title: Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge.
abstract: Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2-12 h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although proinflammatory cytokine expression in microglia peaked 2-4 h after LPS, astrocyte cytokine, and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba-1(+)) and astrocytes (GFAP(+)), however, were undetected during this 2-12 h timeframe. Increased Iba-1 immunoreactivity and de-ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared with acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge.
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Norden
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio.
authors.forename: Paige J
authors.initials: PJ
authors.lastname: Trojanowski
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Villanueva
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio.
authors.forename: Elisa
authors.initials: E
authors.lastname: Navarro
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio.|Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Godbout
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000276:immunology / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009043:Motor Activity / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D012333:RNA, Messenger; C528900:glial fibrillary astrocytic protein, mouse
keywords: astrocytes; lipopolysaccharide; microglia; neuroinflammation; sickness behavior