Neuropeptide modulation of behavior in C. elegans

描述(申请人提供)：神经肽是神经元用来调节行为和生理的主要信号之一，神经肽受体是治疗疾病的重要靶点。这项提议分两部分来研究线虫体内的神经肽信号。在第一部分(特定目标1)中，我提出了一系列实验，以阐明血管催产素对神经回路的调节。血管催产素是线虫中一种新的哺乳动物神经肽血管加压素和催产素的同系物。这些实验旨在定义在模式生物中调节行为的神经肽能回路的最小成分。在第二部分(特定目标2和3)中，我描述了两种新方法的发展，用于对蠕虫中的神经肽信号进行细胞特异性分析。第一种技术将能够阻止单个细胞内所有神经肽的产生(特定目标2)，第二种技术将能够在成熟神经系统中的单个神经元内对神经肽翻译进行全基因组分析(特定目标3)。我进一步描述了我将如何应用这些技术来测试关于两个电路的假说，这两个电路据信利用神经肽信号，但其特定的神经肽介体仍然是谜：AFD神经元对温度趋向性的调节和ASI神经元对寿命的调节。 公共卫生相关性：神经肽信号是调节生理和行为的重要机制，神经肽与从精神障碍到糖尿病的各种人类疾病有关。我们的研究旨在揭示在实验上容易驯化的模式生物线虫中控制神经肽信号的神经元和基因的复杂网络。

DESCRIPTION (provided by applicant): Neuropeptides are one of the major signals that are used by neurons to modulate behavior and physiology, and neuropeptide receptors are important therapeutic targets for the treatment of disease. This proposal explores neuropeptide signaling in the nematode C. elegans in two parts. In the first part (Specific Aim 1), I propose a series of experiments that will elucidate the neural circuit regulated by vasotocin, a novel C. elegans ortholog of the mammalian neuropeptides vasopressin and oxytocin. These experiments aim to define the minimal components of a neuropeptidergic circuit that regulates behavior in a model organism. In the second part (Specific Aims 2 and 3), I describe the development of two new approaches for the cell-specific analysis of neuropeptide signaling in the worm. The first technique will enable the blockade of all neuropeptide production within a single cell (Specific Aim 2) and the second will enable the genome-wide profiling of neuropeptide translation within single neurons in the mature nervous system (Specific Aim 3). I further describe how I will apply these technologies to test hypotheses about two circuits that are believed to utilize neuropeptide signaling, but for which the specific neuropeptide mediators remain enigmatic: the regulation of thermotaxis by AFD neurons and the regulation of longevity by ASI neurons. PUBLIC HEALTH RELEVANCE: Neuropeptide signaling is an important mechanism that regulates physiology and behavior, and neuropeptides have been linked to human diseases ranging from psychiatric disorders to diabetes. Our studies aim to uncover the complex network of neurons and genes that control neuropeptide signaling in an experimentally tractable model organism, C. elegans.