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.
|Most, Dana; Leiter, Courtney; Blednov, Yuri A et al. (2016) Synaptic microRNAs Coordinately Regulate Synaptic mRNAs: Perturbation by Chronic Alcohol Consumption. Neuropsychopharmacology 41:538-48|
|Blednov, Yuri A; Black, Mendy; Benavidez, Jillian M et al. (2016) PPAR Agonists: II. Fenofibrate and Tesaglitazar Alter Behaviors Related to Voluntary Alcohol Consumption. Alcohol Clin Exp Res 40:563-71|
|Blednov, Yuri A; Black, Mendy; Benavidez, Jillian M et al. (2016) PPAR Agonists: I. Role of Receptor Subunits in Alcohol Consumption in Male and Female Mice. Alcohol Clin Exp Res 40:553-62|
|Mayfield, J; Arends, M A; Harris, R A et al. (2016) Genes and Alcohol Consumption: Studies with Mutant Mice. Int Rev Neurobiol 126:293-355|
|Marballi, K; Genabai, N K; Blednov, Y A et al. (2016) Alcohol consumption induces global gene expression changes in VTA dopaminergic neurons. Genes Brain Behav 15:318-26|
|Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2015) Role of interleukin-1 receptor signaling in the behavioral effects of ethanol and benzodiazepines. Neuropharmacology 95:309-20|
|Farris, Sean P; Pietrzykowski, Andrzej Z; Miles, Michael F et al. (2015) Applying the new genomics to alcohol dependence. Alcohol 49:825-36|
|Bajo, M; Herman, M A; Varodayan, F P et al. (2015) Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic transmission in the central amygdala. Brain Behav Immun 45:189-97|
|Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2015) Glycine receptors containing Î±2 or Î±3 subunits regulate specific ethanol-mediated behaviors. J Pharmacol Exp Ther 353:181-91|
|Mayfield, Jody; Blednov, Yuri A; Harris, R Adron (2015) Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction. Int Rev Neurobiol 123:279-313|
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