title: Cecal Ligation and Puncture Results in Long-Term Central Nervous System Myeloid Inflammation.
abstract: Survivors of sepsis often experience long-term cognitive and functional decline. Previous studies utilizing lipopolysaccharide injection and cecal ligation and puncture in rodent models of sepsis have demonstrated changes in depressive-like behavior and learning and memory after sepsis, as well as evidence of myeloid inflammation and cytokine expression in the brain, but the long-term course of neuroinflammation after sepsis remains unclear. Here, we utilize cecal ligation and puncture with greater than 80% survival as a model of sepsis. We found that sepsis survivor mice demonstrate deficits in extinction of conditioned fear, but no acquisition of fear conditioning, nearly two months after sepsis. These cognitive changes occur in the absence of neuronal loss or changes in synaptic density in the hippocampus. Sepsis also resulted in infiltration of monocytes and neutrophils into the CNS at least two weeks after sepsis in a CCR2 independent manner. Cellular inflammation is accompanied by long-term expression of pro-inflammatory cytokine and chemokine genes, including TNFα and CCR2 ligands, in whole brain homogenates. Gene expression analysis of microglia revealed that while microglia do express anti-microbial genes and damage-associated molecular pattern molecules of the S100A family of genes at least 2 weeks after sepsis, they do not express the cytokines observed in whole brain homogenates. Our results indicate that in a naturalistic model of infection, sepsis results in long-term neuroinflammation, and that this sustained inflammation is likely due to interactions among multiple cell types, including resident microglia and peripherally derived myeloid cells.
authors: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors: Benjamin H
authors: BH
authors: Singer
authors: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors: Michael W
authors: MW
authors: Newstead
authors: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors: Xianying
authors: X
authors: Zeng
authors: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Christopher L
authors: CL
authors: Cooke
authors: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Robert C
authors: RC
authors: Thompson
authors: Department of Pediatrics, Division of Endocrinology and Metabolism, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors: Kanakadurga
authors: K
authors: Singer
authors: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors: Ramya
authors: R
authors: Ghantasala
authors: Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors: Jack M
authors: JM
authors: Parent
authors: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, United States of America.|Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors: Geoffrey G
authors: GG
authors: Murphy
authors: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.|Center for Clinical Management Research, VA Ann Arbor Health System, Ann Arbor, Michigan, United States of America.
authors: Theodore J
authors: TJ
authors: Iwashyna
authors: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors: Theodore J
authors: TJ
authors: Standiford
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002432:Cecum / Q000503:physiopathology*; D002469:Cell Separation; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology*; D003213:Conditioning, Psychological; D016207:Cytokines / Q000378:metabolism; D049229:Dendritic Spines / Q000473:pathology; D004195:Disease Models, Animal; D005239:Fear; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D008024:Ligands; D008026:Ligation; D008070:Lipopolysaccharides / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia; D009000:Monocytes / Q000166:cytology; D009504:Neutrophils / Q000166:cytology; D011677:Punctures; D018805:Sepsis / Q000503:physiopathology
chemical_list: D016207:Cytokines; D008024:Ligands; D008070:Lipopolysaccharides