| Prenatal influenza infections have been associated with increased risk for neurodevelopmental disorders. Evidence from rodent models demonstrates that prenatal immunological events can alter fetal brain development---an effect that is mediated in part by the maternal inflammatory response. Studies have also shown that the gestational timing of an infection results in different behavioral and neural abnormalities in the offspring. Neuroimmune interactions between maternal, placental, and fetal systems are inherently complex. Thus, the first nonhuman primate model of maternal influenza infection was created to investigate the impact on offspring brain and behavioral development, following viral exposure either during mid- or late-gestation.;Pregnant rhesus monkeys, in the Mid-Influenza (MI) cohort (n=19) or in the Late-Influenza (LI) cohort (n=24), were infected with influenza virus, A/Sydney/5/97(H3N2), during their 169-day gestation either at Day 105 or Day 125, respectively. Nasal swabs and blood samples confirmed viral infection and immune activation in experimental animals. Infants in the MI cohort included 12 experimental (n=7 males, n=5 females) and 12 control monkeys (n=8 males, n=4 females). Infants in the LI cohort included 12 experimental (n=7 males, n=5 females) and 7 control monkeys (n=3 males, n=4 females). Brain development was examined in yearling offspring with MRI for structural alterations at global and regional levels. Behavioral assessments and cortisol levels were also examined.;Maternal infection was mild and self-limiting. Reductions in global and cortical gray matter (GM) were found in LI offspring (p<.05) from influenza pregnancies. These offspring also evinced regional reductions in cingulate and parietal areas (p<.05) accompanied by increases in cingulate WM. MI offspring showed increases in total brain volumes, specific to males. These animals also evinced regional volume increases in GM occipital and temporal-limbic regions (p<.05) over control males.;Gestational timing appeared to influence the specific effects of prenatal influenza infection on neural development in opposing ways. It is unclear whether these differences were due to variation in maternal responses to infection, fetal sex-steroid production, or greater vulnerability of the fetal brain at certain points in cortical development. However, the observed alterations in brain maturation may increase the risk for pathology later in development. |
