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。虽然几个对瘙痒很重要的神经元种群 已经确定了，我们缺乏对检测到背根瘙痒刺激的神经元的人群级别的视野 神经节（DRG）在背喇叭中整合了瘙痒，并将瘙痒传达给大脑。而且，尽管卡帕阿片类药物 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 瘙痒。我们建议用2光（2p）CA2+神经元成像的知识弥补这些关键差距 涉及瘙痒的人群以及受到Kor激动剂抑制的人群。网络视图 关于最初鲁ritic信息的方式以及Kor激动剂抑制此电路的方式 - 将提供 对瘙痒的神经编码的关键见解，并可能阐明新的治疗途径。在这里，我们建议 在离体体感觉准备中使用2p Ca2+成像来定义由三个参与的神经元 与疾病相关的瘙痒类型：肿瘤细胞脱粒，干燥皮肤的AEW模型和 接触性皮炎的SADBE模型。在AIM 1中，我们将表征介导瘙痒的DRG神经元。在目标2中 我们将表征脊柱兴奋神经元和脊柱投射神经元的相应反应； 在目标3中，我们将分析这种活动模式在存在的情况下如何改变，而Kor激动剂的存在 抑制瘙痒。总体而言，我们将测试以下假设：不同类型的瘙痒参与常见的兴奋性中间神经元 和常见的脊柱输出神经元，并且kor激动剂减少了其中一个或多个人群的活动， 包括脊柱输出神经元。这些实验将为介导的神经元提供新的见解 与疾病相关的瘙痒以及如何通过人口观点来抑制这一电路 在外周中检测到瘙痒的神经元，在背角中整合瘙痒，并将其传达给大脑。