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

Abstract

Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be colocalized with and reciprocal to XO-XX differences in anatomy. These overlaps identify the lateral septum, BNST, ventral group thalamic nuclei and periaqueductal gray matter as regions with replicable sensitivity to X chromosome dose across two SCAs. We then harness anatomical variation across all four karyotype groups in our study—XO, XX, XY and XXY—to create an agnostic data-driven segmentation of the mouse brain into five distributed clusters which (1) recover fundamental properties of brain organization with high spatial precision, (2) define two previously uncharacterized systems of relative volume excess in females vs. males (“forebrain cholinergic” and “cerebelo-pontine-thalamo-cortical”), and (3) adopt stereotyped spatial motifs which delineate ordered gradients of sex chromosome and gonadal influences on volumetric brain development. Taken together, these data provide a new framework for the study of sexually dimorphic influences on brain development in health and disrupted brain development in SCA.

Signatures of sex: Sex differences in gene expression in the vertebrate brain

“…Conversely, the MPOA is larger in males, and male rats in particular have a pronounced sexually dimorphic nucleus (SDN) of the POA-the first sexually dimorphic brain region to be identified in mammals (Gorski, Gordon, Shryne, & Southam, 1978). The MeApd and BNSTp are also larger in males (Hines, Allen, & Gorski, 1992;Raznahan et al, 2015), and a sex difference in BNSTp volume has been described in humans (Allen & Gorski, 1990). A post-mortem study of cisgender men, cisgender women, and transgender women found that BNSTp volume is similar in cisgender and transgender women, which is approximately 50% of the volume in cisgender men (Zhou, Hofman, Gooren, & Swaab, 1995).…”

“…Studying mice and humans with sex chromosome aneuploidies has provided insight into how sex chromosome dosage affects sex differences in gene expression, brain structure, and behavior (Arnold et al, ; Lin et al, ; Raznahan et al, , ; Reardon et al, ). It is likely that sex differences in gene dosage partially underlie sex differences in gene expression in the brain.…”

Imaging sex/gender and autism in the brain: Etiological implications

“…Each of the common SCAs has a greater‐than‐expected autism comorbidity (Bruining et al, ; Baron‐Cohen et al, ). In a recent series of studies on XO, XX, XY, and XXY mice, Raznahan and colleagues discovered a stepwise pattern of effect in the size of the BNST, MPOA, and MeA, with XO < XX < XY < XXY (Raznahan et al, ). Other brain regions, in particular in cerebellum, pons, and cortex, showed the inverse.…”

Phonemic and Semantic Verbal Fluency in Sex Chromosome Aneuploidy: Contrasting the Effects of Supernumerary XversusY Chromosomes on Performance

“…To truly understand these relationships, future research should combine genetic expression studies, detailed cognitive phenotyping, and neuroimaging. Additionally, murine models of SCAs (e.g., Raznahan et al, 2015) may provide insights into the genetic underpinnings of atypical brain development in these groups.…”