Cellular neuroscienceBoth estrogen receptor α and estrogen receptor β agonists enhance cell proliferation in the dentate gyrus of adult female rats
Section snippets
Experimental procedures
All experiments were conducted in accordance with the policies established by the University of British Columbia, the Canadian Council on Animal Care and National Institutes of Health Guide for the Care and Use of Laboratory Animals regarding the ethical treatment of animals used for research. All efforts were made to reduce the number and the suffering of animals.
Estradiol-induced enhanced cell proliferation is mediated by both ER-α and ER-β in the dentate gyrus of adult OVX female rats
As expected, estradiol increased cell proliferation at the 4 h time period, with EB-treated females having significantly more labeled cells relative to OIL-treated females (P≤0.002; Fig. 1; main effect: F(9,42)=6.42; P≤0.00001). There was no statistical difference between the two vehicles groups, OIL and DMSO (P>0.14). The ER-α agonist, PPT significantly increased cell proliferation, relative to vehicle only at a dose of 2.5 mg (P≤0.0002; Fig. 1). However, analysis demonstrated that the ER-β
Both ER-α and ER-β are involved in estradiol-induced upregulation of cell proliferation
Consistent with previous literature we found that exposure to a high dose of estradiol for 4 h increased the number of BrdU-labeled cells (assessed 24 h post-BrdU) in adult female rats (Nagy et al 2006, Ormerod et al 2003). The ER-β agonist, DPN, showed a significant increase in cell proliferation at all three administered doses (1.25, 2.5 and 5 mg), whereas the ER-α agonist, PPT, demonstrated a significant increase in cell proliferation at a dose of 2.5 mg, relative to vehicle-treated rats.
Conclusions
In conclusion, we have shown that both ERs, α and β, are involved in estradiol-induced enhancement of hippocampal neurogenesis in the female rat. We also found that 24 h after treatment, there was co-localization of Ki-67 expressing cells with both ER-α and ER-β mRNA in the dentate gyrus. Our previous studies have demonstrated that estradiol has the ability to increase proliferation in a time-dependent manner and future studies will determine whether this increase in neurons has a functional
Acknowledgments
We gratefully acknowledge the technical assistance of Cindy Barha, Ziba Rajaei and Jennifer Barker. We thank Heather Cameron for her help with the confocal pictures. This work was funded by CIHR operating grants to L.A.M.G. and V.V. V.V. is a CHIR and MSFHR New Investigator. L.A.M.G. is a MSFHR Senior Scholar.
References (54)
- et al.
Estrogen-receptor-dependent regulation of neural stem cell proliferation and differentiation
Mol Cell Neurosci
(2002) - et al.
Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat
Neuroscience
(1993) - et al.
Interactions of estrogens and insulin-like growth factor-I in the brainimplications for neuroprotection
Brain Res Brain Res Rev
(2001) - et al.
Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons
Neuron
(1999) - et al.
Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons
Neuron
(1999) - 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) - et al.
Two estrogen replacement therapies differentially regulate expression of estrogen receptors alpha and beta in the hippocampus and cortex of ovariectomized rat
Brain Res Mol Brain Res
(2005) - et al.
Estrogen receptor alpha, but not beta, is expressed in the interneurons of the hippocampus in prepubertal ratsan in situ hybridization study
Brain Res Dev Brain Res
(2000) - et al.
Reproductive status influences cell proliferation and cell survival in the dentate gyrus of adult female meadow volesa possible regulatory role for estradiol
Neuroscience
(2001) - et al.
Evidence for novel estrogen binding sites in the rat hippocampus
Neuroscience
(2000)
Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer’s disease
Am J Med
Increased number of BrdU-labeled neurons in the rostral migratory stream of the estrous prairie vole
Horm Behav
Neurotrophins and activity-dependent plasticity
Prog Brain Res
Estrogen and insulin synergism in neurite growth enhancement in vitromediation of steroid effects by interactions with growth factors?
Brain Res
Blood-brain barrier permeabilityregional alterations after acute and chronic administration of ethinyl estradiol
Neurosci Lett
Localization of estrogen receptor beta-immunoreactivity in astrocytes of the adult rat brain
Glia
Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus
Eur J Neurosci
Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists
Mol Pharmacol
Anatomical evidence for transsynaptic influences of estrogen on brain-derived neurotrophic factor expression
J Comp Neurol
Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus
J Comp Neurol
Estrogen receptors ER alpha and ER beta in proliferation in the rodent mammary gland
Proc Natl Acad Sci U S A
Response-specific and ligand dose-dependent modulation of estrogen receptor (ER) alpha activity by ERbeta in the uterus
Endocrinology
Estrogen and nerve growth factor-related systems in brain. Effects on basal forebrain cholinergic neurons and implications for learning and memory processes and aging
Ann N Y Acad Sci
Learning enhances adult neurogenesis in the hippocampal formation
Nat Neurosci
Some new, simple and efficient stereological methods and their use in pathological research and diagnosis
APMIS
The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens
Endocrinology
Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat
Proc Natl Acad Sci U S A
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2022, Vitamins and HormonesCitation Excerpt :Furthermore, ERα, ERβ, and GPERs can activate cell signaling cascades that affect neuroplasticity (Foster, 2012; Waters et al., 2011). It is important to emphasize that the concentration of ERs or ARs in the hippocampus varies by hippocampus subfields, estrous cycle, exposure to exogenous estrogens, age, and sex (Adams et al., 2002; Bohacek & Daniel, 2009; Cui et al., 2013; Duarte-Guterman, Lieblich, et al., 2019; González et al., 2007; Hamson et al., 2013; Han et al., 2013; Matsuda et al., 2008; Mazzucco et al., 2006; Mitra et al., 2003; Mitterling et al., 2010; Xiao & Jordan, 2002). Evidence from several rodent species shows that endogenous estrogens (including estradiol and estrone) can influence hippocampal neurogenesis (Galea & McEwen, 1999; Ormerod and Galea, 2001; Ormerod, Lee, & Galea, 2003; Tanapat et al., 1999; Tanapat, Hastings, & Gould, 2005; Tzeng et al., 2014; Rummel, Epp, & Galea, 2010; reviewed in Galea et al., 2008; Duarte-Guterman, Yagi, Chow, & Galea, 2015).