Cell types of interoception and their response to acute injury

Abstract

Interoception is the ability of an organism to sense and regulate its internal states. Just as external sensory organs transduce environmental cues of various modalities, specialized cells are responsible for monitoring internal conditions within the body. However, unlike our exteroceptive abilities, the sensory mechanisms and circuits that underlie interoception are not well characterized and remain less understood. Cells that comprise the sensory tissues important for interoception are highly specialized and express unique proteins that confer their ability to perform their specific function. Single-cell RNA (scRNA) sequencing provides a snapshot of the transcriptome of individual cells and provides a comprehensive and unbiased approach to interrogating molecular diversity that enables transduction and transmission of internal status. To gain a better understanding of the molecular diversity that permits interoception, I have worked on multiple projects atlasing interoceptive sites. The first site assayed mixed primary and higher-order sensory neurons of the Area Postrema, an anatomically privileged brain region that is responsible for conveying the sense of visceral malaise. The second site includes enteroendocrine cells (EECs) - primary sensory cells of the gut responsible for communicating nutrient status in the digestive tract. Collaborative work on these projects highlights the advantage single-cell transcriptomics offers to the facilitation of scientific discovery. One major body-to-brain connection that has benefited from cell-type analysis in recent years is the vagus nerve. In the mouse, the vagus nerve is fused with the glossopharyngeal nerve. Afferents of these cranial nerves (CN IX and X) serve a wide array of physiological functions, helping establish tonic control of breathing, nutrient intake, blood pressure maintenance, and more. The cell bodies of CN IX and X reside in the nodose, petrosal, and jugular ganglia (NPJg) and are diverse in their transcriptomic landscapes. However, mapping the transcriptionally defined identity of a neuron to its physiological role has proven difficult. My thesis work combines the anatomy and physiology of interoception with single-cell transcriptomics, focusing on adding more biological context to NPJg scRNA data. Using single-nucleus RNA sequencing, we provide the first detailed molecular characterization of the response to acute axotomy in the NPJg. We observe that a common transcriptional program is activated in response to injury. We further investigate vagal subtypes based on transcriptomic profiles and their branch contributions, offering new insights into the relationship between molecular identity and the complex branching anatomy of the vagus and glossopharyngeal nerves.