Molecular genetics of sensory modulation of motor programs

运动程序感觉调节的分子遗传学

• 批准号: 10414440
• 负责人: Niels Ringstad
• 金额: $ 58.69万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414440
• 关键词: Affect; Animal Behavior; Animals; Behavior; Behavior Control; Biochemical Genetics; Brain; Caenorhabditis elegans; Carbon Dioxide; Clinical; Complex; Development; Experimental Models; Genes; Genetic Screening; Genetic study; Goals; Hermaphroditism; Human; Invertebrates; Link; Mental Depression; Mental disorders; Microbe; Modeling; Molecular; Molecular Genetics; Mood Disorders; Motor; Nematoda; Nervous system structure; Neurobiology; Neuromodulator; Neurons; Neuropeptides; Parkinson Disease; Psychiatric therapeutic procedure; Reproductive Behavior; Respiration; Schizophrenia; Sensory; Serotonin; Serotonin Agonists; Signal Pathway; Signal Transduction; Stereotyping; System; Therapeutic; Toll-like receptors; addiction; base; behavioral study; drug of abuse; gene discovery; genetic analysis; host-microbe interactions; in vivo; insulin signaling; interest; microbial; nervous system disorder; neural circuit; neuronal excitability; neuroregulation; pathogenic microbe; programs; reproductive; transcription factor

PROJECT SUMMARY Neuromodulators such as serotonin and neuropeptides can exert widespread and lasting effects on neural circuits and behavior. This mode of signaling is critical for brain function. Dysfunctional neuromodulator signaling causes a host neurological and psychiatric disorders, and neuromodulator signaling pathways are targets of clinically important therapeutics and drugs of abuse. The goal of this project is to advance understanding of molecular mechanisms that regulate the development and function of neuromodulatory systems that control behavior. For this, we study the roundworm C. elegans, whose small and accessible nervous system is endowed with most of the neuromodulators found in the human brain. Many behaviors of C. elegans require specific neuromodulators and are amenable to genetic analysis, which permits unbiased discovery of factors required for neuromodulator signaling or the development of neuromodulatory systems. We have found a circuit that combines two types of neuromodulation to control a simple and stereotyped C. elegans behavior. Chemosensory BAG neurons release neuropeptides that potently inhibit a pair of serotonergic neurons in the reproductive neuromusculature of the C. elegans hermaphrodite - the HSNs. Through genetic studies of behaviors generated by this circuit we have discovered genes required for the development and function of peptidergic BAGs and factors required for neuropeptides to modulate HSN function and reproductive behavior. In addition to serving as a model for neuromodulation, this circuit allows us to investigate the neurobiology of animal-microbe interactions. BAG neurons detect the carbon dioxide generated by microbial respiration, and they function in a circuit that evaluates the quality of environmental microbes and that allows C. elegans to discriminate between nutritive microbes and pathogens. We have linked our interest in host-microbe interactions to our interest in neuromodulation through a study of microbial metabolites that function as agonists of serotonin signaling to affect animal behavior. To date our studies have revealed functions in the development and function of neuromodulatory systems for a Toll-like receptor and its associated signaling pathway, insulin signaling, evolutionarily conserved transcription factors, and regulators of neuronal excitability. Biochemical and genetic screens based on these discoveries continue to yield new factors, and we expect that this circuit will continue to serve as a powerful platform for understanding molecular mechanisms of neuromodulation.

项目摘要 神经调节剂（例如5-羟色胺和神经肽）会对神经产生广泛和持久的影响 电路和行为。这种信号传导对于大脑功能至关重要。功能失调的神经调节剂信号传导 引起宿主神经和精神疾病，神经调节剂信号通路是 临床上重要的虐待治疗和药物。该项目的目的是提高对 调节控制神经调节系统的发展和功能的分子机制 行为。为此，我们研究round虫秀丽隐杆线虫，其小且可及的神经系统被赋予 在人脑中发现的大多数神经调节剂。秀丽隐杆线虫的许多行为都需要特定 神经调节剂，并且适合遗传分析，这允许无偏见的发现所需的因素 用于神经调节剂信号或神经调节系统的发展。我们找到了一个电路 结合了两种类型的神经调节，以控制一种简单而定型的秀丽隐杆线虫行为。化学感应 袋神经元释放神经肽，可有效抑制一对血清素能神经元的生殖神经元 秀丽隐杆线虫雌雄同体的神经肌肉 - hsns。通过产生的行为的遗传研究 通过该电路，我们发现了肽袋的开发和功能所需的基因和 神经肽需要调节HSN功能和生殖行为所需的因素。除了服务 作为神经调节的模型，该电路允许我们研究动物 - 菌的神经生物学 互动。袋神经元检测微生物呼吸产生的二氧化碳，它们在A中起作用 评估环境微生物质量的电路，并允许秀丽隐杆线虫区分 营养微生物和病原体。我们已经将我们对宿主互动的兴趣与我们的兴趣联系在一起 通过研究微生物代谢物的神经调节，该代谢物充当5-羟色胺信号的激动剂来影响 动物行为。迄今为止，我们的研究揭示了在开发和功能中的功能 Toll样受体及其相关信号通路的神经调节系统，胰岛素信号传导， 进化保守的转录因子和神经元兴奋性的调节剂。生化和遗传 基于这些发现的屏幕继续产生新的因素，我们预计该电路将继续 用作理解神经调节的分子机制的强大平台。