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.

概括 动物具有对环境中威胁的反应的内在能力，但潜在的机制是 理解不佳。对这些复杂的压力引起的行为的完全理解需要 表征所有参与神经元，它们的连接及其与其他组织的相互作用 （包括肠道中的交感神经联系，循环系统，肌肉等）。但是，这个水平 在复杂的脊椎动物中很难进行分析。一种合理的方法是分析这些 在简单的无脊椎动物模型中的过程。该建议旨在了解神经机制 编码无脊椎动物模型系统中的威胁响应（行为和生理）。线虫， 秀丽隐杆线虫提供了一个独特的机会，可以分析调节的基因，细胞和电路 复杂的行为。 Chalasani实验室已经开发了一种新颖的威胁行为模型 秀丽隐杆线虫与第二种掠食性线虫物种之间的相互作用Pristionchus Pacificus。挨饿 P. Pacificus将在30分钟内进攻并吞噬秀丽隐杆线虫。秀丽隐杆线虫反过来试图避免太平洋假单胞菌 及其分泌物。 Chalasani实验室表征了一种新型的冗余神经回路，该神经回路检测P。 太平洋捕食者并推动了快速回避行为，这需要运动逆转 广角转。除了这种快速回避之外，该实验室还发现秀丽隐杆线虫暴露于 长时间（30分钟）长时间的捕食者分泌表现出慢速运动（冻结），鸡蛋降低 铺设行为，以及多个组织中线粒体应激的诱导。这些回应持续到一个 消除捕食者提示后的一小时，并让人联想到其他捕食者中观察到的防御行为 猎物模型。试点遗传筛选鉴定出SEB-3（C.秀丽隐杆线虫同源物的释放因子 这些长期行为和生理变化所需的受体1（CRFR1））。这是第一个 CRF信号传导会影响行为和生理的证据，以应对外部威胁 无脊椎动物。此外，使用细胞培养测定系统来识别同源配体NLP-49，即 激活SEB-3受体。在这里，遗传方法将用于表征CRF扮演的角色 响应外部威胁的行为和生理变化的协调和生理变化的信号传导。目标1意志 探测CRF信号传导成分（SEB-3受体，NLP-49配体和其他电势）的作用 配体）驱动捕食者介导的行为变化。下层神经回路将被映射。在 AIM 2，神经元中CRF信号传导传递到其他组织的机制，导致诱导 将确定线粒体应力的。在AIM 3中，将进行集中的遗传屏幕以识别 CRF信号通路的其他组成部分，这些组件负责压力引起的行为和 生理变化。这些研究将揭示神经回路和CRF信号通路如何 有关环境威胁产生自适应压力反应的信息。