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 知觉；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 在多种瘙痒疾病中作为治疗瘙痒的靶标。我们对瘙痒的大脑机制的理解 在过去的几十年里取得了很大进步。以前的研究确定了与瘙痒有关的一个关键大脑回路，其中包括 丘脑至岛叶后皮质(PIC)的上行通路和起源的网络 从照片上看。此外，多巴胺被发现是与瘙痒相关的一种关键神经递质。这些 研究成果还确定了两个必须理解才能产生有效瘙痒的重要主题 针对大脑的治疗。首先，瘙痒的大脑回路类似于疼痛，尽管瘙痒和疼痛是相似的 明显不同的感觉。还没有发现瘙痒特有的上升途径和网络 电路(瘙痒特定的电路)。其次，可能存在决定多巴胺能基因多态的因素 瘙痒知觉的个体差异。如果发现了这种多态，脑成像研究的重点是 这些基因可以识别在瘙痒特定回路中调节瘙痒感觉的关键基因。这项工作将会 最终使我们能够开发基于大脑的、量身定做的瘙痒治疗方法。为此，识别瘙痒是至关重要的- 特定回路和多巴胺能基因多态影响个体对瘙痒知觉的差异。我们的 研究提案将解决这一重大差距。AIMS 1和2将使用fMRI来确定瘙痒特异性 通过比较瘙痒和疼痛刺激的大脑活动来提升通路和网络。Aim 3将使用我们的 定量评估遗传对瘙痒的影响以识别多巴胺能基因多态性的新方法 这会影响个体对瘙痒的感知差异。我们项目的成功最终将导致 开发基于大脑的量身定做的瘙痒治疗方法，这将推动慢性瘙痒的治疗 潜在的病因学。

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.