Sexual Differentiation of the Rodent Brain: Dogma and Beyond

Lenz, Kathryn M.; Nugent, Bridget M.; McCarthy, Margaret M.

doi:10.3389/fnins.2012.00026

Cited by 150 publications

(110 citation statements)

References 187 publications

(211 reference statements)

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“…Such study also has potential to be used for understanding the mechanisms of the development of sexual dimorphism in brain function. Also, it will be important for future studies to look at the role of DNA methylation in regulating the use of alternative promoters and alternative splicing of transcripts in zebrafish [55]. Further, it will be important to determine whether the unique DMC clusters play role in in determining sex-specific phenotypes.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Sex differences in DNA methylation and expression in zebrafish brain: a test of an extended ‘male sex drive’ hypothesis

Chatterjee

Lagisz

Rodger

et al. 2016

Gene

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Sex differences in DNA methylation and expression in zebrafish brain: a test of an extended 'male sex drive ' hypothesis, Gene (2016' hypothesis, Gene ( ), doi: 10.1016' hypothesis, Gene ( /j.gene.2016 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 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. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 3 ABSTRACTThe sex drive hypothesis predicts that stronger selection on male traits has resulted in masculinization of the genome. Here we test whether such masculinizing effects can be detected at the level of the transcriptome and methylome in the adult zebrafish brain.Although methylation is globally similar, we identified 914 specific differentially methylated CpGs (DMCs) between males and females (435 were hypermethylated and 479 were hypomethylated in males compared to females). These DMCs were prevalent in gene body, intergenic regions and CpG island shores. We also discovered 15 distinct CpG clusters with striking sex-specific DNA methylation differences. In contrast, at transcriptome level, more female-biased genes than male-biased genes were expressed, giving little support for the male sex drive hypothesis.Our study provides genome-wide methylome and transcriptome assessment and sheds light on sex-specific epigenetic patterns and in zebrafish for the first time.

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Section: Accepted M Manuscriptmentioning

confidence: 99%

Sex differences in DNA methylation and expression in zebrafish brain: a test of an extended ‘male sex drive’ hypothesis

Chatterjee

Lagisz

Rodger

et al. 2016

Gene

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“…Following the discovery that neonatal exposure to testosterone and its metabolite oestradiol cause permanent and irreversible changes to the rodent central nervous system, considerable effort has been devoted to investigating the molecular and cellular mechanisms through which these hormones act to organize the sexual differentiation of the brain [26,27] exhaustive list, cell death, cell survival, glial cell regulation and epigenetic changes have all been shown to play a role in the establishment of sex differences in the brain [28 -33].…”

Section: Introductionmentioning

confidence: 99%

Hypothalamic control of the male neonatal testosterone surge

Clarkson¹,

Herbison²

2016

Phil. Trans. R. Soc. B

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Sex differences in brain neuroanatomy and neurophysiology underpin considerable physiological and behavioural differences between females and males. Sexual differentiation of the brain is regulated by testosterone secreted by the testes predominantly during embryogenesis in humans and the neonatal period in rodents. Despite huge advances in understanding how testosterone, and its metabolite oestradiol, sexually differentiate the brain, little is known about the mechanism that actually generates the male-specific neonatal testosterone surge. This review examines the evidence for the role of the hypothalamus, and particularly the gonadotropin-releasing hormone (GnRH) neurons, in generating the neonatal testosterone surge in rodents and primates. Kisspeptin–GPR54 signalling is well established as a potent and critical regulator of GnRH neuron activity during puberty and adulthood, and we argue here for an equally important role at birth in driving the male-specific neonatal testosterone surge in rodents. The presence of a male-specific population of preoptic area kisspeptin neurons that appear transiently in the perinatal period provide one possible source of kisspeptin drive to neonatal GnRH neurons in the mouse.

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“…Sexual differentiation of the brain begins during prenatal development following the production of steroid hormones, such as testosterone (T), by the fetal testes (Lenz, Nugent, & McCarthy, 2012). The classic Organizational-Activational Hypothesis proposed by Phoenix et al (1959), states that gonadal hormones organize brain regions during a critical period in development, which produces differences in brain development and behavior between the sexes (Phoenix, 1959).…”

Section: Prenatal Steroid Hormonesmentioning

confidence: 99%

“…The classic Organizational-Activational Hypothesis proposed by Phoenix et al (1959), states that gonadal hormones organize brain regions during a critical period in development, which produces differences in brain development and behavior between the sexes (Phoenix, 1959). More recently, sex differences in brain molecular, cellular, and neural systems have been described (Spring, Lerch, & Henkelman, 2007), including roles for de novo neurosteroidogenesis (Lenz et al, 2012). These sexual dimorphisms can affect how each sex develops a disease, their signs and symptoms of that disease, and their response to therapy (Becker et al, 2005).…”

Section: Prenatal Steroid Hormonesmentioning

confidence: 99%

“…Interestingly, immune cells in the brain are implicated in the development of sexually dimorphic brain regions. To date, there are no clinical studies in this area given that most of the research into the impact of sex steroid hormones on brain development is carried out in animals (primarily rodents) (Lenz et al, 2012;McCarthy, Arnold, Ball, Blaustein, & De Vries, 2012;Park, Baum, Paredes, & Tobet, 1996;Tobet, Basham, & Baum, 1993). However, connections between immune activation and mechanisms leading to increased vulnerability to ASD in males can be informed by research using rodent models.…”

Section: Environmental Mechanismsmentioning

confidence: 99%

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Using a mouse model to investigate male bias in autism spectrum disorder incidence.

Gordon¹

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The review (Chapter 1) overviews our current understanding of the sex bias in autism spectrum disorders (ASD), whereby males are 4 times more likely to develop the condition. The longstanding uncertainty surrounding the etiology of autism can be informed by inclusion of both sexes in future research to better understand the mechanism responsible for this sex bias. Both clinical studies and animal models are useful tools to elucidate the underlying cause(s) of sexual dimorphic morphological, physiological, and behavioral differences in the ASD phenotype.Sex differences in social behaviors are common across species, underscoring the importance of assessing baseline sex differences in behavior, especially when sexually dimorphic effects on behavior are expected. I examined pre-pubertal behavior (Chapter 2) in 3 strains of mice (C57BL/6, CFW, and CF1) using a wheel-running assay developed to be relevant to autism-like behaviors. The results indicated no sex differences in wheel running behaviors or social interaction with all mouse strains displaying typical wheel running behavior, i.e. more time running on the wheel when it would turn and increased performance of other activities when it was jammed. iv Studies have found that elevated levels of fetal testosterone (fT) are correlated with later ASD diagnosis. Prenatal valproic acid (VPA) treatment is a common animal model of ASD in rodents, mimicking many of the features of ASD including increased male vulnerability. I used the VPA model (Chapter 3) to evaluate sex-specific responses to prenatal VPA treatment, and to assess if masculinization of females with perinatal testosterone propionate (TP) after prenatal VPA treatment would masculinize their susceptibility for abnormalities in development relevant to ASD. My findings confirmed that VPA exposure results in impaired motor development abilities, and provide novel evidence that the combined effects of VPA, TP, and maleness (triple hit) led to more severe motor development deficiencies in some tasks. I also present evidence that the triple hit resulted in reduced anxiety, but elevated cognitive rigidity and self-grooming compared to control females. The results provide some evidence for increased vulnerability of triple hit males to behavioral deficits relevant to ASD, but more research is needed to better understand this effect.

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Sexual Differentiation of the Rodent Brain: Dogma and Beyond

Cited by 150 publications

References 187 publications

Sex differences in DNA methylation and expression in zebrafish brain: a test of an extended ‘male sex drive’ hypothesis

Sex differences in DNA methylation and expression in zebrafish brain: a test of an extended ‘male sex drive’ hypothesis

Hypothalamic control of the male neonatal testosterone surge

Using a mouse model to investigate male bias in autism spectrum disorder incidence.

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