Project Summary
Nausea is an unpleasant sensation of visceral malaise, with underlying molecular and neuronal pathways
remaining mysterious. Current anti-nausea medications display variable success across patient cohorts, with
nausea being the major reason why cancer patients cannot adhere to treatment regimens. New strategies for
nausea intervention are needed, and may be enabled by a mechanistic understanding of how the sensation of
nausea arises. Classical studies involving brain lesion and stimulation revealed a tiny brain structure termed
the area postrema that mediates nausea responses to several visceral threats. The area postrema is a
circumventricular organ containing brain-resident sensory neurons that are anatomically poised to receive
inputs from both circulating factors and vagal afferents. However, the diversity of area postrema cell types and
receptors was previously uncharted.
In preliminary data, we built an area postrema cell atlas through single-nucleus RNA sequencing, revealing
four excitatory and three inhibitory neuron types. Transcriptome analysis revealed signature genes expressed
in different neuronal clusters, as well as many cell surface receptors that guide cellular responses. We
generated Cre knock-in mice for genetic access to various area postrema neurons, and adapted approaches
for cell-specific chemogenetics, optogenetics, ablation, imaging, and anatomical mapping. We found two
excitatory neuron types (clusters 2 and 4) that provide powerful aversion teaching signals, and one (cluster 1)
that does not. In Aim 1, we will use genetic tools to ask whether cell clusters 2 and 4, and the receptors they
express, mediate behavioral responses to a panel of nausea-inducing stimuli. In Aim 2, we will measure the
responses of cell clusters 2 and 4 to humoral factors, genetically defined vagal afferents, and various nausea-
inducing stimuli. In Aim 3 we will investigate the roles of newly charted inhibitory neurons in the area postrema,
which project locally and are excellent candidates to suppress nausea or other area postrema-mediated
behaviors. Together, these experiments will reveal the basic organization of area postrema circuitry, and
provide a framework towards understanding and therapeutically controlling nausea.