Role of Parabrachial Nucleus Neuropeptides in Feeding

描述（由申请人提供）：肥胖治疗的进展可以通过介导瘦素、生长激素释放肽和胰岛素反应的神经回路的持续解析来提供。最近相当多的研究已经详细说明了下丘脑区域中对瘦素、胰岛素和生长激素释放肽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）和食欲素-A（ORX），以及原阿片黑皮质素产物（MC），在前脑和后脑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前脑核相互作用（例如，下丘脑）对瘦素、生长素释放肽和胰岛素敏感。这项建议将继续评估NPY，MC和ORX受体配体对进食和电生理味觉和脑桥臂旁核（PBN）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，从下丘脑接收直接的NPY，MC和ORX输入，并将输出发送到控制口腔运动的脑干核团。第一个实验评估了直接PBN微量注射NPY、MC和ORX受体拮抗剂对摄食微结构的影响。以下实验评估当将NPY、MC和ORX激动剂应用于脑室或将其拮抗剂直接显微注射到PBN神经元周围时，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PBN应用NPY、MC或ORX受体配体影响进食，则应在神经生理学水平上观察到这一点，并有助于更好地阐明下丘脑神经肽在脑干中的功能作用。饮食和代谢紊乱，如肥胖、厌食、贪食、发育不良、胃反流、恶病质、早饱、胃排空延迟、味觉障碍和嗅觉丧失，会导致包括高血压、中风、糖尿病和心脏病在内的疾病，并造成许多医疗保健费用。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。该提案将继续探索脑干作为摄食相关下丘脑神经肽作用位点的作用，从而有助于基础研究，有助于确定潜在的药理学治疗靶点。

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.