This is a renewal application to the P60-Portland Alcohol Research Center (PARC). In the past funding period we added key knowledge to our understanding of the predictive nature of corticostriatal circuitry and cognitive flexibility in mediating risk for chronic heavy alcohol drinking in rhesus monkeys. The monkey model has also provided evidence that chronic heavy drinking results in synaptic remodeling and an imbalance in striatal output towards glutamatergic excitatory tone[1,2]. Finally, genomic data from the PFC and the nucleus accumbens of heavy drinking monkeys (preliminary data) point to the extracellular matrix (ECM) component of the ?tetrapartite synapse?[3] in mediating excessive alcohol drinking and impaired cognitive flexible behavior. A main constituent of the ECM related to synaptic function is the glycosaminoglycan Hyaluronic Acid (HA)[4,5]. Data supporting the importance of HA to the function of ECM in synaptic plasticity is expanding rapidly[6]. To our knowledge, there are no studies that directly link ethanol-associated changes in HA synthesis and metabolism to altered synaptic plasticity. Nevertheless, our preliminary data show that ethanol leads to altered expression of hyaluronidases, HA synthases and HA-binding proteins in support of the hypothesis that heavy alcohol drinking alters HA metabolism in synaptic ECM and perineuronal nets (PNNs) to alter striatal neuronal activity. Thus, this proposal seeks to provide pivotal information on HA as a target for ethanol-induced adaptations to Medium Spiny Neurons (MSNs), the projection neurons of the striatum. To determine the effect of chronic drinking on HA composition and subsequent alterations in striatal MSN synaptic plasticity, we propose a combination of molecular, histological and electrophysiological techniques. These findings will then be placed into a larger framework of functional measures of corticostriatal circuitry involved in chronic heavy alcohol drinking as mapped by fMRI (monkeys) and cognitive flexibility (mice and monkeys). We posit that this circuitry, particularly corticostriatal loops conveying sensory-motor information, are involved in both the risk for heavy alcohol drinking as well as the propagation of heavy drinking once it is established. We will use the proposed research PARC cores and integrate these findings with the PARC projects to gain a deeper understanding of other ECM constituents in chronic alcohol drinking. Overall, if successful, this project will provide critical information establishing a link between HA-ECM content and ethanol-associated synaptic adaptations within the sensorimotor corticostriatal circuitry that promote habitual (inflexible) behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
2P60AA010760-26
Application #
10056069
Study Section
Special Emphasis Panel (ZAA1)
Project Start
1996-12-01
Project End
2025-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
26
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Iancu, Ovidiu D; Colville, Alexander; Walter, Nicole A R et al. (2018) On the relationships in rhesus macaques between chronic ethanol consumption and the brain transcriptome. Addict Biol 23:196-205
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Gavin, David P; Hashimoto, Joel G; Lazar, Nathan H et al. (2018) Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure. Front Genet 9:346
Purohit, Kush; Parekh, Puja K; Kern, Joseph et al. (2018) Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge-Like Alcohol Drinking in Mice. Alcohol Clin Exp Res 42:879-888
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Iancu, Ovidiu Dan; Colville, Alex M; Wilmot, Beth et al. (2018) Gender-Specific Effects of Selection for Drinking in the Dark on the Network Roles of Coding and Noncoding RNAs. Alcohol Clin Exp Res :
Kafkafi, Neri; Agassi, Joseph; Chesler, Elissa J et al. (2018) Reproducibility and replicability of rodent phenotyping in preclinical studies. Neurosci Biobehav Rev 87:218-232
Qiu, J; Wagner, E J; Rønnekleiv, O K et al. (2018) Insulin and leptin excite anorexigenic pro-opiomelanocortin neurones via activation of TRPC5 channels. J Neuroendocrinol 30:

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