Gut microbiota signatures of vulnerability to food addiction in mice and humans.

OBJECTIVE: Food addiction is a multifactorial disorder characterised by a loss of control over food intake that may promote obesity and alter gut microbiota composition. We have investigated the potential involvement of the gut microbiota in the mechanisms underlying food addiction. DESIGN: We used the Yale Food Addiction Scale (YFAS) 2.0 criteria to classify extreme food addiction in mouse and human subpopulations to identify gut microbiota signatures associated with vulnerability to this disorder. RESULTS: Both animal and human cohorts showed important similarities in the gut microbiota signatures linked to food addiction. The signatures suggested possible non-beneficial effects of bacteria belonging to the Proteobacteria phylum and potential protective effects of Actinobacteria against the development of food addiction in both cohorts of humans and mice. A decreased relative abundance of the species Blautia wexlerae was observed in addicted humans and of Blautia genus in addicted mice. Administration of the non-digestible carbohydrates, lactulose and rhamnose, known to favour Blautia growth, led to increased relative abundance of Blautia in mice faeces in parallel with dramatic improvements in food addiction. A similar improvement was revealed after oral administration of Blautia wexlerae as a beneficial microbe. CONCLUSION: By understanding the crosstalk between this behavioural alteration and gut microbiota, these findings constitute a step forward to future treatments for food addiction and related eating disorders.

Differential expression of miR-1249-3p and miR-34b-5p between vulnerable and resilient phenotypes of cocaine addiction.

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.

Genomics and epigenomics of addiction.

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.

miRNA signatures associated with vulnerability to food addiction in mice and humans.

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.

Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons drives overconsumption of palatable food and obesity.

Palatable food can promote overfeeding beyond homeostatic requirements, thereby constituting a major risk to obesity. Here, the lack of cannabinoid type 1 receptor (CB1) in dorsal telencephalic glutamatergic neurons (Glu-CB1-KO) abrogated the overconsumption of palatable food and the development of obesity. On low-fat diet, no genotype differences were observed. However, under palatable food conditions, Glu-CB1-KO mice showed decreased body weight and food intake. Notably, Glu-CB1-KO mice were protected from alterations in the reward system after high-fat diet feeding. Interestingly, obese wild-type mice showed a superior olfactory detection as compared to mutant mice, suggesting a link between overconsumption of palatable food and olfactory function. Reconstitution of CB1 expression in olfactory cortex in high-fat diet-fed Glu-CB1-KO mice using viral gene delivery partially reversed the lean phenotype concomitantly with improved odor perception. These findings indicate that CB1 in cortical glutamatergic neurons regulates hedonic feeding, whereby a critical role of the olfactory cortex was uncovered as an underlying mechanism.

An Operant Conditioning Model Combined with a Chemogenetic Approach to Study the Neurobiology of Food Addiction in Mice.

The study of food addiction comprises 3 hallmarks that include the persistence to response without an outcome, the strong motivation for palatable food, and the loss of inhibitory control over food intake that leads to compulsive behavior in addicted individuals. The complex multifactorial nature of this disorder and the unknown neurobiological mechanistic correlation explains the lack of effective treatments. Our operant conditioning model allows deciphering why some individuals are vulnerable and develop food addiction while others are resilient and do not. It is a translational approach since it is based on the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) and the Yale Food Addiction Scale (YFAS 2.0). This model allows to evaluate the addiction criteria in 2 time-points at an early and a late period by grouping them into 1) persistence to response during a period of non-availability of food, 2) motivation for food with a progressive ratio, and 3) compulsivity when the reward is associated with a punishment such as an electric foot-shock. The advantage of this model is that it allows us to measure 4 phenotypic traits suggested as predisposing factors related to vulnerability to addiction. Also, it is possible to evaluate the long food addiction mouse model with mice genetically modified. Importantly, the novelty of this protocol is the adaptation of this food addiction model to a short protocol to evaluate genetic manipulations targeting specific brain circuitries by using a chemogenetic approach that could promote the rapid development of this addictive behavior. These adaptations lead to a short food addiction mouse protocol, in which mice follow the same behavioral procedure of the early period in the long food addiction protocol with some variations due to the surgical viral vector injection. To our knowledge, there is no paradigm in mice allowing us to study the combination of such a robust behavioral approach that allows uncovering the neurobiology of food addiction at the brain circuit level. We can study using this protocol if modifying the excitability of a specific brain network confers resilience or vulnerability to developing food addiction. Understanding these neurobiological mechanisms is expected to help to find novel and efficient interventions to battle food addiction.

A specific prelimbic-nucleus accumbens pathway controls resilience versus vulnerability to food addiction.

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.