Mouse MRI shows brain areas relatively larger in males emerge before those larger in females

Abstract

Sex differences exist in behaviors, disease and neuropsychiatric disorders. Sexual dimorphisms however, have yet to be studied across the whole brain and across a comprehensive time course of postnatal development. Here, we use manganese-enhanced MRI (MEMRI) to longitudinally image male and female C57BL/6J mice across 9 time points, beginning at postnatal day 3. We recapitulate findings on canonically dimorphic areas, demonstrating MEMRI’s ability to study neuroanatomical sex differences. We discover, upon whole-brain volume correction, that neuroanatomical regions larger in males develop earlier than those larger in females. Groups of areas with shared sexually dimorphic developmental trajectories reflect behavioral and functional networks, and expression of genes involved with sex processes. Also, post-pubertal neuroanatomy is highly individualized, and individualization occurs earlier in males. Our results demonstrate the ability of MEMRI to reveal comprehensive developmental differences between male and female brains, which will improve our understanding of sex-specific predispositions to various neuropsychiatric disorders.

Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development

“…The delayed onset in females is particularly intriguing, especially since the phenotype becomes similar to the male phenotype in adulthood, indicating different growth rates for each sex. This is consistent with the emergence of sex differences, shown by Qiu et al, in male and female mice in general 25 . In that study, they show that brain regions that are larger in adult male mice emerge earlier than those that are larger in adult female mice.…”

“…Findings in the ex vivo experiments, and the fact that Arid1b haploinsufficiency is relevant to NDDs, highlighted the need to examine the developmental time course of the neuroanatomical differences. Therefore, a longitudinal study was performed to track the development of the neuroanatomy from birth to adulthood, similar to previous work 25,26 . 24 hours prior to the scan, a 0.4 mmol/kg dose of 30mM manganese chloride (MnCl2) was administered as a contrast agent.…”

“…These registrations were performed with a combination of mni_autoreg tools 28 and ANTS (advanced normalization tools) 29,30 . A two-level registration pipeline was used on the in vivo images and has been detailed in previous studies 25 .…”

“…As detailed in previous studies 31,32 , the Jacobian determinants of the deformation fields were computed and analyzed to measure the volume differences between subjects at every voxel. A pre-existing classified MRI atlas was warped onto the population atlas (containing 282 different segmented structures encompassing cortical lobes, large white matter structures such as the corpus callosum, ventricles, cerebellum, brain stem, and olfactory bulbs 25,[33][34][35][36] ) to compute the volume of brain structures in all the input images. A linear model with a genotype predictor was used to assess the significance of genotype.…”

Preliminary evidence that maternal immune activation specifically increases diagonal domain volume in the rat brain during early postnatal development

“…Main effects of sex were also found for the relative volumes of 3/23 (13%) atlas ROIs, including the bed nucleus of the stria terminalis (BNST), the cerebellum and the ventricular system, although these did not survive correction for multiple comparisons ( Table 1 ). Nonetheless, these trend-level results are consistent with known sexually dimorphic regions in the rodent brain [43, 44]. A significant main effect of MIA was found for the relative volume of the diagonal domain (DD), with subtly increased volume in POL as compared to CON offspring (+4.4%; p <0.05, q <0.1; partial η 2 = 0.44; Table 1 ; Figure 2 ).…”