Birth triggers an inflammatory response in the neonatal periphery and brain.

Birth is preceded by inflammation at the fetal/maternal interface. Additionally, the newborn experiences stimuli that under any other circumstance could elicit an immune response. It is unknown, however, whether birth elicits an inflammatory response in the newborn that extends to the brain.

X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons.

Several X-linked genes are involved in neuronal differentiation and may contribute to the generation of sex dimorphisms in the brain. Previous results showed that XX hypothalamic neurons grow faster, have longer axons, and exhibit higher expression of the neuritogenic gene neurogenin 3 (Ngn3) than XY before perinatal masculinization. Here we evaluated the participation of candidate X-linked genes in the development of these sex differences, focusing mainly on Kdm6a, a gene encoding for an H3K27 demethylase with functions controlling gene expression genome-wide.

DNA Methylation and Demethylation Underlie the Sex Difference in Estrogen Receptor Alpha in the Arcuate Nucleus.

Introduction: Neurons expressing estrogen receptor (ER) ɑ in the arcuate (ARC) and ventromedial (VMH) nuclei of the hypothalamus sex-specifically control energy homeostasis, sexual behavior, and bone density. Females have more ERɑ neurons in the VMH and ARC than males, and the sex difference in the VMH is eliminated by neonatal treatment with testosterone or a DNA methylation inhibitor.

Objective: Here, we tested the roles of testosterone and DNA methylation/demethylation in development of ERɑ in the ARC.

Birth elicits a conserved neuroendocrine response with implications for perinatal osmoregulation and neuronal cell death.

Long-standing clinical findings report a dramatic surge of vasopressin in umbilical cord blood of the human neonate, but the neural underpinnings and function(s) of this phenomenon remain obscure. We studied neural activation in perinatal mice and rats, and found that birth triggers activation of the suprachiasmatic, supraoptic, and paraventricular nuclei of the hypothalamus. This was seen whether mice were born vaginally or via Cesarean section (C-section), and when birth timing was experimentally manipulated.

Estradiol-dependent axogenesis and Ngn3 expression are determined by XY sex chromosome complement in hypothalamic neurons.

Hypothalamic neurons show sex differences in neuritogenesis, female neurons have longer axons and higher levels of the neuritogenic factor neurogenin 3 (Ngn3) than male neurons in vitro. Moreover, the effect of 17-β-estradiol (E2) on axonal growth and Ngn3 expression is only found in male-derived neurons. To investigate whether sex chromosomes regulate these early sex differences in neuritogenesis by regulating the E2 effect on Ngn3, we evaluated the growth and differentiation of hypothalamic neurons derived from the "four core genotypes" mouse model, in which the factors of "gonadal sex" and "sex chromosome complement" are dissociated.

Neonatal Inhibition of DNA Methylation Disrupts Testosterone-Dependent Masculinization of Neurochemical Phenotype.

Many neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERα) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown.

Developmental changes and sex differences in DNA methylation and demethylation in hypothalamic regions of the mouse brain.

DNA methylation is dynamically modulated during postnatal brain development, and plays a key role in neuronal lineage commitment. This epigenetic mark has also recently been implicated in the development of neural sex differences, many of which are found in the hypothalamus. The level of DNA methylation depends on a balance between the placement of methyl marks by DNA methyltransferases (Dnmts) and their removal, which is catalyzed by ten-eleven translocation (Tet) methylcytosine dioxygenases.

Does Leave an Epigenetic Imprint on the Brain?

The words "sex" and "gender" are often used interchangeably in common usage. In fact, the Merriam-Webster dictionary offers "sex" as the definition of gender. The authors of this review are neuroscientists, and the words "sex" and "gender" mean very different things to us: sex is based on biological factors such as sex chromosomes and gonads, whereas gender has a social component and involves differential expectations or treatment by conspecifics, based on an individual's perceived sex.

Interaction of sex chromosome complement, gonadal hormones and neuronal steroid synthesis on the sexual differentiation of mammalian neurons.

Female mouse hippocampal and hypothalamic neurons growing in vitro show a faster development of neurites than male mouse neurons. This sex difference in neuritogenesis is determined by higher expression levels of the neuritogenic factor neurogenin 3 in female neurons. Experiments with the four core genotype mouse model, in which XX and XY animals with male gonads and XX and XY animals with female gonads are generated, indicate that higher levels of neurogenin 3 in developing neurons are determined by the presence of the XX chromosome complement.

Regulation of aromatase expression in the anterior amygdala of the developing mouse brain depends on ERβ and sex chromosome complement.

During development sex differences in aromatase expression in limbic regions of mouse brain depend on sex chromosome factors. Genes on the sex chromosomes may affect the hormonal regulation of aromatase expression and this study was undertaken to explore that possibility. Male E15 anterior amygdala neuronal cultures expressed higher levels of aromatase (mRNA and protein) than female cultures.

Sex chromosome complement involvement in angiotensin receptor sexual dimorphism.

This study aimed to define whether sex chromosome complement (SCC) may differentially modulate sex differences in relative gene expression of basal Agtr1a, Agtr2, and Mas1 receptors at fore/hindbrain nuclei and at medulla/cortical kidney. Samples were collected from gonadectomized male (XX and XY) and female (XX and XY) mice of the "four core genotypes" model. At brain level, a SCC effect at the area postrema was demonstrated.

Sex chromosome complement determines sex differences in aromatase expression and regulation in the stria terminalis and anterior amygdala of the developing mouse brain.

Aromatase, which converts testosterone in estradiol, is involved in the generation of brain sex dimorphisms. Here we used the "four core genotypes" mouse model, in which the effect of gonadal sex and sex chromosome complement is dissociated, to determine if sex chromosomes influence the expression of brain aromatase. The brain of 16 days old XY mouse embryos showed higher aromatase expression in the stria terminalis and the anterior amygdaloid area than the brain of XX embryos, independent of gonadal sex.

Neurogenin 3 mediates sex chromosome effects on the generation of sex differences in hypothalamic neuronal development.

The organizational action of testosterone during critical periods of development is the cause of numerous sex differences in the brain. However, sex differences in neuritogenesis have been detected in primary neuronal hypothalamic cultures prepared before the peak of testosterone production by fetal testis. In the present study we assessed the hypothesis of that cell-autonomous action of sex chromosomes can differentially regulate the expression of the neuritogenic gene neurogenin 3 (Ngn3) in male and female hypothalamic neurons, generating sex differences in neuronal development.

Effect of sex chromosome complement on sodium appetite and Fos-immunoreactivity induced by sodium depletion.

Previous studies indicate a sex chromosome complement (SCC) effect on the angiotensin II-sexually dimorphic hypertensive and bradycardic baroreflex responses. We sought to evaluate whether SCC may differentially modulate sexually dimorphic-induced sodium appetite and specific brain activity due to physiological stimulation of the rennin angiotensin system. For this purpose, we used the "four core genotype" mouse model, in which the effect of gonadal sex and SCC is dissociated, allowing comparisons of sexually dimorphic traits between XX and XY females as well as in XX and XY males.