Obesity is a major health problem in the United States and a leading contributor to cardiovascular disease, diabetes mellitus and stroke. One region essential for appetite control is the nucleus of the solitary tract (NTS) in the brainstem. Visceral afferent fibers carrying satiety information terminate in the NTS and NTS neurons filter this information before relaying it on to other brain regions. Catecholamine neurons in the NTS (NTS-CA neurons) are one population critical for the control of food intake. In the previous funding period we showed that these neurons are 1) directly activated by vagal afferents, including gastric afferents; 2) activated by compounds that inhibit food intake, such as CCK, oxytocin and serotonin, and inhibited by factors that stimulate intake, such as ghrelin and opioids; and 3) that the activity of NTS-CA neurons is dependent on glutamate inputs, which can be increased by both serotonin (5-HT) through 5-HT3 receptors (Rs) and nicotine through nicotinic acetylcholine receptors (nAChRs). Serotonin and nicotine are two powerful inhibitors of food intake and adjusting the size of their effects could provide a sensitive way to adjust the strength of activation of a satiety pathway to adapt to energy needs. The central hypothesis of this proposal is that the expression of both 5-HT3Rs and nAChRs can be up and down regulated by different conditions to control glutamate release and alter the firing rate of NTS-CA neurons, resulting in the differential release of the transmitters, norepinephrine and glutamate. A multidisciplinary approach of electrophysiology, behavior and molecular genetics will be used to powerfully and comprehensively test the central hypothesis by pursuing the following specific aims.
Aim 1. Establish how the response of NTS-CA neurons to serotonergic inputs is altered by changes in energy state, e.g. glucose concentration, fasting, obesity and diet.
Aim 2. Establish how the response of NTS-CA neurons to cholinergic inputs is altered by changes in energy state, e.g. glucose concentration, fasting, obesity and high fat diet.
Aim 3. Determine whether the feeding effects of serotonin and nicotine are plastic and whether they stimulate release of norepinephrine or glutamate from NTS-CA neurons. The expected outcomes of these experiments are that we will have a better understating of how different energy states alter activation of NTS neurons to control transmitter release and how this impacts feeding behaviors. These results are expected to positively impact the field by identifying how key mechanisms that control body weight are altered; knowledge that may eventually help lead to therapeutic strategies to alleviate the problems associated with obesity.
The proposed research is relevant to public health because obesity is a major health problem in the United States and is a leading contributor to cardiovascular disease, diabetes mellitus and stroke. The expected contribution of these studies will be the identification of two novel mechanisms by which one group of critical neurons control food intake and how these are altered in obesity, hyperglycemia and by high fat diet. The expectation is that increasing our understanding of these mechanisms will lead to more precisely targeted approaches for the prevention and treatment of obesity.
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