Elsevier

Neuroscience

Volume 130, Issue 2, 2005, Pages 445-456
Neuroscience

Differential distribution of estrogen receptor (ER)-α and ER-β in the midbrain raphe nuclei and periaqueductal gray in male mouse: Predominant role of ER-β in midbrain serotonergic systems

https://doi.org/10.1016/j.neuroscience.2004.09.028Get rights and content

Abstract

We examined the distribution of estrogen receptor (ER)-α and ER-β immunoreactive (ir) cells in the dorsal (DRN) and median/paramedian (MPRN) raphe nuclei in male mice. ER-α ir neurons were scattered across the three subdivisions (ventral, dorsal, and lateral) of the DRN and the MPRN. Robust ER-β ir cells were observed throughout the raphe nuclei, and were particularly abundant in the ventral and dorsal subdivisions of the DRN. Using dual-label immunocytochemistry for ER-α or ER-β with tryptophan hydroxylase (TPH), the rate-limiting enzyme for 5-hydroxytryptamine (5-HT) synthesis, over 90% of ER-β ir cells exhibited TPH-ir in all DRN subdivisions, whereas only 23% of ER-α ir cells contained TPH. Comparisons of ER-α knockout (αERKO) as well as ER-β knockout (βERKO) mice with their respective wild-type (WT) littermates revealed that gene disruption of either ER-α or ER-β did not affect the other ER subtype expression in the raphe nuclei. In situ hybridization histochemistry revealed that there was a small but statistically significant decrease in TPH mRNA expression in the ventral DRN subdivision in βERKO mice compared with βWT mice, whereas TPH mRNA levels were not affected in αERKO mice. These findings support a hypothesis that ER-β activation may contribute to the estrogenic regulation of neuroendocrine and behavioral functions, in part, by acting directly on 5-HT neurons in the raphe nuclei in male mice.

Section snippets

Mice

Gonadally intact adult male αERKO (Lubahn et al., 1993) and βERKO (Krege et al., 1998) mice and their respective WT (αWT and βWT) littermates at age 9–14 weeks were used. They were obtained from the αERKO and the βERKO breeding colonies maintained at the Rockefeller University by mating heterozygous male and female mice. Original breeding pairs (mixed background of C57BL/6J and 129) were obtained from the National Institute of Environmental Health Sciences. Mice were group-housed (four to five

Distribution of ER-α ir and effects of ER-β gene disruption on the expression of ER-α in the midbrain raphe nuclei

ER-α ir neurons, with weak to moderate staining intensity, were observed scattered across the three subdivisions of the DRN (dorsal, ventral and lateral subdivisions) and the MPRN of βWT mice (Figs. 1A and 2A). Quantitative analysis revealed that the number of ER-α cells in the dorsal, ventral, and lateral subdivisions of the DRN peaked at the level of Bregma approximately −4.60 to approximately −4.72 (Fig. 1A), whereas in the MPRN, the number of ER-α cells decreased toward caudal levels.

Discussion

The present study provides the first detailed report on the distribution of ER-α and ER-β across the subdivisions of the DRN, the MPRN, and the PAG, in the intact male murine brain. We have found that ER-β is much more abundant than ER-α in the raphe nuclei, while the ER-α predominates in the PAG. Differential distribution of ER-α and ER-β in the DRN was particularly pronounced in serotonergic neurons, as we found that ER-β ir cells co-localized with TPH ir cells in the DRN to a much greater

Acknowledgments

The authors are thankful to Dr. V. Giguere at McGill University for his kind gift of ER-β cDNA and Dr. H. Tanaka at the University of Kumamoto and Dr. S. Hayashi at Yokohama City University for their kind gift of the ER-β probes. The authors also thank Dr. E. G. Mirasol, Ms I. Dorfman, and Ms L. Durbak for their technical assistance. Support and encouragement for this study by Dr. B. S. McEwen is greatly appreciated. MN was a recipient of postdoctoral fellowships for research abroad from the

References (57)

  • M. Pecins-Thompson et al.

    Ovarian steroid regulation of serotonin-1A autoreceptor messenger RNA expression in the dorsal raphe of rhesus macaques

    Neuroscience

    (1999)
  • M. Pecins-Thompson et al.

    Regulation of serotonin re-uptake transporter mRNA expression by ovarian steroids in rhesus macaques

    Brain Res Mol Brain Res

    (1998)
  • E.F. Rissman et al.

    Sex with knockout models: behavioral studies of estrogen receptor alpha

    Brain Res

    (1999)
  • N.G. Simon et al.

    Testosterone and its metabolites modulate 5HT1A and 5HT1B agonist effects on intermale aggression

    Neurosci Biobehav Rev

    (1998)
  • N.G. Simon et al.

    Sexual differentiation of androgen-sensitive and estrogen-sensitive regulatory systems for aggressive behavior

    Horm Behav

    (1987)
  • V.G. VanderHorst et al.

    Estrogen receptor-alpha-immunoreactive neurons in the periaqueductal gray of the adult ovariectomized female cat

    Neurosci Lett

    (1998)
  • M. Vergnes et al.

    Selective increase of offensive behavior in the rat following intrahypothalamic 5,7-DHT-induced serotonin depletion

    Behav Brain Res

    (1988)
  • M. Warembourg et al.

    Presence of estrogen receptor immunoreactivity in the oxytocin-containing magnocellular neurons projecting to the neurohypophysis in the guinea-pig

    Neuroscience

    (1991)
  • S.R. Wersinger et al.

    Masculine sexual behavior is disrupted in male and female mice lacking a functional estrogen receptor alpha gene

    Horm Behav

    (1997)
  • T. Yamamoto et al.

    Characteristics in aggressive behavior induced by midbrain raphe lesions in rats

    Physiol Behav

    (1977)
  • S.E. Alves et al.

    Estrogen-regulated progestin receptors are found in the midbrain raphe but not hippocampus of estrogen receptor alpha (ER alpha) gene-disrupted mice

    J Comp Neurol

    (2000)
  • S.E. Alves et al.

    Immunocytochemical localization of nuclear estrogen receptors and progestin receptors within the rat dorsal raphe nucleus

    J Comp Neurol

    (1998)
  • C.L. Bethea

    Colocalization of progestin receptors with serotonin in raphe neurons of macaque

    Neuroendocrinology

    (1993)
  • C.L. Bethea

    Regulation of progestin receptors in raphe neurons of steroid-treated monkeys

    Neuroendocrinology

    (1994)
  • K.B.J. Franklin et al.

    The mouse brain in stereotaxic coordinates

    (1997)
  • B. Greco et al.

    Coexpression of ER beta with ER alpha and progestin receptor proteins in the female rat forebrain: effects of estradiol treatment

    Endocrinology

    (2001)
  • G.R. Heninger

    Serotonin, sex, and psychiatric illness

    Proc Natl Acad Sci USA

    (1997)
  • S. Janusonis et al.

    Topographic organization of serotonergic dorsal raphe neurons projecting to the superior colliculus in the Mongolian gerbil (Meriones unguiculatus)

    J Comp Neurol

    (1999)
  • Cited by (64)

    • Kamishoyosan (a Japanese traditional herbal formula), which effectively reduces the aggressive biting behavior of male and female mice, and potential regulation through increase of Tph1, Tph2, and Esr2 mRNA levels

      2021, Brain Research
      Citation Excerpt :

      Indeed, we found that Tph2 mRNA induction in the DRN of male mice was abolished by preadministration of ER antagonists. It was previously reported that around the midbrain, ERβ is predominantly distributed in the DRN, whereas ERα is predominantly distributed in the periaqueductal gray (Mitra et al., 2003; Nomura et al., 2005). ER, when bound to agonists, dimerize and interact with regulatory DNA sequences to modulate gene transcription (Klinge, 2001; Powell and Xu, 2008; Yaşar et al., 2017).

    • Estrogenic regulation of social behavior and sexually dimorphic brain formation

      2020, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Although the exact mechanism of this ERβ-mediated action has not been specified, it is hypothesized that the serotonergic system may be involved. Previous studies have shown that a large proportion of ERβ expressing neurons in the DRN are serotonergic (Nomura et al., 2005) and send projections to the hypothalamic regions (Lu et al., 2001) where activation of 5HT-1 A receptors inhibit sexual behavior (Snoeren et al., 2014; Uphouse and Caldarola-Pastuszka, 1993). Furthermore, activation of ERβ by 17β-E or ERβ specific agonists, diarylpropionitrile (DPN) in ovariectomized female rats is reported to enhance mRNA expression of tryptophan hydroxylase 2 (TPH 2) in the DRN (Donner and Handa, 2009).

    View all citing articles on Scopus
    1

    Present address: Department of Urology, University of Occupational and Environmental Health, 1-1 Iseigaolea, Yahatanishi-ku, Kitakyushu-city 807-8555, Japan.

    View full text