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Endocrinology Vol. 145, No. 2 736-742
Copyright © 2004 by The Endocrine Society

Estrogen Regulation of Neurokinin B Gene Expression in the Mouse Arcuate Nucleus Is Mediated by Estrogen Receptor {alpha}

Tammy L. Dellovade and Istvan Merchenthaler

Wyeth Research, Collegeville, Pennsylvania 19426

Address all correspondence and requests for reprints to: Istvan Merchenthaler, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426. E-mail: merchei{at}wyeth.com.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Neurokinin B (NKB) gene expression is elevated in the infundibular (arcuate) nucleus of the hypothalamus in postmenopausal women. Estrogen replacement decreases both the number of NKB mRNA-expressing neurons and the level of expression within individual cells. Similarly, NKB gene expression is elevated in ovariectomized rats and reduced after estrogen treatment. The actions of estrogen in the brain can be mediated via either estrogen receptor {alpha} (ER{alpha}) or estrogen receptor ß (ERß). In the rodent arcuate nucleus (ARC), more ER{alpha}- than ERß-containing cells are present, suggesting that ER{alpha} might be directly responsible for estrogen regulation of NKB gene expression. However, an indirect effect via ERß could not be ruled out. Here we used ER{alpha} knockout and ERß knockout mice to identify the type of ER responsible for mediating estrogen action on NKB gene expression in the ARC. Using in situ hybridization histochemistry, we have found that estrogen treatment significantly reduced NKB gene expression in the ARC of ovariectomized ERß knockout mice, but had no effect on NKB mRNA levels in ER{alpha} knockout mice. These data indicate that ER{alpha} mediates the increase in NKB gene expression associated with ovariectomy in rodents and might also be responsible for the increase in NKB in postmenopausal women.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
MENOPAUSE IS ASSOCIATED with a variety of physiological changes including ovarian failure, increased secretion of pituitary gonadotropins, and hot flushes (1, 2, 3). In addition, a subpopulation of hypothalamic neurons, located in the infundibular (arcuate) region, is enlarged in postmenopausal women (4, 5, 6). These hypertrophied neurons express estrogen receptors (ER), neurokinin B (NKB) and substance P (SP) (5, 7). In postmenopausal women, the number of cells and level of gene expression for both NKB and SP are elevated compared with premenopausal women (5). Neurokinin B, neurokinin A and SP belong to the family of neuropeptides named tachykinins. Tachykinins are peptides that contain the sequence Phe-X-Gly-Leu-Met-NH2 at their carboxyl terminus (8, 9, 10). The variable amino acid (X) can be either an aromatic (Phe/Tyr) or a branched-chain aliphatic (Val/Ile). The three tachykinins are the products of at least two genes: preprotachykinin A (SP and neurokinin A) and preprotachykinin B (NKB). Based on the distribution of these tachykinins in the central nervous system, they seem to function as neurotransmitters/neuromodulators affecting numerous other neurotransmitters/neuromodulator systems.

Although animal studies have demonstrated a role for SP in the regulation of gonadotropin secretion (11), to date, the importance of NKB in the regulation of the reproductive axis remains unclear. However, a few studies have demonstrated estrogen regulation of NKB gene expression in rats. Similar to humans, it was found that long-term ovariectomy increases the number of neurons expressing NKB mRNA and mRNA content of neurons in the arcuate (12, 13) compared with estrogen-treated females. Contradictory observations were obtained recently in ewes after short-term (4 h vs. 8 h) treatments. Although Pillon et al. (14) have found that NKB mRNA expression was increased in the arcuate nucleus (ARC) 4 h after estrogen treatment, Goubillon et al. (15) did not see changes after 8 h treatment with estrogen. In contrast to humans, few SP-immunoreactive neurons were found in the rat ARC, and mRNA levels of SP were not altered by changes in estrogen status (16). Finally, in male rats, gonadectomy also increases mRNA levels of NKB, similar to the effect of aging in men (17, 18). Taken together, these data demonstrate that estrogen can regulate, either directly or indirectly, the expression of NKB in both rodents and humans.

In the brain, estrogen effects are mediated via two ERs, ER{alpha} and ERß. In the rodent ARC, the major ER present is ER{alpha} (19, 20) suggesting that estrogen effects on NKB gene expression are mediated via this receptor. However, it remained possible that NKB expression might also be affected via indirect actions through ERß. To directly examine this question, we studied estrogen regulation of NKB mRNA in the ARC of ovariectomized ER{alpha} knockout (ER{alpha}KO) and ERß knockout (ERßKO) mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Mice used in this study were from breeding colonies located in Wyeth Research facilities and maintained in accordance with Wyeth IACUC regulations. Animals were in a 12:12 (light:dark) light cycle (lights on at 0700 h) and provided food and water ad libitum. Adult (>60 d old) ER{alpha} (wild-type)WT (ER{alpha}WT), ER{alpha}KO (C57-BL/6Jx129), ERßWT and ERßKO (129) (n = 12/genotype) mice were ovariectomized and implanted subcutaneously with a Silastic tube containing either sesame oil (n = 6/genotype) or 17ß-estradiol (50 µg in sesame oil, n = 6/genotype). One week later, mice were euthanized by carbon dioxide overdose, brains were quickly removed, and frozen on dry ice.

In situ hybridization histochemistry
To evaluate NKB gene expression in the ARC, in situ hybridization histochemistry was used as previously described (21). In brief, brains were cryosectioned (20 µm), and sections through the medial basal hypothalamus were collected onto gelatin-coated glass slides. A S35-uridine 5'-triphosphate cRNA probe was generated using our NKB-615 plasmid (22) linearized with EcoR I (sense; control) or Hind III (antisense). Processed section-mounted slides were hybridized with 200 µl of antisense or sense (control) riboprobe (6 x 106 disintegrations per min/slide) in 50% formamide hybridization mix and incubated overnight at 55 C. The slides were washed at 67 C, dehydrated, and apposed to BioMax (BMR-1; Kodak, Rochester, NY) x-ray film for 48 h. Slides were then dipped in Kodak NTB3 autoradiographic emulsion and stored in light tight boxes at 4 C for 2 wk. Slides were then developed, counter stained with cresyl violet, dehydrated, cleared, and coverslipped. The slides from all animals were hybridized, washed, exposed, and photographically processed together to eliminate differences due to interassay variations in conditions.

Immunohistochemistry
To determine the distribution of ER{alpha} and ERß immunoreactive cells in the mouse ARC ovariectomy, ER{alpha}WT and ERßWT mice (n = 3/genotype) were deeply anesthetized with tribromoethanol (1 ml/100 g body weight, ip of a 2.5% solution) and perfused through the aorta with saline followed by 4% paraformaldehyde with 3.75% acrolein in 0.1M phosphate buffer (pH 7.4). After perfusion, brains were rapidly removed, cryoprotected in 30% sucrose, and frozen in cold isopentane. Immunohistochemistry was conducted on 30-µm free-floated sections as previously described (20). In brief, sections were pretreated with 1% glycine followed by a 30-min incubation in a blocking solution containing 1% BSA, 10% normal donkey serum, 1% hydrogen peroxide, and 0.3% Triton X-100 in 0.01 M PBS (pH 7.5). Sections were then incubated for 36–48 h at 4 C in either a rabbit polyclonal antiserum raised against the C terminus of ER{alpha} (FMS-ER7, diluted 1:7,000; ref) or a rabbit polyclonal antiserum raised against the C terminus of ERß (Z8P; Zymed, diluted 1: 15,000). The sections were then rinsed well, incubated in PBS containing biotinylated donkey antirabbit serum (Jackson Laboratories, West Grove, PA; 1:1000), and followed by incubation with Elite ABC reagents (Vector Laboratories, Inc., Burlingame, CA). Immunoreactive elements were revealed as dark gray/black reaction product using 0.025% 3,3'-diaminobenzidine with 0.1% nickel ammonium sulfate as substrate with 0.02% hydrogen peroxide in Tris-buffered saline (pH 7.2 at RT). Sections were mounted onto gelatin-coated slides, dehydrated, cleared, and coverslipped.

Data analysis
To quantify the level of gene expression in the ARC nucleus, the density of grains over the region was analyzed in emulsion-dipped slides using a computer-assisted image analysis system (R & M Biometrics, Inc., Nashville, TN). To obtain grain density readings captured images (10x) in the region of interest were corrected for background and 6 readings (40 µm apart) through the rostral-caudal extent of the ARC were measured in each animal. Readings were obtained from one side of the brain in each animal and were anatomically matched. The six density readings per animal were averaged to obtain an estimate of the density of grains over the region for each animal. Group means were analyzed by one-way ANOVA followed by least significant difference post hoc between-group analysis (P < 0.05).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
ER{alpha}-immunoreactive neurons are present in the mouse ARC
The mouse ARC has many more ER{alpha}- than ERß-immunoreactive cells (Fig. 1Go). The entire rostral to caudal extent of the nucleus contains ER{alpha} expressing neurons and only scattered ERß-immunoreactive cells are present. Interestingly, the density of ERß neurons increases in more caudal regions of the ARC, but are still modest in comparison to ER{alpha}-immunoreactive cells. These results are similar to what is seen using in situ hybridization histochemistry for ER{alpha} and ERß mRNA (19, 20).



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  		FIG. 1. ER{alpha}- and ERß-immunoreactive cells in the medial basal hypothalamus of WT mice. Note the presence of ER{alpha} immunoreactivity in the arcuate (AN) and ventromedial (VMN) nuclei of the hypothalamus. ERß-immunoreactive cells are sparse or not present in these hypothalamic nuclei. ME, Median eminence.

 
Estrogen treatment does not affect NKB mRNA expression in ovariectomized ER{alpha}KO mice
The mouse hypothalamus had many regions with high levels of NKB mRNA or NKB immunoreactivity. These include the medial preoptic area, bed nucleus of the stria terminalis, the anterior and lateral hypothalamic areas, the ARC, and the lateral mammillary nucleus (23). The present study, however, focuses specifically on the effect of ovariectomy and estrogen replacement on NKB gene expression in the ARC of WT and ER{alpha}KO and ERßKO mice.

In the ARC of ovariectomized, vehicle-treated WT (ER{alpha}WT) mice (mixed genetic background), high levels of NKB mRNA are present throughout the rostro-caudal extent of the ARC (Fig. 2Go, A and A’). In estrogen-treated, ovariectomized ER{alpha}WT mice, a dramatic reduction in NKB gene expression in the ARC was observed (Fig. 2Go, B and B').



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  		FIG. 2. NKB mRNA expression in the ARC of ovariectomized WT mice (mixed genetic background) treated with vehicle (A and A') or estrogen (B and B') with small (A and B) and large (A' and B') magnifications. Arrows show the same cell group with small (A and B) and large (A' and B') magnifications. Note the dramatic down-regulation of NKB mRNA expression after estrogen treatment. Estrogen reduces both the number of neurons expressing NKB mRNA and the intensity of NKB mRNA, represented by silver grains, within cells. ME, median eminence. *, Third ventricle.

 
In vehicle-treated, ovariectomized ER{alpha}KO mice (mixed genetic background) high levels of NKB mRNA were present throughout the rostro-caudal extent of the ARC (Fig. 3Go, A and A'). In estrogen-treated, ovariectomized ER{alpha}KO mice, NKB gene expression in the ARC did not change (Fig. 3Go, B and B'). The level of NKB expression was similar in WT and ER{alpha}KO mice. Quantification of these results showed that estrogen significantly decreased grain density over the ARC in ER{alpha}WT and not in ER{alpha}KO females (Fig. 4Go). These data indicate that estrogen regulation of NKB gene expression in the mouse ARC is mediated by ERa.



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  		FIG. 3. NKB mRNA expression in the ARC of ovariectomized ER{alpha}KO mice (mixed genetic background) treated with vehicle (A, A') or estrogen (B, B’) with small (A and B) and large (A' and B') magnifications. Arrows show the same cell group with small (A and B) and large (A' and B') magnifications. Note the lack of action of estrogen treatment on NKB mRNA expression. The number of cells expressing NKB mRNA and the intensity of their label are similar in ER{alpha}KO vehicle-treated and ER{alpha}KO estrogen-treated mice. ME: median eminence. *, Third ventricle.

 


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  		FIG. 4. Quantitative analysis of NKB gene expression in the ARC of ER{alpha}WT and ER{alpha}KO after vehicle or estrogen treatment. Note that although estrogen dramatically reduces NKB gene expression in ER{alpha}WT mice compared with vehicle treatment, it does not reduce NKB mRNA expression in ER{alpha}KO animals.

 
Estrogen treatment reduces NKB mRNA levels in ovariectomized ERßKO mice
Similar to ER{alpha}KO mice, NKB mRNA was seen throughout the hypothalamus in ERßKO and ERßWT mice (129 background).

In ovariectomized, vehicle-treated ERßWT and ERßKO mice, high levels of NKB mRNA were seen throughout the rostral-caudal extent of the ARC (Fig. 5AGo and 6AGo). After estrogen treatment, a marked reduction in NKB mRNA expression was detected in both the ERßWT and ERßKO mice (Figs. 5BGo and 6BGo). These data indicate that ERß is not necessary for the estrogen-mediated reduction in NKB gene expression. Quantification of these results showed that estrogen significantly decreased grain density over the ARC both in ERßWT and ERßKO female mice (Fig. 7Go). These data indicate that estrogen-induced down-regulation of NKB gene expression in the mouse ARC is mediated by ER{alpha} and not by ERß.



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  		FIG. 5. NKB mRNA expression in the ARC of ovariectomized WT mice (129 background) treated with vehicle (A, A') or estrogen (B, B') with small (A and B) and large (A' and B') magnifications. Arrows show the same cell group with small (A and B) and large (A' and B') magnifications. Note the dramatic down-regulation of NKB mRNA expression after estrogen treatment. Estrogen reduces both the numbers of neurons expressing NKB mRNA and the intensity of NKB mRNA, represented by silver grains, within cells. ME, median eminence. *, Third ventricle.

 


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  		FIG. 6. NKB mRNA expression in the ARC of ovariectomized ERßKO mice (129 background) treated with vehicle (A, A') or estrogen (B, B') with small (A and B) and large (A' and B' magnifications). Arrows show the same cell group with small (A and B) and large (A' and B') magnifications. Note the dramatic down-regulation of NKB mRNA expression after estrogen treatment. Estrogen reduces both the number of neurons expressing NKB mRNA and the intensity of NKB mRNA, represented by silver grains, within cells. ME, median eminence. *, Third ventricle.

 


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  		FIG. 7. Quantitative analysis of NKB gene expression in the ARC of ERßWT and ERßKO after vehicle or estrogen treatment. Note that estrogen dramatically reduces NKB gene expression both in ERßWT and ERßKO mice compared with vehicle treatment.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this study indicate that estrogen regulation of NKB gene expression in the ARC is ER{alpha} mediated in mice. Estrogen treatment in ovariectomized ERßKO mice decreased NKB mRNA levels compared with controls. However, in ER{alpha}KO mice, estrogen had no effect, such that both ovariectomized and estrogen-treated mice had elevated NKB mRNA levels.

There are numerous studies in laboratory animals and humans showing modulation of reproductive functions by one of the tachykinins, SP, but the role of NKB in the regulation of reproductive axis has been relatively unexplored. The similar location of SP and NKB in the ARC and the similar response of their expression to estrogen treatment suggest that NKB might also participate in the regulation of pituitary function. NKB is synthesized by neurons in the ARC that have access to the hypophysial portal circulation (24), and thereby it could directly influence anterior pituitary release of LH and FSH. Hypertrophy of NKB-expressing neurons in the infundibular nucleus of postmenopausal women is associated with elevated neuronal activity (7). The removal of the inhibitory effect of estrogen is also associated with infundibular neuronal hypertrophy in hypogonadal men (25), in women suffering from postpartum pypopituitarism with complete gonadal atrophy (6) and in young ovariectomized women without estrogen replacement therapy (7). The numbers of NKB mRNA-expressing or NKB-i neurons do not change in aged rats or humans (26). These observations together with the finding that increased tachykinin gene expression in the ARC can also be seen in young, ovariectomized rats (13), and NKB expression changes during the estrous cycle in rats (13) strongly suggests that changes in the ARC of postmenopausal women are secondary to ovarian failure and not the result of aging. The presence of ER mRNA within these hypertrophied, tachykinin (primarily NKB)-expressing neurons in postmenopausal women further indicate that they are targets for estrogen action (7). At the time of these studies, the second form of ER, ERß, was not identified, so it was not known what type of ER was present in tachykinins-expressing neurons. Our studies, using ER{alpha}KO and ERßKO mice, clearly show that the inhibitory action of estrogen is mediated via ER{alpha}.

The elevation in NKB neuronal activity may have in turn influence several neuronal systems that are innervated by this neuropeptide. Although no unequivocal evidence is available, several observations suggest that one of these is likely to be the LH-releasing hormone (LHRH) neuronal system. The close correlation between elevated NKB expression and LH secretion (13, 27) and the observations that many NKB-i fibers are in close proximity to LHRH neurons in the ewe preoptic area and also intermingled with LHRH fibers in the external zone of the median eminence (15) suggest an interaction between the NKB and LHRH neuronal systems. It is known that after ovariectomy, aging, and surgical and natural menopause, the lack of the negative feedback action of estrogen on LHRH and gonadotropin secretion results in their levels being elevated. The negative feedback action of estrogen at the pituitary is mediated via ER{alpha} present in gondotropin-secreting cells. However, the mechanism of action for the negative feedback effect of estrogen on LHRH release is not clearly understood. For decades, it was generally accepted that LHRH neurons do not contain ERs (28). Therefore, it was believed that both the negative and positive feedback actions of estrogen were mediated indirectly by ER-containing neurons (even perhaps glial cells) that synthesized other neurotransmitters, neuropeptides, and excitatory amino acids that innervated LHRH neurons. Neurokinin B-expressing neurons are among the many neuronal systems that express ERs, and therefore, may participate in mediating the feedback effects of estrogen. However, our view on estrogen-regulated LHRH neuronal activity might change in the future, because independent studies have recently reported the colocalization of ERß with LHRH (29, 30). In addition to the presence of the classical, nuclear ERß in LHRH neurons (29, 30), recent reports by Abraham et al. (31) provide strong evidence for the nongenomic action of estrogen. Using both in vitro and in vivo paradigms, this group showed rapid, ERß-mediated estrogen action on phosphorylation of cAMP response element-binding protein in LHRH neurons. The effect of estrogen on cAMP response element-binding protein phosphorylation was normal in ER{alpha}KO mice but completely absent in ERßKO mice. Thus, these observations provided the first evidence for a role of ERß in nongenomic estrogen signaling within the rodent brain.

As stated above, in addition to the idea that elevated NKB expression seen in aged or postmenopausal women or hypogonadal men, may contribute to elevated LHRH neuronal activity, NKB might also affect other neuronal systems innervated by NKB neurons in the ARC. Elevated LHRH neuronal activity and the potential changes in the activity of other neuropeptide/neurotransmitter systems may contribute to the symptoms menopausal or postmenopausal women experience, including hot flushes, change in body weight, mood, etc. Menopausal hot flushes are of particular interest because they are tightly associated with estrogen withdrawal, although the relationship between levels of estrogen and number/severity of hot flushes is not well substantiated (1, 32). A clear temporal relationship does exist however between the pulsatile release of LH and the initiation of hot flushes, indicating a link between the control of LHRH release and the onset of hot flushes (32, 33). Although no data are available on the effect of NKB, infusion of SP, another tachykinins, in normal human subjects causes flushing (34). In addition, hot flushes present in carcinoid tumors have been proposed to be mediated, at least in part, by tachykinins. Therefore, a periodic discharge of NKB with or without SP could provide an explanation for the observations that menopausal flushes coincide with pulses of LH (32, 33). However, because hot flushes are present in hypophysectomized women (32), the elevated LH release alone cannot be responsible for triggering hot flushes. Rather, elevated LHRH, perhaps together with other factors, seems to play a key role in the generation of hot flushes.

In summary, we have provided convincing evidence for the pivotal role of ER{alpha} in regulating NKB gene expression in the ARC of mice. Using ER KO models, we have shown that although estrogen down-regulates NKB expression induced by ovariectomy in WT and ERßKO mice, the same treatment failed to down-regulate NKB gene expression in ER{alpha}KO mice. The data support the original findings of Rance and Young (5) that the over-expression of NKB in the infundibular nucleus (the human homolog of the rat ARC) of postmenopausal women is the result of ovarian failure and the loss of estrogen secretion rather than of aging.


   Footnotes
 
Present address for T.D.: Neuroscience Group, Curis, Inc, 45 Moulton Street, Cambridge, Massachusetts. E-mail: tdellovade{at}curis.com.

Abbreviations: ARC, Arcuate nucleus; ER, estrogen receptor; ER{alpha}KO, ER{alpha} knockout (mice); ERßKO, ERß knockout (mice); NKB, neurokinin B; SP, substance P; RH, releasing hormone; WT, wild-type (mice).

Received July 17, 2003.

Accepted for publication October 21, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Regulation of Gonadotropin-Releasing Hormone Secretion by Kisspeptin/Dynorphin/Neurokinin B Neurons in the Arcuate Nucleus of the Mouse
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