Dissecting neural circuits for mechanical itch

剖析机械性瘙痒的神经回路

• 批准号: 10320424
• 负责人: Bo Duan
• 金额: $ 43.31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320424
• 关键词: Affect; Amyloid beta-Protein; Atopic Dermatitis; Behavior; Brain; Cell Separation; Cells; Chemicals; Clinical; Data; Disease; Disinhibition; Dorsal; Future; Goals; Human; Interneurons; Label; Lead; Maps; Mechanics; Mechanoreceptors; Modeling; Molecular; Neurons; Pain; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Physiological; Population; Process; Proteins; Pruritus; Quality of life; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Slice; Spinal; Spinal Cord; Spinal Ganglia; Stimulus; Synapses; Synaptic Transmission; Systemic disease; Testing; Therapeutic; Touch sensation; Whole-Cell Recordings; Work; central sensitization; chronic itch; common symptom; design; electrical property; excitatory neuron; experience; experimental study; genetic approach; ineffective therapies; inhibitory neuron; insight; mechanical stimulus; mouse model; neural circuit; neuropeptide Y; novel; novel therapeutics; rabies viral tracing; response; sensory input; skin disorder; spinal nerve posterior root; therapeutic target; transmission process; urocortin

Chronic itch is a severe clinical problem that afflicts a large number of humans and it is very difficult to treat. Understanding the chronic itch circuitry and molecular mechanisms is critical to developing new therapies for this intractable disease. Mechanical itch sensitization (alloknesis) is one common symptom in many of chronic itch patients. Our previous work has identified neuropeptide Y-positive (NPY+) spinal inhibitory interneurons that gates mechanical itch. Our findings raise two fundamental questions: 1) What are the specific excitatory neurons in the dorsal spinal cord that transmit mechanical itch? 2) Does dysregulation of this pathway lead to chronic itch? Recently we have identified that spinal excitatory interneurons expressing Urocortin 3::Cre (Ucn3+) are mechanical itch-transmission neurons, which do not transmit touch, pain and chemical itch. Retrograde rabies virus tracing showed that NPY+ neurons monosynaptically connect to Ucn3+ neurons in the dorsal spinal cord. The goal of this project is to elucidate the spinal circuits that transmit and gate mechanical itch, and to study how the circuits are altered in chronic itch conditions. Aim 1: Delineate the functional organization of the spinal microcircuit that processes mechanical itch. We will examine the functional connections from NPY+ neurons onto Ucn3+ neurons. We will map the sensory inputs from dorsal root ganglion (DRG) neurons onto Ucn3+ and NPY+ neurons. Aim 2: Determine the mechanisms of mechanical itch sensitization in chronic itch conditions. We will test the mechanical itch sensitization and spontaneous itch behaviors in various chronic itch conditions after ablating spinal Ucn3+ interneurons. We will characterize the electrical properties of Ucn3+ and NPY+ neurons and synaptic transmission in the spinal mechanical itch circuits in chronic itch conditions. We will investigate whether disinhibition of spinal mechanical itch circuits is a common mechanism of mechanical itch sensitization in various chronic itch conditions. Finally, we will determine the disinhibition mechanisms in chronic itch.

慢性瘙痒是一种严重的临床问题，困扰着大量的人，并且很难治疗。 了解慢性瘙痒的电路和分子机制对于开发新的治疗方法至关重要。 这种难治的疾病。机械性瘙痒致敏（感觉异常）是许多慢性瘙痒症中的一种常见症状。 瘙痒患者。我们以前的工作已经确定了神经肽Y阳性（NPY+）脊髓抑制性中间神经元， 盖茨机械痒。我们的发现提出了两个基本问题：1）什么是特定的兴奋性神经元 传递机械性瘙痒的神经系统2)这条通路的失调是否会导致慢性 痒吗最近，我们发现表达Urocortin 3：：Cre（Ucn3+）的脊髓兴奋性中间神经元是一种神经元， 机械性瘙痒传递神经元，不传递触觉、疼痛和化学性瘙痒。逆行性狂犬病 病毒示踪显示，在脊髓背侧，NPY+神经元与Ucn 3+神经元单突触连接。 这个项目的目标是阐明脊髓电路，传输和门机械痒，并研究如何 在慢性瘙痒的情况下，这些回路会发生改变。 目的1：描述处理机械性瘙痒的脊髓微回路的功能组织。我们将 检查从NPY+神经元到Ucn 3+神经元的功能连接。我们将绘制感官输入 从背根神经节（DRG）神经元到Ucn 3+和NPY+神经元。 目的2：确定慢性瘙痒条件下机械性瘙痒致敏的机制。我们将测试 消融后各种慢性瘙痒条件下的机械瘙痒致敏和自发瘙痒行为 脊髓Ucn 3+中间神经元。我们将描述Ucn 3+和NPY+神经元的电特性， 慢性瘙痒条件下脊髓机械瘙痒回路中的突触传递。我们将调查是否 脊髓机械性瘙痒回路的去抑制是各种动物中机械性瘙痒致敏的常见机制， 慢性瘙痒症最后，我们将确定慢性瘙痒的去抑制机制。