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, D; Ferguson, L; Blednov, Y et al. (2015) The synaptoneurosome transcriptome: a model for profiling the emolecular effects of alcohol. Pharmacogenomics J 15:177-88|
|Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2015) Peroxisome proliferator-activated receptors ? and ? are linked with alcohol consumption in mice and withdrawal and dependence in humans. Alcohol Clin Exp Res 39:136-45|
|Robinson, Gizelle; Most, Dana; Ferguson, Laura B et al. (2014) Neuroimmune pathways in alcohol consumption: evidence from behavioral and genetic studies in rodents and humans. Int Rev Neurobiol 118:13-39|
|Bajo, Michal; Madamba, Samuel G; Roberto, Marisa et al. (2014) Innate immune factors modulate ethanol interaction with GABAergic transmission in mouse central amygdala. Brain Behav Immun 40:191-202|
|Trudell, James R; Messing, Robert O; Mayfield, Jody et al. (2014) Alcohol dependence: molecular and behavioral evidence. Trends Pharmacol Sci 35:317-23|
|Ferguson, Laura B; Most, Dana; Blednov, Yuri A et al. (2014) PPAR agonists regulate brain gene expression: relationship to their effects on ethanol consumption. Neuropharmacology 86:397-407|
|Agrawal, Rajiv G; Owen, Julie A; Levin, Patricia S et al. (2014) Bioinformatics analyses reveal age-specific neuroimmune modulation as a target for treatment of high ethanol drinking. Alcohol Clin Exp Res 38:428-37|
|Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2014) Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice. Front Neurosci 8:129|
|Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2014) GABAA receptors containing ?1 subunits contribute to in vivo effects of ethanol in mice. PLoS One 9:e85525|
|Osterndorff-Kahanek, Elizabeth; Ponomarev, Igor; Blednov, Yuri A et al. (2013) Gene expression in brain and liver produced by three different regimens of alcohol consumption in mice: comparison with immune activation. PLoS One 8:e59870|
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