Genetic identification of vagal sensory neurons that control feeding

Energy homeostasis requires precise measurement of the quantity and quality of ingested food. The vagus nerve innervates the gut and can detect diverse interoceptive cues, but the identity of the key sensory neurons and corresponding signals that regulate food intake remains unknown. Here we use an approach for target-specific, single-cell RNA sequencing to generate a map of the vagal cell types that innervate the gastrointestinal tract. We show that unique molecular markers identify vagal neurons with distinct innervation patterns, sensory endings, and function. Surprisingly, we find that food intake is most sensitive to stimulation of mechanoreceptors in the intestine, whereas nutrient-activated mucosal afferents have no effect. Peripheral manipulations combined with central recordings reveal that intestinal mechanoreceptors, but not other cell types, potently and durably inhibit hunger-promoting AgRP neurons in the hypothalamus. These findings identify a key role for intestinal mechanoreceptors in the regulation of feeding. Nodose ganglion single cell mRNA profiles of 6 to 12-week-old C57BL/6JN mice were generated by deep sequencing, using either 10x Genomics (sample 1) or Smart-seq2 protocol (all other samples).能量稳态（Energy homeostasis）需要对摄入食物的数量与质量进行精准评估。迷走神经（vagus nerve）支配胃肠道，并可感知多种内感受信号，但调控进食的关键感觉神经元及其对应信号的身份仍未明确。本研究采用靶向特异性单细胞RNA测序（single-cell RNA sequencing）技术，绘制了支配胃肠道的迷走神经细胞类型图谱。研究表明，独特的分子标志物可区分具有不同支配模式、感觉末梢及功能的迷走神经元。令人意外的是，本研究发现进食行为对肠道内机械感受器（mechanoreceptors）的刺激最为敏感，而经营养物质激活的黏膜传入神经则无此效应。外周操作结合中枢记录实验显示，肠道机械感受器而非其他细胞类型，可强效且持久地抑制下丘脑（hypothalamus）中促进饥饿的AgRP神经元（AgRP neurons）。上述研究结果明确了肠道机械感受器在进食调控中的关键作用。本研究通过深度测序获取了6至12周龄C57BL/6JN小鼠的结状神经节（nodose ganglion）单细胞mRNA表达谱，测序分别采用10x Genomics（样本1）与Smart-seq2（其余所有样本）技术方案。