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Role of Primed Microglia in the Aging Brain in Prolonged Sickness and Depressive Behavior Concomitant with Peripheral Immune Stimulation

Henry, Christopher John

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Biochemistry Program, Ohio State.

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 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 both adult and aged mice, but the microglial response to ex vivo IL-4 treatment was significantly lower in microglia from aged mice than adults.

These findings support the hypothesis that aging primes microglia to give an exaggerated inflammatory response to peripheral immune stimulation, that this amplified neuroinflammation leads to behavioral deficits such as prolonged sickness and depressive-like behaviors, and that age-associated impairments in microglial anti-inflammatory signaling such as IL-4 signaling may play a significant role in the amplified and prolonged microglia activation in the aged brain following peripheral immune stimulation.

Jonathan Godbout, Ph.D. (Advisor)
Brian Kaspar, Ph.D. (Committee Member)
Jeanette Marketon, Ph.D. (Committee Member)
William Lafuse, Ph.D. (Committee Member)
185 p.

Recommended Citations

Citations

  • Henry, C. J. (2011). Role of Primed Microglia in the Aging Brain in Prolonged Sickness and Depressive Behavior Concomitant with Peripheral Immune Stimulation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299556425

    APA Style (7th edition)

  • Henry, Christopher. Role of Primed Microglia in the Aging Brain in Prolonged Sickness and Depressive Behavior Concomitant with Peripheral Immune Stimulation. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1299556425.

    MLA Style (8th edition)

  • Henry, Christopher. "Role of Primed Microglia in the Aging Brain in Prolonged Sickness and Depressive Behavior Concomitant with Peripheral Immune Stimulation." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299556425

    Chicago Manual of Style (17th edition)