A new view of sexual differentiation of mammalian brain
Open accessAbstract
Establishment of enduring sex differences in brain and behavior occurs during pre- or perinatal development, depending on species. For over 50 years the focus has been on gonadal steroid production by male fetuses and the impact on developing brain. An increasing awareness of the importance of sex chromosome complement has broadened the focus but identifying specific roles in development has yet to be achieved. Recent emphasis on transcriptomics has revealed myriad and unexpected differences in gene expression in specific regions of male and female brains which may produce sex differences, serve a compensatory role or provide latent sex differences revealed only in response to challenge. More surprising, however, has been the consistent observation of a central role for inflammatory signaling molecules and immune cells in masculinization of brain and behavior. The signal transduction pathways and specific immune cells vary by brain region, as does the neuroanatomical substrate subject to differentiation, reflecting substantial complexity emerging from what may be a common origin, the maternal immune system. A working hypothesis integrating these various ideas is proposed.
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Recent evidence suggests that sex chromosome complement may play an important role in sex differences in brain (beyond the classic organizational model), including large adult sex differences in brain regional transcriptome expression profiles and in expression of neuroinflammatory mediators of immune signaling.
“Recent evidence suggests that sex chromosome complement may play an important role in sex differences in brain (beyond the classic organizational model), including large adult sex differences in brain regional transcriptome expression profiles and in expression of neuroinflammatory mediators of immune signaling (McCarthy, 2020).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as McCarthy, 2020
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Comparative neuroimaging of sex differences in human and mouse brain anatomyPreprint
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- Authors
- McCarthy, M. M.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- McCarthy, Margaret M.
- Venue
- Journal of Comparative Physiology A
- Published
- 2019-11-08
- Volume
- 206
- Issue
- 3
- Pages
- 369-378
- ISSN
- 0340-7594 (ISSN-L)
- 1432-1351
- PMC
- PMC7196030
- OpenAlex
- W2988879465
- Cited by
- 85
- References
- 63
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 12 · 2023: 16 · 2022: 9 · 2021: 15 · 2020: 9
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Comparative Physiology A (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (RO1MH52716, R01DA039062)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- sexual differentiation of the brain, sex differences in brain development, sex chromosome complement, sex steroids, fetal brain development, transcriptomics, gene expression differences, inflammatory signaling, maternal immune system, signaling pathways, neuroanatomical substrates
- MeSH terms
- Animals, Behavior, Animal, Brain, Female, Histamine, Humans, Immune System, Male, Prostaglandins, Sex Characteristics, Sex Chromosomes, Sex Differentiation, Sex Factors, Signal Transduction, Cell Death, Inflammation Mediators, Transcriptome
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