Investigating the Neural Circuits of Itch

摘要 慢性瘙痒严重降低生活质量。虽然有几个神经元群体对瘙痒很重要 我们缺乏一个群体水平的观点，神经元检测瘙痒刺激的背根 神经节（DRG），整合痒在背角，并传达痒到大脑。此外，尽管Kappa阿片类药物 受体（KOR）激动剂抑制瘙痒，我们还没有一个清晰的理解的神经基础的抑制 的痒。我们建议通过神经元的双光子（2 P）Ca 2+成像来弥补这些关键的知识差距 参与响应瘙痒的群体和被KOR激动剂抑制的群体。的网络视图 关于过敏信息最初是如何整合的，以及KOR激动剂在哪里起作用来抑制这种回路， 关键洞察神经编码的瘙痒，并可能阐明新的治疗途径。在此，我们建议 在离体躯体感觉制备中使用2 P Ca 2+成像来定义由三个参与的神经元， 疾病相关瘙痒的类型：由大量细胞脱颗粒引起的荨麻疹，干燥皮肤瘙痒的AEW模型，以及 接触性皮炎的SADBE模型。在目标1中，我们将表征介导瘙痒的DRG神经元;在目标2中， 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; 在目标3中，我们将分析在KOR激动剂存在下，这种活性模式如何改变， 抑制瘙痒。总的来说，我们将测试不同类型的瘙痒参与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激动剂降低这些群体中的一个或多个中的活性， 包括脊髓输出神经元。这些实验将提供新的见解神经回路，调解 疾病相关的瘙痒，以及如何通过KOR激动剂抑制这种电路，通过人口的观点， 神经元检测周围的瘙痒，将瘙痒整合到背角，并将瘙痒传达到大脑。

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.