Integrative strukturelle, funktionelle und transkriptomische Analysen der geschlechtsspezifischen Gehirnorganisation bei den Geschlechtern

Eine interessante Studie zur unterschiedlichen Gehirnorganisation bei den Geschlechrtern

Sex differences in brain organization are theoretically important for our understanding of sex differences in human cognition and behavior. However, neurobiological sex differences have been easier to characterize in mice than in humans. Recent murine work has revealed a highly reproducible spatial patterning of gray matter volume (GMV) sex differences that is centered on systems for socioreproductive behavior and correlated with regional expression of sex chromosome genes. We integrate neuroimaging and transcriptomic data to establish that these same characteristics also apply to GMV sex differences in humans. These findings establish conserved aspects of sex-biased brain development in humans and mice, and update our understanding of the consistency, candidate causes, and potential functional corollaries of sex-biased brain anatomy in humans.

Humans display reproducible sex differences in cognition and behavior, which may partly reflect intrinsic sex differences in regional brain organization. However, the consistency, causes and consequences of sex differences in the human brain are poorly characterized and hotly debated. In contrast, recent studies in mice—a major model organism for studying neurobiological sex differences—have established:

  1. highly consistent sex biases in regional gray matter volume (GMV) involving the cortex and classical subcortical foci,
  2. a preponderance of regional GMV sex differences in brain circuits for social and reproductive behavior, and
  3. a spatial coupling between regional GMV sex biases and brain expression of sex chromosome genes in adulthood.

Here, we directly test translatability of rodent findings to humans. First, using two independent structural-neuroimaging datasets (n > 2,000), we find that the spatial map of sex-biased GMV in humans is highly reproducible (r > 0.8 within and across cohorts). Relative GMV is female biased in prefrontal and superior parietal cortices, and male biased in ventral occipitotemporal, and distributed subcortical regions. Second, through systematic comparison with functional neuroimaging meta-analyses, we establish a statistically significant concentration of human GMV sex differences within brain regions that subserve face processing. Finally, by imaging-transcriptomic analyses, we show that GMV sex differences in human adulthood are specifically and significantly coupled to regional expression of sex-chromosome (vs. autosomal) genes and enriched for distinct cell-type signatures. These findings establish conserved aspects of sex-biased brain development in humans and mice, and shed light on the consistency, candidate causes, and potential functional corollaries of sex-biased brain anatomy in humans.

Quelle:Integrative structural, functional, and transcriptomic analyses of sex-biased brain organization in humans

Aus den Ergebnissen:

Our findings provide several insights into sex-biased human brain anatomy, which

  1. address active controversies regarding the consistency of neuroanatomical sex differences,
  2. demonstrate that sex differences in regional GMV are aligned with functional systems for face processing,
  3. provide evidence for a close spatial relationship between sex differences in human brain anatomy and regional expression sex-chromosome genes, and
  4. establish that genes which are most closely coupled to regional sex differences in cortical GMV anatomy are strongly associated with specific biological processes and cell types. We address each of these insights below.

We quantitatively demonstrate that the spatial patterning of regional GMV sex differences in humans (after control for sex differences in total GMV) is highly reproducible within and between two large cohorts of healthy adults (r > 0.8 correlation across voxels, Fig. 1). Such consistency in the spatial patterning of sex-biased brain anatomy in humans could arise through

1) sex differences in the innate biological programs that shape regional brain volume, and/or

2) systematic sex differences in exposure to, or experience of, environmental factors that can modify regional brain volume.

Definitively arbitrating between these two contrasting mechanistic scenarios requires experimental approaches that are hard to implement in humans. However, four lines of evidence argue that sex-biased influences on regional brain volume can operate in a manner that is largely independent from environmental input. First, where experimental data are available from rodent models, stereotyped sex differences in regional brain volume have been linked to intrinsic male-female differences in sex-steroid signaling, which reflect genetically determined sexual differentiation of the gonads rather than sex-biased external environmental exposures (17). Second, in humans, observational studies in rare medical disorders have established that the two fundamental candidate sources for intrinsic, programmed sex differences in human development—sex steroids and sex chromosome dosage—can both influence the volume of those brain regions which show sex-biased anatomy in the general population (39–43). Third, sex biases in regional human brain anatomy have been reported at birth (44), when sources of neuroanatomical variation are limited to genes and the in utero environment. Finally, our observation in this study of a closespatial coupling between regional GMV sex differences and regional expression of sex-chromosome genes (further discussed below) is hard to parsimoniously incorporate into a purely environmental account for the stereotyped patterning of regional GMV sex differences. Thus, while human males and females undoubtedly experience systematically different environments at multiple levels of analysis, and while it is crucial to recognize the complex interplay between sex and gender (45), we propose that environmental factors are unlikely to be a primary driver of the highly reproducible spatial patterning of GMV sex differences observed in our current report.

Although our findings clearly establish that humans show highly reproducible sex differences in regional brain volume from in vivo imaging, it remains to be seen if these differences have any bearing for the many well-established sex biases in cognition, behavior, and mental health (1–8). We identify a statistically significant spatial overlap—albeit of relatively weak effect size—between regions of male-biased GMV, and a set of brain regions that are preferentially activated during face processing. By so highlighting face-processing systems after a broad screen of functional neuroanatomy through metaanalysis of >11,000 neuroimaging studies, our study provides an objective evidence base for targeting studies on the potential behavioral relevance of sex-biased regional GMV in humans. However, because experimentally testing for a causal relationship between neuroanatomical and behavioral sex differences is especially challenging in humans, these future studies would need to leverage emerging datasets (46) that, when fully assembled, will capture interindividual variation in multivariate neuroimaging and face-processing measures within large longitudinal samples of males and females over development.

Auch hier also wieder deutliche Geschlechterunterschiede im Gehirn.

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