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Scaplen K1, Feyder M1, Ledru N1, Petruccelli E1, Kaun KR1

1Brown University, Providence, RI, USA

Dopamine is central to encoding memories of the intoxicating effects of alcohol. However, due to the complexity and heterogeneity of dopamine circuits in the mammalian brain the precise circuit mechanisms through which dopamine encodes and predicts alcohol reward are not well elucidated. Dopaminergic circuitry in the fruit fly, Drosophila melanogaster, is definable at the single neuron level and shares general features of dopamine reward circuitry in mammals. Thus the fruit fly offers a detailed anatomical framework for understanding how alcohol intoxication experiences are encoded and remembered as rewarding. We have previously shown that flies readily associate an odor cue with alcohol intoxication, and this association is dependent on dopamine signaling. We sought to understand the precise circuit mechanisms by which dopamine encodes and predicts alcohol reward. We found that encoding alcohol memories requires activity of a large population of dopamine neurons, but expressing these memories requires only a subset of these neurons. Further, we identified a glutamatergic feedback loop required for re-activation of this subset of dopamine neurons during memory expression. This circuit explains how a sensory cue activates dopamine neurons that predict reward. To understand how alcohol affects plasticity within this circuit, we identified a molecular signaling pathway through which alcohol regulates transcription of D2 receptors. Together, this work reveals a highly conserved neuro-molecular mechanism that clarifies how alcohol cravings differ from other forms of appetitive memories.