Comparative neuroimaging of sex differences in human and mouse brain anatomy
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eLife assessment
In this important study, Guma and colleagues describe the use of structural neuroimaging to assess the cross-species convergence of sex differences in global and regional brain volumes in humans and mice. The goal of the work is to inform to what extent mouse studies of these aforementioned sex differences have relevance to humans. The authors suggest which aspects of brain anatomy (as measured by volume) are conserved or not, across species, which has theoretical and practical implications beyond a single sub-field. The evidence to support the findings is solid, it uses methods and data analysis that are appropriate and validated.
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Abstract
In vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-specific brain development, there have been no attempts to formally compare human and mouse neuroanatomical sex differences to ascertain how well they translate. Addressing this question would shed critical light on the use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use structural magnetic resonance imaging to conduct the first comparative neuroimaging study of sex-specific neuroanatomy of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous regions ( r =0.30). This cross-species congruence is greater in the cortex ( r =0.33) than non-cortex ( r =0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-specific brain development in mice to brain regions that best echo sex-specific brain development in humans.
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eLife assessment
In this important study, Guma and colleagues describe the use of structural neuroimaging to assess the cross-species convergence of sex differences in global and regional brain volumes in humans and mice. The goal of the work is to inform to what extent mouse studies of these aforementioned sex differences have relevance to humans. The authors suggest which aspects of brain anatomy (as measured by volume) are conserved or not, across species, which has theoretical and practical implications beyond a single sub-field. The evidence to support the findings is solid, it uses methods and data analysis that are appropriate and validated.
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Joint Public Review:
Summary:
Guma and colleagues set out to compare to what extent differences in total and regional brain volumes, as measured by structural magnetic resonance imaging (MRI) are conserved or not, between humans and mice. The rationale for this work is to inform the best use of the mouse as a model system to carry out mechanistic studies of how sex differences arise in brain volumes, based on convergence to humans. This has practical implications for multiple fields in neuroscience. The authors find a modest convergence on these measures highlighting important areas for further mechanistic study.Strengths:
The main strengths of the study lie in the use of a cross-species technology, i.e. structural MRI, using tools and methods that have been extensively validated.Weaknesses:
Limitations of the study include, as …Joint Public Review:
Summary:
Guma and colleagues set out to compare to what extent differences in total and regional brain volumes, as measured by structural magnetic resonance imaging (MRI) are conserved or not, between humans and mice. The rationale for this work is to inform the best use of the mouse as a model system to carry out mechanistic studies of how sex differences arise in brain volumes, based on convergence to humans. This has practical implications for multiple fields in neuroscience. The authors find a modest convergence on these measures highlighting important areas for further mechanistic study.Strengths:
The main strengths of the study lie in the use of a cross-species technology, i.e. structural MRI, using tools and methods that have been extensively validated.Weaknesses:
Limitations of the study include, as acknowledged by the authors, the focus on a specific age range in mice and humans (which may not be congruent) and the lack of information regarding sex differences earlier or later in life. This has relevance with regard to the ages of onset for psychiatric and neurological disorders for example, which show apparent sex differences in prevalence. The paper also does provide data for an intermediate phylogenic level of analysis, such as data from primates. Lastly, these data do not provide any evidence as to the mechanisms underlying sex differences, when they arise, and to what extent they impact behavior. -
