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.

项目概要 血清素和神经肽等神经调节剂可以对神经产生广泛而持久的影响 电路和行为。这种信号传导模式对于大脑功能至关重要。神经调节信号功能失调 导致宿主神经和精神疾病，而神经调节信号通路是其目标 临床上重要的治疗方法和滥用药物。该项目的目标是增进对 调节神经调节系统发育和功能的分子机制 行为。为此，我们研究了线虫，它的神经系统较小且易于接近 与人脑中发现的大多数神经调节剂一起。线虫的许多行为都需要特定的 神经调节剂并且易于进行遗传分析，从而可以公正地发现所需的因素 用于神经调节信号传导或神经调节系统的开发。我们发现了一个电路 结合两种类型的神经调节来控制简单且刻板的秀丽隐杆线虫行为。化学感应 BAG 神经元释放神经肽，有效抑制生殖系统中的一对血清素能神经元 线虫雌雄同体的神经肌肉系统 - HSN。通过对行为的基因研究产生 通过这个回路，我们发现了肽能 BAG 的发育和功能所需的基因， 神经肽调节 HSN 功能和生殖行为所需的因素。除了服务之外 作为神经调节的模型，该电路使我们能够研究动物微生物的神经生物学 互动。 BAG 神经元检测微生物呼吸产生的二氧化碳，它们的功能是 评估环境微生物质量并允许秀丽隐杆线虫区分的电路 营养微生物和病原体。我们将对宿主-微生物相互作用的兴趣与我们对 通过对微生物代谢物的研究来进行神经调节，这些代谢物作为血清素信号传导的激动剂来影响 动物行为。迄今为止，我们的研究已经揭示了发育和功能中的功能 Toll 样受体的神经调节系统及其相关信号通路、胰岛素信号传导、 进化上保守的转录因子和神经元兴奋性的调节因子。生化和遗传 基于这些发现的屏幕不断产生新的因素，我们预计该电路将继续 充当理解神经调节分子机制的强大平台。