Dissection of a new spinal cord circuit in pain sensation

疼痛感觉中新脊髓回路的解剖

• 批准号: 9509575
• 负责人: Wenqin Luo
• 金额: $ 49.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9509575
• 关键词: Acute; Acute Pain; Amyloid beta-Protein; Anatomy; Behavior; Behavioral Assay; Brain; Characteristics; Chronic; Coupled; Data; Diphtheria Toxin; Disinhibition; Dissection; Dorsal; Equilibrium; GABA Receptor; Genes; Genetic; Glycine; Glycine Receptors; Goals; Health; Histology; Human; Hypersensitivity; In Situ Hybridization; Individual; Injury; Interneurons; Label; Lead; Ligands; Light; Mediating; Modality; Molecular; Molecular Profiling; Morphology; Mus; Neonatal; Neurons; Neurotransmitters; Nociception; Optics; Output; Pain; Pain management; Parvalbumins; Pathologic; Pharmacology; Physiological; Population; Process; Property; Pruritus; Research; Slice; Spinal Anesthesia; Spinal Cord; Spinal Injections; Stains; Stimulus; Structure; Synapses; Temperature; Testing; Thinking; Touch sensation; Toxin; Transplantation; Virus; Work; behavioral response; chronic pain; chronic painful condition; dorsal horn; experimental study; gamma-Aminobutyric Acid; improved; inhibitory neuron; insight; mechanical allodynia; microscopic imaging; nervous system disorder; neural circuit; novel; optogenetics; pain sensation; prevent; protein kinase C gamma; proto-oncogene protein c-ret; receptor; reduce symptoms; relating to nervous system; somatosensory; synaptic inhibition; transmission process

Nociception, or the sense of noxious stimuli, is essential for our daily lives. Normal acute nociception prevents us from potential damage or repetitive injuries, while distorted neural circuits in pathological conditions gener- ate chronic pain, which is a huge human health problem. At present, our understanding of neural circuits in mediating and modulating pain sensation under normal and pathological conditions is surprisingly incomplete. We proposed to study a population of inhibitory dorsal spinal cord interneurons, which express the receptor tyrosine kinase RET neonatally and makes up about one third of inhibitory interneurons in laminae III to V (deep layer). Our preliminary study showed that these deep layer early RET+ inhibitory interneurons are unique and their circuits and functions in nociception have not been defined before. Aim 1. Define molecular, physiological, and anatomical properties of deep layer early RET+ inhibitory interneurons. In this aim, we will genetically label deep layer early RET+ inhibitory interneurons to study their gross anatomy, identities of inhibitory neural transmitter, physiological properties, and single neuron morpholo- gy. Our anticipated results will reveal unique features of deep layer early RET+ inhibitory interneurons and pro- vide an insight into their potential connections and functions. Aim 2. Dissect neural circuits associated with deep layer early RET+ inhibitory interneurons. In this aim, we will use both light/electronic microscopy imaging and spinal cord slice recording coupled with electric and optical stimuli to determine input and output of deep layer early RET+ inhibitory interneurons. Together, our work will reveal functional connections associated with this new population of DH inhibitory interneurons. Aim 3. Determine functions of deep layer early RET+ inhibitory interneurons in acute pain and chronic pain. In this aim, we will either ablate deep layer early RET+ inhibitory interneurons using toxin or acutely acti- vate them using optogenetic and pharmacological approach and test mouse nociceptive behavioral responses under acute and chronic pain conditions. With these experiments, we anticipate revealing important functions of deep layer early RET+ inhibitory interneurons in modulating acute and chronic pain. In short, our proposed study will elucidate circuits and function of a new population of DH inhibitory interneu- rons in governing the transmission and modulation of nociceptive information. Our work would lead to a better understanding about DH circuits and provide potential new thoughts for chronic pain treatment.

伤害感受，或有害刺激的感觉，对于我们的日常生活至关重要。正常的急性伤害感受可预防 我们免受潜在的损害或重复性伤害，而病理条件下的神经回路扭曲 吃慢性疼痛，这是一个巨大的人类健康问题。目前，我们对神经回路的认识 在正常和病理条件下介导和调节痛觉是令人惊讶的不完整。 我们提议研究一群抑制性背脊髓中间神经元，它们表达受体 新生儿酪氨酸激酶 RET 约占 III 至 V 层抑制性中间神经元的三分之一 （深层）。我们的初步研究表明这些深层早期 RET+ 抑制性中间神经元是独特的 它们在伤害感受中的回路和功能以前尚未被定义。 目标 1. 定义深层早期 RET+ 抑制的分子、生理和解剖特性 中间神经元。为此，我们将对深层早期 RET+ 抑制性中间神经元进行基因标记，以研究其 大体解剖学、抑制性神经递质的特性、生理特性和单个神经元形态 吉。我们预期的结果将揭示深层早期 RET+ 抑制性中间神经元和亲-的独特特征。 深入了解它们的潜在联系和功能。 目标 2. 剖析与深层早期 RET+ 抑制性中间神经元相关的神经回路。为了这个目标， 我们将使用光学/电子显微镜成像和脊髓切片记录以及电和 光刺激来确定深层早期 RET+ 抑制性中间神经元的输入和输出。在一起，我们的 这项工作将揭示与新的 DH 抑制性中间神经元群相关的功能连接。 目标 3. 确定深层早期 RET+ 抑制性中间神经元在急性疼痛和慢性疼痛中的功能 疼痛。为了实现这一目标，我们将使用毒素或急性激活来消融深层早期 RET+ 抑制性中间神经元。 使用光遗传学和药理学方法对它们进行评估并测试小鼠的伤害性行为反应 在急性和慢性疼痛情况下。通过这些实验，我们预计会揭示重要的功能 深层早期 RET+ 抑制性中间神经元在调节急性和慢性疼痛中的作用。 简而言之，我们提出的研究将阐明新的 DH 抑制性中间体群体的回路和功能。 rons 控制伤害性信息的传输和调制。我们的工作将带来更好的结果 了解 DH 回路，为慢性疼痛治疗提供潜在的新思路。