title: Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage.
abstract: Toll-like receptors (TLRs) play an important role in the innate immune response, and emerging evidence indicates their role in brain injury and neurodegeneration. Our recent results have demonstrated that ethanol is capable of activating glial TLR4 receptors and that the elimination of these receptors in mice protects against ethanol-induced glial activation, induction of inflammatory mediators and apoptosis. This study was designed to assess whether ethanol-induced inflammatory damage causes behavioral and cognitive consequences, and if behavioral alterations are dependent of TLR4 functions. Here we show in mice drinking alcohol for 5months, followed by a 15-day withdrawal period, that activation of the astroglial and microglial cells in frontal cortex and striatum is maintained and that these events are associated with cognitive and anxiety-related behavioral impairments in wild-type (WT) mice, as demonstrated by testing the animals with object memory recognition, conditioned taste aversion and dark and light box anxiety tasks. Mice lacking TLR4 receptors are protected against ethanol-induced inflammatory damage, and behavioral associated effects. We further assess the possibility of the epigenetic modifications participating in short- or long-term behavioral effects associated with neuroinflammatory damage. We show that chronic alcohol treatment decreases H4 histone acetylation and histone acetyltransferases activity in frontal cortex, striatum and hippocampus of WT mice. Alterations in chromatin structure were not observed in TLR4(-/-) mice. These results provide the first evidence of the role that TLR4 functions play in the behavioral consequences of alcohol-induced inflammatory damage and suggest that the epigenetic modifications mediated by TLR4 could contribute to short- or long-term alcohol-induced behavioral or cognitive dysfunctions.
authors.affiliation: Department of Cell Pathology, Príncipe Felipe Research Center, Avda. Autopista del Saler 16, 46012 Valencia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Pascual
authors.forename: Pablo
authors.initials: P
authors.lastname: Baliño
authors.forename: Silvia
authors.initials: S
authors.lastname: Alfonso-Loeches
authors.forename: Carlos M G
authors.initials: CM
authors.lastname: Aragón
authors.forename: Consuelo
authors.initials: C
authors.lastname: Guerri
mesh_terms: D000107:Acetylation; D019973:Alcohol-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D000438:Alcohols / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage*; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000438:Alcohols; D006657:Histones; D051197:Toll-Like Receptor 4; D000431:Ethanol