Dissertation
NMDA RECEPTORS CONTRIBUTE TO THE SENSITIVITY OF NTS LEPTIN RECEPTOR-EXPRESSING NEURONS TO VAGAL FEEDBACK, LEPTIN AND CHOLECYSTOKININ
Doctor of Philosophy (PhD), Washington State University
01/2020
Handle:
https://hdl.handle.net/2376/112263
Abstract
Obesity is a complex metabolic disorder that presents a significant threat to human health. Obesity results from an imbalance in energy intake and expenditure, two processes controlled by the nervous system. The anorexigenic hormone leptin plays a pivotal role in regulating energy homeostasis through its effects in the nervous system, and individuals with disrupted leptin signaling develop obesity. Leptin is produced by adipose tissue and acts at several brain sites that regulate metabolism and feeding behavior, such as the hypothalamus and ventral tegmental area. One site of action is the nucleus of the solitary tract (NTS) in the brainstem, which receives gastrointestinal information from the vagus nerve and then relays this information to nuclei important for energy expenditure, appetite control, and feeding behavior. Direct injection of leptin into the NTS reduces food intake, stimulates energy expenditure, and enhances the intake-suppressive effects of satiety signals, such as cholecystokinin (CCK). However, the cellular mechanism underlying the effects of leptin in the NTS are not well understood. Described in the following chapters, I used patch-clamp techniques in mouse brain slices to determine the effects of leptin and CCK on NTS leptin receptor expressing (lepR) neurons. In Chapter II, I show that NTS lepR neurons are directly connected to the vagus-containing solitary tract (ST) and that leptin increases NMDA receptor-mediated currents in these cells. This effect of leptin on postsynaptic NMDARs lead to a functional increase in ST-NTS synaptic throughput, suggesting that leptin increases NTS activity via NMDAR activation. This idea was supported by a feeding study demonstrating that leptin’s effects on food intake are attenuated by intra-NTS NMDAR antagonists. In Chapter III, I further characterized excitatory input to NTS lepR neurons and show that the vast majority of these cells receive direct input from CCK-sensitive C fibers. CCK-induced glutamate release was sufficient to drive neuronal firing, and these effects were mediated by CCKR1. Interestingly, the effects of CCK on firing were significantly increased with NMDAR activation. Collectively, these data suggest that leptin enhances NTS NMDAR function and increases the sensitivity of lepR neurons to vagus-mediated satiety signals, leading to reduced food intake.
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Details
- Title
- NMDA RECEPTORS CONTRIBUTE TO THE SENSITIVITY OF NTS LEPTIN RECEPTOR-EXPRESSING NEURONS TO VAGAL FEEDBACK, LEPTIN AND CHOLECYSTOKININ
- Creators
- Drew Mackenzie Neyens
- Contributors
- Suzanne M Appleyard (Advisor)Gary A Wayman (Committee Member)Robert C Ritter (Committee Member)James H Peters (Committee Member)David J Rossi (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
- 182
- Identifiers
- 99900581702801842
- Language
- English
- Resource Type
- Dissertation