Deciphering a neuronal circuit that mediates appetite

摘要

Hypothalamic neurons that co-express agouti-related protein (AgRP), neuropeptideY and γ-aminobutyric acid {GABA) are known to promote feeding and weight gain by integration of various nutritional, hormonal, and neuronal signals. Ablation of these neurons in mice leads to cessation of feeding that is accompanied by activation of Fos in most regions where they project. Previous experiments have indicated that the ensuing starvation is due to aberrant activation of the parabrachial nucleus (PBN) and it could be prevented by facilitating GABA_A receptor signalling in the PBN within a critical adaptation period. We speculated that loss of GABA signalling from AgRP-expressing neurons (AgRP neurons) within the PBN results in unopposed excitation of the PBN, which in turn inhibits feeding. However, the source of the excitatory inputs to the PBN was unknown. Here we show that glutamatergic neurons in the nucleus tractus solitarius (NTS) and caudal serotonergic neurons control the excitability of PBN neurons and inhibit feeding. Blockade of serotonin (5-HT_3) receptor signalling in the NTS by either the chronic administration of ondansetron or the genetic inactivation of Tph2 in caudal serotonergic neurons that project to the NTS protects against starvation when AgRP neurons are ablated. Likewise, genetic inactivation of glutamatergic signalling by the NTS onto N-methyl D-aspartate-type glutamate receptors in the PBN prevents starvation. We also show that suppressing glutamatergic output of the PBN reinstates normal appetite after AgRP neuron ablation, whereas it promotes weight gain without AgRP neuron ablation. Thus we identify the PBN as a hub that integrates signals from several brain regions to bidirectionally modulate feeding and body weight.%特定类型的丘脑下部神经元在促进进食和增重时会对内部和外部信号做出反应。这些神经元的失去，会导致啮齿类动物发生致命性的拒食症（进食停止）。在这项研究中，Wu等人对驱动这种进食行为的回路进行了解剖，发现由表达AgRP的丘脑下部神经元诱导的“臂旁核”（PBN）的抑制，会保护实验动物不患拒食症，并促进增重。而且，他们还发现，PBN是一个集成中心，双抽调制进食和体重。了解在调制进食行为和体重中所涉及的神经回路，对于包括神经性厌食和恶心在内的各种与进食有关的疾病的治疗方法的研究可能会有价值。