Genetic analysis of state-dependent chemosensory processing

状态依赖性化学感应处理的遗传分析

• 批准号: 10585464
• 负责人: Chih-Ying Su
• 金额: $ 43.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585464
• 关键词: Address; Amino Acid Transporter; Amino Acids; Animals; Aphrodisiacs; Assimilations; Behavior; Cells; Complex; Consumption; Cues; Data; Diet; Dietary Proteins; Drosophila genus; Energy Supply; Enteroendocrine Cell; Event; Exhibits; Family; Female; Food; Genetic; Hormones; Impairment; Individual; Ingestion; Instinct; Interoception; Intestines; Light; Logic; Macronutrients Nutrition; Mammals; Mediating; Messenger RNA; Modeling; Modernization; Molecular; Moods; Mothers; Names; Neurons; Neurophysiology - biologic function; Neurotransmitters; Nose; Nutrient; Olfactory Receptor Neurons; Outcome; Partner in relationship; Peptides; Peripheral; Pheromone; Physiological; Postpartum Period; Proteins; Publishing; Recovery; Regulation; Reproductive Behavior; Research; Role; Signal Pathway; Signal Transduction; Surveys; System; Testing; Time; Up-Regulation; building materials; detection of nutrient; dietary; experimental study; fly; genetic analysis; improved; innovation; insight; knock-down; member; neuroregulation; nutrition; peptide hormone; relating to nervous system; response; sensor; social; success; tool; transcriptome

PROJECT SUMMARY/ABSTRACT This proposal aims to determine how interoceptive nutrient detection modulates chemosensory responses and innate behavior. Protein-rich foods are widely considered beneficial to postpartum mothers by supplying energy and cellular building materials, or improving moods by acting as precursors for neurotransmitters. However, it remains unclear whether the nutrient’s restorative effect can also arise from other means: specifically, whether and how dietary amino acids can trigger signaling events to modulate neuronal function and behavior. To address these complex questions, it is necessary to dissociate the multifaceted functions of dietary proteins in neuromodulation or nutrition. Gut enteroendocrine cells, found in both flies and mammals, present excellent opportunities to address these questions, because these cells release peptide hormones in a nutrient-specific manner and, with modern genetic tools, can be specifically manipulated to release their hormones without ingestion of the nutrients. Using fruit flies as a model, this project leverages the powerful genetic toolkit and tractable nervous & gut enteroendocrine systems of D. melanogaster. Preliminary data showed that high-protein diet can accelerate receptivity recovery in mated females. At the molecular level, a subset of enteroendocrine cells exhibits heightened sensitivity to amino acids, thereby increasing the likelihood of releasing a specific peptide hormone from those cells upon protein ingestion. At the neuronal level, high-protein diet heightens the sensitivity of two types of olfactory receptor neurons (ORNs) to external social cues. Importantly, the specific gut-released peptide hormone is necessary for the ORN sensitization as well as the restorative effect of high protein on postmating receptivity. This proposal will test the hypothesis that mated females employ a “gut-to-nose” signaling pathway whereby dietary amino acids trigger the release of a peptide hormone from the gut to regulate sensitivity to social cues and restore critical innate behavior. The proposed experiments will characterize the regulation and function of the gut-released peptide hormone (Aim 1), identify the molecular mechanism by which the specific enteroendocrine cell subset responds to amino acids (Aim 2), and determine the role of peripheral chemosensory neuromodulation on receptivity recovery (Aim 3). The mechanistic insights expected from this research will shed light on how macronutrients impinge on particular internal physiological states to influence neuronal function and behavior—in a manner beyond nutrient assimilation or energy supply. Importantly, the proposed research reveals that nutrient responses of gut enteroendocrine cells can be modulated by mating status, and that the outcome of this modulated interoception (elevated release of a peptide hormone by dietary proteins) can in turn impact exteroception of social cues (ORNs’ sensitization to pheromones).

项目摘要/摘要 这项建议旨在确定互感营养检测如何调节化学感觉反应和 先天行为。富含蛋白质的食物被广泛认为对产后母亲有益，因为它能提供能量。 和细胞建筑材料，或通过充当神经递质的前体来改善情绪。然而，它 目前尚不清楚这种营养素的恢复作用是否还可以通过其他方式产生：具体地说，是否和 饮食氨基酸如何触发信号事件来调节神经元的功能和行为。要解决这些问题 复杂的问题，有必要分离的多方面功能的饮食蛋白质在神经调节或 营养。在苍蝇和哺乳动物中都发现的肠道内分泌细胞提供了很好的机会来解决 这些问题，是因为这些细胞以营养特有的方式释放多肽激素，并与现代 基因工具可以被特别操纵，在不摄取营养的情况下释放荷尔蒙。vbl.使用 以果蝇为模型，这个项目利用了强大的遗传工具箱和易处理的神经和肠道内分泌 黑腹盘藻的系统。初步数据显示，高蛋白饮食可加速大鼠感受性恢复 交配的雌性。在分子水平上，一部分肠内分泌细胞对氨基酸表现出高度的敏感性。 酸，从而增加从这些细胞向蛋白质释放特定多肽激素的可能性 摄取。在神经元水平上，高蛋白饮食提高了两种嗅觉感受器神经元的敏感性 (Orns)对外部社会线索的反应。重要的是，特定的肠道释放的多肽激素对于ORN是必要的。 以及高蛋白对交配后感受性的恢复作用。这项提案将考验 交配雌性采用“肠道到鼻子”信号通路的假说，由此饮食氨基酸触发 从肠道释放一种多肽荷尔蒙，以调节对社会暗示的敏感性并恢复关键的先天状态 行为。拟议中的实验将表征肠道释放肽的调节和功能。 激素(目标1)，确定特定的内分泌细胞亚群反应的分子机制 氨基酸(目标2)，并确定外周化学感觉神经调节在感受性恢复中的作用 (目标3)。从这项研究中期待的机械论见解将阐明大量营养素是如何影响 影响神经元功能和行为的特殊内部生理状态--以一种超越营养的方式 同化或能量供应。重要的是，这项拟议的研究揭示了肠道的营养反应 肠内分泌细胞可以通过交配状态进行调节，而这种调节内感觉的结果 (食物蛋白质释放的多肽荷尔蒙增加)反过来会影响社会暗示的外感(Orns‘s 对信息素敏感)。