Dissecting neural mechanisms integrating multiple inputs in C.elegans

剖析线虫中整合多种输入的神经机制

• 批准号: 10396076
• 负责人: Sreekanth H. Chalasani
• 金额: $ 48.1万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396076
• 关键词: Acids; Adult; Affect; Agonist; Animals; Automobile Driving; Behavior; Behavioral; Biochemical; Brain; Caenorhabditis elegans; Cell Adhesion Molecules; Cells; Chemicals; Complementary DNA; Complex; Copper; Data; Defect; Development; Disease; Drug Targeting; Exhibits; Foundations; Fragile X Syndrome; Genes; Genetic; Goals; Human; Image; Imaging Device; Ligands; Light; Link; Maps; Measures; Mediating; Methods; Modeling; Molecular; Molecular Target; Mutate; Mutation; Nematoda; Nervous system structure; Neurons; Neuropeptide Y Receptor; Nipecotic Acids; Pathway interactions; Pharmaceutical Preparations; Process; Proteins; Schizophrenia; Sensory; Signal Pathway; Signal Transduction; Site; Solid; Stimulus; Synapses; Therapeutic Intervention; Time; Transgenic Animals; analog; autism spectrum disorder; avoidance behavior; base; behavioral response; cell type; cellular targeting; diagnostic tool; gamma-Aminobutyric Acid; genetic analysis; genetic approach; high resolution imaging; human disease; imaging platform; inhibitor; insight; molecular drug target; mutant; neural circuit; neuroligin 1; neuromechanism; new therapeutic target; presynaptic; protein function; receptor; response; reuptake; sensory stimulus; small molecule; small molecule libraries; social; synaptic function; young adult

Summary Atypical sensory-based behaviors are a common feature of a number of human conditions, including autism spectrum disorder, schizophrenia, fragile X, etc. Despite this, little is known about how the genes associated with these conditions affect sensory behavior. A complete understanding of this process requires a thorough characterization of the underlying neural circuitry, along with the ability to measure and perturb the activity of these circuits. The nematode, Caenorhabditis elegans, provides a unique opportunity to analyze genes, cells, and circuits regulating complex behaviors, as its nervous system consists of just 302 neurons interconnected via identified synapses that utilize highly conserved synaptic machineries. The Chalasani lab has shown that C. elegans homologs of the human autism-associated genes (neurexin (NRX) and neuroligin (NLG)) affect sensitivity to specific sensory stimuli, and that mutations in these genes result in hyposensitivity to a repellent copper stimulus. They propose to identify the specific C. elegans synapses where these two synaptic proteins function to modify sensory behaviors. Additionally, they plan to identify the developmental time window in which these genes are required to generate a typically behaving young adult (Aim 1). Moreover, they have shown that sensory defects associated with neuroligin mutants (nlg-1) are rescued by mutations in the gene npr-1, a gene that when mutated alone results in a “social” aggregation behavior. They propose to identify the neural mechanisms that underlie this interaction and reveal components of the NPR-1 signaling pathway that act to suppress nlg-1 behavioral defects (Aim 2). Finally, they have identified Nipecotic acid and CGP-13501 as candidate small molecules that suppress nlg-1 behavioral deficits. They plan to map the cellular and molecular targets of these drugs in C. elegans, analyzing the genetic pathways modifying NRX-1/NLG-1 signaling in this model (Aim 3). These studies will reveal mechanisms by which NRX-NLG signaling modifies sensory behavior at the level of genes, synapses, circuits, and whole animals, providing a solid foundation for further analyses in vertebrate models. As both NLG and NRX have been implicated in autism spectrum disorder, results may shed light on molecular and circuit mechanisms underlying human disorders that have been linked to abnormalities in sensory processing.

概括 基于感觉的行为是许多人类状况的常见特征，包括自闭症 谱系障碍，精神分裂症，脆弱的X等。尽管如此，与与之相关的Genessect。 这些条件会影响感觉行为。 表征下面的神经回路，以及测量和扰动活性的能力 这些电路。 并且电路调节复杂行为，因为它的神经系统仅由302个神经元组成 鉴定出使用高度保守的突触机器的突触。 人类自闭症相关基因（NEUREXIN（NRX）和Neuroligin（NLG））的秀丽隐杆线虫同源物影响 对特定感觉刺激的敏感性，这些基因的突变导致驱虫剂的敏感性 铜刺激。他们提议识别这两个突触蛋白 修改感觉行为的功能。 这些基因需要产生一个典型的年轻人（AIM 1）。 与神经素突变体相关的感觉缺陷（NLG-1）通过基因NPR-1中的突变挽救了基因 然后，单独进行叛变导致“社会”聚集行为。 这种相互作用并揭示了该动作的NPR-1信号通路的组成部分的机制。 抑制NLG-1的行为缺陷（AIM 2）。 抑制NLG-1行为缺陷的候选小分子计划映射细胞和分子 秀丽隐杆线虫中这些药物的靶标，分析了修改NRX-1/NLG-1信号传导的遗传途径 模型（AIM 3）。 在基因，突触，电路和全动物的水平上，为进一步分析提供了坚实的基础 脊椎动物模型作为NLG和NRX都与自闭症谱系有关 关于分子和电路机制的照明人类疾病的人类疾病，这些人疾病已被异常 感官处理。

项目成果

Divergent and convergent roles for insulin-like peptides in the worm, fly and mammalian nervous systems.

• DOI: 10.1007/s10158-013-0166-9
• 发表时间: 2014-09
• 期刊: INVERTEBRATE NEUROSCIENCE
• 作者: Lau, Hiu E.;Chalasani, Sreekanth H.
• 通讯作者: Chalasani, Sreekanth H.

From genes to circuits and behaviors: Neuropeptides expand the coding potential of the nervous system.

• DOI: 10.4161/worm.27730
• 发表时间: 2014
• 期刊: Worm
• 作者: Leinwand SG;Chalasani SH
• 通讯作者: Chalasani SH

Sonogenetics is a non-invasive approach to activating neurons in Caenorhabditis elegans.

• DOI: 10.1038/ncomms9264
• 发表时间: 2015-09-15
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Ibsen S;Tong A;Schutt C;Esener S;Chalasani SH
• 通讯作者: Chalasani SH

Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans.

• DOI: 10.1038/nn.3511
• 发表时间: 2013-10
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Leinwand, Sarah G.;Chalasani, Sreekanth H.
• 通讯作者: Chalasani, Sreekanth H.

Altered Sensory Code Drives Juvenile-to-Adult Behavioral Maturation in Caenorhabditis elegans.

• DOI: 10.1523/eneuro.0175-16.2016
• 发表时间: 2016-11
• 期刊: eNeuro
• 影响因子: 3.4
• 作者: Hale LA;Lee ES;Pantazis AK;Chronis N;Chalasani SH
• 通讯作者: Chalasani SH