Circuit and molecular mechanisms through which alcohol influences natural reward

About This Grant

PROJECT SUMMARY: Alcohol acts on the brain’s natural reward circuits and has a multifaceted influence on food reward circuits. Consumption of alcohol primes the release of dopamine and can alter the physiology of the reward system, profoundly affecting circuit homeostasis, plasticity and function. This results in aberrant reward encoding, leading to aberrant value-based choices and maladaptive behavior. However, the heterogeneity of the mammalian reward system makes targeting distinct subpopulations of cells difficult, which has precluded a detailed understanding of how reward is encoded. The reduced numerical complexity of the Drosophila reward/dopaminergic system provides a tractable alternative to study cellular resolution mechanisms of reward memory and reward seeking. Like mammalian mesolimbic dopamine neurons, reward-encoding dopaminergic neurons that innervate the Drosophila mushroom body are diverse in molecular composition, neural connectivity and function. Moreover, we have shown that dopaminergic activation of the mushroom bodies underlies that rewarding effects of alcohol in flies. This provides an ideal functional framework for investigating the cellular and molecular mechanisms through which rewards with different values, such as sugar and alcohol, are encoded and how they interact. This work will reveal mechanisms through which relative reward value is encoded and how alcohol influences reward circuit function to elicit unconstrained reward seeking. Although we all have an intuitive understanding of what is very rewarding, and what is less rewarding, our memories of reward change with experience. Our first goal is to understand how absolute and relative sugar rewards are encoded in a dopaminergic memory circuit. Our second goal is to understand the mechanisms through which alcohol is weighted relative to sugar, and how prior experience with alcohol alters how sugar reward is encoded. Our third goal is to identify the molecular mechanisms through which alcohol can alter sugar motivation by addressing how alcohol-induced alternative splicing impacts sucrose response and encoding. Overall, this research will identify causal physiological and molecular mechanisms through which alcohol influences the formation and expression of reward memory.