Faculty Opinions recommendation of Sex differences in the brain: Implications for behavioral and biomedical research.

Organizational and activational effects of sex steroids were first discovered in laboratory animals, but these concepts extend to hormonal actions in the human central nervous system. This chapter begins with a brief overview of how sex steroids act in the brain and how the organizational-activational hypothesis originated in the field of endocrinology. It then reviews common methods used to study these effects in humans. Interestingly, certain cognitive functions appear to be subject to modification by sex steroids, and these endocrine influences may help explain the sex differences often seen in these functions. The chapter considers spatial cognition as a representative example because the spatial family of functions has received the most study by researchers interested in the biological roots of sex differences in cognition. The chapter reviews evidence that supports an influence of both androgens and estrogens on spatial functions, and concludes with a glimpse of where the field is headed.

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Abstract TP274: Orosomucoid-1 Protein Increases Following Ischemic Stroke in the Brain and Periphery

Stroke ◽

10.1161/str.47.suppl_1.tp274 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Hetal Mistry ◽

Madeline Levy ◽

Meaghan Roy-O'Reilly ◽

Louise McCullough

Keyword(s):

Sex Differences ◽

Ischemic Stroke ◽

Rna Sequencing ◽

Multiple Testing ◽

Enzyme Linked Immunosorbent Assay ◽

Mrna Levels ◽

Stroke Patients ◽

Post Stroke ◽

Protein Levels ◽

The Brain

Background and Purpose: Orosomucoid-1 (ORM-1) is an abundant protein with important roles in inflammation and immunosuppression. We utilized RNA sequencing to measure mRNA levels in human ischemic stroke patients, with confirmation by serum ORM-1 protein measurements. A mouse model of ischemic stroke was then used to examine post-stroke changes in ORM-1 within the brain itself. Hypothesis: We tested the hypothesis that ORM-1 levels increase following ischemic stroke, with sex differences in protein dynamics over time. Methods: RNA sequencing was performed on whole blood from ischemic stroke patients (n=23) and controls (n=12), with Benjamini-Hochberg correction for multiple testing. Enzyme-linked immunosorbent assay was performed on serum from ischemic stroke patients (n=28) and controls (n=8), with analysis by T-test. For brain analysis, mice (n=14) were subjected to a 90-minute middle cerebral artery occlusion (MCAO) surgery and sacrificed 6 or 24 hours after stroke. Control mice underwent parallel “sham” surgery without occlusion. Western blotting was used to detect ORM-1 protein levels in whole brain, with analysis by two-way ANOVA. Results: RNA sequencing showed a 2.8-fold increase in human ORM-1 at 24 hours post-stroke (q=.0029), an increase also seen in serum ORM-1 protein levels (p=.011). Western blot analysis of mouse brain revealed that glycosylated (p=0.0003) and naive (p=0.0333) forms of ORM-1 were higher in female mice compared to males 6 hours post-stroke. Interestingly, ORM-1 levels were higher in the brains of stroke mice at 6 hours (p=.0483), while at 24 hours ORM-1 levels in stroke mice were lower than their sham counterparts (p=.0212). In both human and mouse data, no sex differences were seen in ORM-1 levels in the brain or periphery at 24 hours post-stroke. Conclusion: In conclusion, ORM-1 is a sexually dimorphic protein involved in the early (<24 hour) response to ischemic stroke. This research serves as an initial step in determining the mechanism of ORM-1 in the ischemic stroke response and its potential as a future therapeutic target for both sexes.

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Sex differences in neural and behavioral signatures of cooperation revealed by fNIRS hyperscanning

Scientific Reports ◽

10.1038/srep26492 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 57

Author(s):

Joseph M. Baker ◽

Ning Liu ◽

Xu Cui ◽

Pascal Vrticka ◽

Manish Saggar ◽

...

Keyword(s):

Sex Differences ◽

Temporal Cortex ◽

Neural Correlates ◽

Behavioral Signatures ◽

Computer Based ◽

Males And Females ◽

Brain And Behavior ◽

The Right ◽

And Behavior ◽

The Brain

Abstract Researchers from multiple fields have sought to understand how sex moderates human social behavior. While over 50 years of research has revealed differences in cooperation behavior of males and females, the underlying neural correlates of these sex differences have not been explained. A missing and fundamental element of this puzzle is an understanding of how the sex composition of an interacting dyad influences the brain and behavior during cooperation. Using fNIRS-based hyperscanning in 111 same- and mixed-sex dyads, we identified significant behavioral and neural sex-related differences in association with a computer-based cooperation task. Dyads containing at least one male demonstrated significantly higher behavioral performance than female/female dyads. Individual males and females showed significant activation in the right frontopolar and right inferior prefrontal cortices, although this activation was greater in females compared to males. Female/female dyad’s exhibited significant inter-brain coherence within the right temporal cortex, while significant coherence in male/male dyads occurred in the right inferior prefrontal cortex. Significant coherence was not observed in mixed-sex dyads. Finally, for same-sex dyads only, task-related inter-brain coherence was positively correlated with cooperation task performance. Our results highlight multiple important and previously undetected influences of sex on concurrent neural and behavioral signatures of cooperation.

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Multifaceted origins of sex differences in the brain

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0106 ◽

2016 ◽

Vol 371 (1688) ◽

pp. 20150106 ◽

Cited By ~ 71

Author(s):

Margaret M. McCarthy

Keyword(s):

Sex Differences ◽

State Of The Art ◽

Human Subjects ◽

Special Issue ◽

Molecular Analyses ◽

The Past ◽

Current State ◽

Biological Variable ◽

Males And Females ◽

The Brain

Studies of sex differences in the brain range from reductionistic cell and molecular analyses in animal models to functional imaging in awake human subjects, with many other levels in between. Interpretations and conclusions about the importance of particular differences often vary with differing levels of analyses and can lead to discord and dissent. In the past two decades, the range of neurobiological, psychological and psychiatric endpoints found to differ between males and females has expanded beyond reproduction into every aspect of the healthy and diseased brain, and thereby demands our attention. A greater understanding of all aspects of neural functioning will only be achieved by incorporating sex as a biological variable. The goal of this review is to highlight the current state of the art of the discipline of sex differences research with an emphasis on the brain and to contextualize the articles appearing in the accompanying special issue.

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Epigenetic mechanisms in sexual differentiation of the brain and behaviour

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0114 ◽

2016 ◽

Vol 371 (1688) ◽

pp. 20150114 ◽

Cited By ~ 34

Author(s):

Nancy G. Forger

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Sexual Differentiation ◽

Wide Distribution ◽

Epigenetic Modifications ◽

Epigenetic Mechanism ◽

Epigenetic Mechanisms ◽

Genome Wide ◽

The Brain

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

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What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues?

Frontiers in Neuroendocrinology ◽

10.1016/j.yfrne.2008.11.001 ◽

2009 ◽

Vol 30 (1) ◽

pp. 1-9 ◽

Cited By ~ 295

Author(s):

Arthur P. Arnold ◽

Xuqi Chen

Keyword(s):

Sex Differences ◽

Mouse Model ◽

The Brain

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Patterns of brain asymmetry associated with polygenic risks for autism and schizophrenia implicate language and executive functions but not brain masculinization

10.1101/2021.03.19.436120 ◽

2021 ◽

Author(s):

Zhiqiang Sha ◽

Dick Schijven ◽

Clyde Francks

Keyword(s):

Sex Differences ◽

Executive Functions ◽

Autism Spectrum ◽

Brain Asymmetry ◽

Risk Scores ◽

Imaging Data ◽

Polygenic Risk ◽

Left Right Asymmetry ◽

The Uk ◽

The Brain

AbstractAutism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing versus empathizing cognitive styles, with resemblances to male versus female average sex differences. Left-right asymmetry of the brain is an important aspect of its organization that shows average differences between the sexes, and can be altered in both ASD and schizophrenia. Here we mapped multivariate associations of polygenic risk scores (PRS) for ASD and schizophrenia with asymmetries of regional cerebral cortical surface area, thickness and subcortical volume measures in 32,256 participants from the UK Biobank. PRS for the two disorders were positively correlated (r=0.08, p=7.13×10−50), and both were higher in females compared to males, consistent with biased participation against higher-risk males. Each PRS was associated with multivariate brain asymmetry after adjusting for sex, ASD PRS r=0.03, p=2.17×10−9, schizophrenia PRS r=0.04, p=2.61×10−11, but the multivariate patterns were mostly distinct for the two PRS, and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both PRS were associated with asymmetries of regions important for language and executive functions, consistent with behavioural associations that arose in phenome-wide association analysis. Overall, the results indicate that distinct patterns of subtly altered brain asymmetry may be functionally relevant manifestations of polygenic risk for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies.

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