Area Postrema Cell Types that Mediate Nausea-Associated Behaviors

Abstract

Nausea, the unpleasant sensation of visceral malaise, remains a mysterious process. The area postrema is implicated in some nausea responses and is anatomically privileged to detect blood-borne 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 to agonists of identified area postrema receptors were observed 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 toward understanding and therapeutically controlling nausea.

Keywords: Calcium sensing receptor (CaSR); GDF15; GFRAL; Glucagon-like peptide 1 receptor (GLP1R); circumventricular organs; conditioned flavor avoidance; emesis; exendin-4; lithlum chloride; parabrachial nucleus CGRP neurons.