A pontomesencephalic-mesolimbic circuit modulates activity-based anorexia

Anorexia nervosa (AN) is a psychiatric disorder with a high mortality rate. The compulsive nature of the disorder leads to an emerging dopamine (DA)-centered hypothesis. However, the circuit mechanism of AN remains elusive. By examining a pontomesencephalic-mesolimbic circuit, which is implicated in anorexia-like and reinforcement behaviors in naïve mice, we found that this pathway modulates activity-based anorexia (ABA), a well-established animal model of AN. Specifically, glutamatergic lateral parabrachial nucleus (LPBN) neurons indirectly inhibited medial ventral tegmental area (VTA) DA neurons through local GABAergic interneurons. Chronic activation of the LPBN-VTA circuit exacerbated ABA symptoms, whereas circuit suppression alleviated them, demonstrating its sufficiency and necessity. Moreover, VTA DA neurons exhibited impaired high-conductance calcium- and voltage-dependent potassium (BK) channel currents. Pharmacological enhancement of this channel improved the retention rate in ABA mice. Our results elucidate the critical role of the LPBN-VTA circuit and potential channel pathology, which may serve as a key to the development of drug treatments and intervention strategies for AN.