Wilcox, T. D. | bioRxiv Science

bioRxiv2025

A shared genetic regulator of metabolism and addiction-related behavior in mice and humans

Substance use disorders and other mental health conditions often co-occur with metabolic disorders, suggesting shared biological underpinnings1. These heightened behavioral and physiological responses may have evolved to promote survival during resource scarcity but can become maladaptive in modern environments2. The genetic mechanisms linking these traits have remained elusive. Here, we show that a variable gene enhancer in mice jointly regulates genes encoding an epigenetic factor (Eed) and a mitochondrial enzyme (Me3) thereby influencing propensity to addiction-related behaviors and mitochondrial function. We further identify variation in a corresponding enhancer in humans regulating EED and ME3 associated with substance use, psychiatric and metabolic disorders. These findings reveal a convergent genetic regulatory network linking mitochondrial biology to behavioral and metabolic risk, offering insight into how genetic variation in beneficial regulatory pathways can predispose individuals to substance use disorders and related conditions.

genetics↗

bioRxiv2025

Behavioral variation across multiple phases of intravenous cocaine self-administration among genetically diverse mouse populations

Genetic and other predisposing factors can influence the progression from initiation of drug intake to compulsive substance use through distinct biobehavioral processes. Operant cocaine self-administration studies in laboratory mice offer a powerful method to dissect the biology of this progression from initiation, dose-response, extinction, and cued reinstatement in a controlled, tractable system. However, many such studies encompass limited genetic diversity and rarely examine self-administration behaviors beyond the acquisition stage. Here, we study three high-diversity mouse populations - 50 strains from the Collaborative Cross (CC) reference panel, a large sample of Diversity Outbred (J:DO) population and their eight founder strains - to characterize the varied phenotypic manifestation of behaviors across multiple phases of cocaine intravenous self-administration (IVSA) in both sexes. We observed distinct strain differences among the founders and CC strains in all phases of self-administration, with heritability estimates ranging from 0 to 0.585 and many CC and J:DO phenotypic values exceeding the range of founders including the C57BL/6J strain. Sex differences were common across behaviors, some manifesting as main effects, others as strain interactions. Finally, by adopting a multi-stage design, we identified extreme strains for various cocaine intake and response traits and evaluated whether these strains exhibited differences in behavioral assays that model compulsive drug seeking. Together, these findings demonstrate the utility of extended self-administration protocols in advanced mouse populations for discovery and characterization of biological mechanisms of substance use traits and for preclinical studies in relevant, complex mouse models.

genetics↗