PROJECT SUMMARY 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.