Role of Primed Microglia in the Aging Brain in Prolonged Sickness and Depressive Behavior Concomitant with Peripheral Immune Stimulation
Year: 2011
Type: article
Abstract: In the elderly, systemic infection is associated with an increased frequency of behavioral and cognitive complications such as depression and delirium.These complications negatively affect quality of life and are associated with increased morbidity and mortality.An excessive neuroinflammatory response to peripheral infection may underlie the impairments in affect and cognition in the aged and this excessive response may be caused by microglia that have become primed in the course of normal aging to give a dysregulated immune response to peripheral immune activation.In support of this notion, we and others have shown an exaggerated neuroinflammatory response to peripheral immune stimulation in aged mice.Moreover, this exaggerated neuroinflammation is accompanied by prolonged sickness and depressive-like behavior.To clarify if the brain is the origin of the dysregulated immune response that leads to exaggerated neuroinflammation and prolonged sickness behavior in the aged, adult and aged mice were given an intracerebroventricular immune challenge and sickness behavior, inflammatory markers, and markers of glial activation were measured.Central immune challenge elicited a prolonged sickness response in aged mice which was accompanied by protracted expression of inflammatory cytokines in cerebellum and hippocampus.Plasma IL-6 concentrations were also elevated by central immune iii challenge and the magnitude and duration of these increases were greater in aged mice compared to adults.To determine if aging leads to an imbalance in LPS-induced microglial expression of pro-and anti-inflammatory mediators, microglia were isolated from adult and aged mice after intraperitoneal LPS injection and assayed for mRNA and protein expression of pro-inflammatory IL-1β and anti-inflammatory IL-10.Microglia isolated from aged mice showed higher mRNA and protein induction of both IL-1β and IL-10 compared to adults.Furthermore, primed (MHC II + ) microglia from aged mice showed the most prominent induction of IL-1β.To determine if minocycline, a purported microglia inhibitor, could attenuate LPS-induced microglia activation, reduce neuroinflammation, and impact sickness behavior, mice were pretreated with minocycline then given an intraperitoneal injection of LPS.Minocycline pretreatment facilitated recovery from LPS-induced sickness, attenuated LPS-induced microglial expression of TLR2, a marker of microglial activation, and decreased LPS-induced markers of neuroinflammation (IL-1β, IL-6, and IDO) in the hippocampus and cortex.To determine if defects in IL-4 signaling could play a role in the exaggerated microglial response to peripheral immune stimulation in aged mice, adult and aged mice received an intraperitoneal injection of LPS and microglia were isolated and treated with IL-4 ex vivo.Lipopolysaccharide treatment led to an increase in expression of IL-4Rα in Thanks to my lab mates for cheerfully helping me with my experiments.A special thanks to Yan Huang for training me in nearly every lab technique I learned in the Godbout lab.Thanks also to Yan for keeping the lab stocked and running smoothly, no one could have done a better job unless they were a mind reader.Thanks to Angela Wynne-Corona for your encouragement when the times got tough, and for showing that there is more than one way to make scientific discoveries.A big thanks to Ashley Fenn for enthusiastically driving my (our?) project forward from the moment you entered the lab; your intelligence and work ethic will take you far.Thanks to Eric Wohleb for bringing a measure of balance to the lab, your cool head and easy going demeanor were much needed.Thanks to Mike Bailey and Mark Hanke for teaching me flow cytometry; those were the most exciting experiments for me.
Author: Christopher John Henry
Institution: The Ohio State University
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W2600104156