High resolution whole brain imaging of anatomical variation in XO, XX, and XY mice

Abstract

The capacity of sex to modify behavior in health and illness may stem from biological differences between males and females. One such difference – fundamental to the biological definition of sex - is inequality of X chromosome dosage. Studies of Turner syndrome (TS) suggest that X-monosomy profoundly alters mammalian brain development. However, use of TS as a model for X chromosome haplonsufficiency is complicated by karyotypic mosaicism, background genetic heterogeneity and ovarian dysgenesis. Therefore, to better isolate X chromosome effects on brain development and identify how these overlap with normative sex differences, we used whole-brain structural imaging to study X-monosomic mice (free of mosaicism and ovarian dysgenesis) alongside their karyotypical normal male and female littermates. We demonstrate that murine X-monosomy (XO) causes (i) accentuation of XX vs XY differences in a set of sexually dimorphic structures including classical foci of sex-hormone action, such as the bed nucleus of the stria terminal and medial amygdala, (ii) parietal and striatal abnormalities that recapitulate those reported TS, and (iii) abnormal development of brain systems relevant for domains of altered cognition and emotion in both murine and human X-monosomy. Our findings suggest an unexpected role for X-linked genes in shaping sexually dimorphic brain development, and an evolutionarily conserved influence of X-linked genes on both cortical and subcortical development in mammals. Furthermore, our murine findings highlight the bed nucleus of the stria terminalis and periaqueductal gray matter as novel neuroanatomical candidates for closer study in TS. Integration of these data with existing genomic knowledge generates a set of novel, testable hypotheses regarding candidate mechanisms for each observed pattern of anatomical variation across XO, XX and XY groups.

In vivo magnetic resonance images reveal neuroanatomical sex differences through the application of voxel-based morphometry in C57BL/6 mice

“…Recently, more emphasis has been placed on factors outside of gonadal hormones in the formation of neural sex (Arnold, 2009a). For example, sex chromosomes, epigenetics, and environmental factors have all been shown to produce sex differences in the brain (McCarthy and Arnold, 2011; Raznahan et al, 2013). Striving to uncover the basis of neural sex differences will lead to an improved understanding of sexually dimorphic behavior and disease.…”

“…For example, males and females of the same mouse strain have the same genetic makeup and are housed in similar environments, and controlling for as many variables as possible may allow observed differences in male and female brain structure to be attributed strictly to sex. However, only a few prior studies have provided a thorough analysis of neural sex differences in mice (Corre et al, 2014; Raznahan et al, 2013; Spring et al, 2007). These watershed studies provide invaluable information about sexual dimorphism in the brain, but it is also important to validate and expand this work with carefully-controlled, well-powered studies with meaningful differences in image acquisition and analysis.…”

Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies

“…However, advances in structural magnetic resonance image (sMRI) acquisition and processing have now made it possible to conduct a highly efficient and technically homogenous survey of anatomy across the entire mouse brain in a spatially unbiased manner (Lerch et al 2011). We recently applied these methods in XO mice, and found evidence for X chromosome gene-dosage effects at classical sites of androgen-dependent sexual dimorphism within the brain (Raznahan et al 2013). Here, we extend this earlier work in three new directions.…”

“…First, we chart neuroanatomical alterations in the XXY SCA mouse model for the first time. We were specifically interested in determining (1) if foci of sexually dimorphic murine brain volume that are detectible by sMRI, such as relative male volume excess in BNST and amygdala relative to females (Raznahan et al 2013), are preserved in XXY males, and (2) if XXY mice recapitulate any of the better-replicated anatomical alterations in studies of XXY humans [e.g., amygdala and hippocampal volume reductions relative to typically developing males (Bryant et al 2011; Steinman et al 2009)]. Second, we use reciprocal anatomical abnormalities in XXY and XO mice to detect replicable X-dosage effects on the brain that are independent of gonadal or Y chromosome status.…”

“…Second, we use reciprocal anatomical abnormalities in XXY and XO mice to detect replicable X-dosage effects on the brain that are independent of gonadal or Y chromosome status. Our prior work in XO mice identified multiple regions where murine brain volume may be influenced by X gene dosage, including the olfactory bulb, BNST, amygdala, nucleus accumbens, thalamus, hypothalamus, periaqueductal gray matter and parieto-temporal cortex (Raznahan et al 2013). Finally, we apply data triangulation methods across XO, XX, XY and XXY mice to fractionate the brain based on its sensitivity to differences in gonad and sex chromosome complement.…”