Influenza infection induces neuroinflammation and impacts hippocampal structure and function

Cognition;Neuroinflammation;Influenza;Hippocampus;Cytokines;Neurotrophic factors;Environmental enrichment;Microglia;Neuron morphology

Jurgens, Heidi

关键词: Cognition;    Neuroinflammation;    Influenza;    Hippocampus;    Cytokines;    Neurotrophic factors;    Environmental enrichment;    Microglia;    Neuron morphology;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/30955/Jurgens_Heidi.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Influenza remains a leading cause of illness and death throughout the world, making it a serious health concern as well as a significant economic burden. While the role that the peripheral immune system plays in influenza is well-characterized, it is unknown if infection with this common viral pathogen can result in a central inflammatory response, neuronal damage, and long-term neurobehavioral effects. Therefore, the broad aim of this research was to determine if peripheral infection with live influenza virus elicits a neuroimmune response and impacts hippocampal structure and function. Initial studies determined that influenza infection induced deficits in spatial learning and memory in adult mice at day 7 post-infection. These cognitive impairments were paralleled by increased hippocampal expression of proinflammatory cytokines (IL1-β, IL6, TNF-α, and IFN-α), and the loss of neurotrophic (BDNF, NGF), and immunomodulatory (CD200, CX3CL1) factors. To better understand the cellular mechanisms underlying these effects, changes in microglia reactivity and hippocampal neuron morphology were assessed at the same timepoint in which heightened inflammation and cognitive deficits were evident. Influenza infected mice had increased microglial activation throughout the hippocampus, and exhibited significant alterations in the architecture of both CA1 pyramidal neurons and dentate gyrus granule cells. Taken together, these data suggest that neuroinflammation and changes in hippocampal structural plasticity may underlie cognitive dysfunction associated with influenza infection. The loss of immunomodulatory factors important for neuron-microglia interactions, along with reduced neurotrophic support, could leave the brain vulnerable to inflammatory damage during influenza infection. A potential strategy for increasing brain plasticity and resiliency and improving cognitive function is environmental enrichment. The enhanced social, cognitive, and physical stimulation provided by environmental enrichment has been shown to benefit brain function and behavior in many central nervous system (CNS) disorders, but its therapeutic potential during peripheral viral infection remains unknown. Therefore, the objective of the next series of studies was to determine if long-term exposure to environmental enrichment could prevent and/or attenuate the negative impact of influenza infection on the hippocampus and spatial cognition. Continuous exposure to environmental enrichment during rearing and throughout influenza infection helped modulate inflammation, preserve levels of neurotrophic and immunomodulatory factors, and reduce deficits in hippocampal-dependent learning and memory. Overall, these data establish the potential for environmental enrichment to mitigate the detrimental effects of peripheral infection on CNS function and cognitive behavior. As lasting neurobehavioral changes have been associated with viral infection, it was next determined if neuroinflammation, reduced neurotrophic support, and cognitive dysfunction persisted during/following recovery from influenza infection.Changes in the hippocampal expression of inflammatory, neurotrophic, and immunomodulatory factors were determined at timepoints corresponding to partial (day 14 post-infection) and full (day 25 post-infection) recovery from influenza infection. In addition, spatial learning and memory was assessed following recovery to determine if influenza infection induced prolonged cognitive impairment.At partial recovery from influenza infection, TNF-α and IL-1β remained elevated, and levels of CD200 were still decreased compared to control mice. Following full recovery from influenza infection, mice demonstrated intact cognitive function, and alterations in the hippocampal expression of cytokines, neurotrophic, and immunomodulatory factors were no longer evident. These findings suggest that while there are some relatively longstanding changes in hippocampal gene expression induced by influenza infection, neuroinflammation and cognitive dysfunction do not appear to persist following recovery from illness.Collectively, these novel data indicate that peripheral infection with influenza virus elicits a central inflammatory response and impacts hippocampal structure and function. While there was no indication of prolonged cognitive dysfunction following recovery from illness, the heightened levels of inflammation concurrent with reduced neurotrophic support during acute sickness and continuing through the recovery period could leave the brain vulnerable to subsequent inflammatory insult. In addition, these findings are the first to demonstrate a possible role for environmental enrichment in reducing the negative consequences of influenza infection on the brain and behavior, and suggest that a more regulated neuroimmune response and/or maintenance of neurotrophic potential may underlie these neuroprotective effects.