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Understanding Brain Sexual Dimorphisms and Reproductive Physiology in the Four Core Genotypes Rat Model


Since the development of the Four Core Genotypes (FCG) mouse model, a variety of studies have identified sex chromosome effects on sex differences in behaviors (e.g., aggression and nociception), gene expression (e.g., septal vasopressin), and susceptibility to disease (e.g., multiple sclerosis and pulmonary hypertension). This is due to the ability of the FCG model to produce four unique groups (XX and XY gonadal males, XX and XY gonadal females) which allow for the independent comparison of gonadal hormone and sex chromosome effects that contribute to any phenotypic sex difference. A limitation of the model is that these effects can only be measured in mice, creating “mousified” results which might not reflect sex chromosome effects in other species. This has led to an attempt to create an FCG rat model which utilizes CRISPR technology to delete the testis-determining function from the Y chromosome, and transgenesis to insert an Sry transgene onto an autosome. Thus far, the model generates three types of gonadal males (XY wild-type, XY(SryTG+), and XX(SryTG+)) along with two types of gonadal females (XX and XYΔ). The present study utilizes the FCG rat model to characterize sex differences in the cell number, cell size, and volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) as well as the reproductive physiology between gonadal females (XX and XYΔ). Brains from each of the five unique genotypes were collected and immunolabeled for calbindin (CALB) to identify the SDN-POA in the rat hypothalamus. The cell number, cell size, and volume of the nucleus were observed to be significantly larger in the gonadal males than in the gonadal females, suggesting the influence of gonadal hormone effects on the presence of the brain dimorphism. No differences were ascertained between XX and XY rats with the same type of gonad. No differences were noted in estrous cycle duration shows no significant differences between gonadal female groups (XX and XYΔ) suggesting no sex chromosome effects. Taken together, these findings suggest that XX and XY rats with the same type of gonad appear to have comparable levels of gonadal hormones during development and adulthood, which cause sex differences in these dependent variables.

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