HYPOTHALAMIC ENSEMBLES DRIVING MALADAPTIVE BEHAVIOUR IN AN ANOREXIA MOUSE MODEL

Anorexia nervosa (AN) is an eating disorder characterized by fear of weight gain, body image disturbance, low body weight, and hyperactivity. Its mortality rate among adolescents exceeds that of any other mental disorder. Due to lack of mechanisms there are no biology-based therapies. As AN is a metabotropic-psychiatric disorder, we hypothesized that neurons affected by changes in energy balance related to AN will reveal potential targets for novel therapies.
In this study, we used TRAP2 mice, in which 2A-iCreER^T2 is knocked into the Fos locus to enable cue-dependent neuronal labelling, to investigate neuronal ensembles involved in the Activity-Based Anorexia (ABA) model. We specifically sought to identify and chemogenetically manipulate neurons active during the food-anticipatory phase of the ABA model (a marker of AN-like behavior).
Mice exposed to the ABA model showed a significantly higher number of labelled neurons in several hypothalamic regions compared to controls (5 groups, n = 7-8 each, p < 0.05, using a one-way ANOVA followed by Dunnett’s post-hoc test). We characterized these neurons using single-cell RNA sequencing (3 groups, n = 3 each) and immunohistochemistry (ABA group, n = 6). Chemogenetic modulation (3 groups, n = 11-16 each) of these neuronal ensembles, allowed us to dissect their role in anorexic behaviors.
Our results identify hypothalamic ensembles central to AN-like behaviors, particularly hyperactivity, which contributes to disease onset and severity. These findings highlight the potential of hypothalamic ensembles as drivers of AN pathophysiology and as targets for developing more effective treatments.