Clinical Medical Sciences Building, Wadsworth Center, New York State Department of Health, New Scotland Avenue, Albany, NY 12208, USA; Department of Environmental Health Science, School of Public Health, State University of New York at Albany, Wadsworth Center, Empire State Plaza, NY 12201-0509, USA.
Brain Behav Immun. 2013 Oct;33:153-63. doi: 10.1016/j.bbi.2013.07.002. Epub 2013 Jul 20.
The prevalence of neurodevelopmental disorders such as autism is increasing, however the etiology of these disorders is unclear and thought to involve a combination of genetic, environmental and immune factors. A recent epidemiological study found that gestational viral exposure during the first trimester increases risk of autism in offspring by twofold. In mice gestational viral exposures alter behavior of offspring, but the biological mechanisms which underpin these behavioral changes are unclear. We hypothesized that gestational viral exposure induces changes in affiliative hormones, brainstem autonomic nuclei and neurotransmitters which are associated with behavioral alterations in offspring. To address this hypothesis, we exposed pregnant mice to influenza A virus (H3N2) on gestational day 9 and determined behavioral, hormonal and brainstem changes in male and female offspring. We found that gestational flu exposure induced dose-dependent alterations in social and aggressive behaviors (p≤0.05) in male and female offspring and increases in locomotor behaviors particularly in male offspring (p≤0.05). We found that flu exposure was also associated with reductions in oxytocin and serotonin (p≤0.05) levels in male and female offspring and sex-specific changes in dopamine metabolism. In addition we found changes in catecholaminergic and microglia density in brainstem tissues of male flu exposed offspring only (p≤0.05). This study demonstrates that gestational viral exposure induces behavioral changes in mice, which are associated with alterations in affiliative hormones. In addition we found sex-specific changes in locomotor behavior, which may be associated with sex-specific alterations in dopamine metabolism and brainstem inflammation. Further investigations into maternal immune responses are necessary to unravel the molecular mechanisms which underpin abnormal hormonal, immune and behavioral responses in offspring after gestational viral exposure.
神经发育障碍（如自闭症）的患病率正在增加，但其病因尚不清楚，被认为涉及遗传、环境和免疫因素的综合作用。最近的一项流行病学研究发现，妊娠早期的病毒暴露会使后代患自闭症的风险增加两倍。在老鼠中，妊娠期间的病毒暴露会改变后代的行为，但这些行为变化的生物学机制尚不清楚。我们假设妊娠病毒暴露会诱导与后代行为改变相关的亲附激素、脑干自主神经核和神经递质的变化。为了验证这一假设，我们在妊娠第 9 天用甲型流感病毒（H3N2）感染怀孕的老鼠，并确定雄性和雌性后代的行为、激素和脑干变化。我们发现，妊娠流感暴露会导致雄性和雌性后代的社交和攻击行为出现剂量依赖性改变（p≤0.05），并增加运动行为，特别是雄性后代（p≤0.05）。我们还发现，流感暴露与雄性和雌性后代的催产素和血清素水平降低（p≤0.05）以及多巴胺代谢的性别特异性变化有关。此外，我们还发现，只有雄性流感暴露的后代的脑干组织中的儿茶酚胺能和小胶质细胞密度发生变化（p≤0.05）。这项研究表明，妊娠病毒暴露会导致老鼠出现行为改变，这些改变与亲附激素的变化有关。此外，我们还发现运动行为存在性别特异性变化，这可能与多巴胺代谢和脑干炎症的性别特异性改变有关。进一步研究母体免疫反应对于揭示妊娠病毒暴露后后代异常激素、免疫和行为反应的分子机制是必要的。
