Neural circuits regulating activity-based anorexia

Evolutionarily conserved neural circuits evolved that mediate switching between feeding and foraging for food, depending on environmental conditions such as food scarcity and internal state [1-3]. Activity-based anorexia is a phenomenon observed ubiquitously in normal mammals that emerges under conditions of time-restricted food availability and continuous access to running wheels. Under these experimental conditions, rodents progressively lose body weight and develop paradoxical hypophagia and compulsive wheel running, which can prove fatal if left unchecked. On the other hand, rodents survive indefinitely under conditions of either time-restricted food access or running wheel availability. In this review, we discuss preclinical studies within the past decade which used modern genetic circuit-dissecting tools including chemogenetic, optogenetic, and calcium imaging, to dissect the neural circuitry modulating activity-based anorexia. We highlight how circuits interconnecting the hypothalamus, prefrontal cortex, amygdala, mesolimbic system, and monoaminergic nuclei, interact to modulate animals' decision to feed or forage in the activity-based anorexia paradigm. We then highlight how these recent findings have aided in identifying pathophysiological mechanisms underlying neuropsychiatric disorders characterized by the maladaptive prioritization of exercise over feeding. Finally, we suggest approaches for the development of targeted therapeutics for anorexia nervosa, which has no approved pharmacological treatments.