While energy balance is critical to survival, many factors influence food intake beyond caloric need or “hunger.” Despite this, some neurons that drive feeding in mice are routinely referred to as “hunger neurons,” whereas others are not. To understand how specific hypothalamic circuits control interoceptive hunger, we trained mice to discriminate fasted from sated periods. We then manipulated three hypothalamic neuronal populations with well-known effects on feeding while mice performed this task. While activation of ARC^AGRP neurons in sated mice caused mice to report being food-restricted, LH^VGAT neuron activation or LH^VGLUT2 neuron inhibition did not. In contrast, LH^VGAT neuron inhibition or LH^VGLUT2 neuron activation in fasted mice attenuated natural hunger, whereas ARC^AGRP neuron inhibition did not. Each neuronal population evoked distinct effects on food consumption and reward. After satiety- or sickness-induced devaluation, ARC^AGRP neurons drove calorie-specific feeding, while LH^VGAT neurons drove calorie-indiscriminate food intake. Our data support a role for ARC^AGRP neurons in homeostatic feeding and implicate them in driving a hunger-like internal state that directs behavior toward caloric food sources. Moreover, manipulations of LH circuits did not evoke hunger-like effects in sated mice, suggesting that they may govern feeding more related to reward, compulsion, or generalized consumption than to energy balance, but also that these LH circuits can be powerful negative appetite modulators in fasted mice. This study highlights the complexity of hypothalamic feeding regulation and can be used as a framework to characterize how other neuronal circuits affect hunger and identify potential therapeutic targets for eating disorders.

虽然能量平衡对生存至关重要，但除了热量需求或“饥饿”之外，还有许多因素会影响食物摄入。尽管如此，一些驱动小鼠进食的神经元通常被称为“饥饿神经元”，而另一些则不是。为了了解特定的下丘脑回路如何控制内感受性饥饿，我们训练小鼠区分禁食期和饱食期。然后，当小鼠执行这项任务时，我们操纵了三个对喂养有众所周知的影响的下丘脑神经元群。虽然在饱食的小鼠中激活 ARC ^AGRP神经元导致小鼠报告食物受限，但 LH ^VGT神经元激活或 LH ^VGLUT2神经元抑制没有。相反，LH ^VGT神经元抑制或 LH ^VGLUT2禁食小鼠的神经元激活减弱了自然饥饿感，而 ARC ^AGRP神经元抑制没有。每个神经元群体都对食物消耗和奖励产生了不同的影响。在饱腹感或疾病引起的贬值后，ARC ^AGRP神经元驱动卡路里特异性进食，而 LH ^VGAT神经元驱动卡路里不加选择的食物摄入。我们的数据支持 ARC ^{AGRP的角色}体内平衡喂养的神经元，并暗示它们驱动一种类似于饥饿的内部状态，这种状态将行为导向热量食物来源。此外，LH 回路的操作并没有在饱食的老鼠身上引起类似饥饿的效应，这表明它们可能控制与奖励、强迫或广义消耗相关的进食，而不是能量平衡，而且这些 LH 回路可以是强大的负面食欲调节剂在禁食的老鼠身上。这项研究强调了下丘脑进食调节的复杂性，可以作为一个框架来描述其他神经元回路如何影响饥饿并确定饮食失调的潜在治疗靶点。