Drosophila learning and memory centers and the actions of drugs of abuse

Abstract

Drug addiction and the circuitry for learning and memory are intimately intertwined. Drugs of abuse create strong, inappropriate, and lasting memories that contribute to many of their destructive properties, such as continued use despite negative consequences and exceptionally high rates of relapse. Studies in Drosophila melanogaster are helping us understand how drugs of abuse, especially alcohol, create memories at the level of individual neurons and in the circuits where they function. Drosophila is a premier organism for identifying the mechanisms of learning and memory. Drosophila also respond to drugs of abuse in ways that remarkably parallel humans and rodent models. An emerging consensus is that, for alcohol, the mushroom bodies participate in the circuits that control acute drug sensitivity, not explicitly associative forms of plasticity such as tolerance, and classical associative memories of their rewarding and aversive properties. Moreover, it is becoming clear that drugs of abuse use the mushroom body circuitry differently from other behaviors, potentially providing a basis for their addictive properties.

Figure 1.

Circuit and genetic functions of the mushroom body Kenyon cell–intrinsic neurons for the actions of drugs of abuse. The functions of mushroom body inputs and outputs (dopamine neurons, APL, DPM, and MBON output neurons) are detailed in the text of this review.

Figure 2.

Mushroom body circuitry for alcohol-associative preference. (A) Diagram of the mushroom bodies, depicting the vertical (α′, α) and horizontal (β′, β, γ) lobe Kenyon cells, overlayed with the compartments that are defined by dopaminergic input neurons and mushroom body output neurons (MBONs). The PAM dopaminergic input neurons are required for the acquisition of alcohol-associative preference and innervate the horizontal lobes in a precise pattern. (B) PAM dopaminergic inputs and MBON outputs are important for the retrieval of alcohol-associative preference memories. Inset depicts a possible site of action for the dopamine D2 receptor D2R. Highlighted in green are the Kenyon cells that support acquisition and retrieval. The α′/β′ neurons support consolidation. The diagrams are adapted, with permission, from Scaplen et al. (2020).