Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Nature. 2021 Jul;595(7869):695-700. doi: 10.1038/s41586-021-03729-3. Epub 2021 Jul 14.
Agouti-related peptide (AGRP)-expressing neurons are activated by fasting-this causes hunger, an aversive state that motivates the seeking and consumption of food. Eating returns AGRP neuron activity towards baseline on three distinct timescales: rapidly and transiently following sensory detection of food cues, slowly and longer-lasting in response to nutrients in the gut, and even more slowly and permanently with restoration of energy balance. The rapid regulation by food cues is of particular interest as its neurobiological basis and purpose are unknown. Given that AGRP neuron activity is aversive, the sensory cue-linked reductions in activity could function to guide behaviour. To evaluate this, we first identified the circuit mediating sensory cue inhibition and then selectively perturbed it to determine function. Here, we show that a lateral hypothalamic glutamatergic → dorsomedial hypothalamic GABAergic (γ-aminobutyric acid-producing) → AGRP neuron circuit mediates this regulation. Interference with this circuit impairs food cue inhibition of AGRP neurons and, notably, greatly impairs learning of a sensory cue-initiated food-acquisition task. This is specific for food, as learning of an identical water-acquisition task is unaffected. We propose that decreases in aversive AGRP neuron activity mediated by this food-specific circuit increases the incentive salience of food cues, and thus facilitates the learning of food-acquisition tasks.
刺鼠相关肽 (AGRP) 表达神经元在禁食时被激活——这会引起饥饿，一种令人不快的状态，促使人们寻找和进食。进食会使 AGRP 神经元活动在三个不同的时间尺度上恢复到基线：快速且短暂地响应食物线索的感官检测，缓慢且持久地响应肠道中的营养物质，甚至更缓慢且永久性地恢复能量平衡。快速的食物线索调节尤其引人注目，因为其神经生物学基础和目的尚不清楚。鉴于 AGRP 神经元活动是令人不快的，与感觉线索相关的活动减少可能有助于指导行为。为了评估这一点，我们首先确定了介导感觉线索抑制的回路，然后选择性地干扰它以确定其功能。在这里，我们表明，下丘脑外侧的谷氨酸能 → 下丘脑背内侧 GABA 能（产生 γ-氨基丁酸）→AGRP 神经元回路介导了这种调节。干扰该回路会损害食物线索对 AGRP 神经元的抑制作用，值得注意的是，会极大地损害由感觉线索引发的食物获取任务的学习。这是特异性的食物，因为对相同的水获取任务的学习不受影响。我们提出，这种食物特异性回路介导的令人不快的 AGRP 神经元活动的减少增加了食物线索的激励价值，从而促进了食物获取任务的学习。
