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: 10887010
• 负责人: Sreekanth H. Chalasani
• 金额: $ 63.94万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10887010
• 关键词: Adult; Affect; Afferent Neurons; Animal Behavior; Animal Feed; Animals; Attenuated; Automobile Driving; Behavior; Behavioral; Biological Assay; Brain; Caenorhabditis elegans; Candidate Disease Gene; Cells; Complex; Diagnosis; Disease; Dyes; Food; Fragile X Syndrome; Functional Imaging; Gene Modified; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Glutamates; Homologous Gene; Homologous Protein; Human; Image; Intestines; Life Cycle Stages; Link; Maps; Measures; Mediating; Methods; Modeling; Molecular Probes; Nematoda; Nervous System; Neurons; Neuropeptides; Pathway interactions; Patients; Peptide Signal Sequences; Phenotype; Physiological; Physiology; Process; Quantitative Trait Loci; Resolution; Role; Schizophrenia; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Social Behavior; Stains; Structure; Synapses; Testing; Therapeutic Intervention; Variant; aged; autism spectrum disorder; candidate identification; cytomatrix; diagnostic tool; gastrointestinal; genome wide association study; glutamatergic signaling; imaging modality; individuals with autism spectrum disorder; insight; intestinal barrier; loss of function; multisensory; mutant; neural circuit; neuromechanism; neurotransmission; new therapeutic target; postsynaptic; presynaptic; risk variant; sensory stimulus; social; tool; transcriptome; uptake; whole genome

Summary Atypical sensory-based behaviors are a common feature of a number of human conditions, including autism spectrum disorder, schizophrenia, 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 machinery. The Chalasani, Hart, and Pierce labs have shown that loss-of-function mutants in C. elegans homologs of the human autism-associated genes (neurexin (NRX) and neuroligin (NLG)) greatly attenuate aggregation behavior in both wild and lab strains. In addition, the Chalasani and Hart labs have found that NRX is required in specific chemosensory neurons and intact glutamate signaling to modify aggregation behavior. They propose to map the synaptic signaling pathways that are modified by NRX-NLG signaling to regulate aggregation behavior (Aim 1). The Pierce lab has recently found evidence for natural genetic variation that interacts with NRX and NLG to modify aggregation deficits. They propose to identify the relevant genes and validate them using QTL mapping, revealing insights into the NRX-, and NLG-genome interactions critical for animal behavior and intestine physiology (Aim 2). The Chalasani lab has discovered that NRX, but not NLG loss-of-function mutants have leaky intestines. Next, they obtained intestinal-specific transcriptomes to identify candidate genes whose expression is selectively altered in NRX mutants. They propose to use genetic methods to confirm roles for these genes in affecting intestinal integrity. Notably, these signaling pathways, whose mammalian homologs might be relevant to gastrointestinal issues observed in individuals with an ASD diagnosis (Aim 3). These studies will reveal the genes, neurons, synapses, and signaling pathways by which NRX-NLG signaling drives sensory behavior and animal physiology. Importantly, this proposal brings together three labs with complementary expertise to make rapid progress toward revealing the mechanisms underlying the complex NRX-NLG phenotypes.

总结 非典型的基于感觉的行为是包括自闭症在内的许多人类疾病的共同特征 尽管如此，人们对与这些疾病相关的基因是如何产生的知之甚少。 条件影响感官行为。要完全理解这一过程， 沿着测量和干扰神经元活动的能力， 这些电路。线虫，秀丽隐杆线虫，提供了一个独特的机会，分析基因，细胞， 和控制复杂行为的电路，因为它的神经系统只有302个神经元， 识别出利用高度保守的突触机制的突触。查拉萨尼哈特和皮尔斯实验室 表明C.人类孤独症相关基因（neurexin）的同源物 (NRX)和神经连接素（NLG））极大地减弱了野生型和实验室菌株中的聚集行为。此外该 Chalasani和哈特实验室发现，特定的化学感受神经元和完整的谷氨酸需要NRX 信令以修改聚合行为。他们建议绘制被修饰的突触信号通路 通过NRX-NLG信号传导来调节聚集行为（目标1）。皮尔斯实验室最近发现了 与NRX和NLG相互作用以改变聚集缺陷的天然遗传变异。他们建议确定 相关基因，并使用QTL作图验证它们，揭示了对NRX和NLG基因组的见解 对动物行为和肠道生理学至关重要的相互作用（目的2）。查拉萨尼实验室发现， NRX，而不是NLG功能丧失突变体有肠漏。接下来，他们获得了 转录组来鉴定其表达在NRX突变体中选择性改变的候选基因。他们 建议使用遗传学方法来确认这些基因在影响肠道完整性中的作用。值得注意的是， 信号通路，其哺乳动物同源物可能与胃肠道问题有关， 患有ASD诊断的人（目标3）。这些研究将揭示基因、神经元、突触和信号传导 NRX-NLG信号传导驱动感觉行为和动物生理学的途径。重要的是这 该提案汇集了三个具有互补专业知识的实验室，以便在揭示 复杂NRX-NLG表型的潜在机制。