Food addiction is linked to obesity and eating disorders and is characterized by a loss of behavioral control and compulsive food intake. Here, using a food addiction mouse model, we report that the lack of cannabinoid type-1 receptor in dorsal telencephalic glutamatergic neurons prevents the development of food addiction-like behavior, which is associated with enhanced synaptic excitatory transmission in the medial prefrontal cortex (mPFC) and in the nucleus accumbens (NAc). In contrast, chemogenetic inhibition of neuronal activity in the mPFC-NAc pathway induces compulsive food seeking. Transcriptomic analysis and genetic manipulation identified that increased dopamine D2 receptor expression in the mPFC-NAc pathway promotes the addiction-like phenotype. Our study unravels a new neurobiological mechanism underlying resilience and vulnerability to the development of food addiction, which could pave the way towards novel and efficient interventions for this disorder.

Recent progress in the genomics and epigenomics of addiction has contributed to improving our understanding of this complex mental disorder's etiology, filling the gap between genes, environment, and behavior. We review the behavioral genetic studies reporting gene and environment interactions that explain the polygenetic contribution to the resilience and vulnerability to develop addiction. We discuss the evidence of polymorphic candidate genes that confer susceptibility to develop addiction as well as the studies of specific epigenetic marks that contribute to vulnerability and resilience to addictive-like behavior. A particular emphasis has been devoted to the miRNA changes that are considered potential biomarkers. The increasing knowledge about the technology required to alter miRNA expression may provide promising novel therapeutic tools. Finally, we give future directions for the field's progress in disentangling the connection between genes, environment, and behavior.

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Cocaine addiction is a complex brain disorder involving long‐term alterations that lead to loss of control over drug seeking. The transition from recreational use to pathological consumption is different in each individual, depending on the interaction between environmental and genetic factors. Epigenetic mechanisms are ideal candidates to study psychiatric disorders triggered by these interactions, maintaining persistent malfunctions in specific brain regions. Here we aim to study brain‐region‐specific epigenetic signatures following exposure to cocaine in a mouse model of addiction to this drug. Extreme subpopulations of vulnerable and resilient phenotypes were selected to identify miRNA signatures for differential vulnerability to cocaine addiction. We used an operant model of intravenous cocaine self‐administration to evaluate addictive‐like behaviour in rodents based on the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition criteria to diagnose substance use disorders. After cocaine self‐administration, we performed miRNA profiling to compare two extreme subpopulations of mice classified as resilient and vulnerable to cocaine addiction. We found that mmu‐miR‐34b‐5p was downregulated in the nucleus accumbens of vulnerable mice with high motivation for cocaine. On the other hand, mmu‐miR‐1249‐3p was downregulated on vulnerable mice with high levels of motor disinhibition. The elucidation of the epigenetic profile related to vulnerability to cocaine addiction is expected to help find novel biomarkers that could facilitate the interventions to battle this devastating disorder.

Food addiction is characterized by a loss of behavioral control over food intake and is associated with obesity and other eating disorders. The mechanisms underlying this behavioral disorder are largely unknown. We aimed to investigate the changes in miRNA expression promoted by food addiction in animals and humans and their involvement in the mechanisms underlying the behavioral hallmarks of this disorder. We found sharp similitudes between miRNA signatures in the medial prefrontal cortex (mPFC) of our animal cohort and circulating miRNA levels in our human cohort, which allowed us to identify several miRNAs of potential interest in the development of this disorder. Tough decoy (TuD) inhibition of miRNA-29c-3p in the mouse mPFC promoted persistence of the response and enhanced vulnerability to developing food addiction, whereas miRNA-665-3p inhibition promoted compulsion-like behavior and also enhanced food addiction vulnerability. In contrast, we found that miRNA-137-3p inhibition in the mPFC did not lead to the development of food addiction. Therefore, miRNA-29c-3p and miRNA-665-3p could be acting as protective factors with regard to food addiction. We believe the elucidation of these epigenetic mechanisms will lead to advances toward identifying innovative biomarkers and possible future interventions for food addiction and related disorders based on the strategies now available to modify miRNA activity and expression.