Dataset Information

Sex Differences in Biological Processes and Nitrergic Signaling in Mouse Brain.

ABSTRACT: Nitric oxide (NO) represents an important signaling molecule which modulates the functions of different organs, including the brain. S-nitrosylation (SNO), a post-translational modification that involves the binding of the NO group to a cysteine residue, is a key mechanism of nitrergic signaling. Most of the experimental studies are carried out on male animals. However, significant differences exist between males and females in the signaling mechanisms. To investigate the sex differences in the SNO-based regulation of biological functions and signaling pathways in the cortices of 6-8-weeks-old mice, we used the mass spectrometry technique, to identify S-nitrosylated proteins, followed by large-scale computational biology. This work revealed significant sex differences in the NO and SNO-related biological functions in the cortices of mice for the first-time. The study showed significant SNO-induced enrichment of the synaptic processes in female mice, but enhanced SNO-related cytoskeletal processes in the male mice. Proteins, which were S-nitrosylated in the cortices of mice of both groups, were more abundant in the female brain. Finally, we investigated the shared molecular processes that were found in both sexes. This study presents a mechanistic insight into the role of S-nitrosylation in both sexes and provides strong evidence of sex difference in many biological processes and signalling pathways, which will open future research directions on sex differences in neurological disorders.

SUBMITTER: Khaliulin I

PROVIDER: S-EPMC7277573 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Sex Differences in Biological Processes and Nitrergic Signaling in Mouse Brain.

Khaliulin Igor I Kartawy Maryam M Amal Haitham H

Biomedicines 20200515 5

Nitric oxide (NO) represents an important signaling molecule which modulates the functions of different organs, including the brain. S-nitrosylation (SNO), a post-translational modification that involves the binding of the NO group to a cysteine residue, is a key mechanism of nitrergic signaling. Most of the experimental studies are carried out on male animals. However, significant differences exist between males and females in the signaling mechanisms. To investigate the sex differences in the ...[more]

PMID: 32429146

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Project description: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-biased brain development in mammals, there have been no attempts to formally compare mouse and human sex differences across the whole brain to ascertain how well they translate. Addressing this question would shed critical light on 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 cross-species structural magnetic resonance imaging to carry out the first comparative neuroimaging study of sex-biased neuroanatomical organization 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 brain regions (r=0.30; e.g.: M>F amygdala, hippocampus, bed nucleus of the stria terminalis, and hypothalamus and F>M anterior cingulate, somatosensory, and primary auditory cortices). 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-biased brain development in mice to brain regions that best echo sex-biased brain development in humans.

Project description:The presence, magnitude, and significance of sex differences in the human brain are hotly debated topics in the scientific community and popular media. This debate is largely fueled by studies containing strong, opposing conclusions: either little to no evidence exists for sex differences in human neuroanatomy, or there are small-to-moderate differences in the size of certain brain regions that are highly reproducible across cohorts (even after controlling for sex differences in average brain size). Our Commentary uses the specific comparison between two recent large-scale studies that adopt these opposing views-namely the review by Eliot and colleagues (2021) and the direct analysis of ~ 40k brains by Williams and colleagues (2021)-in an effort to clarify this controversy and provide a framework for conducting this research. First, we review observations that motivate research on sex differences in human neuroanatomy, including potential causes (evolutionary, genetic, and environmental) and effects (epidemiological and clinical evidence for sex-biased brain disorders). We also summarize methodological and empirical support for using structural MRI to investigate such patterns. Next, we outline how researchers focused on sex differences can better specify their study design (e.g., how sex was defined, if and how brain size was adjusted for) and results (by e.g., distinguishing sexual dimorphisms from sex differences). We then compare the different approaches available for studying sex differences across a large number of individuals: direct analysis, meta-analysis, and review. We stress that reviews do not account for methodological differences across studies, and that this variation explains many of the apparent inconsistencies reported throughout recent reviews (including the work by Eliot and colleagues). For instance, we show that amygdala volume is consistently reported as male-biased in studies with sufficient sample sizes and appropriate methods for brain size correction. In fact, comparing the results from multiple large direct analyses highlights small, highly reproducible sex differences in the volume of many brain regions (controlling for brain size). Finally, we describe best practices for the presentation and interpretation of these findings. Care in interpretation is important for all domains of science, but especially so for research on sex differences in the human brain, given the existence of broad societal gender-biases and a history of biological data being used justify sexist ideas. As such, we urge researchers to discuss their results from simultaneously scientific and anti-sexist viewpoints.

Dataset Information

Sex Differences in Biological Processes and Nitrergic Signaling in Mouse Brain.

Publications

Sex Differences in Biological Processes and Nitrergic Signaling in Mouse Brain.

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