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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：
10550142
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10550142
关键词：
Ablation 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 Quantitative Reverse Transcriptase PCR Role Signal Pathway Slice Spinal Spinal Cord Spinal Ganglia Stimulus Synaptic Transmission Systemic disease Testing Therapeutic Touch sensation Vertebral column 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 neurotransmission novel novel therapeutics postsynaptic 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，困扰着大量的人类，而且很难治疗。了解慢性瘙痒的回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。机械性瘙痒敏感化(异位膝曲)是许多慢性病的常见症状之一瘙痒的病人。我们以前的工作已经鉴定出神经肽Y阳性(NPY+)的脊髓抑制性中间神经元盖茨的机械之痒。我们的发现提出了两个基本问题：1)什么是特殊的兴奋性神经元在传递机械性瘙痒的脊髓背侧？2)这一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机械性瘙痒传递神经元，不传递触摸、疼痛和化学瘙痒。逆行狂犬病病毒示踪显示，NPY+神经元与脊髓背侧Ucn3+神经元单突触连接。这个项目的目标是阐明传递和控制机械性瘙痒的脊髓回路，并研究如何在慢性瘙痒的情况下，电路会发生变化。目的1：描述处理机械性瘙痒的脊髓微回路的功能组织。我们会观察NPY+神经元与Ucn3+神经元之间的功能联系。我们将绘制感官输入的地图从背根神经节(DRG)神经元到Ucn3+和NPY+神经元。目的2：确定慢性瘙痒条件下机械性瘙痒敏化的机制。我们将测试消融后各种慢性瘙痒状态下的机械性瘙痒敏感化和自发性瘙痒行为脊髓Ucn3+中间神经元。我们将描述Ucn3+和NPY+神经元的电学特性和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瘙痒通路的去抑制是各种不同类型的机械瘙痒敏化的共同机制。慢性瘙痒症状。最后，我们将确定慢性瘙痒的去抑制机制。