Alp M. Ummet ¹, Trudy F. C. Mackay¹, Robert R. H. Anholt¹

Previous studies revealed natural genetic variation in cocaine consumption and preference among the wild-derived, inbred lines of the Drosophila Genetic Reference Panel and implicated the mushroom bodies, brain structures that mediate experience-dependent behavior (Highfill et al., PLoS Genet. (2019) 15, e1007834). Previous studies also showed correlations between variation in mushroom body structure and behavior such as aggression and sleep. (Zwarts et al., Nat. Commun. (2015) 6, 10115). To assess whether variation in mushroom body morphology is correlated with variation in cocaine preference, we conducted an initial study by selecting six DGRP lines, three cocaine-preferring lines in which at least one sex showed preference for a cocaine-supplemented sucrose solution over control solution and three lines with mean aversion scores for cocaine preference. We dissected brains and stained mushroom bodies from males and females separately with an anti-fasciclin-II antibody. We quantified three-dimensional morphometrics of the alpha and beta lobes by confocal microscopy. We also observed the absence of lobes, bilateral asymmetry, and anatomical abnormalities. Our initial studies showed variation in mushroom body morphology and suggested a correlation of cocaine preference with alpha lobe structure and asymmetry. To consolidate these observations with statistical significance, we will expand this initial study to a larger sample of 48 lines. Based on evolutionary conservation of fundamental biological processes, correlations between variation in mushroom body morphology and cocaine preference in the fly brain raise the possibility that subtle variations in neural circuitry in the human brain could contribute to risk for cocaine use disorder.

1 Institute for Human Genetics, Department of Genetics and Biochemistry, Clemson University, Greenwood SC, USA.

Funding Support: Supported by grant DA041613 from the National Institute on Drug Abuse (NIDA) to TFC Mackay and RRH Anholt.