Role of Parabrachial Nucleus Neuropeptides in Feeding

描述(申请人提供)：肥胖治疗的进展可以通过持续分解调节瘦素、Ghrelin和胰岛素反应的神经回路来提供。最近相当多的研究详细描述了对瘦素、胰岛素和Ghrelin输入敏感的下丘脑区域的一级和二级位置。在整个大脑中表达神经肽的前脑神经元对这些激素敏感，并作为下游中介影响摄食和新陈代谢。这些神经肽，如神经肽Y(NPY)、食欲素A(ORX)和阿片促黑素皮质素原产物(MC)，作用于或具有前脑和后脑的受体。未来研究的一个重要目标是确定这些神经肽在脑干核团中的功能，并确定这些核团如何与对瘦素、Ghrelin和胰岛素敏感的前脑核团(如下丘脑)相互作用。该提案将继续评估NPY、MC和ORX受体配体对桥臂旁核(PBN)摄食和电生理味觉和内脏反应的影响。桥臂旁核是脑干核团，接受显著重叠的味觉和内脏传入输入，从下丘脑直接接受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向PBN微量注射NPY、MC和ORX受体拮抗剂对喂养微结构的影响。以下实验评估了当NPY、MC和ORX激动剂应用于脑室或其拮抗剂直接在PBN神经元周围显微注射时，NPY、MC和ORX受体拮抗剂对神经PBN味觉和胃胀反应的影响。如果外周核直接应用NPY、MC或ORX受体配体影响摄食，应在神经生理学水平进行观察，这将有助于更好地阐明下丘脑神经肽在脑干中的功能作用(S)。与公共健康相关的喂养和代谢紊乱，如肥胖、厌食、暴食症、不能茁壮成长、胃反流、恶病质、早饱、胃排空延迟、运动障碍和嗅觉障碍等，会导致高血压、中风、糖尿病和心脏病等疾病，并占许多医疗费用。因此，阐明控制摄食的神经系统是临床和基础科学的基本目标。这项提案将继续探索脑干作为与摄食相关的下丘脑神经肽活动部位的作用，从而有助于基础研究，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.