Exploring the Link between Hedonic Overeating and Prefrontal Cortex Dysfunction in the Ts65Dn Trisomic Mouse Model

Abstract

Abstract Individuals with Down syndrome (DS) have a higher prevalence of obesity compared to the general population. Conventionally, this has been attributed to endocrine issues and lack of exercise. However, recent research suggests that deficits in neural reward responses and dopaminergic disturbances in DS may be contributing factors. To investigate further, we focused on a mouse model (Ts65Dn) bearing some triplicated genes homologous to trisomy 21. Through detailed meal pattern analysis in Ts65Dn mice, we observed an increased preference for energy-dense food, pointing towards a potential "hedonic" overeating behavior. Moreover, trisomic mice exhibited higher scores in compulsivity and inflexibility tests when limited access to energy-dense food and quinine hydrochloride adulteration were introduced, compared to euploid controls. Interestingly, when we activated prelimbic-to-nucleus accumbens projections in Ts65Dn mice using a chemogenetic approach, impulsive and compulsive behaviors significantly decreased, shedding light on a promising intervention avenue. Our findings uncover a novel mechanism behind the vulnerability to overeating and offer potential new pathways for tackling obesity through innovative interventions. However, it is important to acknowledge that the observed phenotype in Ts65Dn mice may be influenced by the presence of triplicated non-HSA21 genes, which is a limitation worth considering for future investigations.