Cited by 526Sexual Differentiation and DisordersNeuroinflammation and Neurodegeneration MechanismsNeuroendocrine regulation and behavior

Microglia Are Essential to Masculinization of Brain and Behavior

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Lenz, Kathryn M., Nugent, Bridget M., Haliyur, Rachana, McCarthy, Margaret M.·2013·The Journal of Neuroscience

Abstract

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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Crossref · 10.1523/jneurosci.1268-12.2013

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Sorted by citations

Authors
Lenz, K. M., Nugent, B. M., Haliyur, R., & McCarthy, M. M.
Affiliations
University of Maryland, Baltimore (US)
Venue
The Journal of Neuroscience
Published
2013-02-13
Volume
33
Issue
7
Pages
2761-2772
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
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
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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