Functional roles of chloride homeostasis and chloride ion channels in thermosensory nociception

氯离子稳态和氯离子通道在热感觉伤害感受中的功能作用

• 批准号: 10219826
• 负责人: Nathaniel John Himmel
• 金额: $ 3.32万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219826
• 关键词: Acute Pain; Afferent Neurons; Animals; Behavior; Behavioral; Behavioral Assay; Bilateral; C Fiber; Chemicals; Chloride Channels; Chloride Ion; Chlorides; Complex; Coupled; Dangerousness; Data; Dendrites; Dose; Drosophila genus; Drosophila melanogaster; Electrophysiology (science); Family; Functional Imaging; Genes; Genetic; Genetic Models; Head; Health; High temperature of physical object; Homeostasis; Human; Hyperalgesia; Hypersensitivity; Image; Insecta; Investigation; Knowledge; Larva; Mechanics; Mediating; Modality; Modernization; Molecular; Molecular Biology; Morphology; Nervous system structure; Neurons; Neurosciences; Nociception; Nociceptors; Organism; Outcomes Research; Pain; Peripheral Nervous System; Physiological; Process; RNA Interference; Role; Route; Sensory; Sensory Thresholds; Signal Transduction; Spinal Ganglia; Stereotyped Behavior; Stimulus; Study models; System; TRP channel; Tail; Temperature; Testing; Touch sensation; Up-Regulation; Withdrawal; Work; allodynia; base; behavioral response; chronic neuropathic pain; chronic pain; cold temperature; differential expression; dopaminergic neuron; knock-down; multimodality; mutant; nervous system disorder; neural patterning; neurogenetics; neurogenomics; nociceptive response; optogenetics; overexpression; painful neuropathy; protective behavior; protein expression; receptor; relating to nervous system; response; sensory stimulus

Project Summary/Abstract Nociception is the mechanism by which animals mediate protective behavioral responses to noxious stimuli, including dangerous high and low temperatures, harmful chemicals, and physically damaging mechanical insults. Noxious stimuli are typically transduced by high-threshold sensory neurons (“nociceptors”), and ultimately elicit protective behaviors. Nociceptors are often multimodal responding to more than one sensory stimulus type; for example, vertebrate C fibers (a class of unmyelinated nociceptive neuron) can transduce innocuous mechanical and thermal stimuli, among others. Elucidating how nervous systems integrate complex information in order to produce relevant behaviors is a fundamental question in neuroscience, and understanding multimodality can have benefits for human health, as the inability to discriminate between noxious and innocuous stimuli can underlie chronic neuropathic pain. Many instances of neuropathic pain present as altered thermosensation (often cold sensing), which is present across organisms, and makes use of highly conserved mechanisms. We have previously demonstrated that Drosophila melanogaster Class III (CIII) sensory neurons are multimodal, and drive distinct, stereotyped behaviors in response to innocuous touch and noxious cold. Further, we have shown that these neurons make use of Transient Receptor Potential (TRP) channels, much like vertebrate nociceptors. However, it is presently unknown how CIII multimodal sensory neurons discriminately detect noxious cold stimuli to elicit nociceptive behavior. Preliminary discoveries have led us to hypothesize that TRP-mediated Ca2+ signaling contributes to CIII multimodality, and more specifically, that Anoctamin/TMEM16 family channels (a family of Ca2+-activated Cl- channel), in concert with chloride ion homeostasis mechanisms, function in a similar capacity in both Drosophila CIII neurons and vertebrate sensory neurons. The project aims and outcomes of this research will significantly advance our knowledge of cold nociception and molecular mechanisms by which multimodal sensory neurons discriminately encode neural activity to elicit stimulus-relevant behaviors. Capitalizing on this system and the genetic tractability of Drosophila, herein we combine neurogenetics, neurogenomics, molecular biology, cellular/functional imaging, optogenetics, electrophysiology, and behavioral analyses to significantly enhance our understanding of mechanisms important to behavior selection, multimodality, and thermosensory nociception.

项目摘要/摘要 伤害感受是动物介导对有害刺激的行为反应的机制， 包括危险的高温和低温，有害化学物质以及物理破坏的机械感染。 有害刺激通常被高阈值的感觉神经元（“伤害感受器”）转导，并最终引起 保护行为。伤害感受器通常是多模式对多种感觉刺激类型的反应。为了 例如，脊椎动物C纤维（一类无髓的伤害性神经元）可以翻译为无效的机械 和热刺激等。阐明神经系统如何整合复杂信息以进行 产生相关行为是神经科学中的一个基本问题，了解多模式可以 为人类健康有好处，因为无法区分有害和无害的刺激可以 慢性神经性疼痛的基础。 许多神经性疼痛的实例存在于改变的热（通常是冷感应），这是存在的 跨生物体，并利用高度保守的机制。我们以前已经证明了 果蝇Melanogaster III类（CIII）感觉神经元是多模式的，并且驱动不同，刻板印象 响应无害的触摸和有害感冒的行为。此外，我们已经表明这些神经元使 使用瞬态受体电位（TRP）通道，就像脊椎动物伤害感受器一样。但是，目前是 未知CIII多模式感觉神经元如何区分发现有害的冷刺激以引起伤害感受性 行为。初步发现使我们假设TRP介导的Ca2+信号有助于 CIII多模态，更具体地说，是Anoctamin/tmem16家族通道（CA2+激活Cl-的家族 频道），与氯离子稳态机制一致，在两种果蝇中都具有相似的能力 CIII神经元和脊椎动物感觉神经元。该项目的目标和结果将大大显着 提高我们对多模式感觉神经元的冷伤害感受和分子机制的了解 歧视编码神经活动以引起与刺激相关的行为。利用该系统和 果蝇的遗传障碍，我们在这里结合了神经遗传学，神经基础学，分子生物学， 细胞/功能成像，光遗传学，电生理学和行为分析，以显着增强 我们对行为选择，多模式和热感应重要机制的理解 伤害感受。