Intrauterine inflammation leads to some sex and age-specific behavior and molecular differences in mice

Background Prenatal inflammation is associated with long-term adverse neurobehavioral outcomes in exposed children. Sex-specific differences in behavior have been observed in anxiety and learning; however, whether these differences manifest differently by age is unknown. This study assesses possible behavioral changes from in utero inflammation as a function of age in neonatal, juvenile, and adult animals. We also tested if the observed behavioral differences correlated to neonatal sex-specific neurogenesis gene expression changes in the hippocampus to suggest a mechanism for observed behavioral differences. Methods CD-1 timed pregnant dams were injected in utero with lipopolysaccharide (LPS, 50μg/animal) or saline at embryonic day 15 (E15). Neonatal behavioral testing was performed on postnatal day (P) 5 on male and female pups born at term using the Ultrasonic Vocalization test (USV). Juvenile and mature animals of each sex were tested in Open Field (OF) and Barnes Maze (BM) on P28 and P67 (OF), and 32-36 and 70-75 (BM). A commercially available array designed to assess the expression of genes involved in mammalian neurogenesis was utilized for profiling gene expression in the hippocampal tissue isolated from LPS and saline-exposed P7 pups. Results There were no differences in stress responses measured by neonatal USV between LPS- and saline-exposed groups of either sex. In contrast, exposure to prenatal inflammation caused a male-specific increase in anxiety in mature but not juvenile animals. Juvenile LPS-exposed females had decreased movement in OF that was not present in adult animals. In addition, we observed improved memory retrieval in response to in utero LPS in the juvenile animals of both sexes. However, there was an impairment of long-term memory in adult LPS-exposed females. Finally, gene expression analyses revealed that LPS induced sex-specific changes in genes involved in hippocampal neurogenesis. Conclusions Intrauterine exposure to inflammation has age and sex-specific effects on anxiety and learning. These differences are not apparent in the neonatal period but begin to be evident in juvenile animals and evolve in adult animals. These sex-specific differences in learning may be correlated to sex-specific disruption of the expression of genes associated with neurogenesis in the hippocampus. ### Competing Interest Statement The authors have declared no competing interest.