Elsevier

Neuroscience

Volume 152, Issue 4, 9 April 2008, Pages 888-902
Neuroscience

Cellular neuroscience
Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats

https://doi.org/10.1016/j.neuroscience.2007.10.071Get rights and content

Abstract

Estradiol has been shown to have neuroprotective effects, and acute estradiol treatment enhances hippocampal neurogenesis in the female brain. However, little is known about the effects of repeated administration of estradiol on the female brain, or about the effects of estradiol on the male brain. Gonadectomized male and female adult rats were injected with 5-bromo-2-deoxyuridine (BrdU) (200 mg/kg), and then 24 h later were given subcutaneous injections of either estradiol benzoate (33 μg/kg) or vehicle daily for 15 days. On day 16, animals were perfused and the brains processed to examine cells expressing Ki-67 (cell proliferation), BrdU (cell survival), doublecortin (young neuron production), pyknotic morphology (cell death), activated caspase-3 (apoptosis), and Fluoro-Jade B (degenerating neurons) in the dentate gyrus. In female rats, repeated administration of estradiol decreased the survival of new neurons (independent of any effects on initial cell proliferation), slightly increased cell proliferation, and decreased overall cell death in the dentate gyrus. In male rats, repeated administration of estradiol had no significant effect on neurogenesis or cell death. We therefore demonstrate a clear sex difference in the response to estradiol of hippocampal neurogenesis and apoptosis in adult rats, with adult females being more responsive to the effects of estradiol than males.

Section snippets

Experimental procedures

All experiments were conducted in accordance with the Canadian Council on Animal Care guidelines and international guidelines regarding appropriate and ethical treatment of animals and were approved by the Animal Care Centre at the University of British Columbia. Every effort was made to minimize the number of animals used per group and to minimize the suffering of animals used throughout all experimental procedures.

Male rats have larger DG volumes than female rats

Overall, as expected, the volumes of the GCL and hilus of the hippocampus were larger in males than in females, and the hilus was larger than the GCL, but there were no other significant effects (main effect of sex: F1,16=15.6, P=0.001; main effect of area: F1,16=819, P<0.001; all other effects except for sex×area: P>0.40; Table 1). There was a significant sex×area interaction effect in volume (F1,16=11.0, P=0.004), post hoc tests revealed that males had larger hilar volume (P<0.001) than

Discussion

The results from the present study demonstrate that estradiol regulates cell death and neurogenesis in the hippocampus of female, but not male rats. Repeated (15-day) administration of estradiol resulted in a decrease in cell death and new neuron survival, with a slight increase in cell proliferation by the end of treatment, in the DG of adult female, but not male, rats. The finding that estradiol decreases overall cell death is consistent with previous reports demonstrating that estradiol can

Conclusion

We have reported here the first evidence of a sex difference in vivo in the effects of repeated administration of estradiol on hippocampal neurogenesis and cell death. Although repeated estradiol exposure increased cell proliferation and decreased cell death in female rats, it had no such effect in male rats. As estradiol has been presented as a potential therapeutic or preventative agent for neurodegenerative diseases, it is important to note that while both men and women suffer from such

Acknowledgments

We thank Stephanie Lieblich and Dr. Mark Spritzer for assistance with laboratory work. Funding for this research was provided by the Canadian Institutes of Health Research (LAMG). J.M.B. is the recipient of a Canadian Graduate Scholarship from the Natural Sciences and Engineering Research Council of Canada. LAMG is a Michael Smith Senior Scholar.

References (80)

  • S.P. Herrick et al.

    Extranuclear estrogen receptor beta immunoreactivity is on doublecortin-containing cells in the adult and neonatal rat dentate gyrus

    Brain Res

    (2006)
  • C. Isgor et al.

    Estrogen receptor alpha and beta mRNA expressions by proliferating and differentiating cells in the adult rat dentate gyrus and subventricular zone

    Neuroscience

    (2005)
  • M. Jin et al.

    Two estrogen replacement therapies differentially regulate expression of estrogen receptors alpha and beta in the hippocampus and cortex of ovariectomized rat

    Mol Brain Res

    (2005)
  • R. Kalb

    The protean actions of neurotrophins and their receptors on the life and death of neurons

    Trends Neurosci

    (2005)
  • N. Kee et al.

    The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis

    J Neurosci Methods

    (2002)
  • C.A. Mazzucco et al.

    Both estrogen receptor alpha and estrogen receptor beta agonists enhance cell proliferation in the dentate gyrus of adult female rats

    Neuroscience

    (2006)
  • H.E. Murray et al.

    Dose- and sex-dependent effects of the neurotoxin 6-hydroxydopamine on the nigrostriatal dopaminergic pathway of adult rats: differential actions of estrogen in males and females

    Neuroscience

    (2003)
  • F. Naftolin et al.

    The formation of estrogens by central neuroendocrine tissues

    Recent Prog Horm Res

    (1975)
  • L.R. Nelson et al.

    Estrogen production and action

    J Am Acad Dermatol

    (2001)
  • B.K. Ormerod et al.

    Reproductive status influences cell proliferation and cell survival in the dentate gyrus of adult female meadow voles: a possible regulatory role for estradiol

    Neuroscience

    (2001)
  • B.K. Ormerod et al.

    Estradiol enhances neurogenesis in the dentate gyri of adult male meadow voles by increasing the survival of young granule neurons

    Neuroscience

    (2004)
  • R.L. Roof et al.

    Testosterone improves maze performance and induces development of a male hippocampus in females

    Brain Res

    (1992)
  • A.-S. Rössler et al.

    The melanocortin agonist, melanotan II, enhances proceptive sexual behaviors in the female rat

    Pharmacol Biochem Behav

    (2006)
  • K. Sato et al.

    beta-Estradiol induces synaptogenesis in the hippocampus by enhancing brain-derived neurotrophic factor release from dentate gyrus granule cells

    Brain Res

    (2007)
  • H. Scharfman et al.

    Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats

    Exp Neurol

    (2005)
  • H. Scharfman et al.

    Similarities between actions of estrogen and BDNF in the hippocampus: coincidence or clue?

    Trends Neurosci

    (2005)
  • L.C. Schmued et al.

    Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration

    Brain Res

    (1997)
  • L.C. Schmued et al.

    Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration

    Brain Res

    (2000)
  • C.K. Wagner et al.

    Neuroanatomical distribution of aromatase mRNA in the rat brain: indications of regional regulation

    J Steroid Biochem Mol Biol

    (1997)
  • C. Westenbroek et al.

    Chronic stress and social housing differentially affect neurogenesis in male and female rats

    Brain Res Bull

    (2004)
  • P.M. Wise et al.

    Estrogens: trophic and protective factors in the adult brain

    Front Neuroendocrinol

    (2001)
  • H.-H. Wu et al.

    Autoregulation of neurogenesis by GDF11

    Neuron

    (2003)
  • Y.Z. Ziylan et al.

    Blood-brain barrier permeability: regional alterations after acute and chronic administration of ethinyl estradiol

    Neurosci Lett

    (1990)
  • S. Bake et al.

    17beta-Estradiol differentially regulates blood-brain barrier permeability in young and aging female rats

    Endocrinology

    (2004)
  • M. Banasr et al.

    Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus

    Eur J Neurosci

    (2001)
  • M. Blurton-Jones et al.

    Estrogen receptor-beta colocalizes extensively with parvalbumin-labeled inhibitory neurons in the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized adult rats

    J Comp Neurol

    (2002)
  • J.P. Brown et al.

    Transient expression of doublecortin during adult neurogenesis

    J Comp Neurol

    (2003)
  • N.D. Bull et al.

    The adult mouse hippocampal progenitor is neurogenic but not a stem cell

    J Neurosci

    (2005)
  • A.G. Dayer et al.

    Short-term and long-term survival of new neurons in the rat dentate gyrus

    J Comp Neurol

    (2003)
  • C.D. Fowler et al.

    Estrogen regulation of cell proliferation and distribution of estrogen receptor-alpha in the brains of adult female prairie and meadow voles

    J Comp Neurol

    (2005)
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