From Genes to Neural Circuits: Genetic and Systems Mechanisms of Ethanol Sensitivity and Tolerance in Drosophila melanogaster

BMB Rep. 2026 Oct 21:6959. Online ahead of print.

ABSTRACT

Alcohol use disorder (AUD) is a complex neuropsychiatric disease shaped by genetic, environmental, and physiological factors. Over four decades, Drosophila melanogaster has emerged as a powerful model for dissecting the molecular and neural mechanisms underlying ethanol sensitivity, tolerance, preference, and consumption. Its conserved signaling pathways, sophisticated genetic toolkit, and robust behavioral assays have enabled discovery of genes and neural circuits governing alcohol responses across biological levels. This review summarizes major advances in the genetics and neurobiology of ethanol-related behaviors in Drosophila. Forward genetic screens identified conserved regulators of ethanol sensitivity and tolerance, including cAMP/PKA signaling components, ion channels, neurotransmitter receptors, cytoskeletal regulators, and neuropeptide pathways. Subsequent studies revealed distinct roles for the ellipsoid body, mushroom bodies, circadian neurons, and barrier glia in intoxication, tolerance, and reward. Epigenetic studies further established chromatin remodeling and transcriptional regulation as mechanisms of long-term behavioral plasticity, while systems genetics and genome-wide association studies highlighted the polygenic basis of natural variation in alcohol-related traits. Together, these findings advance an integrated view of ethanol action and provide a framework for understanding human AUD. Emerging approaches include single-cell and connectomics analyses, functional testing of human variants, and integration of systems genetics with circuit neuroscience.

PMID:42902570