Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage

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 cognitiveconsequences, and if behavioral alterations are dependent of TLR4 functions. Here we show in mice drinking alcohol for 5 months, 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 withcognitive 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, andbehavioralassociated effects. We further assess the possibility of the epigenetic modifications participating in short- or long-term behavioral effects associated with neuroinflammatorydamage. We show that chronicalcohol 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 behavioralconsequences of alcohol-induced inflammatory damage and suggest that the epigenetic modifications mediated by TLR4 could contribute to short- or long-term alcohol-inducedbehavioral orcognitivedysfunctionsThis work has been supported by grants from the Spanish Ministry of Science and Innovation (SAF-2009-07503), and the Spanish Ministry of Health: The Institute of Heath, Carlos III (RTA-Network, RD06/0019 and RD06/0028) and PNSD (Exp. 20101037), General Direction on Drug Dependence (GV