Elucidating the mechanisms employed by Agouti-related peptide neurons to decrease activity-based anorexia behavior in mice - Anorexia nervosa (AN) is a deadly mental health disorder characterized by pronounced low bodyweight resulting from reduced food intake and oftentimes simultaneous hyperactivity, typically through compulsive exercise. Individuals experiencing AN, who are at least 75% more likely to identify as female, bear the brunt of this condition. AN has the second highest mortality rate among mental health disorders, recently surpassed only by opioid-use disorder. In addition to the strikingly low bodyweight, AN leads to chronic medical conditions and lifetime disability. The overwhelming majority of deaths in AN patients are attributed to either unknown medical complications or suicide. Interestingly, the prioritization of hyperactivity over food intake, a prominent feature in many individuals with AN, has been observed not only in humans but also in various species, including rodents. Leveraging this parallel, researchers have employed the activity-based anorexia (ABA) rodent model to shed light on the evolutionarily conserved motivational drives potentially underlying AN. Nevertheless, the specific neurobiological factors driving these maladaptive behaviors in ABA and AN are still largely unknown. Our previous studies have implicated hypothalamic hunger-promoting agouti-related peptide (AgRP) cells as potential contributors to the valence reassignment that occurs in AN between hunger, feeding, and hyperactivity. Notably, we have demonstrated that increasing AgRP neural activity can promote bodyweight gain in ABA mice, offering a potential therapeutic target for reversing weight loss in ABA and, potentially, AN. However, the precise mechanisms through which AgRP neurons coordinate these effects and whether they modulate valence associations with hunger, physical activity and feeding behavior in ABA remain elusive. The objective of this proposal is to determine the neurobiological mechanisms employed by AgRP neurons to orchestrate the re- prioritization of feeding behavior over hyperactivity in ABA, utilizing cutting-edge behavioral technologies and knock-in mouse models. In Aim 1, we will expand upon our previous findings to determine if AgRP cells can sense and modulate both hyperactivity and feeding during ABA. Through in vivo fiber photometry and optogenetics, we monitor and manipulate AgRP populations, respectively, in ABA and control mice while they are freely behaving on the behavioral paradigm. In Aim 2, we will unravel the circuits involved in AgRP-mediated bodyweight gain in ABA mice using projection-defined chemogenetics. By defining and characterizing the cellular and circuit functions of AgRP neurons in female ABA mice, our research endeavors hold the potential to identify a therapeutic target for the re-prioritization of feeding over exercise in AN. Ultimately, our findings have the potential to alleviate the chronic disability associated with AN, leading to improved survival and enhanced quality of life for individuals affected by this severe disorder.
