Florey Department of Neuroscience and Mental Health - Research Publications

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    Estrogen - the good, the bad, and the unexpected
    Simpson, ER ; Misso, M ; Hewitt, KN ; Hill, RA ; Boon, WC ; Jones, ME ; Kovacic, A ; Zhou, J ; Clyne, CD (ENDOCRINE SOC, 2005-05-01)
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    Estrogen deficiency leads to apoptosis in dopaminergic neurons in the medial preoptic area and arcuate nucleus of male mice
    Hill, RA ; Pompolo, S ; Jones, MEE ; Simpson, ER ; Boon, WC (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2004-12-01)
    The aromatase knockout (ArKO) mouse is unable to synthesize estrogens. Immunohistochemical studies on active caspase-3 and tyrosine hydroxylase (TH) revealed apoptosis of dopaminergic neurons in the medial preoptic area (MPO) and arcuate nucleus (Arc) of the hypothalamus of 1-year-old (1yo) male ArKO mice while no active caspase-3 was detected in wild type (WT). Furthermore, the number of TH-positive cells in the MPO and caudal Arc was significantly decreased in 1yo ArKO compared to WT. RNase protection assays support the presence of apoptosis in 1yo ArKO hypothalamus, revealing an up-regulation of pro-apoptotic genes: FASL, FADD, and caspase-8. Concomitantly, the ratio of bcl-2-related anti-apoptotic genes to pro-apoptotic genes in the hypothalamus of 1yo ArKO mice was significantly down-regulated. Previously, we have reported that no such changes were observed in the hypothalamus of female ArKO mice. Thus, we have provided direct evidence that estrogen is required to maintain the survival and functional integrity of dopaminergic neurons in the MPO and Arc of male, but not female mice.
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    Estrogen deficient male mice develop compulsive behavior
    Hill, RA ; McInnes, KJ ; Gong, ECH ; Jones, MEE ; Simpson, ER ; Boon, WC (ELSEVIER SCIENCE INC, 2007-02-01)
    BACKGROUND: Aromatase converts androgen to estrogen. Thus, the aromatase knockout (ArKO) mouse is estrogen deficient. We investigated the compulsive behaviors of these animals and the protein levels of catechol-O-methyltransferase (COMT) in frontal cortex, hypothalamus and liver. METHODS: Grooming was analyzed during the 20-min period immediately following a water-mist spray. Running wheel activity over two consecutive nights and barbering were analyzed. COMT protein levels were measured by Western analysis. RESULTS: Six-month old male but not female ArKO mice develop compulsive behaviors such as excessive barbering, grooming and wheel-running. Excessive activities were reversed by 3 weeks of 17beta-estradiol replacement. Interestingly, the presentation of compulsive behaviors is accompanied by concomitant decreases (p < .05) in hypothalamic COMT protein levels in male ArKO mice. These values returned to normal upon 17beta-estradiol treatment. In contrast, hepatic and frontal cortex COMT levels were not affected by the estrogen status, indicating region- and tissue-specific regulation of COMT levels by estrogen. No differences in COMT levels were detectable between female animals of both genotypes. CONCLUSIONS: This study describes the novel observation of a possible link between estrogen, COMT and development of compulsive behaviors in male animals which may have therapeutic implications in obsessive compulsive disorder (OCD) patients.
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    Fas/FasL-mediated apoptosis in the arcuate nucleus and medial preoptic area of male ArKO mice is ameliorated by selective estrogen receptor alpha and estrogen receptor beta agonist treatment, respectively
    Hill, RA ; Chow, J ; Fritzemeier, K ; Simpson, ER ; Boon, WC (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2007-10-01)
    The aromatase (ArKO) knockout mouse is estrogen deficient. Our previous analysis revealed apoptosis of dopaminergic neurons in the arcuate nucleus (Arc) and medial preoptic area (MPO) of 1-year-old male ArKO mice. We sought to determine which estrogen receptor (ER) is involved in the anti-apoptotic action of estrogen. Male ArKO (9.5-month-old) mice were treated with 16alpha-LE(2) (ERalpha-specific agonist) or 8beta-VE(2) (ERbeta-specific agonist). Daily injections (6 weeks) with 16alpha-LE(2) prevented dopaminergic cell death in the Arc of male ArKO mice, with no significant effect of 8beta-VE(2) treatment. In contrast, 8beta-VE(2) prevented dopaminergic cell death in the MPO, while 16alpha-LE(2) had no significant effect. Concomitant decreases in Fas and FasL protein levels were found upon 16alpha-LE(2) and 8beta-VE(2) treatment in the Arc and MPO, respectively. Our results indicate that anti-apoptotic effects of estrogen are ER mediated, and the specific ER subtype involved in regulating apoptosis depends on the particular brain nucleus in question.
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    Evidence for the existence of an estrogen-responsive sexually dimorphic group of cells in the medial preoptic area of the 129SvEv mouse strain
    Hill, RA ; Simpson, ER ; Boon, WC (NATURE PUBLISHING GROUP, 2008-05-01)
    The current study describes the presence of sexually dimorphic cell groups within the MPO of the 129SvEv, but not the C57BL/6J strain of mice. We detected galanin-positive clusters of cells located in the MPO of 129SvEv and C57BL/6J mice, with sex differences found only in the 129SvEv strain. Aromatase-positive and dense Nissl-counterstained clusters of cells were identified only in the MPO of 129SvEv mice, but not in the C57BL/6J strain. Furthermore, this study has demonstrated that the volume of these sexually dimorphic cell groups is regulated by estrogen, but not testosterone, as male aromatase knockout mice (which have high levels of testosterone, but no estrogen) show reduced cell group volumes. These structural changes, which occur in an estrogen-deficient state may influence male sexual behaviors.
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    Estrogen deficiency results in apoptosis in the frontal cortex of adult female aromatase knockout mice
    Hill, RA ; Chua, HK ; Jones, MEE ; Simpson, ER ; Boon, WC (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2009-05-01)
    The aromatase knockout (ArKO) mouse is completely estrogen deficient. We previously detected apoptosis in the hypothalamus of 1 year-old male ArKO mice. This study shows that 12 week-old female ArKO mice display spontaneous apoptosis of pyramidal neurons in the frontal cortex while wild-type (WT) littermates show no signs of apoptosis. Concomitantly, bcl-2 related anti-apoptotic genes are down-regulated whereas the pro-apoptotic gene TRADD is up-regulated in the female ArKO frontal cortex. This phenotype can be rescued by 3-week replacement of 17beta-estradiol. Furthermore, the apoptosis phenotype is exacerbated in 12-15 month-old female ArKO mice, which have 30% less neurons in the frontal cortex and lower brain weights than WT counterparts. These data show that estrogens are essential for the survival of female cortical neurons even in the absence of pathological conditions or external assaults. Our observations also demonstrate the sexually dimorphic susceptibility of neurons to estrogen deficiency.