Year of Award

2013

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Other Degree Name/Area of Focus

Integrative Microbiology and Biochemistry, Cellular and Molecular Biology

Department or School/College

Department of Chemistry and Biochemistry

Committee Co-chair

Scott Wetzel, Byron Caughey

Commitee Members

D. Scott Samuels, Jesse Hay

Abstract

During the perinatal time period, the mammalian brain is developing rapidly and is particularly sensitive to inflammation. Inflammation during this time period may be linked to later neurological illness in humans. Disease-associated alterations in learning and behavior can be modeled in rodents using perinatal immune stimulation with either infectious agents or Toll-like receptor (TLR) agonists. Although the gestational period is a particularly sensitive time for neurodevelopment, it is not known for how long after birth this sensitivity persists. In mice, susceptibility to neurological infection declines dramatically during the first weeks of life. Therefore, we sought to compare the neuroinflammatory responses of neonatal and weanling mice. To do so, we injected neonatal and weanling mice intracerebrally (IC) with lipopolysaccharide (LPS) or CpG oligodinucleotides (CpG), ligands of TLRs 4 and 9, respectively. We compared the production of inflammatory mediators and immune cell activation in the brain at each age. Despite lower Tlr mRNA expression in neonatal brains, TLR4 and TLR9 stimulation induced substantially higher levels of some cytokines in neonatal brains. We also detected age-associated differences in expression of a subset of microglial activating and inhibitory receptors, as well as age-associated differences in the immune populations present in the brain. We specifically examined whether the prion protein, PrPc , plays an immunomodulatory role in the brain. PrPc expression influences immune cell activation in the periphery, increases in the brain with age, and influences several aspects of glial cell function. Since glia are the primary immune-responsive cells in the brain, we hypothesized that PrPc would influence the neuroinflammatory response. However, we found no PrPc –dependent differences in cytokine production or glial activation in vivo in neonatal or weanling mice. Collectively, our data demonstrate that the neuroinflammatory response to TLR stimulation is developmentally regulated in young mice, although independent of PrPc expression.

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© Copyright 2013 Leah Beth Christensen