Synaptic target selection in the thermotaxis neural circuit of C. elegans

线虫趋热神经回路中的突触目标选择

• 批准号: 7891988
• 负责人: DANIEL A COLON-RAMOS
• 金额: $ 1.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891988
• 关键词: Address; Affect; Afferent Neurons; Animals; Autistic Disorder; Axon; Behavior; Behavioral; Biological Models; Brain; Caenorhabditis elegans; Cells; Chemotaxis; Cloning; Complex; Defect; Dendrites; Development; Environment; Exhibits; Future; Genetic Screening; Goals; Grant; Human; Imagery; Immunoglobulins; Interneurons; Label; Lead; Learning; Location; Molecular; Nematoda; Neurites; Neurodevelopmental Disorder; Neurons; Pattern; Phenotype; Play; Presynaptic Terminals; Proteins; Research; Research Project Grants; Role; Schizophrenia; Signal Pathway; Signal Transduction; Site; Sorting - Cell Movement; Specific qualifier value; Specificity; Structure; Synapses; Synaptic Vesicles; System; Visual; Work; axon guidance; base; behavior influence; human disease; immunoglobulin receptor; in vivo; insight; multidisciplinary; mutant; neural circuit; novel; postsynaptic; presynaptic; programs; research study; rib bone structure; synaptogenesis

The human brain consists of approximately 100 billion neurons, which form over 100 trillion synapses with specific targets. How neurons find the correct targets and how the correct wiring of the brain influences behavior are central questions, and the focus of this proposal. The nematode C. elegans offers an excellent model system to explore how synaptic specificity is achieved in vivo, and how correct synaptic choices influence the formation of neuronal circuits, and behavior. AIY, an important interneuron in the C. elegans brain, receives inputs from multiple sensory neurons to modulate behaviors such as thermotaxis, chemotaxis and learning. During development AIY contacts many neurites, but selects only three neurons (RIA, RIB and AIZ) as its postsynaptic partners. The molecular mechanisms used by AIY to discriminate between potential targets and form functional neuronal circuits are not understood. Here I propose to characterize how synaptogenesis is regulated in the complex environment of the C. elegans brain by studying synaptic formation in the thermotaxis neural circuit. A visual forward genetic screen on AIY synapses has yielded multiple mutants with abnormal synaptic patterns. I will identify AIY synaptic specificity molecules by characterizing these mutants. Initial characterization of one class of mutants indicates that immunoglobulin superfamily protein UNC-40/DCC directs AIY synaptogenesis in a cell autonomous manner. In unc-40 mutant, AIY exhibits normal axon trajectory with abnormal presynaptic locations. UNC-40 localizes to AIY presynaptic sites in wild type animals. Furthermore, mislocalization of UNC-40 leads to ectopic presynaptic terminal formation at the location of mislocalized UNC-40. Further experiments will identify the mechanism by which unc-40 directs synaptic target selection in AIY. Future characterization of mutants with similar AIY phenotype as unc-40 will determine the molecular signaling pathway that leads to correct AIY synaptogenesis. Together our work promises to lend us insights into the molecular components that direct correct synaptogenesis in the C. elegans brain. Altered synaptogenesis might lead to a number of neurodevelopmental disorders and human diseases such as schizophrenia and autism. Understanding correct synaptogenesis should provide insights into how functional neuronal circuits are constructed during development and how the correct formation of these circuits affects behavior.

人类大脑由大约1000亿个神经元组成，这些神经元形成超过100万亿个突触， 具体目标。神经元如何找到正确的目标以及大脑的正确布线如何影响 行为是中心问题，也是本提案的重点。线虫C. elegans提供了一个很好的 模型系统来探索突触特异性是如何在体内实现的，以及正确的突触选择是如何实现的。 影响神经回路的形成和行为。AIY是C. elegans 大脑，接收来自多个感觉神经元的输入以调节行为，例如趋热性、趋化性 和学习在发育过程中，AIY接触许多神经突，但仅选择三种神经元（RIA、RIB和RIA）。 AIZ）作为其突触后伙伴。AIY用于区分潜在的 目标和形式的功能神经元回路是不理解的。在这里，我建议描述如何 突触发生在C. elegans大脑通过研究突触 趋热性神经回路的形成。对AIY突触的视觉遗传筛查已经产生了 多个突变体的突触模式异常我将通过以下方式识别AIY突触特异性分子 描述这些突变体。一类突变体的初步表征表明，免疫球蛋白 超家族蛋白NAT-40/DCC以细胞自主的方式指导AIY突触发生。在unc-40中 突变体，AIY表现出正常的轴突轨迹与异常的突触前位置。AE 40本地化到AIY 野生动物的突触前位点。此外，错误定位的α-40导致异位突触前 在错误定位的α-40的位置处形成末端。进一步的实验将确定其机制 unc-40通过其指导AIY中的突触靶选择。具有类似AIY的突变体的未来表征 表型为unc-40将决定导致正确AIY的分子信号通路 突触发生我们的工作有望帮助我们深入了解 在C.优雅的大脑突触发生的改变可能会导致一些 神经发育障碍和人类疾病如精神分裂症和自闭症。理解 正确的突触发生应该提供关于功能性神经元回路是如何在 以及这些回路的正确形成如何影响行为。