Role of Parabrachial Nucleus Neuropeptides in Feeding

描述（由申请人提供）：肥胖治疗的进展可能是通过对介导瘦素、胃促生长素和胰岛素反应的神经回路的持续解析来实现的。最近的大量研究已经详细介绍了下丘脑区域中对瘦素、胰岛素和胃饥饿素输入敏感的一级和二级位点。在整个大脑中表达神经肽的前脑神经元对这些激素敏感，并作为下游介质影响摄食和代谢。这些神经肽，如神经肽Y （NPY）、食欲素a （ORX）和前阿片黑素皮质素产物（MC），在前脑和后脑的位置起作用或具有受体。未来研究的一个重要目标是确定这些神经肽如何在脑干核中起作用，并确定这些核如何与对瘦素、胃饥饿素和胰岛素敏感的前脑核（如下丘脑）相互作用。本研究将继续评估NPY、MC和ORX受体配体对脑干脑桥臂旁核（PBN）的进食和电生理味觉和内脏反应的影响，PBN是一个脑干核，接收明显重叠的味觉和内脏传入输入，接收来自下丘脑的直接NPY、MC和ORX输入，并将输出发送到控制口腔运动的脑干核。第一个实验评估了PBN直接显微注射NPY、MC和ORX受体拮抗剂对摄食微观结构的影响。当NPY、MC和ORX受体拮抗剂应用于脑室或其拮抗剂直接在PBN神经元周围微注射时，以下实验评估了NPY、MC和ORX受体拮抗剂对神经PBN味觉和胃扩张反应的影响。如果直接应用PBN的NPY、MC或ORX受体配体影响进食，这应该在神经生理学水平上观察，并将有助于更好地阐明下丘脑神经肽在脑干中的功能作用。喂养和代谢紊乱，如肥胖、厌食症、暴食症、发育不良、胃反流、恶病质、早饱、胃排空延迟、嗅觉障碍和嗅觉缺失，会导致高血压、中风、糖尿病和心脏病等疾病，并导致许多医疗保健费用。因此，阐明控制进食的神经系统是临床和基础科学的基本目标。本研究将继续探索脑干作为与进食相关的下丘脑神经肽作用部位的作用，从而为基础研究做出贡献，有助于确定潜在的药物治疗靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.