The gastrointestinal (GI) tract informs the brain of the quantity and quality of food consumed during meals. Hence, GI signals drive satiation, and are seminal to control of food intake, regardless of the conditions that initiate it. This application or renewal continues an enduring interest in neural mechanisms by which satiation signals are communicated to the hindbrain nucleus of the solitary tract (NTS) and integrated with other controls of food intake. Glutamate is the principal neurotransmitter released by vagal afferent terminals in the NTS. As such, glutamate receptors in the NTS are pivotal to the transmission and processing of vagal satiation signals. Our prior investigations revealed that activation of NMDA-type glutamate receptors in the NTS participate in control of meal size. Moreover, delay of meal termination by NTS injection of NMDAr antagonists depends on intact vagal afferent terminals in the NTS. Finally, activation NMDAr in the NTS is required for CCK-evoked MAPK signaling and consequent reduction of food intake by cholecystokinin (CCK), the archetypical GI satiation peptide. Nevertheless, we remain ignorant of the specific mechanisms by which NMDAr enable CCK- induced reduction of food intake. Therefore, one aim of this application is to use multiple in vivo and ex vivo preparations to test the nested hypotheses that reduction of food intake by CCK requires NMDAr-dependent activation of MAPK signaling in vagal afferent terminals in the NTS;that MAPK signaling results in pERK1/2- mediated phosphorylation of synapsin 1 in vagal afferent terminals;and leads to strengthened vagal afferent synaptic function in the NTS with consequent reduction of food intake. Other investigators have reported that hindbrain melanocortin receptor activation (MC4r) contributes to CCK-evoked MAPK signaling in the hindbrain and reduction of food intake. This report, taken together with our findings that NTS NMDAr activation is necessary for reduction of feeding by CCK, suggests an important interaction between NTS MC4r and NMDAr in control of food intake. Therefore, the second aim of this application is to establish a basic relationship between NTS NMDAr and MC4r that makes both crucial for CCK-induced reduction of food intake. Specifically we will apply pharmacological and immunochemical methods to determine whether NTS NMDAr activation is functionally upstream or downstream of NTS MC4r in control of food intake by CCK. In addition we will assess the possibility that NTS NMDAr participate in control of food intake by endogenous MC4r ligands in the NTS, and thereby may participate in the integration of melanocortinergic controls of food intake with those arising from vagal afferent activation. Our long-term goal is to determine how the unique properties of NMDAr contribute to the process of satiation and integration of GI satiation signals with other controls of food intake. Detailed appreciation of NTS NMDAr contributions to control of food intake is of significance to human health because it may provide avenues for therapeutic intervention in eating disorders and obesity.
Glutamate is the principal neurotransmitter released by vagal afferent neurons, which communicate information from the GI tract to the hindbrain. The NMDA-type glutamate receptor participates in the control of food intake by GI signals in the hindbrain. The proposed work will delineate the neural mechanisms by which hindbrain NMDA receptors contribute to the processes that reduce food intake, and determine how these receptors interact with other hindbrain receptors involved in control of food intake. Results will provide new insights into the process of satiation and potential points for therapeutic intervention in eating disorders and development of obesity.
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