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: 9277049
• 负责人: Niels Ringstad
• 金额: $ 26.24万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277049
• 关键词: Afferent Neurons; Autistic Disorder; Behavior Control; Brain; Brain Diseases; Breathing; Caenorhabditis elegans; Carbon Dioxide; Critical Pathways; Development; Functional disorder; Gene Expression; Genes; Genetic; Glutamates; Human; Invertebrates; Link; Mediating; Mental disorders; Modality; Molecular; Molecular Genetics; Motor; Nervous system structure; Neuromodulator; Neurons; Neuropeptide Receptor; Neuropeptides; Neurotransmitters; Parkinson Disease; Process; Psychiatric therapeutic procedure; Reproductive Behavior; Respiration; Schizophrenia; Sensory; Serotonin; Signal Pathway; Signal Transduction; System; Transcriptional Regulation; addiction; avoidance behavior; gene discovery; gene function; genetic analysis; glutamatergic signaling; human disease; in vivo; microbial; nervous system disorder; neural circuit; neurodevelopment; neuron development; neuronal excitability; programs; respiratory gas; targeted treatment; therapeutic target

PROJECT SUMMARY Neuromodulator and neurotransmitter signaling pathways are critical for brain function and are targeted for the treatment of diverse neurological and psychiatric disorders. The nervous system of the simple invertebrate Caenorhabditis elegans is endowed with many of the same neurotransmitters and neuromodulators that are critical for brain function and whose dysfunction is linked to human disease. We study a C. elegans neural circuit in which sensory neurons use neuropeptides to modulate serotonin neurons that drive reproductive behavior and the neurotransmitter glutamate to mediate avoidance behavior. Genetic analysis of the function of this circuit and its development permits the discovery of molecular mechanisms required in vivo for inhibitory neuropeptide signaling and excitatory glutamate signaling. Sensory neurons that coordinately regulate locomotory and reproductive behaviors are activated by carbon dioxide (CO2) evolved by microbial respiration. This simple circuit, therefore, also offers the opportunity to study mechanisms by which neurons sense respiratory gases - a critical chemosensory modality that in humans controls breathing rhythms and remains poorly understood at the molecular level. Our studies of this circuit have yielded genes that are conserved between invertebrates and humans, and we have discovered functions for these genes in transcriptional control of gene expression during sensory neuron development, CO2-chemosensing, control of glutamate release from neurons, and control of neuronal excitability by neuropeptide receptors. Our studies have yielded more genes that function in these processes and that remain to be characterized, and we expect that this sensory-motor circuit will continue to serve as a powerful platform for the discovery of genes that function in neuromodulator and neurotransmitter signaling and that might be eventually be developed as therapeutic targets.

项目概要 神经调节剂和神经递质信号通路对于大脑功能至关重要，并且针对 治疗多种神经和精神疾病。简单无脊椎动物的神经系统 秀丽隐杆线虫具有许多与线虫相同的神经递质和神经调节剂。 对大脑功能至关重要，其功能障碍与人类疾病有关。我们研究秀丽隐杆线虫神经 感觉神经元使用神经肽来调节驱动生殖的血清素神经元的电路 行为和神经递质谷氨酸介导回避行为。功能的遗传分析 该电路的研究及其发展允许发现体内抑制所需的分子机制 神经肽信号传导和兴奋性谷氨酸信号传导。协调调节的感觉神经元 运动和生殖行为是由微生物呼吸产生的二氧化碳（CO2）激活的。 因此，这个简单的电路也提供了研究神经元感知机制的机会 呼吸气体 - 人类控制呼吸节律和保持的重要化学感应方式 在分子水平上了解甚少。我们对该电路的研究产生了保守的基因 在无脊椎动物和人类之间，我们发现了这些基因在转录中的功能 感觉神经元发育过程中基因表达的控制、CO2 化学传感、谷氨酸控制 从神经元释放，并通过神经肽受体控制神经元兴奋性。我们的研究取得了成果 更多在这些过程中发挥作用且仍有待表征的基因，我们预计这 感觉运动回路将继续作为发现功能基因的强大平台 神经调节剂和神经递质信号传导，最终可能被开发为治疗药物 目标。