Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal anti-inflammatory treatment.

Adverse experiences during gestation such as maternal stress and
infection are known risk factors for neurodevelopmental disorders,
including schizophrenia, autism, and attention deficit/hyperactivity
disorder. The mechanism by which distinct exposures may confer similar
psychiatric vulnerability remain unclear, although likely involve
pathways common to both stress and immune responses at the
maternal-fetal interface. We hypothesized that maternal stress-induced
activation of immune pathways within the placenta, the sex-specific
maternal-fetal intermediary, may contribute to prenatal stress
programming effects on the offspring. Therefore, we assessed for markers
indicative of stress-induced placental inflammation, and examined the
ability of maternal anti-inflammatory treatment (NSAID) to ameliorate
placental effects, and thereby rescue the stress-dysregulation phenotype
observed in our established mouse model of early prenatal stress (EPS).
As expected, placental gene expression analyses revealed increased
levels of immune response genes, including the pro-inflammatory
cytokines interleukin-6 (IL6) and interleukin 1-β (IL1β), specifically
in male placentas. NSAID treatment partially ameliorated these EPS
effects. Similarly, in adult offspring, males displayed stress-induced
locomotor hyperactivity, a hallmark of dopaminergic dysregulation, which
was ameliorated by maternal NSAID treatment. Fitting with these
outcomes and supportive of dopamine pathway involvement, expression of
dopamine D1 and D2 receptors were altered by EPS in males. These studies
support an important interaction between maternal stress and a
pro-inflammatory state in the long-term programming effects of maternal

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