tetano
Editor, Senior Moderator
Brain Behav Immun
. 2024 Jun 24:S0889-1591(24)00466-5.
doi: 10.1016/j.bbi.2024.06.025. Online ahead of print. Brain region-specific alterations in gene expression trajectories in the offspring born from influenza a infected mice
Stella Liong[SUP] 1 [/SUP], K H Christopher Choy[SUP] 2 [/SUP], Simone N De Luca[SUP] 1 [/SUP], Felicia Liong[SUP] 1 [/SUP], Madison Coward-Smith[SUP] 1 [/SUP], Osezua Oseghale[SUP] 1 [/SUP], Mark A Miles[SUP] 1 [/SUP], Ross Vlahos[SUP] 1 [/SUP], Celine Valant[SUP] 2 [/SUP], Jess Nithianantharajah[SUP] 3 [/SUP], Christos Pantelis[SUP] 4 [/SUP], Arthur Christopoulos[SUP] 5 [/SUP], Stavros Selemidis[SUP] 6 [/SUP]
Affiliations
Influenza A virus (IAV) infection during pregnancy can increase the risk for neurodevelopmental disorders in the offspring, however, the underlying neurobiological mechanisms are largely unknown. To recapitulate viral infection, preclinical studies have traditionally focused on using synthetic viral mimetics, rather than live IAV, to examine consequences of maternal immune activation (MIA)-dependent processes on offspring. In contrast, few studies have used live IAV to assess effects on global gene expression, and none to date have addressed whether moderate IAV, mimicking seasonal influenza disease, alters normal gene expression trajectories in different brain regions across different stages of development. Herein, we show that moderate IAV infection during pregnancy, which causes mild maternal disease and no overt foetal complications in utero, induces lasting effects on the offspring into adulthood. We observed behavioural changes in adult offspring, including disrupted pre-pulse inhibition, dopaminergic hyper-responsiveness, and spatial recognition memory deficits. Gene profiling in the offspring brain from neonate to adolescence revealed persistent alterations to normal gene expression trajectories in the hippocampus, cerebellum, prefrontal cortex, and hypothalamus. Alterations were found in genes involved in inflammation and neurogenesis, which were predominately dysregulated in neonatal and early adolescent offspring. Notably, late adolescent offspring born from IAV infected mice displayed altered microglial morphology in the hippocampus. In conclusion, we show that moderate IAV during pregnancy perturbs neurodevelopmental trajectories in the offspring, including alterations in the neuroinflammatory gene expression profiled and microglial number and morphology in the hippocampus, resulting in behavioural changes in adult offspring. Such early perturbations may underlie the vulnerability in human offspring for the later development of neurodevelopmental disorders, including schizophrenia. Our work highlights the importance of using live IAV in developing novel preclinical models that better recapitulate the real-world impact of inflammatory insults during pregnancy on the offspring neurodevelopmental trajectory and disease susceptibility later in life.
Keywords: Hippocampus; Influenza A virus; Maternal immune activation; Microglia; Neurodevelopmental Disorders; Neuroinflammation; Offspring neurodevelopment; Pregnancy; Viral infection.
. 2024 Jun 24:S0889-1591(24)00466-5.
doi: 10.1016/j.bbi.2024.06.025. Online ahead of print. Brain region-specific alterations in gene expression trajectories in the offspring born from influenza a infected mice
Stella Liong[SUP] 1 [/SUP], K H Christopher Choy[SUP] 2 [/SUP], Simone N De Luca[SUP] 1 [/SUP], Felicia Liong[SUP] 1 [/SUP], Madison Coward-Smith[SUP] 1 [/SUP], Osezua Oseghale[SUP] 1 [/SUP], Mark A Miles[SUP] 1 [/SUP], Ross Vlahos[SUP] 1 [/SUP], Celine Valant[SUP] 2 [/SUP], Jess Nithianantharajah[SUP] 3 [/SUP], Christos Pantelis[SUP] 4 [/SUP], Arthur Christopoulos[SUP] 5 [/SUP], Stavros Selemidis[SUP] 6 [/SUP]
Affiliations
- PMID: 38925418
- DOI: 10.1016/j.bbi.2024.06.025
Influenza A virus (IAV) infection during pregnancy can increase the risk for neurodevelopmental disorders in the offspring, however, the underlying neurobiological mechanisms are largely unknown. To recapitulate viral infection, preclinical studies have traditionally focused on using synthetic viral mimetics, rather than live IAV, to examine consequences of maternal immune activation (MIA)-dependent processes on offspring. In contrast, few studies have used live IAV to assess effects on global gene expression, and none to date have addressed whether moderate IAV, mimicking seasonal influenza disease, alters normal gene expression trajectories in different brain regions across different stages of development. Herein, we show that moderate IAV infection during pregnancy, which causes mild maternal disease and no overt foetal complications in utero, induces lasting effects on the offspring into adulthood. We observed behavioural changes in adult offspring, including disrupted pre-pulse inhibition, dopaminergic hyper-responsiveness, and spatial recognition memory deficits. Gene profiling in the offspring brain from neonate to adolescence revealed persistent alterations to normal gene expression trajectories in the hippocampus, cerebellum, prefrontal cortex, and hypothalamus. Alterations were found in genes involved in inflammation and neurogenesis, which were predominately dysregulated in neonatal and early adolescent offspring. Notably, late adolescent offspring born from IAV infected mice displayed altered microglial morphology in the hippocampus. In conclusion, we show that moderate IAV during pregnancy perturbs neurodevelopmental trajectories in the offspring, including alterations in the neuroinflammatory gene expression profiled and microglial number and morphology in the hippocampus, resulting in behavioural changes in adult offspring. Such early perturbations may underlie the vulnerability in human offspring for the later development of neurodevelopmental disorders, including schizophrenia. Our work highlights the importance of using live IAV in developing novel preclinical models that better recapitulate the real-world impact of inflammatory insults during pregnancy on the offspring neurodevelopmental trajectory and disease susceptibility later in life.
Keywords: Hippocampus; Influenza A virus; Maternal immune activation; Microglia; Neurodevelopmental Disorders; Neuroinflammation; Offspring neurodevelopment; Pregnancy; Viral infection.