title: 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 co-localized 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.
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Rm 4C108, Building 20, 10 Center Drive, Bethesda, MD, 20815, USA. raznahana@mail.nih.gov.
authors.forename: Armin
authors.initials: A
authors.lastname: Raznahan
authors.affiliation: Division of Endocrinology, Department of Medicine, Los Angele Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: YanHe
authors.initials: Y
authors.lastname: Lue
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Probst
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Rm 4C108, Building 20, 10 Center Drive, Bethesda, MD, 20815, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Greenstein
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Rm 4C108, Building 20, 10 Center Drive, Bethesda, MD, 20815, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Giedd
authors.affiliation: Division of Endocrinology, Department of Medicine, Los Angele Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Wang
authors.affiliation: Mouse Imaging Centre and Program in Neuroscience and Mental, The Hospital for Sick Children Hospital, Toronto, ON, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Lerch
authors.affiliation: Division of Endocrinology, Department of Medicine, Los Angele Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Swerdloff
mesh_terms: D000679:Amygdala / Q000033:anatomy & histology; D000782:Aneuploidy; D000818:Animals; D001921:Brain / Q000033:anatomy & histology*; D005260:Female; D007621:Karyotyping; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D059906:Neuroimaging / Q000379:methods; D012686:Septal Nuclei / Q000033:anatomy & histology; D012727:Sex Characteristics; D012730:Sex Chromosomes
keywords: Brain anatomy; Sexual dimorphism; XO; XXY