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CHOLECYSTOKININ SIGNALING IN THE NUCLEUS OF THE SOLITARY TRACT
Embargoed Access, Embargo ends: 02/26/2027
Dissertation
CHOLECYSTOKININ SIGNALING IN THE NUCLEUS OF THE SOLITARY TRACT: SOURCES, RELEASE, AND EFFECTS OF DIET
Doctor of Philosophy (PhD), Washington State University
2025
Abstract
Obesity and its associated disorders are some of the largest worldwide public health issues. Obesity rates continue to go up worldwide, and their increase correlates with an increase in portion sizes and increased consumption of a high fat high sugar diet (HFHSD). Both of these factors suggest that a disruption of gut-brain signaling may be involved. Vagal afferents innervating the gastrointestinal (GI) tract are sensitive to a number of factors including cholecystokinin (CCK), which is released from the small intestine primarily following ingestion of fats and peptides. CCK binds to CCK 1 receptors (CCK1Rs) found on peripheral vagal afferent terminals. This signal then propagates to the nucleus of the solitary tract (NTS) in the hindbrain, where afferents form direct excitatory synapses with NTS neurons. Central vagal afferents also express CCK1Rs, and activation of these central CCK1Rs leads to a decrease in food intake. One potential source of local CCK is a subpopulation of CCK-expressing NTS (NTS-CCK) neurons. These neurons are activated following a meal and by ingestion of carbohydrates and peptides, and activating them via optogenetic stimulation decreases food intake. However, it remains unclear what types of vagal afferents drive these neurons and whether they can serve as a source of CCK that acts on central CCK1Rs. It also remains unclear whether CCK signaling in the NTS is blunted by a HFHSD.This dissertation seeks to answer these questions using a combination of electrophysiology, pharmacology, and optogenetics. In chapter 2, I found that NTS-CCK neurons are directly connected to primarily CCK-sensitive vagal afferents, while some are also downstream of 5-HT-sensitive afferents. In chapter 3, I found that optogenetic stimulation of CCK neurons evokes CCK release that activates NTS neurons. In chapter 4, I found that CCK signaling in the NTS is blunted by a three-week HFHSD in male and not female mice. Taken together, these findings provide evidence that NTS-CCK neurons serve as a local source of CCK in the NTS that can activate NTS neurons independent of peripheral signaling and that central CCK signaling may play a role in the satiety altering effects of a HFHSD, which lead to weight gain and obesity. The work in this dissertation contributes significantly to our understanding of CCK signaling mechanisms in the NTS and, together with previous work, will inform the development of better treatments for obesity.
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Details
- Title
- CHOLECYSTOKININ SIGNALING IN THE NUCLEUS OF THE SOLITARY TRACT: SOURCES, RELEASE, AND EFFECTS OF DIET
- Creators
- Eric Thomas Winzenried
- Contributors
- Suzanne M Appleyard (Advisor)Travis E Brown (Committee Member)James H Peters (Committee Member)Emily Qualls-Creekmore (Committee Member)Gary A Wayman (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Program in Neuroscience
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 183
- Identifiers
- 99901357690401842
- Language
- English
- Resource Type
- Dissertation