Food addiction, characterized by loss of behavioral control and compulsive food intake, is linked to obesity and eating disorders. While its existence is debated, its prevalence and socio-economic costs are significant. This study investigates the neurobiological mechanisms underlying vulnerability and resilience to food addiction, a disorder sharing neurobiological mechanisms with drug addiction. Both involve the brain's reward circuit, particularly dopamine release in the nucleus accumbens (NAc). However, addiction progresses from initial hedonic intake to loss of control, necessitating long-lasting reward system adaptations. Three major networks (basal ganglia, extended amygdala, and medial prefrontal cortex (mPFC)) are implicated. The mPFC, crucial for cognitive flexibility, decision-making, and inhibitory control, shows hypoactivity in human and rodent addiction models. Within the mPFC, the prelimbic (PL) and infralimbic (IL) cortices project to the NAc, influencing behavioral inhibitory control. This study aims to decipher the neurobiological mechanisms underpinning resilience and vulnerability to food addiction using a validated mouse model, incorporating genetic manipulations, electrophysiology, transcriptomics, and chemogenetic techniques to examine genetic, cellular, circuit, and behavioral levels.

Existing literature highlights the increasing prevalence of food addiction and its association with obesity and eating disorders. The neurobiological mechanisms overlap significantly with drug addiction, both involving the brain's reward circuitry and adaptations to repeated exposure to reinforcers. Studies indicate a crucial role for the mPFC in top-down control of behavior, with hypoactivity observed in addiction. While animal models have been used to study food addiction, the precise neurobiological mechanisms at the circuit and molecular levels remain unclear. This study builds upon previous research by investigating specific pathways and molecular mechanisms within the mPFC-NAc circuitry.

The study utilized a validated mouse operant food addiction model. Conditional glutamatergic CB1R mutant mice (Glu-CB1-KO) and their wild-type (WT) littermates were trained to self-administer chocolate-flavored pellets under varying schedules of reinforcement (FR1 and FR5). Three addiction-like criteria were assessed: persistence to response (non-reinforced responses during pellet-free periods), motivation (breaking point during progressive ratio schedule), and compulsivity (responses despite aversive consequences). Ex vivo electrophysiological recordings were conducted to examine synaptic transmission in the mPFC and NAc. Transcriptomic analysis (RNA sequencing) compared gene expression profiles in the mPFC of addicted and non-addicted mice. Chemogenetic techniques were employed to inhibit activity in the mPFC-NAc pathway, specifically targeting PL neurons projecting to the NAc core, using a combined chemogenetic and retrograde AAV approach. Finally, viral-mediated overexpression of the dopamine D2 receptor (D2R) in the PL-NAc core projection was used to investigate its role in compulsive eating behavior. Statistical analyses included t-tests, Mann-Whitney U tests, ANOVA, and Pearson correlation.

Glu-CB1-KO mice showed resilience to food addiction, with a significantly lower percentage of mice meeting addiction criteria compared to WT mice. This resilience was correlated with increased excitatory synaptic transmission in the PL and NAc. Chemogenetic inhibition of the PL-NAc core pathway in WT mice induced compulsive eating, while overexpression of D2R in this pathway also promoted compulsivity. Transcriptomic analysis revealed upregulation of Drd2 (dopamine receptor type 2) in the mPFC of addicted mice, independent of genotype. Furthermore, the increased compulsivity observed after D2R overexpression was associated with decreased excitability of PL-NAc core projection neurons, resulting in reduced glutamatergic transmission to the NAc core.

This study provides evidence for a critical role of the glutamatergic PL-NAc core pathway in regulating resilience and vulnerability to food addiction. The increased activity of this pathway, modulated by CB1R and D2R signaling, contributes to resilience. The findings extend previous research by identifying specific pathways and molecular mechanisms within this circuitry. The upregulation of Drd2 in the mPFC of addicted mice suggests a novel mechanism contributing to the loss of inhibitory control over food intake. The results highlight the complex interplay between endocannabinoid and dopaminergic systems in regulating this behavior. The transdiagnostic nature of compulsive behaviors suggests that these findings may be relevant to other psychiatric disorders.

This research identifies the glutamatergic PL-NAc core pathway, modulated by CB1R and D2R, as a key mechanism in the control of food seeking and consumption. Increased activity in this pathway promotes resilience, while decreased activity and D2R upregulation contribute to vulnerability. The findings provide new mechanistic insights into food addiction and offer potential targets for preventive interventions. Further research should explore the role of other PL projections and the interaction of D1R in this pathway.

The study primarily utilized a mouse model, which may not fully capture the complexity of human food addiction. The specific manipulation of the PL-NAc core pathway may not encompass the full influence of the mPFC in this behavior. Additionally, the study focuses on specific molecular targets, and other contributing factors remain to be fully investigated.