Investigating the Neural Circuits of Itch

研究瘙痒的神经回路

• 批准号: 10657234
• 负责人: H Richard Koerber
• 金额: $ 63.83万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-11 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657234
• 关键词: Affect; Afferent Neurons; Agonist; Brain; Cell Degranulation; Cells; Chloroquine; Classification; Clinical; Code; Contact Dermatitis; Coupled; Detection; Disease; Dryness; Genetic Recombination; Image; Interneurons; Knowledge; Mediating; Modeling; Monitor; Nerve; Neurons; Opioid agonist; Output; Pattern; Pharmaceutical Preparations; Pharmacology; Population; Positioning Attribute; Preparation; Pruritus; Quality of life; Role; Skin; Spinal; Spinal Cord; Spinal Ganglia; Stimulus; Testing; Urticaria; Vertebral column; Visualization; cell type; cellular targeting; chronic itch; dorsal horn; excitatory neuron; experimental study; insight; kappa opioid receptors; neural; neural circuit; neuroimaging; novel; response; somatosensory; tool; two-photon

Abstract Chronic itch severely diminishes quality of life. Although several neuronal populations that are important for itch have been identified, we lack a population-level view of the neurons that detect itch stimuli in the dorsal root ganglia (DRG), integrate itch in the dorsal horn, and convey itch to the brain. Moreover, although kappa opioid receptor (KOR) agonists inhibit itch, we do not yet have a clear understanding of the neural basis of the inhibition of itch. We propose to bridge these critical gaps in knowledge with 2-photon (2P) Ca2+ imaging of neural populations that are engaged in response to itch and those that are inhibited by KOR agonists. A network view of how pruritic information is initially integrated—and where KOR agonists act to inhibit this circuitry—will provide key insight into the neural coding of itch, and may elucidate new avenues for treatment. Here, we propose to use 2P Ca2+ imaging in the ex vivo somatosensory preparation to define the neurons that are engaged by three types of disease-relevant itch: urticaria from mass cell degranulation, the AEW model of dry skin itch, and the SADBE model of contact dermatitis. In Aim 1 we will characterize the DRG neurons that mediate itch; in Aim 2 we will characterize the corresponding responses of spinal excitatory neurons and spinal projection neurons; and in Aims 3 we will analyze how this pattern of activity is altered in the presence of a KOR agonist, which inhibits itch. Overall, we will test the hypothesis that distinct types of itch engage common excitatory interneurons and common spinal output neurons, and that KOR agonists reduce activity in one or more of these populations, including spinal output neurons. These experiments will provide new insight into the neural circuits that mediate disease-relevant itch and how this circuitry can be inhibited by KOR agonists through a population view of the neurons that detect itch in the periphery, integrate itch in the dorsal horn, and convey itch to the brain.

抽象的 慢性瘙痒严重降低了生活质量，尽管有几个对瘙痒很重要的神经元群。 已经确定，我们缺乏检测背根瘙痒刺激的神经元的群体水平视图 神经节（DRG），将瘙痒整合到背角，并将瘙痒传递到大脑。 受体（KOR）激动剂抑制瘙痒，我们尚未清楚地了解抑制的神经基础 我们建议通过 2 光子 (2P) Ca2+ 神经成像来弥补这些关键的知识空白。 参与瘙痒反应的人群和受到 KOR 激动剂抑制的人群 网络视图。 瘙痒信息最初是如何整合的，以及 KOR 激动剂在何处发挥作用来抑制该电路，将提供 对瘙痒神经编码的关键见解，并可能阐明新的治疗途径。 在离体体感准备中使用 2P Ca2+ 成像来定义由三个 与疾病相关的瘙痒类型：大量细胞脱粒引起的荨麻疹、干性皮肤瘙痒的 AEW 模型以及 在目标 1 中，我们将表征目标 2 中介导瘙痒的 DRG 神经元； 我们将表征脊髓兴奋性神经元和脊髓投射神经元的相应反应； 在目标 3 中，我们将分析在 KOR 激动剂存在的情况下这种活动模式是如何改变的， 总的来说，我们将检验不同类型的瘙痒涉及共同的兴奋性中间神经元的假设。 和常见的脊髓输出神经元，并且 KOR 激动剂降低了其中一个或多个群体的活动， 这些实验将为介导神经回路提供新的见解。 与疾病相关的瘙痒以及如何通过 KOR 激动剂抑制该电路 检测外周瘙痒的神经元，整合背角的瘙痒，并将瘙痒传递到大脑。