Microglia Are Essential to Masculinization of Brain and Behavior
Open accessAbstract
Brain sexual differentiation in rodents results from the perinatal testicular androgen surge. In the preoptic area (POA), estradiol aromatized from testosterone upregulates the production of the proinflammatory molecule, prostaglandin E 2(PGE 2) to produce sex-specific brain development. PGE 2 produces a two-fold greater density of dendritic spines in males than in females and masculinizes adult copulatory behavior. One neonatal dose of PGE 2 masculinizes the POA and behavior, and simultaneous treatment with an inhibitor of additional prostaglandin synthesis prevents this masculinization, indicating a positive feedforward process that leads to sustained increases in PGE 2. The mechanisms underlying this feedforward process were unknown. Microglia, the primary immunocompetent cells in the brain, are active neonatally, contribute to normal brain development, and both produce and respond to prostaglandins. We investigated whether there are sex differences in microglia in the POA and whether they influence developmental masculinization. Neonatal males had twice as many ameboid microglia as females and a more activated morphological profile, and both estradiol and PGE 2 masculinized microglial number and morphology in females. Microglial inhibition during the critical period for sexual differentiation prevented sex differences in microglia, estradiol-induced masculinization of dendritic spine density, and adult copulatory behavior. Microglial inhibition also prevented the estradiol-induced upregulation of PGE 2, indicating that microglia are essential to the feedforward process through which estradiol upregulates prostaglandin production. These studies demonstrate that immune cells in the brain interact with the nervous and endocrine systems during development, and are crucial for sexual differentiation of brain and behavior.
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Microglia are highly affected by hormonal and transcriptional changes.
“As microglia are highly affected by hormonal and transcriptional changes, female and male wild-type mice (WT XX and WT XY) were also used for validation [10, 13, 18, 44, 50].”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [18]
The Results section on hormonal dependence reports that estradiol treatment changed microglial morphology in the neonatal preoptic area, supporting the hormonal part of the claim. The cited passages do not establish that microglia are highly affected by transcriptional changes, so that part is unsupported. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia are highly affected by sex hormones.
“Microglia, which are the resident innate immune cells of the CNS, are highly affected by sex hormones [14, 16–20].”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [18]
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- Authors
- Lenz, K. M., Nugent, B. M., Haliyur, R., & McCarthy, M. M.
- Affiliations
- University of Maryland, Baltimore (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-02-13
- Volume
- 33
- Issue
- 7
- Pages
- 2761-2772
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3727162
- OpenAlex
- W2128381336
- Cited by
- 526
- References
- 9
- Citations by year
- 2026: 28 · 2025: 34 · 2024: 42 · 2023: 51 · 2022: 46 · 2021: 59 · 2020: 44 · 2019: 45 · 2018: 39 · 2017: 43 · 2016: 40 · 2015: 23 · 2014: 27 · 2013: 5
- FWCI
- 14.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R01-MH-52716, R01MH052716)
- National Institute of Neurological Disorders and Stroke (T32NS007375, F32NS076327)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- microglia, sexual differentiation of the brain, masculinization, preoptic area, prostaglandin E2, estradiol, dendritic spines, mating behavior, sex differences, feed-forward loop, microglial activation, neuroimmune interactions
- MeSH terms
- Animals, Behavior, Animal, Brain, Brain Chemistry, Cell Count, Cells, Cultured, Estradiol, Female, Fluorescent Antibody Technique, Image Processing, Computer-Assisted, Immunohistochemistry, Male, Minocycline, Nerve Tissue Proteins, Preoptic Area, Sexual Behavior, Animal, Sex Differentiation, Sexual Maturation, Blotting, Western, Dinoprostone, Microglia, Dendritic Spines, Rats
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