 147 - 160.
[Abstract] [PDF]


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J. Neurosci.Home page
M. I. Boulware, H. Kordasiewicz, and P. G. Mermelstein
Caveolin Proteins Are Essential for Distinct Effects of Membrane Estrogen Receptors in Neurons
J. Neurosci., September 12, 2007; 27(37): 9941 - 9950.
[Abstract] [Full Text] [PDF]


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NeurologyHome page
W. A. Rocca, J. H. Bower, D. M. Maraganore, J. E. Ahlskog, B. R. Grossardt, M. de Andrade, and L. J. Melton III
Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause
Neurology, September 11, 2007; 69(11): 1074 - 1083.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
X. Fan, H.-J. Kim, M. Warner, and J.-A. Gustafsson
Estrogen receptor beta is essential for sprouting of nociceptive primary afferents and for morphogenesis and maintenance of the dorsal horn interneurons
PNAS, August 21, 2007; 104(34): 13696 - 13701.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
J. Deschenes, V. Bourdeau, J. H. White, and S. Mader
Regulation of GREB1 Transcription by Estrogen Receptor {alpha} through a Multipartite Enhancer Spread Over 20 kb of Upstream Flanking Sequences
J. Biol. Chem., June 15, 2007; 282(24): 17335 - 17339.
[Abstract] [Full Text] [PDF]


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J. Neurosci.Home page
M. Taziaux, M. Keller, J. Bakker, and J. Balthazart
Sexual Behavior Activity Tracks Rapid Changes in Brain Estrogen Concentrations
J. Neurosci., June 13, 2007; 27(24): 6563 - 6572.
[Abstract] [Full Text] [PDF]


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J PsychopharmacolHome page
C. N. Epperson, Z. Amin, F. Naftolin, A. Cappiello, K. A. Czarkowski, S. Stiklus, G. M. Anderson, and J. H. Krystal
The resistance to depressive relapse in menopausal women undergoing tryptophan depletion: preliminary findings
J Psychopharmacol, June 1, 2007; 21(4): 414 - 420.
[Abstract] [PDF]


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Mol. Endocrinol.Home page
M. Lupien, M. Jeyakumar, E. Hebert, K. Hilmi, D. Cotnoir-White, C. Loch, A. Auger, G. Dayan, G.-A. Pinard, J.-M. Wurtz, et al.
Raloxifene and ICI182,780 Increase Estrogen Receptor-{alpha} Association with a Nuclear Compartment via Overlapping Sets of Hydrophobic Amino Acids in Activation Function 2 Helix 12
Mol. Endocrinol., April 1, 2007; 21(4): 797 - 816.
[Abstract] [Full Text] [PDF]


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Hum Reprod UpdateHome page
A. R. Genazzani, N. Pluchino, S. Luisi, and M. Luisi
Estrogen, cognition and female ageing
Hum. Reprod. Update, March 1, 2007; 13(2): 175 - 187.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
J.-C. Dreher, P. J. Schmidt, P. Kohn, D. Furman, D. Rubinow, and K. F. Berman
Menstrual cycle phase modulates reward-related neural function in women
PNAS, February 13, 2007; 104(7): 2465 - 2470.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
X. Fan, M. Warner, and J.-A. Gustafsson
Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons
PNAS, December 19, 2006; 103(51): 19338 - 19343.
[Abstract] [Full Text] [PDF]


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Endocr. Rev.Home page
J. L. Turgeon, M. C. Carr, P. M. Maki, M. E. Mendelsohn, and P. M. Wise
Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies
Endocr. Rev., October 1, 2006; 27(6): 575 - 605.
[Abstract] [Full Text] [PDF]


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HypertensionHome page
K. Ito, Y. Hirooka, Y. Kimura, Y. Sagara, and K. Sunagawa
Ovariectomy Augments Hypertension Through Rho-Kinase Activation in the Brain Stem in Female Spontaneously Hypertensive Rats
Hypertension, October 1, 2006; 48(4): 651 - 657.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
B. S. Rubin, J. R. Lenkowski, C. M. Schaeberle, L. N. Vandenberg, P. M. Ronsheim, and A. M. Soto
Evidence of Altered Brain Sexual Differentiation in Mice Exposed Perinatally to Low, Environmentally Relevant Levels of Bisphenol A
Endocrinology, August 1, 2006; 147(8): 3681 - 3691.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
P. Mendez and L. M. Garcia-Segura
Phosphatidylinositol 3-Kinase and Glycogen Synthase Kinase 3 Regulate Estrogen Receptor-Mediated Transcription in Neuronal Cells
Endocrinology, June 1, 2006; 147(6): 3027 - 3039.
[Abstract] [Full Text] [PDF]


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J. Neurosci.Home page
J. Qiu, M. A. Bosch, S. C. Tobias, A. Krust, S. M. Graham, S. J. Murphy, K. S. Korach, P. Chambon, T. S. Scanlan, O. K. Ronnekleiv, et al.
A G-Protein-Coupled Estrogen Receptor Is Involved in Hypothalamic Control of Energy Homeostasis
J. Neurosci., May 24, 2006; 26(21): 5649 - 5655.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
R. S. Bridges and E. M. Byrnes
Reproductive Experience Reduces Circulating 17{beta}-Estradiol and Prolactin Levels during Proestrus and Alters Estrogen Sensitivity in Female Rats
Endocrinology, May 1, 2006; 147(5): 2575 - 2582.
[Abstract] [Full Text] [PDF]


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ReproductionHome page
R Aguilar, C Bellido, J C Garrido-Gracia, R Alonso, and J E Sanchez-Criado
Estradiol and its membrane-impermeable conjugate estradiol-BSA inhibit tamoxifen-stimulated prolactin secretion in incubated rat pituitaries.
Reproduction, April 1, 2006; 131(4): 763 - 769.
[Abstract] [Full Text] [PDF]


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Arch Gen PsychiatryHome page
L. S. Cohen, C. N. Soares, A. F. Vitonis, M. W. Otto, and B. L. Harlow
Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles.
Arch Gen Psychiatry, April 1, 2006; 63(4): 385 - 390.
[Abstract] [Full Text] [PDF]


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Exp PhysiolHome page
G. M. Barrett, M. Bardi, A. K. Z. Guillen, A. Mori, and K. Shimizu
Regulation of sexual behaviour in male macaques by sex steroid modulation of the serotonergic system
Exp Physiol, March 1, 2006; 91(2): 445 - 456.
[Abstract] [Full Text] [PDF]


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ReproductionHome page
M. Casais, S. M. Delgado, Z. Sosa, and A. M. Rastrilla
Involvement of the coeliac ganglion in the luteotrophic effect of androstenedione in late pregnant rats
Reproduction, February 1, 2006; 131(2): 361 - 368.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
J. Balthazart, M. Baillien, and G. F. Ball
Rapid Control of Brain Aromatase Activity by Glutamatergic Inputs
Endocrinology, January 1, 2006; 147(1): 359 - 366.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
M. M. Khan, M. Hadman, C. Wakade, L. M. De Sevilla, K. M. Dhandapani, V. B. Mahesh, R. K. Vadlamudi, and D. W. Brann
Cloning, Expression, and Localization of MNAR/PELP1 in Rodent Brain: Colocalization in Estrogen Receptor-{alpha}- But Not in Gonadotropin-Releasing Hormone-Positive Neurons
Endocrinology, December 1, 2005; 146(12): 5215 - 5227.
[Abstract] [Full Text] [PDF]


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Proc R Soc BHome page
M. P Black, J. Balthazart, M. Baillien, and M. S Grober
Socially induced and rapid increases in aggression are inversely related to brain aromatase activity in a sex-changing fish, Lythrypnus dalli
Proc R Soc B, November 22, 2005; 272(1579): 2435 - 2440.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
X. Protopopescu, H. Pan, M. Altemus, O. Tuescher, M. Polanecsky, B. McEwen, D. Silbersweig, and E. Stern
Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle
PNAS, November 1, 2005; 102(44): 16060 - 16065.
[Abstract] [Full Text] [PDF]


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Endocr. Rev.Home page
J. M. Kaufman and A. Vermeulen
The Decline of Androgen Levels in Elderly Men and Its Clinical and Therapeutic Implications
Endocr. Rev., October 1, 2005; 26(6): 833 - 876.
[Abstract] [Full Text] [PDF]


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J EndocrinolHome page
J. E Sanchez-Criado, C. Bellido, R. Aguilar, and J. C Garrido-Gracia
A paradoxical inhibitory effect of oestradiol-17{beta} on GnRH self-priming in pituitaries from tamoxifen-treated rats
J. Endocrinol., July 1, 2005; 186(1): 43 - 49.
[Abstract] [Full Text] [PDF]


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J. Neurosci.Home page
M. I. Boulware, J. P. Weick, B. R. Becklund, S. P. Kuo, R. D. Groth, and P. G. Mermelstein
Estradiol Activates Group I and II Metabotropic Glutamate Receptor Signaling, Leading to Opposing Influences on cAMP Response Element-Binding Protein
J. Neurosci., May 18, 2005; 25(20): 5066 - 5078.
[Abstract] [Full Text] [PDF]


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Endocr. Rev.Home page
R. G. Smith, L. Betancourt, and Y. Sun
Molecular Endocrinology and Physiology of the Aging Central Nervous System
Endocr. Rev., April 1, 2005; 26(2): 203 - 250.
[Abstract] [Full Text] [PDF]


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International Journal of ToxicologyHome page
D. Desaulniers, G. M. Cooke, K. Leingartner, K. Soumano, J. Cole, J. Yang, M. Wade, and A. Yagminas
Effects of Postnatal Exposure to a Mixture of Polychlorinated Biphenyls, p,p'-dichlorodiphenyltrichloroethane, and p-p'-dichlorodiphenyldichloroethene in Prepubertal and Adult Female Sprague-Dawley Rats
International Journal of Toxicology, March 1, 2005; 24(2): 111 - 127.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
I. J. Clarke, V. A. Tobin, S. Pompolo, and A. Pereira
Effects of Changing Gonadotropin-Releasing Hormone Pulse Frequency and Estrogen Treatment on Levels of Estradiol Receptor-{alpha} and Induction of Fos and Phosphorylated Cyclic Adenosine Monophosphate Response Element Binding Protein in Pituitary Gonadotropes: Studies in Hypothalamo-Pituitary Disconnected Ewes
Endocrinology, March 1, 2005; 146(3): 1128 - 1137.
[Abstract] [Full Text] [PDF]


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J. Physiol.Home page
A. G Zabka, G. S Mitchell, and M Behan
Ageing and gonadectomy have similar effects on hypoglossal long-term facilitation in male Fischer rats
J. Physiol., March 1, 2005; 563(2): 557 - 568.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
T. D. Lund, T. Rovis, W. C. J. Chung, and R. J. Handa
Novel Actions of Estrogen Receptor-{beta} on Anxiety-Related Behaviors
Endocrinology, February 1, 2005; 146(2): 797 - 807.
[Abstract] [Full Text] [PDF]


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Exp. Biol. Med.Home page
T. R. Chakraborty, G. Rajendren, and A. C. Gore
Expression of Estrogen Receptor {alpha} in the Anteroventral Periventricular Nucleus of Hypogonadal Mice
Experimental Biology and Medicine, January 1, 2005; 230(1): 49 - 56.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
N. J. MacLusky, V. N. Luine, T. Hajszan, and C. Leranth
The 17{alpha} and 17{beta} Isomers of Estradiol Both Induce Rapid Spine Synapse Formation in the CA1 Hippocampal Subfield of Ovariectomized Female Rats
Endocrinology, January 1, 2005; 146(1): 287 - 293.
[Abstract] [Full Text] [PDF]


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Exp. Biol. Med.Home page
T. R. Chakraborty and A. C. Gore
Aging-Related Changes in Ovarian Hormones, Their Receptors, and Neuroendocrine Function
Experimental Biology and Medicine, November 1, 2004; 229(10): 977 - 987.
[Abstract] [Full Text] [PDF]


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Toxicol SciHome page
I. A. T. M. Meerts, H. Lilienthal, S. Hoving, J. H. J. van den Berg, B. M. Weijers, A. Bergman, J. H. Koeman, and A. Brouwer
Developmental Exposure to 4-hydroxy-2,3,3',4',5-pentachlorobiphenyl (4-OH-CB107): Long-Term Effects on Brain Development, Behavior, and Brain Stem Auditory Evoked Potentials in Rats
Toxicol. Sci., November 1, 2004; 82(1): 207 - 218.
[Abstract] [Full Text] [PDF]


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StrokeHome page
L. M. Brass
Hormone Replacement Therapy and Stroke: Clinical Trials Review
Stroke, November 1, 2004; 35(11_suppl_1): 2644 - 2647.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
S. Jesmin, H. Togashi, I. Sakuma, C. N. Mowa, K.-I. Ueno, T. Yamaguchi, M. Yoshioka, and A. Kitabatake
Gonadal Hormones and Frontocortical Expression of Vascular Endothelial Growth Factor in Male Stroke-Prone, Spontaneously Hypertensive Rats, a Model for Attention-Deficit/Hyperactivity Disorder
Endocrinology, September 1, 2004; 145(9): 4330 - 4343.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
V. D. Doan, S. Gagnon, and V. Joseph
Prenatal blockade of estradiol synthesis impairs respiratory and metabolic responses to hypoxia in newborn and adult rats
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R612 - R618.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
I. M. Abraham, M. G. Todman, K. S. Korach, and A. E. Herbison
Critical in Vivo Roles for Classical Estrogen Receptors in Rapid Estrogen Actions on Intracellular Signaling in Mouse Brain
Endocrinology, July 1, 2004; 145(7): 3055 - 3061.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
M. Maggiolini, A. Vivacqua, G. Fasanella, A. G. Recchia, D. Sisci, V. Pezzi, D. Montanaro, A. M. Musti, D. Picard, and S. Ando
The G Protein-coupled Receptor GPR30 Mediates c-fos Up-regulation by 17{beta}-Estradiol and Phytoestrogens in Breast Cancer Cells
J. Biol. Chem., June 25, 2004; 279(26): 27008 - 27016.
[Abstract] [Full Text] [PDF]


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Endocr. Rev.Home page
D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon, and C. Ohlsson
Androgens and Bone
Endocr. Rev., June 1, 2004; 25(3): 389 - 425.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
V. Bourdeau, J. Deschenes, R. Metivier, Y. Nagai, D. Nguyen, N. Bretschneider, F. Gannon, J. H. White, and S. Mader
Genome-Wide Identification of High-Affinity Estrogen Response Elements in Human and Mouse
Mol. Endocrinol., June 1, 2004; 18(6): 1411 - 1427.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
A. Hestiantoro and D. F. Swaab
Changes in Estrogen Receptor-{alpha} and -{beta} in the Infundibular Nucleus of the Human Hypothalamus Are Related to the Occurrence of Alzheimer's Disease Neuropathology
J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1912 - 1925.
[Abstract] [Full Text] [PDF]


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J. Neurosci.Home page
R. Dominguez, C. Jalali, and S. de Lacalle
Morphological Effects of Estrogen on Cholinergic Neurons In Vitro Involves Activation of Extracellular Signal-Regulated Kinases
J. Neurosci., January 28, 2004; 24(4): 982 - 990.
[Abstract] [Full Text] [PDF]


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Mol. Pharmacol.Home page
S. Moverare, J. Dahllund, N. Andersson, U. Islander, H. Carlsten, J.-A. Gustafsson, S. Nilsson, and C. Ohlsson
Estren Is a Selective Estrogen Receptor Modulator with Transcriptional Activity
Mol. Pharmacol., December 1, 2003; 64(6): 1428 - 1433.
[Abstract] [Full Text] [PDF]


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Endocr. Rev.Home page
A.-S. Parent, G. Teilmann, A. Juul, N. E. Skakkebaek, J. Toppari, and J.-P. Bourguignon
The Timing of Normal Puberty and the Age Limits of Sexual Precocity: Variations around the World, Secular Trends, and Changes after Migration
Endocr. Rev., October 1, 2003; 24(5): 668 - 693.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
A. M. Etgen and M. Acosta-Martinez
Participation of Growth Factor Signal Transduction Pathways in Estradiol Facilitation of Female Reproductive Behavior
Endocrinology, September 1, 2003; 144(9): 3828 - 3835.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
T. R. Chakraborty, L. Ng, and A. C. Gore
Age-Related Changes in Estrogen Receptor {beta} in Rat Hypothalamus: A Quantitative Analysis
Endocrinology, September 1, 2003; 144(9): 4164 - 4171.
[Abstract] [Full Text] [PDF]


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NeurologyHome page
C. L. Harden
Menopause and bone density issues for women with epilepsy
Neurology, September 1, 2003; 61(90062): S16 - 22.
[Abstract] [Full Text]


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J. Neurosci.Home page
I. M. Abraham, S.-K. Han, M. G. Todman, K. S. Korach, and A. E. Herbison
Estrogen Receptor {beta} Mediates Rapid Estrogen Actions on Gonadotropin-Releasing Hormone Neurons In Vivo
J. Neurosci., July 2, 2003; 23(13): 5771 - 5777.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
H. L. Rincavage, D. P. McDonnell, and C. M. Kuhn
Expression of Functional Estrogen Receptor {beta} in Locus Coeruleus-Derived Cath.a Cells
Endocrinology, July 1, 2003; 144(7): 2829 - 2835.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
S. W. Mitra, E. Hoskin, J. Yudkovitz, L. Pear, H. A. Wilkinson, S. Hayashi, D. W. Pfaff, S. Ogawa, S. P. Rohrer, J. M. Schaeffer, et al.
Immunolocalization of Estrogen Receptor {beta} in the Mouse Brain: Comparison with Estrogen Receptor {alpha}
Endocrinology, May 1, 2003; 144(5): 2055 - 2067.
[Abstract] [Full Text] [PDF]


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J. Neuropsychiatry Clin. Neurosi.Home page
R. N. McLay, P. M. Maki, and C. G. Lyketsos
Nulliparity and Late Menopause Are Associated With Decreased Cognitive Decline
J Neuropsychiatry Clin Neurosci, May 1, 2003; 15(2): 161 - 167.
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Endocr. Rev.Home page
B. B. Sherwin
Estrogen and Cognitive Functioning in Women
Endocr. Rev., April 1, 2003; 24(2): 133 - 151.
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J. Appl. Physiol.Home page
P. M. Schmitt and M. P. Kaufman
High concentrations of 17beta -estradiol attenuate the exercise pressor reflex in male cats
J Appl Physiol, April 1, 2003; 94(4): 1431 - 1436.
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J. Physiol.Home page
H. Widmer, M. Ludwig, F. Bancel, G. Leng, and G. Dayanithi
Neurosteroid regulation of oxytocin and vasopressin release from the rat supraoptic nucleus
J. Physiol., April 1, 2003; 548(1): 233 - 244.
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J. Neurosci.Home page
K. T. Akama and B. S. McEwen
Estrogen Stimulates Postsynaptic Density-95 Rapid Protein Synthesis via the Akt/Protein Kinase B Pathway
J. Neurosci., March 15, 2003; 23(6): 2333 - 2339.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
J. Nilsen and R. D. Brinton
Mechanism of estrogen-mediated neuroprotection: Regulation of mitochondrial calcium and Bcl-2 expression
PNAS, March 4, 2003; 100(5): 2842 - 2847.
[Abstract] [Full Text] [PDF]


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J. Neurophysiol.Home page
K. Okamoto, H. Hirata, S. Takeshita, and D. A. Bereiter
Response Properties of TMJ Units in Superficial Laminae at the Spinomedullary Junction of Female Rats Vary Over the Estrous Cycle
J Neurophysiol, March 1, 2003; 89(3): 1467 - 1477.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
C. S. Nunemaker, M. Straume, R. A. DeFazio, and S. M. Moenter
Gonadotropin-Releasing Hormone Neurons Generate Interacting Rhythms in Multiple Time Domains
Endocrinology, March 1, 2003; 144(3): 823 - 831.
[Abstract] [Full Text] [PDF]


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NEJMHome page
B. L. Riggs and L. C. Hartmann
Selective Estrogen-Receptor Modulators -- Mechanisms of Action and Application to Clinical Practice
N. Engl. J. Med., February 13, 2003; 348(7): 618 - 629.
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Mol. Endocrinol.Home page
J. Sun, J. Baudry, J. A. Katzenellenbogen, and B. S. Katzenellenbogen
Molecular Basis for the Subtype Discrimination of the Estrogen Receptor-{beta}-Selective Ligand, Diarylpropionitrile
Mol. Endocrinol., February 1, 2003; 17(2): 247 - 258.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
L. Wang, S. Andersson, M. Warner, and J.-A. Gustafsson
Estrogen receptor (ER)beta knockout mice reveal a role for ERbeta in migration of cortical neurons in the developing brain
PNAS, January 21, 2003; 100(2): 703 - 708.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
H. A. Harris, J. A. Katzenellenbogen, and B. S. Katzenellenbogen
Characterization of the Biological Roles of the Estrogen Receptors, ER{alpha} and ER{beta}, in Estrogen Target Tissues in Vivo through the Use of an ER{alpha}-Selective Ligand
Endocrinology, November 1, 2002; 143(11): 4172 - 4177.
[Abstract] [Full Text] [PDF]


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ScienceHome page
S. Kousteni, J.-R. Chen, T. Bellido, L. Han, A. A. Ali, C. A. O'Brien, L. Plotkin, Q. Fu, A. T. Mancino, Y. Wen, et al.
Reversal of Bone Loss in Mice by Nongenotropic Signaling of Sex Steroids
Science, October 25, 2002; 298(5594): 843 - 846.
[Abstract] [Full Text] [PDF]


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J. Neurosci.Home page
S. K. Amateau and M. M. McCarthy
A Novel Mechanism of Dendritic Spine Plasticity Involving Estradiol Induction of Prostaglandin-E2
J. Neurosci., October 1, 2002; 22(19): 8586 - 8596.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
R. A. DeFazio and S. M. Moenter
Estradiol Feedback Alters Potassium Currents and Firing Properties of Gonadotropin-Releasing Hormone Neurons
Mol. Endocrinol., October 1, 2002; 16(10): 2255 - 2265.
[Abstract] [Full Text] [PDF]


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Mol. Biol. CellHome page
M. Marino, F. Acconcia, F. Bresciani, A. Weisz, and A. Trentalance
Distinct Nongenomic Signal Transduction Pathways Controlled by 17beta -Estradiol Regulate DNA Synthesis and Cyclin D1 Gene Transcription in HepG2 Cells
Mol. Biol. Cell, October 1, 2002; 13(10): 3720 - 3729.
[Abstract] [Full Text] [PDF]


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Arch Gen PsychiatryHome page
C. N. Epperson, K. Haga, G. F. Mason, E. Sellers, R. Gueorguieva, W. Zhang, E. Weiss, D. L. Rothman, and J. H. Krystal
Cortical {gamma}-Aminobutyric Acid Levels Across the Menstrual Cycle in Healthy Women and Those With Premenstrual Dysphoric Disorder: A Proton Magnetic Resonance Spectroscopy Study
Arch Gen Psychiatry, September 1, 2002; 59(9): 851 - 858.
[Abstract] [Full Text] [PDF]


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J. Neurosci.Home page
I. Kadish and T. van Groen
Low Levels of Estrogen Significantly Diminish Axonal Sprouting after Entorhinal Cortex Lesions in the Mouse
J. Neurosci., May 15, 2002; 22(10): 4095 - 4102.
[Abstract] [Full Text] [PDF]


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Am. J. PsychiatryHome page
J. R. Stevens
Schizophrenia: Reproductive Hormones and the Brain
Am J Psychiatry, May 1, 2002; 159(5): 713 - 719.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
J. P. Greenfield, L. W. Leung, D. Cai, K. Kaasik, R. S. Gross, E. Rodriguez-Boulan, P. Greengard, and H. Xu
Estrogen Lowers Alzheimer beta -Amyloid Generation by Stimulating trans-Golgi Network Vesicle Biogenesis
J. Biol. Chem., March 29, 2002; 277(14): 12128 - 12136.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
H. Brady, S. Desai, L. M. Gayo-Fung, S. Khammungkhune, J. A. McKie, E. O'Leary, L. Pascasio, M. K. Sutherland, D. W. Anderson, S. S. Bhagwat, et al.
Effects of SP500263, a Novel, Potent Antiestrogen, on Breast Cancer Cells and in Xenograft Models
Cancer Res., March 1, 2002; 62(5): 1439 - 1442.
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Proc. Natl. Acad. Sci. USA