Dissecting neural circuits for mechanical itch

剖析机械性瘙痒的神经回路

基本信息

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
项目类别：
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

项目摘要

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.

慢性瘙痒是一个严重的临床问题，遭受了大量人类的困扰，很难治疗。了解慢性瘙痒电路和分子机制对于开发新疗法至关重要这种棘手的疾病。机械瘙痒敏化（Alloknesis）是许多慢性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+）脊柱抑制性神经元，大门机械瘙痒。我们的发现提出了两个基本问题：1）具体的兴奋性神经元是什么在传递机械瘙痒的背脊髓中？ 2）该途径的失调导致慢性痒？最近，我们确定表达泌尿肌素3 :: CRE（UCN3+）的脊柱兴奋性中间神经元是机械瘙痒 - 传递神经元不会传递触摸，疼痛和化学瘙痒。逆行狂犬病病毒追踪表明，NPY+神经元单突触连接到背脊髓中的UCN3+神经元。该项目的目的是阐明传输和栅极机械瘙痒的脊柱电路，并研究如何在慢性瘙痒条件下，电路发生了变化。目标1：描述处理机械瘙痒的脊柱微电路的功能组织。我们将检查NPY+神经元上UCN3+神经元的功能连接。我们将映射感官输入从背根神经（DRG）神经元到UCN3+和NPY+神经元。目标2：确定在慢性瘙痒条件下机械瘙痒敏化的机制。我们将测试消融后各种慢性瘙痒条件下的机械瘙痒敏化和自发瘙痒行为脊髓UCN3+中间神经元。我们将表征UCN3+和NPY+神经元的电气特性以及在慢性瘙痒条件下的脊柱机械瘙痒电路中的突触传播。我们将调查是否脊柱机械瘙痒电路的抑制作用是各种机械瘙痒敏化的常见机制慢性瘙痒状况。最后，我们将确定慢性瘙痒中的抑制作用机制。