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).

项目总结/摘要 该提案旨在确定内感受性营养检测如何调节化学感觉反应， 天生的行为富含蛋白质的食物被广泛认为通过提供能量对产后母亲有益 和细胞建筑材料，或者通过充当神经递质的前体来改善情绪。但 目前尚不清楚这种营养素的恢复作用是否也可以通过其他方式产生：具体来说， 饮食中氨基酸如何触发信号事件来调节神经元功能和行为。解决这些 复杂的问题，有必要分离膳食蛋白质在神经调节或 营养肠道内分泌细胞，在苍蝇和哺乳动物中发现，提供了极好的机会， 这些问题，因为这些细胞释放肽激素在营养特异性的方式，并与现代 基因工具，可以专门操纵释放激素，而不摄入营养素。使用 果蝇作为模型，该项目利用强大的遗传工具包和易处理的神经和肠道肠内分泌 系统D.黑腹菌初步数据表明，高蛋白饮食可以加速感受性恢复， 交配的雌性在分子水平上，肠内分泌细胞的一个子集表现出对氨基的高度敏感性。 酸，从而增加从这些细胞释放特定肽激素的可能性， 摄入在神经元水平，高蛋白饮食提高了两种类型的嗅觉受体神经元的敏感性 （ORN）外部社会线索。重要的是，特定的肠道释放肽激素是ORN所必需的。 致敏以及高蛋白对交配后感受性的恢复作用。这项提案将考验 假设交配的雌性采用“肠到鼻”的信号通路，由此膳食氨基酸触发 从肠道释放肽激素，以调节对社会线索的敏感性，并恢复关键的先天性 行为拟议的实验将表征肠道释放肽的调节和功能 激素（目的1），确定特定的肠内分泌细胞亚群响应的分子机制， 氨基酸（目的2），并确定外周化学感觉神经调节对感受性恢复的作用 (Aim 3）。这项研究预期的机制见解将揭示大量营养素如何影响 特定的内部生理状态影响神经元的功能和行为-在某种程度上超越营养 同化或能量供应。重要的是，拟议的研究表明，肠道的营养反应 肠内分泌细胞可以通过交配状态调节，这种调节的内感受的结果 （饮食蛋白质释放的肽激素增加）反过来又会影响社会线索的外感知（ORN '）。 对信息素敏感）。