title: Gestational flu exposure induces changes in neurochemicals, affiliative hormones and brainstem inflammation, in addition to autism-like behaviors in mice.
abstract: 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.
authors.affiliation: 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. Electronic address: vmiller@wadsworth.org.
authors.forename: V M
authors.initials: VM
authors.lastname: Miller
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: C
authors.initials: C
authors.lastname: Bucher
authors.forename: W
authors.initials: W
authors.lastname: McGinnis
authors.forename: L K
authors.initials: LK
authors.lastname: Ryan
authors.forename: A
authors.initials: A
authors.lastname: Siegel
authors.forename: S
authors.initials: S
authors.lastname: Zalcman
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000276:immunology; D001933:Brain Stem / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000821:virology; D053122:Influenza A Virus, H3N2 Subtype; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000276:immunology* / Q000473:pathology*; D010121:Oxytocin / Q000097:blood*; D010865:Pilot Projects; D011247:Pregnancy; D011897:Random Allocation; D013239:Stereotyped Behavior; D013739:Testosterone / Q000097:blood*
chemical_list: D001786:Blood Glucose; D013739:Testosterone; D010121:Oxytocin
keywords: Behavior; Brainstem; Dose; Mice; Oxytocin; Serotonin; Viral exposure