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Molecular and Functional Taxonomy of Vagal Motor Neurons


Center Boston Area
Award Year 2018
Pilot Study Molecular and Functional Taxonomy of Vagal Motor Neurons
Awardee John N Campbell PhD
Abstract

The parasympathetic nervous system controls glucose metabolism through neurons in the dorsal motor nucleus of the vagus (DMV). A subset of these neurons innervates the pancreas and controls its endocrine activity, including insulin release. Understanding how these DMV neurons function and what receptors and signaling molecules they express will reveal novel strategies for treating diabetes. Furthermore, since DMV provides most of the brain’s control of gut motility, including two DMV neuron populations that oppositely affect gastric muscle tone, its dysregulation in diabetes likely underlies gastroparesis. However, while the DMV is known to be functionally diverse, little is known about its genetic diversity. We therefore profiled gene expression in hundreds of cholinergic DMV neurons by single-nuclei RNA-Seq. Unsupervised clustering of these neurons based on their transcriptomes revealed 10 distinct neuron types and specific markers for each. We will now extend these studies by using a more comprehensive approach, Drop-seq, to profile genome-wide expression in thousands of neurons in and around the DMV and classify neuron types. In addition, using recombinase-based genetic technology, we will determine where each DMV neuron type projects by fluorescently labeling their axons and imaging innervated organs (e.g., stomach, pancreas). We will also determine the physiological role of each DMV neuron type by manipulating its activity in vivo while measuring gastrointestinal functions, including gut motility and blood insulin levels. By characterizing the gene expression, synaptic circuitry, and function of each DMV neuron type, these studies will yield unprecedented insight into neural control of glucose metabolism and digestion.

Public Health Relevance: This study is relevant to public health because it will provide mechanistic insight into how the brain controls glucose metabolism and digestion. While previous studies have shown that different types of motor neurons control different aspects of digestion and glucose metabolism through the vagus nerve, little is known about these motor neurons types, including how they signal to the target organs. Knowing what receptors and signaling molecules are expressed by the vagal motor neuron types that control digestion and glucose metabolism will reveal novel targets for treating gastroparesis and diabetes.