This project is based on INIA-West studies showing changes in neuroimmune gene expression in animal models of alcohol intake and in brain of human alcoholics. We found that deletion of any of six INIA candidate neuroinflammatory genes decreased alcohol consumption and activation of immune signaling increased alcohol consumption. These data suggest that in human alcoholism and in our genetic animal models there is a misregulation of pro-inflammatory signaling in brain. Several of our candidate genes are part of a specific toll-like receptor (TLR4) signaling pathway that we will study behaviorally and biochemically.
Specific Aim 1 will: Define the molecular components of TLR4 signaling that are responsible for promotion of excessive alcohol consumption. These studies will use null mutant mice lacking key components of this system. Neuroinflammatory signaling is also a potential target for medication development for alcoholism and we will test three anti-inflammatory drugs: Minocycline, Pioglitazone and AE1-329.
Specific Aim 2 will: Define the gene networks that are perturbed by excessive alcohol consumption and neuroimmune activation in mouse and compare these to gene expression changes in human alcoholism.
This aim will also define changes in brain cytokines related to regulation of alcohol consumption by measuring cytokine levels in brain of mice treated with anti-inflammatory drugs which reduce alcohol consumption.
Specific Aim 3 is a Core function that will provide behavioral testing of new INIA candidate genes for other INIA projects using RNAi, conditional null mutant mice and pharmacological approaches. INIA Interactions: Genetic manipulation In mice will use RNAi and null mutant mice from the Lasek and Homanics INIA cores. We will provide behavioral testing for the Heberlein and Ponomarev projects and treated mice to Ponomarev. We will collaborate with the Mayfield and Ponomarev projects to compare our data for gene expression profiling (human and mouse), the Roberts/Kosten cores for medication testing and the Siggins and Morrisett projects for electrophysiology.
Alcoholism (alcohol dependence) is one of the most expensive and damaging chronic diseases. Treatment options are limited, and there is a high rate of relapse for all treatments. Our preliminary results suggest that brain neuroinflammatory signals may promote persistent and excessive alcohol consumption. Neuroinflammatory pathways in brain may be unexplored targets for medication development to reduce excessive alcohol consumption and prevent relapse.
|Ponomarev, Igor; Stelly, Claire E; Morikawa, Hitoshi et al. (2017) Mechanistic insights into epigenetic modulation of ethanol consumption. Alcohol 60:95-101|
|Blednov, Yuri A; Black, Mendy; Benavidez, Jillian M et al. (2017) Sedative and Motor Incoordination Effects of Ethanol in Mice Lacking CD14, TLR2, TLR4, or MyD88. Alcohol Clin Exp Res 41:531-540|
|McCarthy, Gizelle M; Warden, Anna S; Bridges, Courtney R et al. (2017) Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling. Addict Biol :|
|Harris, R Adron; Bajo, Michal; Bell, Richard L et al. (2017) Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents. J Neurosci 37:1139-1155|
|Mayfield, Jody; Harris, R Adron (2017) The Neuroimmune Basis of Excessive Alcohol Consumption. Neuropsychopharmacology 42:376|
|Tulisiak, Christopher T; Harris, R Adron; Ponomarev, Igor (2017) DNA modifications in models of alcohol use disorders. Alcohol 60:19-30|
|McCracken, Lindsay M; Lowes, Daniel C; Salling, Michael C et al. (2017) Glycine receptor ?3 and ?2 subunits mediate tonic and exogenous agonist-induced currents in forebrain. Proc Natl Acad Sci U S A 114:E7179-E7186|
|Blednov, Yuri A; Black, Mendy; Chernis, Julia et al. (2017) Ethanol Consumption in Mice Lacking CD14, TLR2, TLR4, or MyD88. Alcohol Clin Exp Res 41:516-530|
|Blednov, Yuri A; Borghese, Cecilia M; Ruiz, Carlos I et al. (2017) Mutation of the inhibitory ethanol site in GABAA ?1 receptors promotes tolerance to ethanol-induced motor incoordination. Neuropharmacology 123:201-209|
|McCarthy, Gizelle M; Bridges, Courtney R; Blednov, Yuri A et al. (2017) CNS cell-type localization and LPS response of TLR signaling pathways. F1000Res 6:1144|
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