Genetic and microbiome control of addiction-like behaviors in mice

The National Institute on Drug Abuse awarded the Jackson Laboratory a $805,077 cooperative agreement on June 1, 2026, under the Drug Use and Addiction Research Programs (CFDA 93.279) to investigate genetic and microbiome control of addiction-like behaviors in mice, with performance extending through March 31, 2031.

The recipient will conduct basic research modeling cocaine use disorder through genetically diverse mouse populations, using advanced metagenomic whole genome shotgun sequencing and untargeted metabolomics to characterize the gut-brain axis and its influence on addiction-related behaviors. Research activities include behavioral assays to assess novelty-seeking, anxiety, and cocaine sensitization; microbiome and metabolomics analyses to identify genetic loci associated with these behaviors; and experimental validation involving gene editing, microbiome or metabolite interventions, and fecal transplants. The study aims to identify specific microbes and metabolites that modulate addiction-related behaviors and to construct multi-omics causal networks linking genetic, microbial, and neural data to establish causation rather than association. Expected outcomes include mapping quantitative trait loci for microbial abundance and behaviors and developing predictive biomarkers and therapeutic approaches for cocaine use disorder.

Place of performance is Bar Harbor, Maine. The Jackson Laboratory passes work to two sub-recipients. Arizona State University, under Dr. Haiwei Gu, performs metabolomics measurements on blood, tissue, and fecal samples using liquid chromatography-mass spectrometry analysis (sub-award awarded September 1, 2026). University of Connecticut Health Center, under Dr. Zhou, conducts microbiome sequencing, data analysis and interpretation, and microbial culture, contributes to study design and experimental planning, and participates in manuscript preparation and conference presentations (sub-award awarded August 31, 2026).

Abstract

The research proposal addresses the urgent need for predictive biomarkers and pharmacological treatments for cocaine use disorder (CUD), a highly heritable disease affecting millions worldwide. Despite advances in understanding the genetic, cellular, and circuit mechanisms of CUD, effective treatments remain elusive. The proposal highlights the GUT microbiome as a significant behavioral modifier, influencing brain function and behavior through metabolites like short-chain fatty acids (scfas). Recent studies suggest that the GUT microbiome can impact addiction-related behaviors, making IT a promising target for novel therapeutic approaches. The study proposes a paradigm shift from traditional brain-centric addiction research to a focus on the GUT-brain axis. Advanced techniques such as metagenomic whole genome shotgun sequencing (mwgs) and untargeted metabolomics will be used to gain functional insights into the microbiome. The approach involves using genetically diverse mouse populations to model addiction-related behaviors and study the GUT-brain axis. Behavioral assays will assess novelty-seeking, anxiety, and cocaine sensitization, while microbiome and metabolomics analyses will identify genetic loci associated with these behaviors. The proposal emphasizes the integration of genetic, microbial, and neural data to construct multi-omics causal networks, advancing beyond associations to establish causation. Experimental validation will involve gene editing, microbiome or metabolite interventions, and fecal transplants to confirm findings and assess their translational potential. The study aims to identify specific microbes and metabolites that can modulate addiction- related behaviors, ultimately developing predictive biomarkers and therapeutic approaches for CUD. Expected outcomes include mapping quantitative trait loci (qtls) for microbial abundance and behaviors, constructing causal networks, and identifying behavioral modifiers. The research will leverage extensive pre- existing datasets and generate new data to uncover novel molecular mechanisms in addiction. The findings will be made publicly available, facilitating further research and potential clinical applications. This comprehensive approach aims to significantly advance the field of addiction research and contribute to the development of effective treatments for CUD.