Estrogen, But Not Androgens, Regulates Androgen Receptor Messenger Ribonucleic Acid Expression in the Developing Male Rat Forebrain

McAbee, Michael D.

doi:10.1210/en.140.8.3674

Cited by 45 publications

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“…For example, if ER signaling regulates AR signaling, and in turn AR regulates genes required for the neurons to participate in the neural circuit, then both AR and ER could be said to mediate mating in an instructive manner. In fact, estrogen signaling has been shown to regulate AR expression in the rat brain during development, consistent with the notion that disruption of ER signaling may mediate some male sex-typical behaviors by modulating AR (McAbee and DonCarlos, 1999). Testosterone or AR have also been shown to regulate the expression of aromatase in several species (Balthazart and Foidart, 1993;Roselli et al, 1987;Veney et al, 2000).…”

Section: The Relative Contributions Of Ar and Er Signaling To Male Masupporting

confidence: 66%

A genetic approach to dissect sexually dimorphic behaviors

Juntti

Coats

Shah

2008

Hormones and Behavior

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It has been known since antiquity that gender-specific behaviors are regulated by the gonads. We now know that testosterone is required for the appropriate display of male patterns of behavior. Estrogen and progesterone, on the other hand, are essential for female typical responses. Research from several groups also indicates that estrogen signaling is required for male typical behaviors. This finding raises the issue of the relative contribution of these two hormonal systems in the control of male typical behavioral displays. In this review we discuss the findings that led to these conclusions and suggest various genetic strategies that may be required to understand the relative roles of testosterone and estrogen signaling in the control of gender specific behavior.All animals exhibit sex differences in behavior that are characteristic of the species. Such gender typical behaviors are often used to court mates, to defend territory and other resources, and to procure food for mates and offspring. These sexual dimorphisms in behavior are often innate and can be displayed without prior social experience or training, suggesting that the neural circuits that mediate these behaviors are developmentally hardwired in the brain. Nevertheless, the display of these behaviors is tightly regulated by external sensory cues as well as internal physiological regulators such as hormones. Such dual control ensures that animals engage in these behaviors only at the appropriate time and circumstance. While we have learned much about the sensory and hormonal control of sexually dimorphic behaviors (Morris et

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Section: The Relative Contributions Of Ar and Er Signaling To Male Masupporting

confidence: 66%

A genetic approach to dissect sexually dimorphic behaviors

Juntti

Coats

Shah

2008

Hormones and Behavior

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“…Furthermore, neonatal DHT administration may not masculinize some areas of the brain because AR expression levels in those areas may depend on ERs (McAbee and DonCarlos, 1999a). Neonatal gonadectomy in male rats decreases AR mRNA, and replacement with T or E2, but not DHT, restores AR mRNA to levels similar to gonadally intact male rats (McAbee and DonCarlos, 1999a;McAbee and DonCarlos, 1999b). These findings suggest that T normally acts through ERs to upregulate AR.…”

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confidence: 89%

“…Therefore DHT treatment alone would not reveal such a normal role for ARs because while it might boost aromatase activity, there would be no aromatizable androgenic precursor to be converted by the enzyme to provide estrogens for ERs. Furthermore, neonatal DHT administration may not masculinize some areas of the brain because AR expression levels in those areas may depend on ERs (McAbee and DonCarlos, 1999a). Neonatal gonadectomy in male rats decreases AR mRNA, and replacement with T or E2, but not DHT, restores AR mRNA to levels similar to gonadally intact male rats (McAbee and DonCarlos, 1999a;McAbee and DonCarlos, 1999b).…”

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confidence: 99%

The role of androgen receptors in the masculinization of brain and behavior: What we've learned from the testicular feminization mutation

Zuloaga

Puts

Jordan

et al. 2008

Hormones and Behavior

213

156

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Many studies demonstrate that exposure to testicular steroids such as testosterone early in life masculinizes the developing brain, leading to permanent changes in behavior. Traditionally, masculinization of the rodent brain is believed to depend on estrogen receptors (ERs) and not androgen receptors (ARs). According to the aromatization hypothesis, circulating testosterone from the testes is converted locally in the brain by aromatase to estrogens, which then activate ERs to masculinize the brain. However, an emerging body of evidence indicates that the aromatization hypothesis cannot fully account for sex differences in brain morphology and behavior, and that androgens acting on ARs also play a role. The testicular feminization mutation (Tfm) in rodents, which produces a nonfunctional AR protein, provides an excellent model to probe the role of ARs in the development of brain and behavior. Tfm rodent models indicate that ARs are normally involved in the masculinization of many sexually dimorphic brain regions and a variety of behaviors, including sexual behaviors, stress response and cognitive processing. We review the role of ARs in the development of the brain and behavior, with an emphasis on what has been learned from Tfm rodents as well as from related mutations in humans causing complete androgen insensitivity. Keywordscomplete androgen insensitivity syndrome -CAIS; vasopressin; anxiety; spatial memory; bed nucleus; medial amygdala; SDN-POA; sexual behavior; aggression; VMH Exposure to testicular steroids such as testosterone (T) early in life masculinizes the developing brain, leading to permanent changes in behavior in a wide variety of animal models (Morris et al., 2004). According to the aromatization hypothesis, T is converted by aromatase into 17-β estradiol (E2), which then acts on estrogen receptors (ERs) to masculinize the brain (Naftolin et al., 1975). Traditionally, aromatization is believed to be the mechanism by which the rodent brain becomes masculinized and defeminized. Some sexually dimorphic regions within the hypothalamus adhere well to this hypothesis, including the sexually dimorphic nucleus of the preoptic area (SDN-POA) and anteroventral periventricular nucleus (AVPV). T spares neuronsCorresponding author: Damian Zuloaga, Neuroscience Program, 108 Giltner Hall, Michigan State University, East Lansing, MI 48824, Phone: Fax: (517) 432-2744, Email: E-mail: zuloagad@msu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript from death in the SDN-POA...

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“…DES is a synthetic estrogen, which in contrast to β-estradiol does not bind to α-fetoprotein and thus produces stable estrogen blood levels (Savu et al, 1979). At this daily dose, DES produces sexual differentiating effects in other brain regions (McAbee and Doncarlos, 1999). DHT is a non-aromatizable androgen, which has been shown to exert sexual differentiating effects (van der Schoot, 1980).…”

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confidence: 99%

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period

Giorgi

Velı́šková

Chudomel

et al. 2007

Neurobiology of Disease

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GABAergic activation of substantia nigra pars reticulata (SNR) at postnatal day (PN) 15 has sexspecific features on seizure control in vivo and electrophysiological responses in vitro. In males, the GABA A -receptor agonist muscimol has proconvulsant effects and induces depolarizing responses. In females, muscimol has no effect on seizures and evokes hyperpolarizing responses. We determined the time period during which sex hormones must be present to produce the sex-specific muscimol effects on seizures and their influence on SNR GABA A receptor-mediated postsynaptic currents. Exposure to testosterone or its metabolites (estrogen or dihydrotestosterone) during PN0-2 in females or males castrated at PN0 was sufficient to produce proconvulsant muscimol effects but did not affect the in vitro GABA responses, which remained hyperpolarizing. The data suggest that the PN0-2 period is critical for the development of the seizure-controlling SNR system; the hormonal effect on seizure control is independent from their effect on GABA conductance. Keywords substantia nigra; sex hormones; muscimol infusions; seizure; GABA; patch clamp During development, circulating sex hormones have organizational effects leading to permanent differences between males and females in distinct brain regions (Gorski, 1984). The presence or absence of testosterone, acting via its metabolites, dihydrotestosterone and estrogen, determines the future "male" or "female" brain phenotype (McEwen, 1992). In humans, the incidence of epilepsy is higher in the youngest age groups and population studies have shown that males have a higher incidence of seizures than females (Hauser, 1997). These epidemiological data strengthen the need to understand mechanisms underlying the sexdependent differentiation of the CNS, especially in relation to structures involved in seizure Correspondence: Jana Velíšková, MD, PhD, Albert Einstein College of Medicine, Department of Neurology, K312, 1410 Pelham Parkway South, Bronx, NY 10461, USA, Phone: (718) 430-2469, Fax: (718) The substantia nigra pars reticulata (SNR), a midbrain structure populated largely by GABAergic neurons, serves as a main output of the basal ganglia. The SNR is involved in the control of seizures in an age-and sex-specific fashion (Velíšková and Moshé, 2001;Velíšková and Moshé, 2006). In immature rats [postnatal day (PN) 15], localized bilateral SNR microinfusions of muscimol, an agonist at GABA A receptors, have proconvulsant effects on flurothyl-induced clonic seizures in males but not in females (Moshé et al., 1994;Velíšková and Moshé, 2001). Additionally, in vitro gramicidin patch clamp recordings in slices from PN14-17 males and females show sex-specific responses of the SNR GABAergic neurons to bath application of muscimol (Galanopoulou et al., 2003b) and to synaptically released GABA (Kyrozis et al., 2006). In males, both have depolarizing effects on the membrane potential of the SNR GABAergic neurons, while in females the response is hyperpolarizing.The majority of sex differenc...

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Estrogen, But Not Androgens, Regulates Androgen Receptor Messenger Ribonucleic Acid Expression in the Developing Male Rat Forebrain

Cited by 45 publications

References 0 publications

A genetic approach to dissect sexually dimorphic behaviors

A genetic approach to dissect sexually dimorphic behaviors

The role of androgen receptors in the masculinization of brain and behavior: What we've learned from the testicular feminization mutation

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period

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