Advances in obesity treatment may be provided by continued resolution of the neural circuits that mediate leptin, ghrelin, and insulin responses. Considerable recent research has detailed first and second order sites in hypothalamic regions that are sensitive to leptin, insulin, and ghrelin input. Forebrain neurons expressing neuropeptides throughout the brain are sensitive to these hormones and act as downstream mediators to influence feeding and metabolism. These neuropeptides, such as neuropeptide Y (NPY), and orexin-A (ORX), and pro- opioimelanocortin products (MC), act or have receptors in forebrain and hindbrain locations. An important goal for future research is to determine how such neuropeptides function in brainstem nuclei and to determine how these nuclei interact with forebrain nuclei (e.g., hypothalamus) that are sensitive to leptin, ghrelin, and insulin. This proposal will continue to evaluate the effects of NPY, MC, and ORX receptor ligands on feeding and electrophysiological taste and visceral responses in the pontine parabrachial nucleus (PBN), a brainstem nucleus that receives significantly overlapping taste and visceral afferent inputs, receives direct NPY, MC, and ORX input from the hypothalamus, and sends output to brainstem nuclei controlling oral movement. The first experiments assess the effects of direct PBN microinjectons of NPY, MC, and ORX receptor antagonists on feeding microstructure. The following experiments assess the effects of NPY, MC, and ORX receptor antagonists on neural PBN gustatory and gastric distension responses when NPY, MC, and ORX agonists are applied to brain ventricles or their antagonists are microinjected directly around PBN neurons. If direct PBN application of NPY, MC, or ORX receptor ligands affect feeding, this should be observed at the neurophysiological level and will serve to better clarify the functional role(s) of hypothalamic neuropeptides in the brainstem.
Feeding and metabolic disorders such as obesity, anorexia, bulimia, failure to thrive, gastric reflux, cachexia, early satiety, delayed gastric emptying, dysgeusia, and anosmia contribute to diseases including hypertension, stroke, diabetes, and heart disease, and they account for many health-care costs. Elucidating the neural systems that control feeding is, therefore, a fundamental goal for clinical as well as basic science. This proposal will continue to explore the role of the brainstem as a site of feeding-related hypothalamic neuropeptide action and thus contribute to basic research that could help to identify potential pharmacological therapeutic targets. ? ? ?
