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

项目总结/摘要 伤害感受是动物介导对伤害性刺激的保护性行为反应的机制， 包括危险的高温和低温、有害的化学物质和物理上有破坏性的机械损伤。 伤害性刺激通常由高阈值感觉神经元（“伤害感受器”）转导，并最终引起神经元的损伤。 保护行为。伤害感受器通常对一种以上的感觉刺激类型做出多模式响应; 例如，脊椎动物的C纤维（一类无髓鞘的伤害性神经元）可以抑制无害的机械刺激。 和热刺激等等。阐明神经系统如何整合复杂的信息， 产生相关行为是神经科学中的一个基本问题，理解多模态可以 对人类健康有益，因为无法区分有害和无害的刺激， 是慢性神经性疼痛的基础 神经性疼痛的许多实例表现为改变的温度感觉（通常是冷感觉），这是存在的。 并利用高度保守的机制。我们之前已经证明， 果蝇III类（CIII）感觉神经元是多模态的，并驱动不同的，刻板的， 对无害的触摸和有害的寒冷的反应。此外，我们已经证明，这些神经元使 使用瞬时受体电位（TRP）通道，非常像脊椎动物的伤害感受器。然而，目前 尚不清楚CIII多模态感觉神经元如何区别性地检测有害的冷刺激以引起伤害性感受 行为初步的发现使我们假设TRP介导的Ca 2+信号通路有助于 CIII多模态，更具体地说，Anoctamin/TMEM 16家族通道（Ca 2+激活的Cl-通道家族） 通道），与氯离子稳态机制一致，在果蝇和果蝇中以类似的能力发挥作用。 CIII神经元和脊椎动物感觉神经元。本研究的项目目标和成果将显著 推进我们对冷伤害感受和多模态感觉神经元的分子机制的认识 有区别地编码神经活动以引发刺激相关行为。利用这个系统和 果蝇的遗传易处理性，在此我们结合联合收割机神经遗传学，神经基因组学，分子生物学， 细胞/功能成像、光遗传学、电生理学和行为分析，以显著增强 我们对行为选择、多模态和热感觉机制的理解 伤害感受

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.