The cerebral cortex and hippocampus are important for the control of cognitive functions and social behaviors, many of which are sexually dimorphic and tightly regulated by gonadal steroid hormones via activation of their respective nuclear receptors. As different levels of sex steroid hormones are present between the sexes during early development and their receptors act as transcription factors to regulate gene expression, we hypothesize that sexually dimorphic gene expression in the developing mouse cortex and hippocampus might result in sex differences in brain structures and neural circuits governing distinct behaviors between the sexes as adults. To test our hypothesis, we used gene expression microarrays to identify 90 candidate genes differentially expressed in the neonatal cortex/hippocampus between male and female mice, including 55 male-biased and 35 female-biased genes. Among these genes, sexually dimorphic expression of eight sex chromosome genes was confirmed by reverse transcription with quantitative PCR (RT-qPCR), including three located on the X chromosome (Xist, Eif2s3x, and Kdm6a), three on the Y chromosome (Ddx3y, Eif2s3y, and Kdm5d), and two in the pseudoautosomal region of the X and Y chromosomes (Erdr1 and Mid1). In addition, five autosomal genes (Cd151, Dab2, Klk8, Meg3, and Prkdc) were also validated for their sexually dimorphic expression in the neonatal mouse cortex/hippocampus. Gene Ontology annotation analysis suggests that many of these sexually dimorphic genes are involved in histone modifications, cell proliferation/death, androgen/estrogen signaling pathways, and synaptic organization, and these biological processes have been implicated in differential neural development, cognitive function, and neurological diseases between the sexes.
Objective Using gene expression microarrays and reverse transcription with quantitative polymerase chain reaction (RT-qPCR), we have recently identified several novel genes that are differentially expressed in the neonatal male versus female mouse cortex/hippocampus (Armoskus et al.). Since perinatal testosterone (T) secreted by the developing testes masculinizes cortical and hippocampal structures and the behaviors regulated by these brain regions, we hypothesized that sexually dimorphic expression of specific selected genes in these areas might be regulated by T during early development. Methods To test our hypothesis, we treated timed pregnant female mice daily with vehicle or testosterone propionate (TP) starting on embryonic day 16 until the day of birth. The cortex/hippocampus was collected from vehicle- and TP-treated, male and female neonatal pups. Total RNA was extracted from these brain tissues, followed by RT-qPCR to measure relative mRNA levels of seven sex chromosome genes and three autosomal genes that have previously showed sex differences. Results The effect of prenatal TP was confirmed as it stimulated Dhcr24 expression in the neonatal mouse cortex/hippocampus and increased the anogenital distance in females. We found a significant effect of sex, but not TP, on expression of three Y-linked (Ddx3y, Eif2s3y, and Kdm5d), four X-linked (Eif2s3x, Kdm6a, Mid1, and Xist), and one autosomal (Klk8) genes in the neonatal mouse cortex/hippocampus. Conclusion Although most of the selected genes are not directly regulated by prenatal T, their sexually dimorphic expression might play an important role in the control of sexually differentiated cognitive and social behaviors as well as in the etiology of sex-biased neurological disorders and mental illnesses.
The central nervous system (CNS) and the periphery are closely associated in the regulation of body homeostasis. In fact, in both physiological and pathological conditions, the CNS showed to be targeted by peripheral system molecules, which are able to generate adaptive responses under the tight control of the hypothalamus. In spite of having a well-recognized importance, the mechanisms underlying this communication are still unclear. Two major routes have been proposed to explain the transmission of information from the periphery to the CNS: a sensory pathway, through the peripheral nerves and a humoral pathway, through the bloodstream. In the present work, in vitro blood-brain barrier cultures and hypothalamic organotypic cultures were characterized with the main goal to enable the establishment of a platform to investigate the communication between the periphery and the CNS through the humoral pathway.Index Terms-in vitro tools; blood-brain barrier cultures; hypothalamic organotypic cultures; humoral pathway I. CONTEXTThe communication between the central nervous system (CNS) and the periphery is the core of body homeostasis studies. Over the years, a bi-directional flow of information between these two systems responsible for the stabilization of body internal conditions has been well-recognized [1][2]. Indeed, physical and/or chemical stimuli generated within or outside the body and perceived by peripheral organs are able to induce an adaptive response by the central nervous system [3]. Besides the CNS activation in physiological situations, as thermoregulation, reproduction, and food intake, the transfer of information from the periphery to the CNS has demonstrated to be increased under pathological demands, as infections, traumas and tumors [2][4].Since there are different mechanisms involved in the communication between CNS and the periphery concerning body homeostasis, a unified control system is essential. In mammals, the hypothalamus has evolved to serve this purpose [5]. In fact, the hypothalamus showed to be the preferential structure to control body homeostasis due to its ability to integrate peripheral signals and to send efferent hormonal and neuronal signals to regulate peripheral organs [6].A major dilemma has been to clarify how the communication between the CNS and the peripheral organs actually occurs. Two major routes have been proposed to explain this communication: a neural pathway, by the activation of peripheral afferent nerves, and a humoral pathway, through the bloodstream [4] [7].The study of the humoral transmission of peripheral system molecules to the brain has been considerably expanded [8].Unveiling the fundamental features of this communication would be useful for the discovery of new and promising findings in nanomedicine and pharmaceutical fields, potentiating advances in drug delivery research and in the development of new CNS-targeted small and large molecules to treat wide-ranging neurological disorders [8] [9]. However, the CNS is highly protected, and for the blood-circul...
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