Itch-specific brain circuit and dopaminergic gene polymorphisms influencing individual differences in itch perception

摘要 瘙痒是一个全球性的健康问题，影响着数千万人。大脑在瘙痒中起着至关重要的作用 感知；因此，大脑中处理瘙痒的特定回路有可能成为一种治疗方法 多种瘙痒性疾病中瘙痒的目标。我们对瘙痒的大脑机制的了解 在过去的几十年里取得了进步。先前的研究发现了与瘙痒相关的关键大脑回路，其中包括 从丘脑投射到后岛叶皮质 (pIC) 的上行通路和起源网络 来自 pIC。此外，多巴胺被发现是与瘙痒相关的关键神经递质。这些 成就还确定了两个必须理解的重要主题，以开发有效的痒 针对大脑的治疗。首先，痒的脑回路与疼痛的脑回路相似，尽管痒和痛是不同的。 明显不同的感觉。尚未确定特定于瘙痒的上升通路和网络 电路（特定于痒的电路）。其次，可能存在决定多巴胺能基因多态性 痒感的个体差异。如果发现了这种多态性，脑成像研究的重点是 这些基因可以识别在瘙痒特异性回路中调节瘙痒感知的关键位点。这一行工作将 最终使我们能够开发出基于大脑的、量身定制的瘙痒治疗方法。为此，识别瘙痒至关重要 特定电路和多巴胺能基因多态性影响瘙痒感知的个体差异。我们的 研究提案将解决这一重大差距。目标 1 和 2 将使用功能磁共振成像来确定瘙痒特异性 通过比较瘙痒和疼痛刺激之间的大脑活动来研究上行通路和网络。目标 3 将使用我们的 定量评估遗传对瘙痒影响以确定多巴胺能基因多态性的新方法 影响瘙痒感知的个体差异。我们项目的成功最终将导致 开发基于大脑的定制瘙痒治疗方法，这将推进慢性瘙痒的治疗 的根本病因学。

Abstract Itch is a global health problem, affecting tens of millions of people. The brain plays a crucial role in itch perception; thus the specific circuit for itch processing in the brain has the potential to become a therapeutic target for itch in a wide range of pruritic diseases. Our understanding about the brain mechanism of itch has advanced in the past decades. Previous studies identified a key brain circuit related to itch, which includes the ascending pathway projecting from the thalamus to the posterior insular cortex (pIC) and networks originating from the pIC. In addition, dopamine was found to be a key neurotransmitter associated with itch. These achievements have also identified two important topics that must be understood to develop effective itch treatment targeting the brain. First, the brain circuit of itch is similar to that of pain, though itch and pain are clearly distinct sensations. An itch-specific ascending pathway and network have not yet been identified within the circuit (an itch-specific circuit). Second, there could be dopaminergic gene polymorphisms that determine individual differences in itch perception. If such polymorphisms are identified, brain imaging studies focusing on these genes can identify key loci regulating itch perception within the itch-specific circuit. This line of work will eventually enable us to develop brain-based, tailored itch treatment. To this end, it is crucial to identify an itch- specific circuit and dopaminergic gene polymorphisms influencing individual differences in itch perception. Our research proposal will address this significant gap. Aims 1 and 2 will use fMRI to determine an itch-specific ascending pathway and network by comparing brain activity between itch and pain stimuli. Aim 3 will use our novel method for quantitatively assessing genetic impacts on itch to identify dopaminergic gene polymorphisms that influence individual differences in itch perception. Success of our project will eventually lead to the development of brain-based tailored itch treatment, which will advance the treatment of chronic itch regardless of the underlying etiology.