Neuro-molecular Mechanisms Underlying a Switch in Memory Valence
We are using a simple model to investigate the neural and molecular mechanisms underlying aversive and appetitive alcohol memories. Alcohol is among the most widely used and abused drugs in the world. Few effective treatment options exist for alcohol-use disorders. It is imperative that we investigate how alcohol affects the brain so we can identify and understand the genetic and molecular factors that affect alcoholism, and use this information to develop better pharmacological therapies. The fruit fly Drosophila melanogaster is an ideal model system to investigate the neural and molecular substrates underlying alcoholism. These animals are similar to mammals in alcohol responses and memories, and a broad spectrum of genetic, and molecular tools are available to manipulate behavior in vivo. The current genetic tools available in the fly make it the only animal model with the resolution to investigate alcohol memories in live, behaving animals at the molecular, single-neuron, and individual circuit levels. We have identified a simple circuit underlying a switch from aversive to appetitive alcohol memory and identified a role for the Notch signaling pathway in mediating the switch in this circuit. We are elucidating how this circuit functions to result in this switch, and identifying transcriptional targets of Notch that underlies the neuronal plasticity required for this switch. This research provides an important step towards a functional understanding of the mechanisms underlying memory for alcohol intoxication associated with alcohol cravings.