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
Fiorenza, Amanda M; Shnitko, Tatiana A; Sullivan, Kaitlin M et al. (2018) Ethanol Exposure History and Alcoholic Reward Differentially Alter Dopamine Release in the Nucleus Accumbens to a Reward-Predictive Cue. Alcohol Clin Exp Res 42:1051-1061
Hwa, Lara S; Neira, Sofia; Pina, Melanie M et al. (2018) Predator odor increases avoidance and glutamatergic synaptic transmission in the prelimbic cortex via corticotropin-releasing factor receptor 1 signaling. Neuropsychopharmacology :
Faccidomo, Sara; Swaim, Katarina S; Saunders, Briana L et al. (2018) Mining the nucleus accumbens proteome for novel targets of alcohol self-administration in male C57BL/6J mice. Psychopharmacology (Berl) 235:1681-1696
Bohnsack, John Peyton; Hughes, Benjamin A; O'Buckley, Todd K et al. (2018) Histone deacetylases mediate GABAA receptor expression, physiology, and behavioral maladaptations in rat models of alcohol dependence. Neuropsychopharmacology 43:1518-1529
Coleman Jr, Leon G; Zou, Jian; Qin, Liya et al. (2018) HMGB1/IL-1? complexes regulate neuroimmune responses in alcoholism. Brain Behav Immun 72:61-77
Fish, E W; Wieczorek, L A; Rumple, A et al. (2018) The enduring impact of neurulation stage alcohol exposure: A combined behavioral and structural neuroimaging study in adult male and female C57BL/6J mice. Behav Brain Res 338:173-184
Beattie, Matthew C; Reguyal, Christopher S; Porcu, Patrizia et al. (2018) Neuroactive Steroid (3?,5?)3-hydroxypregnan-20-one (3?,5?-THP) and Pro-inflammatory Cytokine MCP-1 Levels in Hippocampus CA1 are Correlated with Voluntary Ethanol Consumption in Cynomolgus Monkey. Alcohol Clin Exp Res 42:12-20
Mazzone, C M; Pati, D; Michaelides, M et al. (2018) Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. Mol Psychiatry 23:143-153
Coleman Jr, Leon G; Crews, Fulton T (2018) Innate Immune Signaling and Alcohol Use Disorders. Handb Exp Pharmacol 248:369-396
Stringfield, Sierra J; Boettiger, Charlotte A; Robinson, Donita L (2018) Nicotine-enhanced Pavlovian conditioned approach is resistant to omission of expected outcome. Behav Brain Res 343:16-20

Showing the most recent 10 out of 227 publications