Expression of estrogen receptor (ER) α and β in mouse cerebral cortex: Effect of age, sex and gonadal steroids
Introduction
Estrogen receptor (ER) is a member of the nuclear receptor superfamily of transcription factors, which also includes receptors for sex steroids, thyroid hormone and retinoids as well as many orphan receptors for which no ligand has been identified [19]. There are two types of ERα and ERβ coded by two separate genes located on different chromosomes. Upon binding to its ligand, both receptors undergo conformational changes leading to the formation of either ERα/ERβ homodimer or heterodimer [12], [18]. ERα and ERβ are implicated in several brain functions such as migration of neurons during embryonic development [55], [56], protection against brain injury [14], [60], [61] and improvement in memory and learning [17], [30], [44], increase in choline acetyl transferase activity [34], growth of synapses [7], [46] and decrease of β amyloid level [32].
The brain exhibits sexual differences in its structure and function throughout the animal kingdom [36]. The wide range of effects associated with brain sexual differentiation represents the result of a complex response cascade, initiated by genes and prolonged by the effects of gonadal hormones. Early exposure to a masculine hormonal milieu results in the development of male specific brain while the absence of such a hormonal milieu shifts the development to a female specific brain. Apart from other changes in the brain, variation in the endogenous hormone level was shown to be responsible for differential distribution and density of androgen receptor (AR) and ER [57] in different regions of the brain during early development [36]. Gonadal steroids regulate ER level in the rat brain around 7–10 days after birth [20], [27], thereafter ER concentration declines rapidly and attains the adult pattern. However, in adult female rat brain, the level of ERα mRNA changes during different estrous phases [49]; thus, suggesting the involvement of sex steroids in the control of ER level beyond the early developmental stages. In contrast to adult animals, circulating gonadal hormone level changes with advancing age [28], [50], [51]. While these changes are abrupt in female, they are slow but steady in male [15]. Such sex-related decline in the level of circulating hormones may modulate ERα and ERβ level differentially in male and female during aging [48], [52].
The in situ and immunohistochemical studies conducted in female rat brain revealed that the number of cells expressing ERα and ERβ mRNA and protein show region specific changes during aging [2], [9], [10], [59]. In the present study, Western blot analysis showed differential effect of age, sex and gonadal steroid hormones on the expression of full length ERα and ERβ protein in the cerebral cortex of AKR mice.
Section snippets
Animals and hormone treatment
AKR mice were maintained in a colony at 25 ± 2 °C with free access to standard mice feed and drinking water. They were exposed to 12-h light:12-h dark schedule. The average life span of AKR mice in our colony is 70 ± 5 weeks. We used AKR mice for our study because of their short life span. Experimental protocols were approved by the animal ethical committee of Banaras Hindu University, Varanasi, India. For each experiment, adult (25 ± 2 weeks) and old (65 ± 5 weeks) male and female mice were divided
Age dependent differences in ERα and ERβ level
To know the effect of age, the levels of ERα and ERβ in adults were compared with those in old (Fig. 1, Fig. 2). The adult level was considered as 100%. ERα level did not change in old. In contrast to ERα, ERβ level decreased significantly in both old male (40%, P < 0.05) and female (75%, P < 0.05).
Sex dependent differences in ERα and ERβ level
To know the effect of sex, the level of ERα and ERβ in adult male was considered as 100%. Western blot analysis (Fig. 1) revealed higher level of ERα protein (162%, P < 0.05) in adult female than adult
Discussion
In the present study, we have examined the effect of age, sex and gonadal sex steroid hormones on the levels of ERα and ERβ in the mice cerebral cortex. The cerebral cortex is a recognized target of gonadal sex steroids. In addition to developmental influences [37], behavioral [8] and biochemical [16] studies suggest that estrogen also stimulates the mature cerebrum [35]. Estrogen exerts potent modulatory effects on multiple neuronal networks. Although it is clear that many of the effects of
Acknowledgements
This work was supported by grants from the Department of Biotechnology (BT/PRO831/HRD/15/87/97 and BT/PR3593/Med/14/468/2004) and Department of Science and Technology, Government of India (SP/SO/B05/99) to M.K.T. P.K.S. is a recipient of Junior Research Fellowship from the University Grants Commission, India.
References (62)
- et al.
Expression of 112 kDa estrogen receptor in mouse brain cortex and its autoregulation with age
Biochem Biophys Res Commun
(1997) - et al.
Estrogenic and antiestrogenic regulation of the half-life of covalently labeled estrogen receptor in MCF-7 breast cancer cells
J Steroid Biochem Mol Biol
(1996) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal Biochem
(1976)- et al.
Estrogen receptors α and β form heterodimers on DNA
J Biol Chem
(1997) - et al.
Sexually dimorphic regulation of estrogen receptor alpha mRNA in the ventromedial hypothalamus of adult whiptail lizards is testosterone dependent.
Brain Res
(2004) - et al.
Interaction of age and chronic estradiol replacement on memory and markers of brain aging
Neurobiol Aging
(2003) - et al.
The multifaceted mechanisms of estradiol and estrogen receptor signaling
J Biol Chem
(2001) - et al.
Transcription factor cross-talk: the estrogen receptor and NF-κB
Trends Endocrinol Metab
(2005) - et al.
Androgen receptor mRNA is inversely regulated by testosterone and estradiol in adult mouse brain
Neurobiol Aging
(2004) - et al.
Expression of estrogen receptor-alpha and beta mRNA in the developing and adult mouse striatum
Neurosci Lett
(1999)
Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats
Exp Neurol
Post-training estrogen and memory modulation
Horm Behav
Aromatase activity in the rat brain: hormonal regulation and sex differences
J Steroid Biochem Mol Biol
Estrogen and the brain: beyond ER-α and ER-β
Exp Gerontol
Age differentially influences estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) gene expression in specific regions of the rat brain
Mech Ageing Dev
Estradiol is a protective factor in the adult and aging brain: understanding of mechanisms derived from in vivo and in vitro studies
Brain Res Brain Res Rev
Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain
Endocrinology
Estrogen and aging affect the subcellular distribution of estrogen receptor-α in the hippocampus of female rats
J Neurosci
Thyroid hormone is an inhibitor of estrogen-induced degradation of estrogen receptor-α protein: estrogen-dependent proteolysis is not essential for receptor transactivation function in the pituitary
Endocrinology
17β-estradiol increases the growth and survival of cultured cortical neurons
Neurochem Res
Changes in cognitive task performance across the menstrual cycle
J Comp Physiol Psychol
Aging-related changes in ovarian hormones, their receptors, and neuroendocrine function
Exp Biol Med
Stereologic analysis of estrogen receptor alpha (ER alpha) expression in rat hypothalamus and its regulation by aging and estrogen
J Comp Neurol
Age-related changes in estrogen receptor β in rat hypothalamus: a quantitative analysis
Endocrinology
Estrogen receptor α, not β, is a critical link in estradiol-mediated protection against brain injury
Proc Natl Acad Sci USA
Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study
J Clin Endocrinol Metab
Estrogen control of central neurotransmission: effect on mood, mental state and memory
Cell Mol Neurobiol
Estrogen receptors: structure, mechanisms and function
Rev Endocr Metab Disord
Sexually dimorphic and estrogen-dependent expression of estrogen receptor β in the ventromedial hypothalamus during rat postnatal development
Endocrinology
Estrogen receptors activate atrial natriuretic peptide in rat heart
Proc Natl Acad Sci USA
Estrogen–receptor interaction
Science
Cited by (66)
Catalase, a therapeutic target in the reversal of estrogen-mediated aging
2022, Molecular TherapyTemporal and bidirectional influences of estradiol on voluntary wheel running in adult female and male rats
2020, Hormones and BehaviorCitation Excerpt :In considering this concept, we were drawn to the literature regarding the effects of daily estradiol injection (also called estrogen priming), wherein previous exposure to estradiol impacts future responsiveness to estradiol. For example, at the molecular level, repeated estradiol exposure impacts estradiol signaling via regulating ER expression levels and patterns (Catanuto et al., 2009; Hatae et al., 2009; Patisaul et al., 1999; Saceda et al., 1988; Sharma and Thakur, 2006). Regarding rapid estrogen action at the molecular level, exposure to masculinizing doses of estradiol during the organizational critical period eliminates later rapid estradiol action in female hippocampal neurons as assessed via CREB phosphorylation (Meitzen et al., 2012).
Aging of the Brain
2019, Encyclopedia of Biomedical Gerontology: Volume 1-3Aging of the brain
2019, Encyclopedia of Biomedical Gerontology