title: Morphological and genetic activation of microglia after diffuse traumatic brain injury in the rat.
abstract: Traumatic brain injury (TBI) survivors experience long-term post-traumatic morbidities. In diffuse brain-injured rats, a chronic sensory sensitivity to whisker stimulation models the agitation of TBI survivors and provides anatomical landmarks across the whisker-barrel circuit to evaluate post-traumatic neuropathology. As a consequence of TBI, acute and chronic microglial activation can contribute to degenerative and reparative events underlying post-traumatic morbidity. Here we hypothesize that a temporal sequence of microglial activation states contributes to the circuit pathology responsible for post-traumatic morbidity, and test the hypothesis by examining microglial morphological activation and neuroinflammatory markers for activation states through gene expression and receptor-binding affinity. Adult male, Sprague-Dawley rats were subjected to a single moderate midline fluid percussion injury (FPI) or sham injury. Microglial activation was determined by immunohistochemistry, quantitative real-time PCR and receptor autoradiography in the primary somatosensory barrel field (S1BF) and ventral posterior medial nucleus (VPM) of the thalamus at 7 and 28 days following FPI. Morphological changes indicative of microglial activation, including swollen cell body with thicker, shrunken processes, were evident in S1BF and VPM at 7 and 28 days post-injury. Principally at 7 days post-injury in VPM, general inflammatory gene expression (major histocompatibility complex I, major histocompatibility complex II, translocator protein 18 kDa [TSPO]) is increased above sham level and TSPO gene expression confirmed by receptor autoradiography. Further, CD45, a marker of classical activation, and TGF-βI, an acquired deactivation marker, were elevated significantly above sham at 7 days post-injury. Daily administration of the anti-inflammatory ibuprofen (20mg/kg, i.p.) significantly reduced the expression of these genes. Evidence for alternative activation (arginase 1) was not observed. Thus, these data demonstrate concomitant classical activation and acquired deactivation phenotypes of microglia in diffuse TBI in the absence of overt contusion or cavitation. Anti-inflammatory treatment may further alleviate the neuropathological burden of post-traumatic inflammation.
authors.affiliation: Department of Biology, College of Art and Science, University of Kentucky, Lexington, KY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Cao
authors.forename: T C
authors.initials: TC
authors.lastname: Thomas
authors.forename: J M
authors.initials: JM
authors.lastname: Ziebell
authors.forename: J R
authors.initials: JR
authors.lastname: Pauly
authors.forename: J
authors.initials: J
authors.lastname: Lifshitz
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001930:Brain Injuries / Q000473:pathology* / Q000503:physiopathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology; D005786:Gene Expression Regulation / Q000502:physiology* / Q000528:radiation effects; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D007052:Ibuprofen / Q000627:therapeutic use; D007546:Isoquinolines / Q000493:pharmacokinetics; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D013003:Somatosensory Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D020651:Ventral Thalamic Nuclei / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: C100745:Aif1 protein, rat; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007546:Isoquinolines; D008840:Microfilament Proteins; D011963:Receptors, GABA-A; D014316:Tritium; C069997:Tspo protein, rat; D051546:Cyclooxygenase 2; D007052:Ibuprofen; C037850:PK 11195