Investigating the Neural Circuits of Itch

摘要 慢性瘙痒严重降低了生活质量。尽管有几个神经元群体对瘙痒很重要 已经发现，我们缺乏一个群体水平的神经元来检测背根中的瘙痒刺激 神经节(DRG)，在背角整合瘙痒，并将瘙痒传递到大脑。此外，尽管卡帕阿片类药物 受体(KOR)激动剂抑制瘙痒，我们还没有清楚的神经基础的抑制 怕痒。我们建议用神经的双光子(2P)钙成像来弥合这些关键的知识鸿沟 对瘙痒有反应的人群和被KOR激动剂抑制的人群。网络视角 瘙痒信息最初是如何整合的--以及KOR激动剂在哪里起作用抑制这一回路--将提供 对瘙痒的神经编码的关键洞察，并可能阐明治疗的新途径。在此，我们建议 在体外体感准备中使用2P钙成像来定义由三个神经元参与的神经元 与疾病相关的瘙痒类型：大量细胞脱颗粒所致的荨麻疹，干性皮肤瘙痒的AEW模型，以及 SADBE接触性皮炎模型。在目标1中，我们将描述介导瘙痒的DRG神经元的特征；在目标2中，我们将描述与瘙痒有关的DRG神经元 我们将描述脊髓兴奋性神经元和脊髓投射神经元的相应反应； 在AIMS 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 抑制瘙痒。总体而言，我们将检验不同类型的瘙痒与共同的兴奋性中间神经元相联系的假设。 和共同的脊髓输出神经元，KOR激动剂减少了这些人群中的一个或多个的活动， 包括脊髓输出神经元。这些实验将提供对中介神经回路的新见解 疾病相关的瘙痒，以及KOR激动剂如何通过群体观点抑制这一回路。 感觉周围发痒，在背角整合发痒，并将发痒传递到大脑的神经元。

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.