title: Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways.
abstract: Experimental spinal cord injury (SCI) causes chronic neuropathic pain associated with inflammatory changes in thalamic pain regulatory sites. Our recent studies examining chronic pain mechanisms after rodent SCI showed chronic inflammatory changes not only in thalamus, but also in other regions including hippocampus and cerebral cortex. Because changes appeared similar to those in our rodent TBI models that are associated with neurodegeneration and neurobehavioral dysfunction, we examined effects of mouse SCI on cognition, depressive-like behavior, and brain inflammation. SCI caused spatial and retention memory impairment and depressive-like behavior, as evidenced by poor performance in the Morris water maze, Y-maze, novel objective recognition, step-down passive avoidance, tail suspension, and sucrose preference tests. SCI caused chronic microglial activation in the hippocampus and cerebral cortex, where microglia with hypertrophic morphologies and M1 phenotype predominated. Stereological analyses showed significant neuronal loss in the hippocampus at 12 weeks but not 8 d after injury. Increased cell-cycle-related gene (cyclins A1, A2, D1, E2F1, and PCNA) and protein (cyclin D1 and CDK4) expression were found chronically in hippocampus and cerebral cortex. Systemic administration of the selective cyclin-dependent kinase inhibitor CR8 after SCI significantly reduced cell cycle gene and protein expression, microglial activation and neurodegeneration in the brain, cognitive decline, and depression. These studies indicate that SCI can initiate a chronic brain neurodegenerative response, likely related to delayed, sustained induction of M1-type microglia and related cell cycle activation, which result in cognitive deficits and physiological depression.
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland 21201 jwu@anes.umm.edu.
authors.forename: Junfang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Zaorui
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Boris
authors.initials: B
authors.lastname: Sabirzhanov
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Bogdan A
authors.identifier: http://orcid.org/0000-0002-2501-6434
authors.initials: BA
authors.lastname: Stoica
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Alok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Jacob
authors.initials: J
authors.lastname: Skovira
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000339:Affect / Q000502:physiology*; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology*; D003071:Cognition / Q000502:physiology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology / Q000523:psychology
keywords: brain; cognition; depression; inflammation; neurodegeneration; spinal cord injury