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.

摘要 非典型的基于感觉的行为是许多人类疾病的共同特征，包括自闭症 谱系障碍、精神分裂症、脆性X等。尽管如此，人们对这些基因如何与 这些情况会影响感觉行为。要完全理解这一过程，需要一个彻底的 基本神经回路的特征，以及测量和干扰脑电活动的能力 这些电路。线虫，秀丽线虫，为分析基因，细胞， 以及调节复杂行为的电路，因为它的神经系统只由302个神经元组成，通过 识别出利用高度保守的突触机制的突触。Chalasani实验室已经证明C. 人类自闭症相关基因(NRX和NLG)的线虫同源物影响 对特定感官刺激敏感，这些基因的突变导致对驱避剂的低敏感性 铜刺激。他们建议识别线虫特定的突触，这两种突触蛋白位于 改变感官行为的功能。此外，他们计划确定在什么情况下的发育时间窗口 这些基因是产生典型行为的年轻人所必需的(目标1)。此外，他们还表明， 与神经连接蛋白突变体(NLG-1)相关的感觉缺陷可通过NPR-1基因突变得到修复 当这种基因发生突变时，就会导致一种“社会”聚集行为。他们建议识别神经 这种相互作用的基础机制，并揭示了NPR-1信号通路的组件，这些组件作用于 抑制NLG-1行为缺陷(目标2)。最后，他们确定了新培康酸和cgp-13501为 抑制NLG-1行为缺陷的候选小分子。他们计划绘制细胞和分子的图谱 这些药物在线虫中的靶点，分析在这一过程中修改NRX-1/NLG-1信号的遗传途径 模型(目标3)。这些研究将揭示NRX-NLG信号改变感觉行为的机制 在基因、突触、回路和整个动物的水平上，为进一步分析 脊椎动物模型。由于NLG和NRX都与自闭症谱系障碍有牵连，结果可能会有所下降 阐明人类疾病潜在的分子和电路机制，这些疾病与 感官处理。

项目成果

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

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.

Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans.

神经肽信号转导秀丽隐杆线虫中的化学感应回路组成。

• 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

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