Stress triggers seeking of a starvation-like state in anxiety-prone female mice
1 Beth Israel Deaconess Medical Center
2 National Institute of Diabetes and Digestive and Kidney Dieases
3
Anorexia nervosa (AN) is a complex psychiatric disorder marked by voluntary self-starvation. Stressful early life experience and trauma often precede the onset of its symptoms, which overlap with those of other severe anxiety disorders and depression. Furthermore, patients with AN report self-starvation as a pleasant state, potentially because self-starvation helps reduce extreme anxiety. We tested the hypothesis that stress can cause animals to prefer a starvation-like state. We developed a virtual reality place preference paradigm in which head-fixed mice can voluntarily seek a starvation-like state induced by optogenetic stimulation of hypothalamic agouti-related peptide (AgRP) neurons. Our findings revealed a sex-specific response to stress. Prior to stress, males generally maintained an aversion to AgRP stimulation. In contrast, following stress induction, a subset of females developed a marked preference for this stimulation mimicking seeking of a starvation-like state. Strikingly, the behavior of females was predicted by their predisposition to high anxiety, measured weeks prior to the experiment. Moreover, stress-induced changes in the preferences of female mice were reflected in subtle changes in facial expressions during AgRP stimulation. Our study suggests that stress may cause females predisposed to anxiety to seek a starvation state. Particularly, this behavioral paradigm provides a foundation for future work toward identifying the neural circuits that underlie the voluntary maintenance of long-term starvation states in individuals with anorexia nervosa. Moreover, it enables concurrent tracking of facial expressions and, in the future, simultaneous two-photon calcium imaging, high-density electrophysiology, and recordings of autonomic signals.