Neuroimmune activation and signaling contribute to increased ethanol drinking and possibly alcoholism. Preclinical studies have shown that ethanol preference and drinking are modulated by neuroimmune gene expression and that cycles of ethanol exposure lead to long-lasting changes in expression of neuroimmune genes, including neuronal Toll-like receptor 3 (TLR3). These are highly relevant findings given that we have shown that TLR3 expression in post-mortem human alcoholic brains correlates with lifetime ethanol consumption. Therefore it is important to understand the interaction between neuroimmune signaling and ethanol drinking, and the impact of neuroimmune activation on neurobiological changes that can drive escalated ethanol drinking. As such, the focus of this application is on the effects of the TLR3 agonist Polyinosinic:polycytidylic acid (Poly(I:C)) on escalations in operant ethanol self-administration (SA), the underlying neuroimmune and glutamatergic changes (specifically in relation to metabotropic glutamate receptor 2/3; mGluR2/3) in the nucleus accumbens (Acb) and insular cortex (IC), and the role of the IC?Acb circuit. As such, the primary hypothesis of this application is that neuroimmune signaling (i.e., TLR3 activation) induces glutamatergic adaptations in the Acb and IC?Acb circuitry that drive escalations in ethanol SA. Experiments in Aim 1 will examine changes in neuroimmune signaling and glutamatergic targets in Acb and IC in ethanol SA trained rats following Poly(I:C)-TLR3 activation, and parallel functional glutamatergic adaptations in the AcbC in collaboration with Component 5. Experiments in Aim 2 will examine the ability of an mGluR2/3 agonist and antagonist to block and potentiate, respectively, the escalation in ethanol SA following TLR3 activation, and the role of Acb mGluR2/3. Experiments in Aim 3 will utilize a chemogenetic approach by the incorporation of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to examine the effects of inhibition and activation of IC?AcbC projections on the escalation in ethanol SA following TLR3 activation. Next, fMRI will be used to assess cortico-accumbal functional connectively as a consequence of ethanol SA history, TLR3 activation, and mGluR2/3 activation in conjunction with the Scientific Core. This proposal tests novel neuroimmune signaling and IC-reward circuits that integrate into, benefit from and contribute to the Alcohol Research Center?s focus on neurocircuit plasticity induced by ethanol. The proposed studies investigate novel mechanisms and circuits associated with the development of alcohol use disorders that could lead to new therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
5P60AA011605-24
Application #
10078816
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
24
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Jaramillo, Anel A; Randall, Patrick A; Stewart, Spencer et al. (2018) Functional role for cortical-striatal circuitry in modulating alcohol self-administration. Neuropharmacology 130:42-53
Vetreno, Ryan P; Lawrimore, Colleen J; Rowsey, Pamela J et al. (2018) Persistent Adult Neuroimmune Activation and Loss of Hippocampal Neurogenesis Following Adolescent Ethanol Exposure: Blockade by Exercise and the Anti-inflammatory Drug Indomethacin. Front Neurosci 12:200
Broadwater, Margaret A; Lee, Sung-Ho; Yu, Yang et al. (2018) Adolescent alcohol exposure decreases frontostriatal resting-state functional connectivity in adulthood. Addict Biol 23:810-823
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

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