Sex differences in prefrontal cortex microglia morphology: Impact of a two-hit model of adversity throughout development
Open accessAbstract
Neuroimmune mechanisms play critical roles in brain development and can be impacted by early life adversity. Microglia are the resident immune cells in the brain, with both sex-specific and region-specific developmental profiles. Since early life adversity is associated with several neuropsychiatric disorders with developmental pathogeneses, here we investigated the degree to which maternal separation (MS) impacted microglia over development. Microglia are dynamic cells that alter their morphology in accordance with their functions and in response to stressors. While males and females reportedly display different microglial morphology in several brain regions over development and following immune and psychological challenges, little is known about such differences in the prefrontal cortex (PFC), which regulates several early life adversity-attributable disorders. Additionally, little is known about the potential for early life adversity to prime microglia for later immune challenges. In the current study, male and female rats were exposed to MS followed by lipopolysaccharide administration in juvenility or adolescence. The prelimbic and infralimbic PFC were then separately analyzed for microglial density and morphology. Typically developing males expressed smaller soma and less arborization than females in juvenility, but larger soma than females in adolescence. MS led to fewer microglia in the infralimbic PFC of adolescent males. Both MS and lipopolysaccharide administration affected morphological characteristics in juvenile males and females, with MS exposure leading to a greater increase in soma size following lipopolysaccharide. Interestingly, effects of MS and lipopolysaccharide were not observed in adolescence, while notable sex differences in PFC microglial morphology were apparent. Taken together, these findings provide insight into how PFC microglia may differentially respond to challenges over development in males and females.
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During normal physiological conditions, adult male mice tend to exhibit denser microglia in the hippocampus, cortex, and amygdala, whereas female rats typically display longer and more extensively branched microglial processes in the prefrontal cortex around adolescence.
“During normal physiological conditions, it has been shown that adult male mice tend to exhibit denser microglia in the hippocampus, cortex, and amygdala, whereas female rats typically display longer and more extensively branched microglial processes in the prefrontal cortex around adolescence, indicating possible differences in microglial surveillance between sexes, brain regions and time points [”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [46]
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- Authors
- Gildawie, K. R., Orso, R., Peterzell, S., Thompson, V., & Brenhouse, H. C.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Brenhouse, Heather C.
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 738
- Pages
- 135381
- ISSN
- 0304-3940 (ISSN-L)
- PMC
- PMC7584734
- OpenAlex
- W3085610866
- Cited by
- 46
- References
- 81
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 9 · 2023: 8 · 2022: 6 · 2021: 6
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5R21MH097182-02)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- microglial morphology, sex differences, prefrontal cortex, childhood adversity, maternal separation, lipopolysaccharide, neuroinflammation, prelimbic cortex, infralimbic cortex, developmental programming, adolescence, juvenile development, neuroimmune mechanisms
- MeSH terms
- Animals, Female, Lipopolysaccharides, Male, Maternal Deprivation, Sex Characteristics, Stress, Psychological, Prefrontal Cortex, Microglia
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