This ARC proposal tests the hypothesis that repeated ethanol binges (REB) persistently change neuroimmune signaling that alters neuronal activation in frontal cortical (FC), amygdala (Amyg), ventral striatum (VS, nucleus accumbens) and hippocampus (Hip) that contributes to the psychopathology of alcohol dependence. Progress in the previous funding cycle discovered that neuroimmune signals are activated by REB altering behavior consistent with addiction. Breese progress linked ethanol cycles, stressors and/or brain injection of neuroimmune agonists into Amyg with decreased social interaction, an index of negative affect. In parallel. Crews discovered REB induces neuroimmune genes through glial NFKB transcription of chemokines, cytokines, toll-like receptors (TLR) and the TLR agonist HMGB1 that persist for long periods of abstinence and contribute to neurodegeneratlon and reversal learning cognitive deficits. Increased neuroimmune protein expression was also discovered in post-mortem human alcoholic brain. These labs partner within this renewal component. REB induced changes in neuronal activation using cfos and Zif268 markers (Aim 1) will be related to increases in neuroimmune signals (Aim 2) within FC, Amyg, VS and Hip during abstinenece following REB. These brain regions are networked and associated with the persistent alcohol induced arousal that occurs in alcohol dependence. Optogenetics will investigate changes in FC circuits. Naltrexone, minocycline and knock out mice will test causal relationships between neuroimmune induction and altered neuronal activation (Aim 3) as well as addiction related behaviors (Aim 4). These experiments will enhance understanding of the molecular and cellular mechanisms of alcohol induced brain pathology. Ethanol induced neuroimmune activation could become central to the neurobiology of addiction and translate to new treatments. The ARC broadens and strengthens the proposed experiments with additional related studies on binge induced alterations in neurocircuits, addiction-like behaviors and signaling mechanisms.

Public Health Relevance

This proposal investigates a novel neuroimmune signaling system that is hypothesized to contribute to the psychopathology of addiction. Further, drugs that are used to treat addiction, but thought to act through other mechanisms, will be investigated as well as blockers of neuroimmune activation. These studies could discover new mechanisms of action that lead to new therapies for addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
5P60AA011605-17
Application #
8593204
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
17
Fiscal Year
2014
Total Cost
$200,107
Indirect Cost
$68,458
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Broadwater, Margaret A; Lee, Sung-Ho; Yu, Yang et al. (2017) Adolescent alcohol exposure decreases frontostriatal resting-state functional connectivity in adulthood. Addict Biol :
Elton, Amanda; Smith, Christopher T; Parrish, Michael H et al. (2017) COMT Val158Met Polymorphism Exerts Sex-Dependent Effects on fMRI Measures of Brain Function. Front Hum Neurosci 11:578
Guillen-Sacoto, Maria J; Martinez, Ariel F; Abe, Yu et al. (2017) Human germline hedgehog pathway mutations predispose to fatty liver. J Hepatol 67:809-817
Coleman Jr, Leon G; Zou, Jian; Crews, Fulton T (2017) Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. J Neuroinflammation 14:22
Radke, Anna K; Jury, Nicholas J; Kocharian, Adrina et al. (2017) Chronic EtOH effects on putative measures of compulsive behavior in mice. Addict Biol 22:423-434
Crews, Fulton T; Walter, T Jordan; Coleman Jr, Leon G et al. (2017) Toll-like receptor signaling and stages of addiction. Psychopharmacology (Berl) 234:1483-1498
Jaramillo, Anel A; Agan, Verda E; Makhijani, Viren H et al. (2017) Functional role for suppression of the insular-striatal circuit in modulating interoceptive effects of alcohol. Addict Biol :
Bohnsack, John Peyton; Patel, Vraj K; Morrow, A Leslie (2017) Ethanol Exposure Regulates Gabra1 Expression via Histone Deacetylation at the Promoter in Cultured Cortical Neurons. J Pharmacol Exp Ther 363:1-11
Madayag, Aric C; Stringfield, Sierra J; Reissner, Kathryn J et al. (2017) Sex and Adolescent Ethanol Exposure Influence Pavlovian Conditioned Approach. Alcohol Clin Exp Res 41:846-856
Salling, Michael C; Hodge, Christopher J; Psilos, Kelly E et al. (2017) Cue-induced reinstatement of alcohol-seeking behavior is associated with increased CaMKII T286 phosphorylation in the reward pathway of mice. Pharmacol Biochem Behav 163:20-29

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