Alcoholism is a progressive disorder with detrimental consequences for both the affected individual and society as a whole. Transition into compulsive alcohol use is hypothesized to occur due to alcohol-induced adaptations with in several neural circuits, including the corticotropin-releasing factor (CRF) system, a network of neuropeptide ligands and receptors that orchestrate the stress response. Although previous literature has implicated the CRF system in excessive ethanol (EtOH) intake, the complexity of the CRF system and its multiple ligands and receptors has limite understanding of this process. One such ligand, Urocortin1 (Ucn-1), is known to bind to both CRF-1 and CRF-2 receptors with a higher affinity than CRF itself. In light of this, our lab has provided converging lines of evidence highlighting the contribution of Ucn-1 in excessiv ethanol (EtOH) consumption and sensitivity. In fact, it has been determined that the primary source for Ucn1, the """"""""centrally projecting Edinger Westphal nucleus"""""""" (EWcp) is the only region that, across multiple strains and species of rodents, shows consistently enhanced c-Fos expression following oral self-administration of alcohol. In further support of this notion, electrolytic lesions of the EWcp and genetic deletion of Ucn1 attenuates EtOH consumption. Additionally, genetic deletion of CRF-2 receptors or Ucn-1 attenuates the conditioned rewarding effects of EtOH. These findings clearly indicate that EWcp-Ucn1 neurons contribute to alcohol consumption, however these strategies (lesion and global knockout) have caveats that can be avoided with more precise techniques. Thus, the goal of the current proposal is to utilize in vivo electrophysiology and pharmacosynthetic technology to characterize the role of EWcp-Ucn1 neurons in alcohol self-administration and reward. Based on previous data and my own preliminary research, I hypothesize that alcohol activates EWcp neurons, which in turn promotes alcohol consumption and conditioned reward.

Public Health Relevance

Alcohol use disorders represent a pervasive problem with enormous costs to the individual and society as a whole. Transition to alcoholism is dependent upon dysregulation within stress related neurocircuitry. The proposed work seeks to further elucidate the involvement of a particular neural stress system in animal models of alcohol drinking and reward.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Predoctoral Individual National Research Service Award (F31)
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Biomedical Research Review Subcommittee (AA)
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Liu, Qi-Ying
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Oregon Health and Science University
Other Basic Sciences
Schools of Medicine
United States
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