Publication Date

2019-11-25

Availability

Open access

Embargo Period

2019-11-25

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2019-10-28

First Committee Member

Alejandro Caicedo

Second Committee Member

Stephen Roper

Third Committee Member

Ernesto Bernal-Mizrachi

Fourth Committee Member

Alessia Fornoni

Fifth Committee Member

John Bixby

Abstract

Sensory denervation affects pancreatic islet function, glucose metabolism and diabetes onset, but how islet endocrine cells interact with sensory neurons has not been studied. In this thesis work we attempted to anatomically and physiologically characterize vagal islet-brain pathway in search of the sensory modality that islet is transmitting to the brain. Here we show that the pancreatic islets are innervated by vagal sensory axons expressing substance P, calcitonin-gene related peptide, and serotonin receptor 5HT3R. Vagal neurons projecting to the pancreas terminate in the commissural nucleus of the solitary tract. These neurons respond to chemical but not mechanical stimulation of the pancreas. By recording activity from nodose neurons in vivo and from sensory axons in living pancreas slices, we show that sensory nerves respond to serotonin secreted from stimulated beta cells. Beta cell serotonin is co-released with insulin, in normal physiology promotes glucose uptake, and in conditions of increased beta cell activity, promotes insulin secretion. Hence, islet secretion of serotonin carries information on islet secretory state and capacity to accommodate appropriate glucose clearance, which fits in the bigger picture of peripheral serotonin role in energy metabolism. Our study thus establishes that pancreatic islets communicate with the brain using the neural route and identifies serotonin signaling as a peripheral transduction mechanism.

Keywords

visceral sensory innervation; pancreatic islet; vagus nerve; serotonin; nodose ganglion; beta cell

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