NEUROPEPTIDES AND THEIR PHYSIOLOGICAL CONTROL

神经肽及其生理控制

• 批准号: 6539723
• 负责人: Alan G Watts
• 金额: $ 25.9万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6539723
• 关键词: adrenalectomy; adrenocorticotropic hormone; afferent nerve; body water dehydration; cell osmotic pressure; circadian rhythms; corticosteroid receptors; corticosterone; corticotropin releasing factor; experimental brain lesion; gene expression; homeostasis; hormone regulation /control mechanism; hypothalamus; hypovolemia; immunocytochemistry; in situ hybridization; laboratory rat; neuroanatomy; neuroendocrine system; neuropeptides; organ culture; paraventricular nucleus; physiologic stressor

The long-term goal of this project is to identify the afferent signalling mechanisms, cellular responses, and topography of the limbic forebrain neural circuits that help regulate homeostasis in the rat. This portion of the forebrain is critical for regulating the behavioral, autonomic and endocrine response of the animal to homeostatic disturbance. The central hypothesis is that homeostatic disturbances modify chemically-coded information contained within neurons by modulating the mRNAs that code for singly- and co-expressed neuropeptides. These cell- and stimulus-specific modifications facilitate the appropriate response by the animal, either by modulating the activity of the autonomic nervous system, neuroendocrine function, or perhaps by modifying the central pattern generators that develop and regulate goal-directed behaviors. Because of the relative simplicity of the underlying physiology and behavior along with an extensive literature, the project concentrates on investigating the organization of the circuits and mechanisms controlling fluid balance in the rat. Two experimental models are used; 1), cellular dehydration provided by salt-loading; and 2), extracellular dehydration provided by iso-osmotic volume depletion. Relating the results to important and well documented models allows the interpretation of data within a compelling and contextual framework not possible with many other currently used 'stress' models. The assay methods used-principally in situhybridization and immunocytochemistry-allows the detection of changes in mRNAs and their cognate peptides in anatomically defined regions and cell types of the rat hypothalamus and amygdala in response to these two distinct, but related stimuli. This proposal will investigate the transmitter and signal transduction mechanisms underlying modified peptide gene expression. Similarly, it addresses the possibility that the way corticosterone regulates peptide gene expression may be determined by the animals physiological status. It will begin investigating how the limbic forebrain might integrate inputs from multiple stimuli to formulate an appropriate response. Finally, the proposal will address some topographical aspects of the circuits by looking at peptide (rather that mRNA) responses, and the behavior and possible significance of peptide receptor mRNAs during the imposition of the 2 dehydration stimuli. In the long term, investigating the topography and mechanisms operating within the circuits regulating homeostasis will provide a framework for addressing many of the clinical disorders (eg. hypertension, obesity, eating disorders) currently of central importance to human health, that have perturbed homeostatic regulation at the core of their etiology.

该项目的长期目标是确定传入信号 边缘前脑的机制，细胞反应和地形 有助于调节大鼠体内平衡的神经回路。 这部分的 前脑对于调节行为，自主和 动物对稳态障碍的内分泌反应。 中央 假设是体内平衡干扰修改化学编码 通过调节该编码的mRNA，在神经元中包含的信息 单一和共表达的神经肽。 这些细胞和刺激特异性 修改有助于动物的适当反应 调节自主神经系统的活性神经内分泌 功能，或者也许通过修改中心模式生成器 发展和规范目标行为。 因为亲戚 基础生理和行为的简单性以及 广泛的文献，该项目集中于研究 控制流体平衡的电路和机制 大鼠。 使用了两个实验模型。 1），细胞脱水 通过盐加载；和2），提供的细胞外脱水 等渗体积耗尽。 将结果与重要和良好 有记录的模型允许在引人注目的和 对于许多其他当前使用的“压力”，不可能的上下文框架 型号。 主要使用的分析方法和 免疫细胞化学 - 允许检测mRNA及其的变化 大鼠的解剖区域和细胞类型中的同源肽 下丘脑和杏仁核针对这两个不同但相关 刺激。 该建议将调查发射机和信号 修饰肽基因表达的基础转导机制。 同样，它解决了皮质酮的可能性 调节肽基因表达可以由动物确定 生理状况。 它将开始研究边缘前脑 可能会整合来自多个刺激的输入以制定适当的 回复。 最后，该提案将解决 通过查看肽（而不是mRNA）的反应，这些电路的反应和 行为和肽受体mRNA在此期间的重要性 强加了2个脱水刺激。 从长远来看 在调节电路内运行的地形和机制 体内平衡将提供一个解决许多临床的框架 目前的疾病（例如高血压，肥胖，饮食失调） 对人类健康的占有重要意义 监管其病因的核心。