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Appetite: Serotonin and Corticotropin Releasing Factor

食欲：血清素和促肾上腺皮质激素释放因子

基本信息

批准号：
8212339
负责人：
SuJean Choi
金额：
$ 29.21万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212339
关键词：
Address Affect Anorexia Appetite Regulation Brain Cell Nucleus Cells Corticotropin-Releasing Hormone Data Desire for food Eating Etiology Experimental Designs Feeding Patterns Feeding behaviors Fenfluramine Frequencies Health Hypothalamic structure Injection of therapeutic agent Link Macronutrients Nutrition Measures Mediating Mediator of activation protein Melanocyte stimulating hormone Messenger RNA Neurons Neuropeptides Obesity Peripheral Pharmaceutical Preparations Production Published Comment RNA Interference Rattus Regulation Relative (related person)Research Design Role Serotonin Signal Transduction Site Structure of nucleus infundibularis hypothalami Suggestion Synapses Synaptic Transmission Testing Text alpha-Melanocyte stimulating hormone design energy balance feeding insight mRNA Expression neuronal cell body paraventricular nucleus protein expression receptor research study response transmission process

项目摘要

DESCRIPTION (provided by applicant): This proposal investigates the influence of serotonin (5-HT) and its associated neurons in the hypothalamic paraventricular nuclei (PVN) on neuronal corticotropin releasing factor (CRF) mRNA expression and feeding behavior in rats. PVN CRF neurons are important mediators in the control of feeding behavior; e.g. exogenous application of CRF or stimulation of CRF neurons result in the inhibition of food intake. Similarly, drugs that stimulate synaptic 5-HT transmission in the brain are also well known to inhibit food intake. Anatomically, it is also known that 5-HT terminal projections are found on PVN CRF neurons; this suggests that 5HT agents may suppress appetite through heretofore uncharacterized actions on PVN CRF neurons. A potential functional link between 5-HT is further supported by data demonstrating the presence of mRNAs for 5-HT receptor subtypes linked to appetite regulation in PVN CRF cell bodies. Remarkably, despite the suggestion of a number of studies, there have been no definitive studies to date demonstrating that 5-HT-associated drugs may indeed suppress feeding by stimulating CRF mRNA production and CRF protein expression. In this proposal, we hypothesize that there exists a functional link between serotonin (5-HT) and neuropeptides, such as CRF and melanocyte stimulating hormone (alpha MSH) and their respective neurons residing within the PVN (5-HT, CRF) and the arcuate (ARC) hypothalamic nuclei (alpha MSH), respectfully. Our Specific Aims are to (1) determine if 5-HT release regulates CRF or alpha MSH neurons in the PVN to suppress food intake; (2) Determine if 5-HT release indirectly regulates CRF neurons in the PVN via 1-MSH neurons residing in the arcuate and its associated neurons; and (3) determine downstream targets of hypothalamic CRF and its associated neurons. In our experimental design, we will utilize fenfluramine (FEN), a drug that strongly promotes 5HT synaptic transmission. Central and systemic FEN administration will be used to assess PVN CRF mRNA expression in rats pre-treated with 5-HT receptor antagonists specific to PVN CRF neurons that are appetite-linked (the 5HT-1B, 2A, & 2C subtypes). FEN will also be used to test whether 5-HT affects PVN CRF mRNA expression indirectly; 1-MSH release onto CRF neurons is stimulatory; hence, FEN could stimulate CRF neurons by increasing 1-MSH signaling. RNA interference will be used to eliminate CRF mRNA, to determine if FEN-initiated 5-HT influences appetite suppression by additional downstream mechanisms. These studies should provide new insight into the role of a poorly characterized 5HT-CRF synaptic connection in the control of food intake, and ultimately contribute to understanding if and how this connectivity is important to the regulation of overall energy balance, and the etiology of obesity, anorexia, and other appetite-related health problems. This proposal investigates the influence of serotonin (5-HT) and its associated neurons in the hypothalamic paraventricular nuclei (PVN) on neuronal corticotropin releasing factor (CRF) mRNA expression and feeding behavior in rats. These studies should provide new insight into the role of a poorly characterized 5HT-CRF synaptic connection in the control of food intake, and ultimately contribute to understanding if and how this connectivity is important to the regulation of overall energy balance, and the etiology of obesity, anorexia, and other appetite-related health problems.

描述（申请人提供）：本提案研究了下丘脑室旁核（PVN）中血清素（5-HT）及其相关神经元对大鼠神经元促肾上腺皮质激素释放因子（CRF）mRNA表达和进食行为的影响。 PVN CRF 神经元是控制摄食行为的重要介质；例如外源性应用 CRF 或刺激 CRF 神经元会导致食物摄入的抑制。同样，众所周知，刺激大脑突触 5-HT 传递的药物也会抑制食物摄入。从解剖学上来说，我们还知道在 PVN CRF 神经元上发现了 5-HT 末端投射；这表明 5HT 药物可能通过迄今为止未表征的对 PVN CRF 神经元的作用来抑制食欲。数据进一步支持了 5-HT 之间潜在的功能联系，该数据证明了与 PVN CRF 细胞体中的食欲调节相关的 5-HT 受体亚型 mRNA 的存在。值得注意的是，尽管有许多研究表明，但迄今为止还没有明确的研究证明 5-HT 相关药物确实可以通过刺激 CRF mRNA 产生和 CRF 蛋白表达来抑制摄食。在本提案中，我们假设血清素 (5-HT) 和神经肽（例如 CRF 和黑素细胞刺激素 (α MSH)）及其各自位于 PVN（5-HT、CRF）和弓状 (ARC) 下丘脑核 (α MSH) 内的神经元之间存在功能联系。我们的具体目标是 (1) 确定 5-HT 释放是否调节 PVN 中的 CRF 或 α MSH 神经元以抑制食物摄入； (2) 确定 5-HT 释放是否通过弓状区及其相关神经元中的 1-MSH 神经元间接调节 PVN 中的 CRF 神经元； (3)确定下丘脑CRF及其相关神经元的下游靶标。在我们的实验设计中，我们将使用芬氟拉明 (FEN)，这是一种强烈促进 5HT 突触传递的药物。中枢和全身 FEN 给药将用于评估经 5-HT 受体拮抗剂预处理的大鼠的 PVN CRF mRNA 表达，该 5-HT 受体拮抗剂针对与食欲相关的 PVN CRF 神经元（5HT-1B、2A 和 2C 亚型）。 FEN还将用于测试5-HT是否间接影响PVN CRF mRNA表达； 1-MSH 释放到 CRF 神经元上具有刺激作用；因此，FEN 可以通过增加 1-MSH 信号传导来刺激 CRF 神经元。 RNA 干扰将用于消除 CRF mRNA，以确定 FEN 引发的 5-HT 是否通过其他下游机制影响食欲抑制。这些研究应该对特征不明的 5HT-CRF 突触连接在控制食物摄入中的作用提供新的见解，并最终有助于了解这种连接对于整体能量平衡的调节是否以及如何重要，以及肥胖、厌食和其他与食欲相关的健康问题的病因。本提案研究了下丘脑室旁核 (PVN) 中血清素 (5-HT) 及其相关神经元对神经元促肾上腺皮质激素释放因子 (CRF) mRNA 表达和大鼠摄食行为的影响。这些研究应该对特征不明的 5HT-CRF 突触连接在控制食物摄入中的作用提供新的见解，并最终有助于了解这种连接对于整体能量平衡的调节是否以及如何重要，以及肥胖、厌食和其他与食欲相关的健康问题的病因。