A Pontomesencephalic-Mesolimbic Circuit Underlying Activity-Based Anorexia

Abstract Anorexia nervosa (AN) is a psychiatric disorder with a high mortality rate. The compulsivity of the disorder leads to an emerging dopamine (DA)-centered hypothesis. However, the key underlying mechanism of AN remains elusive. In the present study, we identified a critical circuit from the lateral parabrachial nucleus (LPBN) to the ventral tegmental area (VTA), in a well-established animal model of AN (activity-based anorexia, ABA). Using in vivo and in vitro electrophysiology, optogenetics, chemogenetics, and fiber photometry, we found that the LPBN-VTA circuit bidirectionally modulated the food intake and reinforcement behaviors. Furthermore, the excitability of VTA-projecting LPBN neurons was increased in ABA mice, and inhibition of this circuit significantly increased food intake and survival rate in ABA mice. The LPBN glutamatergic neurons targeted medial VTA DA neurons indirectly via inhibitory GABA interneurons, underlying the hypoactivity of the VTA DA neurons in ABA mice. This hypoactivity was also due to decreased function of the high-conductance calcium- and voltage-dependent potassium (BK) channels on the DA neurons. Notably, intra-VTA infusion of a BK channel agonist rescued DA neuronal firing and survival rate in ABA mice. These results have elucidated the critical role of the LPBN-VTA circuit and the potential channel pathology in the disorder, which may serve as a key to the development of drug treatments and intervention strategies for AN.