title: Greater glucocorticoid receptor activation in hippocampus of aged rats sensitizes microglia.
abstract: Healthy aging individuals are more likely to suffer profound memory impairments following an immune challenge than are younger adults. These challenges produce a brain inflammatory response that is exaggerated with age. Sensitized microglia found in the normal aging brain are responsible for this amplified response, which in turn interferes with processes involved in memory formation. Here, we examine factors that may lead aging to sensitize microglia. Aged rats exhibited higher corticosterone levels in the hippocampus, but not in plasma, throughout the daytime (diurnal inactive phase). These elevated hippocampal corticosterone levels were associated with increased hippocampal 11β-hydroxysteroid dehydrogenase type 1 protein expression, the enzyme that catalyzes glucocorticoid formation and greater hippocampal glucocorticoid receptor (GR) activation. Intracisternal administration of mifepristone, a GR antagonist, effectively reduced immune-activated proinflammatory responses, specifically from hippocampal microglia and prevented Escherichia coli-induced memory impairments in aged rats. Voluntary exercise as a therapeutic intervention significantly reduced total hippocampal GR expression. These data strongly suggest that increased GR activation in the aged hippocampus plays a critical role in sensitizing microglia.
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA. Electronic address: ruth.barrientos@colorado.edu.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Barrientos
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Thompson
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Meagan M
authors.initials: MM
authors.lastname: Kitt
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Amat
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA; School of Psychological Science, La Trobe University, Melbourne Campus, Victoria, Australia.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Hale
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Frank
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Nicole Y
authors.initials: NY
authors.lastname: Crysdale
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Stamper
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Hennessey
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Spencer
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lowry
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism / Q000502:physiology; D000375:Aging / Q000276:immunology*; D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D003345:Corticosterone / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008297:Male; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000517:prevention & control; D017628:Microglia / Q000276:immunology*; D015735:Mifepristone / Q000494:pharmacology / Q000627:therapeutic use; D010805:Physical Conditioning, Animal / Q000502:physiology; D011916:Rats, Inbred F344; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone
keywords: Automated blood sampling; GR activation; In vivo microdialysis; Memory impairments; Microglial immunophenotype; Microglial sensitization; Mifepristone; Normal aging; Voluntary exercise