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Kastor Neurobiology of Aging Laboratories, Fishberg Research Center for Neurobiology, and Brookdale Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, New York 10029
Address all correspondence and requests for reprints to: Andrea C. Gore, Ph.D., Pharmacology/Toxicology A1915, University of Texas, Austin, Texas 78712. E-mail: andrea.gore{at}mail.utexas.edu.
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Introduction |
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and ERß. ERs are nuclear transcription factors that, upon binding with estrogen, dimerize and interact with DNA response elements to modulate the expression of specific target genes (reviewed in Ref.3).
Although estrogen levels and release patterns change with aging, little is known about the corresponding changes in ERs that mediate the response to estrogen. Nevertheless, changes in ERs would potentially impact the ability of the brain and body to respond to circulating estrogens, either endogenous or exogenous from estrogen replacement therapy. Our laboratory and others have shown age-related changes in ER protein and mRNA (4, 5, 6). Far less is known about ERß, the focus of the present study, which is expressed abundantly in specific brain nuclei of rats, including the anteroventral periventricular nucleus (AVPV), principal nucleus of the bed nucleus of the stria terminalis (pBST), medial amygdala, paraventricular nucleus, periventricular nucleus, and others (7, 8, 9). The ERß knockout mouse is subfertile and has other phenotypic abnormalities that suggest roles for ERß in mediating both reproductive and nonreproductive actions of estrogen (10, 11).
To our knowledge, quantitative studies on the number of ERß protein-expressing cells in the brain have never been published. Because of the potential importance of this receptor in mediating effects of changing estradiol levels with aging, in the present study we first undertook an unbiased stereological analysis to quantify the number of ERß-expressing cells in two brain regions of female rats important for reproduction, the AVPV and pBST, both of which express ERß in rats (9, 12), are estrogen sensitive, and are critically involved in reproductive function (13, 14). These experiments were performed in the context of aging, and in addition, we examined the effects of estrogen treatment on ERß cell number. Second, we quantified the number of N-methyl-D-aspartate (NMDA) receptor (NMDAR) subunit 1 (NR1)-immunoreactive cells and the colocalization of ERß with NR1. The coexpression of ERß and NR1 would indicate a potential site at which the actions of glutamate, the principal excitatory neurotransmitter in the brain (15), and those of estrogen could converge on target cells. Moreover, our present analysis on ERß would complement our previous work on ER and its colocalization with NR1 in the hypothalamus (4, 16). Finally, we examined whether the volume of the AVPV and pBST are altered by estrogen and aging in female rats, as this would indicate more global changes in these nuclei.
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Materials and Methods |
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Surgical procedure
The rats were ovariectomized bilaterally under isoflurane anesthesia and were allowed to recover for 2–3 wk. Then rats were again anesthetized with isoflurane anesthesia and implanted sc with SILASTIC brand capsules (Dow Corning, Midland, MI) containing estrogen (10% 17ß-estradiol and 90% cholesterol; n = 6 each for young, middle-aged, and old, respectively) or vehicle (100% cholesterol; n = 5, 5, and 6 for young, middle-aged, and old, respectively). Capsules were made using SILASTIC brand laboratory tubing (inner diameter, 1.96 mm; outer diameter, 3.18 mm; Dow Corning) that was packed with estrogen or vehicle and capped with SILASTIC brand adhesive (100% silicone; Dow Corning), and allowed to dry. They were soaked in saline for at least 24 h before implantation. Young animals received an implant that was 1 cm in length, middle-aged animals received an implant that was 1.5 cm in length, and aged animals received an implant that was 2 cm in length. Different implant lengths were used for animals of different ages to account for differences in body weights. We reported in previous studies that such capsules result in circulating estradiol levels in all three age groups similar to those in young, proestrous rats (17, 18). Two days later, between 1500–1700 h, a time chosen to represent the period of estrogen positive feedback on GnRH and gonadotropin release (19, 20, 21), the animals were deeply anesthetized with 0.35–0.5 ml ketamine (100 mg/ml) and 0.35–0.5 ml xylazine (20 mg/ml). The rats were perfused initially with 3.75% acrolein and 1% paraformaldehyde in PBS (50 ml) at a rate of 50 ml/min, followed by 4% paraformaldehyde in PBS (500 ml) (22). The brains were removed and postfixed for 2–4 h in 4% paraformaldehyde and then transferred into PBS with 0.1% sodium azide (22). Tissue sections (40 µm) were cut on a Vibratome (VT 1000S, Leica Instruments, Nussloch, Germany) and stored in PBS with 0.1% sodium azide.
Immunocytochemistry for stereological analyses
Tissue sections were taken in a 1:2 series across the AVPV and pBST. Sections were treated with 1% sodium borohydride (30 min) and were rinsed in buffer at room temperature on a shaker (22). Then, the sections were treated to eliminate any endogenous peroxide activity (3:1, methanol/3% H2O2, 20 min at room temperature). Sections were then washed, incubated in the rabbit anti-ERß polyclonal antibody (1 µg/ml; Zymed Laboratories, South San Francisco, CA) in 10% normal goat serum and 10% normal horse serum for 3 d at 4 C on a shaker. The validation of this antibody has been described by Hrabovszky et al. (23) and Shughrue and Merchenthaler (12). The sections were then rinsed and incubated in biotinylated antirabbit IgG (1:300; Vector Laboratories, Inc., Burlingame, CA) for 1 h, followed by rinsing in PBS. Then sections were incubated in avidin-biotin-peroxidase complex (Vector Laboratories, Inc.) for 1 h, rinsed in buffer, and developed in a 3,3'-diaminobenzidine/peroxidase reaction. The sections were then rinsed in PBS and incubated in primary antibody to NR1 (54.1; 5 µg/ml dilution) in 10% normal goat serum and 10% normal horse serum for 3 d at 4 C on a shaker. This antibody has also been extensively validated (24, 25). Sections were washed and incubated in biotinylated antimouse IgG (1:300; Vector Laboratories, Inc.) for 1 h. They were then incubated in avidin-biotin-peroxidase complex (Vector Laboratories, Inc.) for 1 h. After a series of washes they were developed in VIP/peroxidase reaction (VIP substrate kit, Vector Laboratories, Inc.). Sections were rinsed, dried at room temperature, dehydrated in a graded alcohols series, stained with cresyl violet, and coverslipped with DPX (Fluka, Steinheim, Germany). Because of the large number of tissues, several immunocytochemistry runs were performed, each containing at least one animal from each of the six treatment groups.
Stereological analysis
For stereological analyses each cresyl violet-counterstained region (AVPV or pBST) was outlined at low magnification (x10) on the live computer image with the help of a rat brain atlas (26). The rostral-caudal borders of the AVPV were approximately anterior-posterior = 8.11–8.39, respectively, based on the brain atlas of Swanson (26), and the AVPV was demarcated most rostrally by the caudal aspect of the organum vasculosum of the lamina terminalis, where the anterior commissure first began to cross, and most caudally by where the anterior commissure was first fully crossed, at the level of the rostral medial preoptic nucleus. The pBST was caudal to the AVPV (anterior-posterior = 8.67–9.11) (26), ranging from the level of the rostral aspect of the suprachiasmatic nucleus, the fornix, and stria terminalis through rostral parts of the paraventricular nucleus. For the AVPV, based on a report showing heterogeneity of ERß expression with a high density of expression in the medial-most 50 µm and lower density in more lateral regions of female rats (8), we subdivided the AVPV into two parts. The 50-µm medial-most portion, including the ependymal layer of the third ventricle, was called the medial AVPV (AVPVm) and the rest of the AVPV was called the lateral AVPV (AVPVl). For the pBST the study was restricted to the posterior division, principal nucleus, a region that highly expresses ERß (27). A x63 immersion oil, 1.4 numerical aperture objective was used to achieve optimal optical sectioning during stereological analysis (16). Following stereological principles, only animals in which a complete 1:2 series across each the AVPV and pBST were included in the analyses (4, 16, 28, 29, 30). Several animals could not be used due to tissue damage, and the final number of rats in each group was: young vehicle, n = 5; young estrogen, n = 5; middle-aged vehicle, n = 5; middle-aged estrogen, n = 5; old vehicle, n = 6; and old estrogen, n = 6. The StereoInvestigator software (MicroBrightField, Colchester, VT) placed dissector frames using a systematic random design within each contour outlining each region on a 50 x 50-µm2 grid, and the diaminobenzidene-labeled ERß nuclei, the VIP-labeled NR1 cells, and those cells double-labeled for ERß and NR1 were counted as three separate categories within 50 x 50-µm optical disector frames on the x-/y-axis. The final postprocessing thickness of the sections was measured by the microcator. As the mounted section thickness was, on the average, 10 µm, the counting frame height was kept at 6 µm for all sections studied. Because the neuronal number estimates were made using the optical fractionator and did not therefore depend on a direct measurement of the volume of reference of the region considered, the shrinkage of the tissue during histological processing should not influence the precision of these estimates. Measurement of the volumes of the AVPV and pBST was performed by drawing the contour at a magnification of x10 and then multiplying by the total thickness and the interslice distance. For calculations, the average postshrinkage value for the z-axis was used, although volume estimates were based on postprocessing materials that have shrunk in all three dimensions. No attempt to introduce correction factors for shrinkage was made because it probably differs in the z and x-y directions. The coefficients of error and variation of the estimates were calculated as described previously (29, 30).
Quantitative analyses were performed using a computer-assisted morphometry system consisting of an Axioplan 2 photomicroscope (Zeiss, Jena, Germany) equipped with an MS-2000XYZ computer-controlled motorized stage (Applied Scientific Instrumentation, Eugene, OR), a DC 330 video camera (DAGE-MTI, Michigan City, IN), a Dell microcomputer (Austin, TX), and StereoInvestigator morphometry and stereology software (MicroBrightField, Inc., Colchester, VT) for all three age groups. Stereological methods using the optical fractionator in MicroBrightField (28) were used to estimate the total number of ERß-immunoreactive nuclei in the regions of interest. Single and double labeling were performed as described previously (16), and examples are presented in Fig. 1
, M–O. Stereological microscopic analyses were performed at high power (x63), and in the live computer image, cells were much larger than they appear in the micrographs shown in Fig. 1 (approximately five or six cells would fill the 17-in. computer monitor). The chromogens used to label ERß (diaminobenzidene), NR1 (VIP), and the cresyl violet stain were all easily distinguishable at this magnification. Nuclei that were single labeled for ERß were visible as dark brown nuclei with no detectable cytoplasmic processes. Cytoplasmic membranes that were single labeled for NR1 had cytoplasmic light brown staining in the absence of nuclear dark brown staining; these cells were labeled with cresyl violet in the nucleus. Cells that were double labeled had light brown cytoplasms indicative of NR1 and a dark brown nuclei. In those very few cases in which there was any ambiguity in determining single or double labeling, the expression of one or both chromogens was confirmed by direct viewing through the microscope. A suitable contrast/brightness setting that yielded a high resolution image for the cells was determined and used to produce the images. The stored images then were transferred to Adobe Photoshop. Only minor adjustments of contrast and brightness were made that in no case altered the appearance of the original materials.
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shows low power micrographs of the AVPV and pBST and their corresponding positions on a rat brain atlas (26). High power images of ERß and NR1 single- and double-labeled cells are shown in Fig. 1, M–O.
Effects of age and estrogen on ERß-immunoreactive cell numbers in AVPV
The effects of age, estrogen, and their interactions on the number of ERß-immunoreactive cells were determined in the medial and lateral parts of the AVPV (Fig. 2, A and B, respectively). ANOVA indicated a significant effect of age in both subregions of the AVPV (AVPVm, P < 0.01; AVPVl, P < 0.05). Post hoc analysis demonstrated that ERß cell numbers were significantly greater in young than in middle-aged or old animals (P < 0.01 and 0.05, respectively) for both the medial and lateral parts of the AVPV. No significant effect of estrogen (AVPVm, P = 0.38; AVPVl, P = 0.14) was found, and no interactions of age and estrogen were detected. Because results were similar in the AVPVm and AVPVl, we also determined effects of age on ERß cell numbers in the entire AVPV (m + l), with results similar to those seen in the two subregions (young vs. middle-aged, P < 0.005; young vs. old, P < 0.01).
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), and no effects of age, estrogen treatment, or interactions on their numbers were detected by ANOVA. Higher numbers of NR1-positive cells were found in the AVPVl compared with the AVPVm (Fig. 3B). A significant effect of age on NR1 cell number was found in the AVPVl (P < 0.05), in which numbers of NR1-positive cells were significantly higher in young than middle-aged (P < 0.05) or old (P < 0.05) animals (Fig. 3B). No significant effect of estrogen (P = 0.12) was found, nor any interaction of age and estrogen.
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, A and B), representing approximately 10% of the total number of ERß-immunoreactive cells. Neither age nor estrogen had any effect on the number of cells expressing both ERß and NR1 in the AVPVm and AVPVl (Fig. 4, A and B, respectively).
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), NR1 (Fig. 5B), or ERß and NR1 colocalized (Fig. 5C) cells. The number of ERß single- and double-labeled cells was comparable to that in the AVPV, whereas the number of NR1 cells in the pBST was considerably higher than that in the AVPV. Overall, approximately 3% of ERß cells in the pBST coexpressed NR1.
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). In the pBST there was a significant effect of age (P < 0.05), but not estrogen (P = 0.15), on pBST volume. Post hoc analysis showed a significant decrease in pBST volume from the young to the middle-aged group (P < 0.05; Fig. 6B). Although there was a trend for volume to be lower in the old compared with the young group, this difference was not significant (P = 0.09; Fig. 6B).
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Age-related changes in ERß in the AVPV
We observed that the distribution of ERß in the AVPV of female rats is heterogeneous, with the greatest concentration in the most medial part of the AVPV and a more diffuse expression in the lateral part of the AVPV. This observation confirms a previous report showing high levels of expression of ERß protein in the medial region of the AVPV in this species (8). Our study extended the analyses to a quantification of the number of ERß protein-expressing cells in aging animals using an unbiased stereological approach. We observed a significant decrease in the number of ERß-immunoreactive cells during aging, with higher numbers in young than middle-aged and old rats in both the medial and lateral regions of the AVPV. Therefore, although the density of expression of ERß is heterogeneous, the age-related decrease in the number of ERß-expressing cells does not differ between the medial and lateral regions of the AVPV. Our measurements of AVPV volume showed that this nucleus as a whole does not change in size during aging. Wilson et al. (6) showed a decrease in ERß mRNA expression in the supraoptic nucleus of middle-aged and old compared with young ovariectomized, estradiol-treated rats. Thus, the brains of female rats appear to undergo specific age-related changes, manifested at least in part by decreases in the numbers of ERß-expressing cells in certain brain regions.
AVPV and NMDARs
The role of estrogen in the brain extends to its interplay with several neurotransmitters, including glutamate, acting through its NMDAR and non-NMDARs (reviewed in Refs. 36 and 37). NMDARs are localized in many of the same brain regions in which ERs are expressed, and the effects of NMDAR activation can be enhanced by estrogen (36, 38). Moreover, the NMDAR system itself undergoes age-related changes in the forebrain, hippocampus, and hypothalamus of old animals (18, 39, 40, 41, 42).
The AVPV is necessary for the estrogen-induced preovulatory GnRH/LH surge, as lesions of this region obliterate the surge and block Fos expression in ipsilateral GnRH neurons during the surge (43, 44). These functions appear to involve glutamate, as blockade of the NMDAR also reduces or attenuates the surge (38, 45), indicating an interaction between the ER and the NMDAR in the regulation of this crucial physiological function. To investigate the relationship between the expression of ERß and NMDAR we performed a quantitative stereological analysis on the number of NR1-immunoreactive cells in the AVPV as well as the percentage of ERß cells that coexpress NR1. We chose the NR1 subunit because it is obligatory for the formation of a functional NMDAR (46). For cells that expressed NR1 alone (no ERß) we found relatively low numbers in the AVPVm compared with the AVPVl, and we saw an age-related decrease that was specific to the AVPVl. We also observed low coexpression of ERß and NR1 in the AVPV in all age groups, with only about 10% of all ERß-immunoreactive cells also coexpressing NR1. There was no age-related difference in the number of ERß/NR1 double-labeled cells. Thus, the number of ERß-immunoreactive cells underwent age-related decreases in both subregions of the AVPV, NR1 underwent an age-related decrease only in the AVPVl, and the number of cells expressing both ERß and NR1 did not change with aging. Therefore, there is heterogeneity in the expression and regulation of molecules in the AVPV during aging.
Comparison of ER and ERß in the AVPV
We recently performed a parallel set of studies on ER expression in the AVPV of ovariectomized female rats subjected to the same experimental conditions as the rats used in the present study for ERß analysis. We found that the number of ER cells increases with age in the AVPV (4) in contrast to the age-related decrease in the number of ERß-expressing cells observed in the present study. Therefore, the age-related decrease in ERß cell number is not generalizable to all cell types. Moreover, our finding that the AVPV volume did not change during aging indicates that there are not global changes in cell number in this brain region. Other differences in the expression of ER and ERß were also found in the AVPV. For example, ER-immunoreactive cells are more evenly distributed throughout the AVPV of the rat (4, 16), unlike ERß, which is expressed more densely in the medial part of the AVPV (8). Approximately 88% of ER-immunoreactive cells also coexpress NR1 (4, 16) but only about 10% of ERß-positive cells also coexpress NR1. In the rat, estrogen levels are maintained at high levels even with advancing age, but the pattern of estrogen release changes from a cyclic to a chronic pattern of release (47). Differences in the expression of ERs in the rat brain may be a consequence of changes in the pattern of estrogen release and may represent a change in the ability of the brain to respond to estrogen. Moreover, a shift in the relative ratio of ER (which increases) to ERß (which decreases) during aging may even be involved in the transition to acyclicity in ovarian-intact rats, although further experiments are necessary to test this hypothesis. Nevertheless, taken together, these findings indicate differential age-related regulation of the two genomic ERs, and that they are found in cells with differential glutamate sensitivity. Our results further suggest that estrogen and glutamate (the latter acting through its NMDA receptor) can interact directly within the same target cells in the hypothalamus, expressing mainly ER and, to a lesser extent, ERß.
ERß, NR1, and their coexpression in the pBST
ERß and NR1 were also expressed in the pBST, as reported previously (7, 9, 35, 48). The numbers of ERß-expressing cells were similar in the pBST and AVPV, whereas NR1 expression was much higher in pBST than the AVPV. In contrast, a smaller percentage of ERß cells in pBST also coexpressed NR1 (
3%) compared with the AVPV (10%). No effect of age or estrogen was observed on the numbers of ERß-immunoreactive cells, NR1 cells, or their colocalization in pBST. We did, however, find a change in pBST volume with aging, with a significant decrease from the young to the middle-aged group. The age-related decrease in the number of ERß and NR1 cells occurring in the AVPV, but not the pBST, indicates that such changes are region specific. For the pBST, although we do not know whether this is due to an overall cell loss or an atrophy of specific cell types, our finding that neither ERß nor NR1 cell number changed in this region with aging suggests that there is not a universal cell loss in the pBST with aging, but that there may be decreases in some cell types that result in a net loss in pBST size.
The expression of ERß in the forebrain has some notable species differences. In the mouse, unlike the rat, ERß may not be expressed in the AVPV, and this may be strain dependent, as indicated by preliminary observations in our laboratory (unpublished observations). In the mouse brain, ERß mRNA expression is lower in the rostral preoptic area and anterior hypothalamus compared with that in the rat (48). The female ERß knockout mouse has reduced fertility (10, 11), suggesting that although the ERß plays a role in reproduction, it is not absolutely obligatory for reproductive competence. The relatively lower expression of ERß in many preoptic and hypothalamic areas of mice compared with rats suggests potential species differences in its function.
In the pBST, ERß is expressed abundantly in all species examined to date, including rat (7, 9, 49), mouse (48), rhesus monkey (50), and sheep (51, 52). Although ERß expression in the AVPV and BST of humans has not been reported, there are differences in the expression of this receptor in several hypothalamic and nonhypothalamic regions between humans and other species (53). Although we do not know whether some of these species differences in ERß distribution may account for or play some role in differences in reproductive physiology, it is possible that such is the case.
In conclusion, we found an age-related decrease in ERß- and NR1-immunoreactive cell numbers in the AVPV, but not in the pBST. The number of cells coexpressing ERß and NR1 was relatively low in the AVPV and pBST (10% and 3%, respectively) and did not differ with aging. Estrogen replacement did not alter any of these parameters. Thus, our results indicate that aging significantly impacts the number of cells expressing ERß and NR1 in the AVPV, independently of the estrogen milieu.
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Acknowledgments |
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Footnotes |
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Abbreviations: AVPV, Anteroventral periventricular nucleus; AVPVl, lateral anteroventral periventricular nucleus; AVPVm, medial anteroventral periventricular nucleus; ER, estrogen receptor; pBST, principal nucleus of the bed nucleus of the stria terminalis; NMDA, N-methyl-D-aspartate; NMDAR, N-methyl-D-aspartate receptor; NR1, NMDAR subunit 1.
Received January 10, 2003.
Accepted for publication June 2, 2003.
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(ER) expression in rat hypothalamus and preoptic area, and its regulation by aging and estrogen. J. Comp Neurol, in press
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and -ß mRNA in the rat central nervous system. J Comp Neurol 388:507–525[CrossRef][Medline]
(ER) and ß (ERß) on mouse reproductive phenotypes. Development 127:4277–4291[Abstract]
and NMDA receptor in the hypothalamus of female rats. Endocrinology 144:299–305 estrogen receptors are located at extranuclear sites. J Comp Neurol 429:355–371[CrossRef][Medline]
and ERß) throughout the rat brain: anatomical evidence of distinct roles of each subtype. J Neurobiol 36:357–378[CrossRef][Medline]
knockout mouse. Endocrinology 138:5649–5652 (ER) and ERß messenger ribonucleic acid in the preoptic area and hypothalamus of the sheep: comparison of males and females. Endocrinology 141:2951–2962 mRNA. J Clin Endocrinol Metab 85:3840–3846This article has been cited by other articles:
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, Data for ovariectomized animals given the vehicle (cholesterol) as a control; 
, data for estrogen-treated animals. In both subregions of the AVPV there was an overall significant effect of age on ERß cell number, with levels higher in young than in middle-aged or old rats (AVPVm, P < 0.01; AVPVl, P < 0.05). Estrogen did not alter ERß cell numbers in the AVPV. chol, Cholesterol-treated (vehicle) rats; MA, middle-aged rats.
