Investigator: Karla Kaun, Brown University

Mentor: Anne Hart, Brown University

Scientific Theme: Neuroscience

Abstract: Despite alcohol being one of the most used and abused drugs in the world, the molecular mechanisms underlying alcohol abuse disorders remain largely unknown. Recent studies in both flies and mammals suggest that signaling pathways that play a large role in development have a secondary role in alcohol induced behaviors in the adult. Our recent genetic screen for alcohol reward memory in Drosophila melanogaster strongly suggests a role for the Notch signaling pathway. Notch signaling is one of the best examples of the brain employing an evolutionarily conserved developmental pathway to regulate higher cognitive function. Drosophila is an ideal model to study this because genetic tools available make it possible to restrict manipulations of Notch expression to small subsets of neurons within the adult brain. The goal of this proposal research is to understand the mechanism by which the Notch affects memory for alcohol reward in the adult brain. We will do this by defining the specific subset of neurons in the adult brain Notch acts in to affect alcohol reward memory. Then, we will identify genes that are the direct targets of Notch within these neurons. The remarkable conservation of Notch signaling between flies and mammals at the molecular level suggests that the findings of this study may be directly applicable to understanding molecular mechanisms underlying human alcohol use disorders (AUDs). If the proposed aims are achieved, they will provide the first direct evidence for a role for Notch signaling in development of addiction. They will also identify genes that are direct targets of Notch, which can both provide candidate genes for the genetics of AUDs in humans, and suggest potential targets for pharmacotherapy.

Human Health Relevance: Alcoholism is a devastating disease, affecting 18 million people in the United States, with few effective treatment options. We use sophisticated neurogenetic tools available in the fruit fly to understand the molecular mechanisms of alcoholism. This will lead to a deeper understanding of the genetic underpinnings of alcoholism and may lead to identification of novel pharmacotherapies for alcohol use disorders.