Dissecting molecular elements of threat behavior

剖析威胁行为的分子要素

• 批准号: 9365800
• 负责人: Sreekanth H. Chalasani
• 金额: $ 48.5万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-07 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9365800
• 关键词: Affect; Afferent Neurons; Alpha Cell; Animals; Anxiety; Automobile Driving; Behavior; Behavioral; Biochemical; Biochemistry; Biological Assay; Biological Models; Blood Circulation; CREB1 gene; CRF receptor type 1; Caenorhabditis elegans; Cardiovascular system; Cell Culture Techniques; Cells; Cellular Stress; Complex; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Cues; Disease; Elements; Environment; Exhibits; Exposure to; Freezing; Gene-Modified; Genes; Genetic; Genetic Models; Genetic Screening; Goals; Homologous Gene; Hour; Human; Imaging Techniques; Individual; Insulin; Interneurons; Intestines; Invertebrates; Knowledge; Ligands; Locomotion; Mammals; Maps; Mediating; Mediator of activation protein; Methods; Mitochondria; Modeling; Molecular; Muscle; Nematoda; Nervous system structure; Neurons; Neuropeptides; Organism; Pathway interactions; Perception; Phenotype; Physiological; Physiology; Play; Process; Recurrence; Role; Sensory; Signal Pathway; Signal Transduction; Staphylococcal Enterotoxin B; Stress; Subcutaneous Tissue; Synapses; System; Therapeutic Intervention; Time; Tissues; Translating; Work; anxiety-related disorders; avoidance behavior; behavioral response; biological adaptation to stress; egg; gain of function; imaging platform; innovation; mutant; neural circuit; neuromechanism; new therapeutic target; novel; novel diagnostics; receptor; response; tool

Summary Animals have an intrinsic ability to respond to threats in their environments, but the underlying mechanisms are poorly understood. A complete understanding of these complex stress-induced behaviors requires the characterization of all participating neurons, their connections, and their interactions with other tissues (including sympathetic connections in the gut, the circulation system, muscles, etc.). However, this level of analysis is difficult to achieve in complex vertebrate organisms. One rational approach is to analyze these processes in simpler invertebrate models. This proposal aims to understand the neural mechanisms that encode threat responses (both behavioral and physiological) in an invertebrate model system. The nematode, Caenorhabditis elegans, provides a unique opportunity to analyze the genes, cells, and circuits that regulate complex behaviors. The Chalasani lab has developed a novel model of threat behaviors that involves interactions between C. elegans and a second predatory nematode species, Pristionchus pacificus. A starving P. pacificus will attack and devour a C. elegans in 30 minutes. C. elegans in turn, seeks to avoid P. pacificus and its secretions. The Chalasani lab has characterized a novel, redundant neural circuit that detects the P. pacificus predator and drives rapid avoidance behavior, which entails a reversal in locomotion followed by a wide-angle turn. In addition to this rapid avoidance, the lab also discovered that C. elegans exposed to predator secretions for a long period of time (30 minutes) exhibit slowed locomotion (freezing), reduced egg- laying behavior, and the induction of mitochondrial stress in multiple tissues. These responses last up to one hour after the predator cue is removed, and are reminiscent of defensive behaviors observed in other predator- prey models. A pilot genetic screen identified seb-3 (the C. elegans homolog of corticotrophin releasing factor receptor 1 (crfr1)) as required for these long-term behavioral and physiological changes. This is the first evidence that CRF signaling affects behavior and physiology in response to an external threat in an invertebrate. Additionally, a cell culture assay system was used to identify a cognate ligand, NLP-49, that activates the SEB-3 receptor. Here, genetic methods will be used to characterize the role played by CRF signaling in coordinating behavioral and physiological changes in response to an external threat. Aim 1 will probe the role of CRF signaling components (the SEB-3 receptor, the NLP-49 ligand, and other potential ligands) in driving predator-mediated behavioral changes. The underlying neural circuits will be mapped. In Aim 2, the mechanism by which CRF signaling in neurons is relayed to other tissues, resulting in the induction of mitochondrial stress, will be determined. In Aim 3, a focused genetic screen will be performed to identify additional components of the CRF signaling pathway that are responsible for stress-induced behavioral and physiological changes. These studies will reveal how neural circuits and the CRF signaling pathway process information about environmental threats to generate adaptive stress responses.

总结 动物有一种内在的能力来应对环境中的威胁，但其潜在的机制是 不太了解。要全面了解这些复杂的压力诱导行为，需要 所有参与神经元的特征，它们的连接，以及它们与其他组织的相互作用 （包括肠道、循环系统、肌肉等中的交感神经连接）。然而，这一水平的 在复杂的脊椎动物生物体中难以实现分析。一个合理的方法是分析这些 简单无脊椎动物模型中的过程。这项提案旨在了解神经机制， 在无脊椎动物模型系统中编码威胁反应（行为和生理）。线虫， 秀丽隐杆线虫，提供了一个独特的机会，分析基因，细胞和电路，调节 复杂的行为Chalasani实验室开发了一种新的威胁行为模型， C之间的相互作用线虫和第二种捕食性线虫物种太平洋棱纹线虫（Pristionchus pacificus）。一个饥饿 P. pacificus会攻击并吞噬C. 30分钟内就能吃到美味的C.反过来，优雅线虫会试图避开太平洋原甲藻， 及其分泌物。Chalasani实验室已经描述了一种新颖的冗余神经回路，它可以检测P。 pacificus捕食者和驱动器快速回避行为，这需要在运动后， 广角转弯除了这种快速回避，实验室还发现C。暴露于 捕食者的分泌物长时间（30分钟）表现出缓慢的运动（冻结），减少产卵， 产蛋行为和多种组织中线粒体应激的诱导。这些反应持续到一个 一小时后，捕食者线索被删除，并让人想起在其他捕食者中观察到的防御行为。 猎物模型一项初步的遗传筛选鉴定了seb-3（C。促肾上腺皮质激素释放因子 受体1（CRFR 1）），如这些长期行为和生理变化所需。这是第一 证据表明，CRF信号影响行为和生理反应，以应对外部威胁， 无脊椎动物另外，使用细胞培养测定系统来鉴定同源配体NLP-49，其 激活SEB-3受体。在这里，遗传学方法将被用来描述CRF所扮演的角色 在协调响应外部威胁的行为和生理变化的信号。目标1将 探索CRF信号传导成分（SEB-3受体，NLP-49配体和其他潜在的 配体）驱动捕食者介导的行为变化。基本的神经回路将被绘制出来。在 目的2、研究CRF信号在神经元中传递到其他组织，导致神经元中CRF信号传导的机制。 线粒体压力的影响。在目标3中，将进行重点基因筛查， CRF信号通路的其他成分，负责应激诱导的行为和 生理变化这些研究将揭示神经回路和CRF信号通路的过程 关于环境威胁的信息，以产生适应性压力反应。