X-chromosome inactivation (XCI) in females is vital for normal brain function and cognition, as many X-linked genetic mutations lead to mental retardation and autism spectrum disorders, such as the fragile X syndrome (FXS). However, the degree by which XCI regulates disease presentation has been poorly investigated. To study this regulation in the mouse, here we quantified the brainwide composition of active-XC cells at single cell resolution using an X-linked MECP2-EGFP allele with known parent-of-origin. We present evidence that whole-brains, including all regions, on average favor maternal XCactive cells by 20%, or 8 million cells. This bias was conserved in heterozygous FXS mutant mice, which also corresponded to disease penetrance in maternal but not paternal FMR1 null mice. To localize the physical source of behavioral penetrance, brain-wide correlational screens successfully mapped mouse performance to cell densities in putative sensorimotor (e.g. sensory hindbrain, thalamus, globus pallidus) and sociability (e.g. visual/entorhinal cortices, bed nucleus stria terminalis, medial preoptic area) behavioral circuits of the open field sensorimotor and 3-chamber sociability assays, respectively. Overall, 50%/50% healthy/mutant cell density ratios in these sub-networks were required for disease presentation in each behavior. These results suggest female X-linked behavioral penetrance of disease is regulated at the distributed level of mutant cell density in behavioral circuits, which is set by XCI that is subject to parent-of-origin effects. This work provides a novel finding behind the broad and varied behavioral phenotypes commonly featured in female patients debilitated by X-linked mental disorders and may offer new entry points for behavioral therapeutics. screens. A) Pearson's correlational analysis conducted amongst behavioral scores and brain-wide healthy ROI cell density. Data is displayed in a 2-dimensional (ROI -y-axis; genotype/behavioral test -x-axis) heat map of significant p-values represented on a double color gradient from 0.05 (black), 0.025 (red), to 0 (yellow). Scale legend is listed at the bottom. Results from FMR1 WT, maternal and paternal FMR1 KO mice (x-axis) are grouped by each behavioral test (left -OFT, center -T-maze, right -3-chamber) and ROIs are listed in order of major hierarchical brain structures. B) Significant ROIs (p=0.01 threshold) from maternal FMR1 KO OFT screening results found in A), heat mapped and overlaid in reference brain space. Individual names of significant ROIs and anterior/posterior location with respect to bregma are listed for each section shown. C) Visualization of structural connectivity weights within the significantly correlated OFT ROI network (Methods). ROI node and edge color assignment is based on major brain structure colors as defined by Allen Brain Atlas (http://atlas.brain-map.org). D) Normalized median connection density of OFT ROI network (red line), and 1000 insilico generated random ROI networks of the same inter-regional distance and ROI amount...
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