title: Social defeat promotes a reactive endothelium in a brain region-dependent manner with increased expression of key adhesion molecules, selectins and chemokines associated with the recruitment of myeloid cells to the brain.
abstract: Repeated social defeat (RSD) in mice causes myeloid cell trafficking to the brain that contributes to the development of prolonged anxiety-like behavior. Myeloid cell recruitment following RSD occurs in regions where neuronal and microglia activation is observed. Thus, we hypothesized that crosstalk between neurons, microglia, and endothelial cells contributes to brain myeloid cell trafficking via chemokine signaling and vascular adhesion molecules. Here we show that social defeat caused an exposure- and brain region-dependent increase in several key adhesion molecules and chemokines involved in the recruitment of myeloid cells. For example, RSD induced distinct patterns of adhesion molecule expression that may explain brain region-dependent myeloid cell trafficking. VCAM-1 and ICAM-1 mRNA expression were increased in an exposure-dependent manner. Furthermore, RSD-induced VCAM-1 and ICAM-1 protein expression were localized to the vasculature of brain regions implicated in fear and anxiety responses, which spatially corresponded to previously reported patterns of myeloid cell trafficking. Next, mRNA expression of additional adhesion molecules (E- and P-selectin, PECAM-1) and chemokines (CXCL1, CXCL2, CXCL12, CCL2) were determined in the brain. Social defeat induced an exposure-dependent increase in mRNA levels of E-selectin, CXCL1, and CXCL2 that increased with additional days of social defeat. While CXCL12 was unaffected by RSD, CCL2 expression was increased by six days of social defeat. Last, comparison between enriched CD11b(+) cells (microglia/macrophages) and enriched GLAST-1(+)/CD11b(-) cells (astrocytes) revealed RSD increased mRNA expression of IL-1β, CCL2, and CXCL2 in microglia/macrophages but not in astrocytes. Collectively, these data indicate that key mediators of leukocyte recruitment were increased in the brain vasculature following RSD in an exposure- and brain region-dependent manner.
authors.affiliation: Divsion of Biosciences, The Ohio State University, 305 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Sawicki
authors.affiliation: Divsion of Biosciences, The Ohio State University, 305 West 12th Avenue, Columbus, OH 43210, USA; Department of Neuroscience, The Ohio State University, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: McKim
authors.affiliation: Divsion of Biosciences, The Ohio State University, 305 West 12th Avenue, Columbus, OH 43210, USA; Department of Neuroscience, The Ohio State University, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Wohleb
authors.affiliation: Divsion of Biosciences, The Ohio State University, 305 West 12th Avenue, Columbus, OH 43210, USA; Department of Neuroscience, The Ohio State University, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Jarrett
authors.affiliation: Divsion of Biosciences, The Ohio State University, 305 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: B F
authors.initials: BF
authors.lastname: Reader
authors.affiliation: Department of Neuroscience, The Ohio State University, 333 West 10th Avenue, Columbus, OH 43210, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Norden
authors.affiliation: Department of Neuroscience, The Ohio State University, 333 West 10th Avenue, Columbus, OH 43210, USA; Institute for Behavioral Medicine Research, The Ohio State University, 460 Medical Center Drive, Columbus, OH 43210, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA. Electronic address: Jonathan.Godbout@osumc.edu.
authors.forename: J P
authors.initials: JP
authors.lastname: Godbout
authors.affiliation: Divsion of Biosciences, The Ohio State University, 305 West 12th Avenue, Columbus, OH 43210, USA; Institute for Behavioral Medicine Research, The Ohio State University, 460 Medical Center Drive, Columbus, OH 43210, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA. Electronic address: John.Sheridan@osumc.edu.
authors.forename: J F
authors.initials: JF
authors.lastname: Sheridan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004727:Endothelium / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019087:Selectins / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological / Q000473:pathology*
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D012333:RNA, Messenger; D019087:Selectins
keywords: adhesion molecules; chemokines; myeloid cell trafficking; neurovascular unit; reactive endothelium; social defeat