Repeated binge alcohol drinking is a major public health problem and is thought to lead to pathophysiological alterations in brain circuitry that contribute to alcohol dependence and addiction. While complex behaviors such as ethanol consumption are likely controlled by a distributed, interconnected network of brain nuclei, corticotropin releasing factor (CRF) producing neurons within the central nucleus of the amygdala (CeA) are thought to play a crucial role in progressively driving pathological ethanol consumption. The CeA is composed of numerous neurochemically distinct neurons, and therefore determining how endogenous CRF signaling modulates neural circuits via their functional connectivity with postsynaptic targets has proven difficult due to technical limitations in evaluating specific long-range synaptic projections. To circumvent this, we propose to use optogenetic techniques coupled with brain slice electrophysiology and behavioral assays to examine the properties of CRF neuronal circuits in the extended amygdala and to determine whether activation or inhibition of CRF containing neural circuit elements can alter binge ethanol intake. We hypothesize that CRF producing neurons within the CeA project to the bed nucleus of the stria terminalis (BNST), and that activation of this pathway will be enhanced and required for repeated binge ethanol intake. We will test this hypothesis using a multi-disiclplinary approach combining both in vivo and ex vivo analysis of function. In total, the proposed research will provide essential information concerning the role that the CRF projection from the CeA to the BNST plays in binge ethanol drinking.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
5P60AA011605-17
Application #
8593211
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
$203,150
Indirect Cost
$69,499
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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