Large-scale effects of prenatal inflammation and early life circadian disruption in mice: Implications for neurodevelopmental disorders

Abstract

Around 80 % of individuals with neurodevelopmental disorders such as schizophrenia and autism spectrum disorders experience disruptions in sleep/circadian rhythms. We explored whether environmental circadian disruption interacts with prenatal infection, a risk factor for neurodevelopmental disorders, to induce sex-specific deficits in mice. A maternal immune activation (MIA) protocol was used by injecting pregnant mice with viral mimic poly IC or saline at E9.5. Juvenile/adolescent male and female offspring (3-7 weeks old) were then subjected to a standard light:dark cycle (12:12LD) or to constant light (LL). Significant interactions between treatment (MIA, control) and lighting (12:12LD, LL) were evident in behaviors related to cognition, anxiety, and sociability. This pattern persisted in our RNA sequencing analysis of the dorsal hippocampus, where poly IC exposure resulted in numerous differentially expressed genes (DEGs) in males, while exposure to both poly IC and LL led to a marked reduction in DEGs. Through WGCNA analysis, many significant gene modules were found to be positively associated with poly IC (vs. saline) and LL (vs. LD) in males (fewer in females). Many of the identified hub-bottleneck genes were homologous to human genes associated with sleep/circadian rhythms and neurodevelopmental disorders as revealed by GWA studies. The MIA- and LL-associated modules were enriched in microglia gene signatures, which was paralleled by trends of effects of each of the factors on microglia morphology. In conclusion, in a mouse model of prenatal infection, circadian disruption induced by LL during adolescence acts as a modulator of the effects of MIA at behavioral, cellular, and molecular levels.

Keywords: Adolescence; Behavior; Circadian disruption; Maternal immune activation; Microglia; Neurodevelopmental disorders; RNA sequencing.