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Updated: Dec 18, 2025
Using a Murine Model of Psychosocial Stress in Pregnancy as a Translationally Relevant Paradigm for Psychiatric Disorders in Mothers and Infants
Published on: June 13, 2021
Prenatal stress causes intrauterine inflammation and serotonergic dysfunction, and long-term behavioral deficits
Helen J Chen1,2,3, Adrienne M Antonson1,3,4, Therese A Rajasekera1,3,5
1Department of Psychiatry and Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Insights
Prenatal stress impacts offspring behavior via maternal microbes and inflammation. Reducing inflammation through genetic modification (CCL2 knockout) or germ-free conditions mitigates these effects, highlighting key interactions.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Prenatal stress (PNS) is linked to offspring neuropsychiatric disorders like anxiety, depression, and autism spectrum disorders.
- Maternal microbes, inflammation, and serotonergic pathways are potential mediators of PNS-induced behavioral changes.
- The interaction between these systems in response to prenatal stress remains unclear.
Purpose of the Study:
- To investigate the role of maternal microbes and inflammation in mediating the effects of prenatal stress on offspring behavior.
- To examine the interplay between the chemokine CCL2, inflammation, and serotonin metabolism following prenatal stress.
Main Methods:
- Utilized late-gestation maternal restraint stress in wild-type (WT), germ-free (GF), and CCL2 knockout (KO) mice.
- Assessed placental and fetal brain inflammation, including cytokine and chemokine levels (CCL2, IL-6).
- Evaluated offspring behavior for sociability and anxiety-like traits.
- Measured placental tryptophan and serotonin (5-HT) levels.
Main Results:
- PNS induced placental and fetal brain inflammation in WT mice, characterized by elevated CCL2.
- Inflammation was significantly reduced in GF mice, underscoring the role of maternal microbes.
- PNS offspring lacking CCL2 showed no increase in IL-6 and exhibited normal sociability and anxiety-like behavior.
- Elevated placental tryptophan and serotonin (5-HT) were observed in WT PNS mice but not in CCL2-/- or GF mice.
Conclusions:
- Maternal microbes are critical mediators of prenatal stress-induced immune responses in utero.
- The chemokine CCL2 and subsequent inflammation play a key role in mediating the behavioral and neurochemical effects of PNS.
- A complex interplay between maternal microbes, inflammation, and serotonin metabolism regulates the emergence of behavioral abnormalities following prenatal stress.
Abstract:
Prenatal stress (PNS) is associated with neuropsychiatric disorders in offspring, including anxiety, depression, and autism spectrum disorders. There is mounting evidence that these behavioral phenotypes have origins in utero. Maternal microbes, inflammation, and serotonergic dysfunction have been implicated as potential mediators of the behavioral consequences of PNS; whether and how these systems interact is unclear. Here, we examine the effects of PNS in utero using late-gestation maternal restraint stress in wild-type (WT), germ-free (GF), and CCL2-/- genetic knock-out (KO) mice. In WT mice, PNS leads to placental and fetal brain inflammation, including an elevation in the chemokine CCL2. This inflammation is largely absent in GF mice, indicating the critical role of maternal microbes in mediating immune processes in utero. Furthermore, PNS in the absence of CCL2 failed to increase pro-inflammatory cytokine IL-6 in the fetal brain. PNS offspring also exhibited deficits in sociability and anxiety-like behavior that were absent in CCL2-/- PNS offspring. Tryptophan and serotonin (5-HT) were elevated in the WT PNS placenta, but not in CCL2-/- and GF animals. Altogether, these findings suggest that a complex interaction between maternal microbes, inflammation, and serotonin metabolism regulates the emergence of behavioral abnormalities following PNS.
