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.

概括 基于感觉的行为是许多人类状况的共同特征，包括自闭症 谱系障碍，精神分裂症等。尽管如此，对这些基因如何相关的知之甚少 条件会影响感觉行为。对这一过程的完全理解需要彻底 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。线虫秀丽隐杆线虫提供了一个独特的机会，可以分析基因，细胞， 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 确定利用高度保守的突触机械的突触。 Chalasani，Hart和Pierce Labs有 表明在人自闭症相关基因的秀丽隐杆线虫同源物中的功能丧失突变体（Neurexin （NRX）和Neuroligin（NLG））极大地减弱了野生和实验室菌株中的聚集行为。另外， Chalasani和Hart Labs发现，在特定的化学感应神经元和完整的谷氨酸中需要NRX 信号以修改聚合行为。他们建议绘制经过修改的突触信号通路 通过NRX-NLG信号传导调节聚合行为（AIM 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自然遗传变异。他们建议确定 相关基因并使用QTL映射验证它们，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（AIM 2）。 Chalasani实验室发现 NRX，但没有NLG功能丧失突变体的肠道泄漏。接下来，他们获得了肠道特异性的 转录组以鉴定其表达在NRX突变体中被选择性改变的候选基因。他们 建议使用遗传方法来确认这些基因影响肠道完整性的作用。值得注意的是 信号通路，其哺乳动物同源物可能与观察到的胃肠道问题有关 患有ASD诊断的个体（AIM 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的途径。重要的是，这个 提案汇集了三个具有互补专业知识的实验室，以迅速发展 复杂的NRX-NLG表型的机制。