Area postrema cell types that mediate nausea-associated behaviors

Nausea, the unpleasant sensation of visceral malaise, remains a mysterious process. The area postrema is implicated in some nausea responses, and contains poorly understood brain-resident sensory neurons that are anatomically privileged to detect bloodborne signals. To investigate nausea mechanisms, we built an area postrema cell atlas through single-nucleus RNA sequencing, revealing a few neuron types. Using mouse genetic tools for cell-specific manipulation, we discovered excitatory neurons that induce nausea-related behaviors, with one neuron type mediating aversion imposed by multiple poisons. Nausea-associated responses were observed to agonists of identified area postrema receptors, and suppressed by targeted cell ablation and/or gene knockout. Anatomical mapping revealed a distributed network of long-range excitatory but not inhibitory projections with subtype-specific patterning. These studies reveal the basic organization of area postrema nausea circuitry, and provide a framework towards understanding and therapeutically controlling nausea. Single-nuclei sequencing of murine area postrema.恶心，即内脏不适带来的不愉快感知，至今仍是一个机制不明的生理过程。最后区（area postrema）参与部分恶心反应的调控，其内存在尚不清楚的脑内常驻感觉神经元，这些神经元在解剖结构上具备直接感知血源性信号的独特优势。为探究恶心的发病机制，我们通过单细胞核RNA测序（single-nucleus RNA sequencing）构建了最后区的细胞图谱，揭示了数种神经元亚型。借助针对细胞特异性操作的小鼠遗传学工具，我们发现了可诱发恶心相关行为的兴奋性神经元，其中一种亚型能够介导多种毒物引发的厌恶反应。针对已鉴定的最后区受体激动剂可诱发恶心相关反应，而靶向细胞消融（cell ablation）或基因敲除（gene knockout）则可抑制此类反应。解剖学图谱分析显示，存在一个由长程兴奋性投射（而非抑制性投射）构成的分布式神经网络，且该网络呈现亚型特异性的分布模式。本研究揭示了最后区恶心调控环路的基本组织结构，为理解恶心的发生机制以及实现恶心的治疗性干预提供了理论框架。小鼠最后区单细胞核测序数据集。