Spinal Cord Nociceptive Circuits that Deliver Outputs to the Brain to Initiate Pain

脊髓伤害感受回路将输出传递到大脑以引发疼痛

• 批准号: 10892412
• 负责人: Jan Drugowitsch
• 金额: $ 110.23万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10892412
• 关键词: Acute; Address; Affective; Afferent Neurons; Analgesics; Anatomy; Animals; Anterolateral; Behavior; Behavioral; Brain; Brain Stem; Brain imaging; Brain region; Chemicals; Cutaneous; Disease; Foundations; G-Protein-Coupled Receptors; Genetic; Goals; Image; Interneurons; Language; Lateral; Logic; Mechanics; Modeling; Morphology; Mus; Neurons; Nociception; Nociceptors; Opioid; Output; Pain; Pathway interactions; Physiological; Pilot Projects; Population; Property; Pruritus; Reaction; Sensory; Signal Transduction; Spinal Cord; Spinal cord posterior horn; Stimulus; Synapses; TACR1 gene; Temperature; Testing; Thalamic structure; Touch sensation; Work; awake; behavioral response; chronic pain; chronic pain management; dorsal horn; glucocorticoid-induced orphan receptor; in vivo; inflammatory pain; midbrain central gray substance; mouse genetics; novel; novel therapeutic intervention; novel therapeutics; pain behavior; pain chronification; pain perception; painful neuropathy; parabrachial nucleus; predictive modeling; prevent; response; sensory input; superior colliculus Corpora quadrigemina; tool

Abstract Our goal is to generate a predictive model of the spinal cord nociceptive circuits that underlie the initiation of pain perception and behavior. Nociceptive signals are conveyed from the periphery to the spinal cord dorsal horn via highly specialized primary sensory neuron subtypes. These sensory neurons, as well as descending modulatory neurons, form synapses upon an array of morphologically and physiologically distinct classes of dorsal horn interneuron and projection neurons. The ascending output signals from the superficial dorsal horn to the brain are conveyed by neurons of the anterolateral tract (ALT), which project to the thalamus, periaqueductal gray, superior colliculus, lateral parabrachial nucleus, and ventral brainstem. The goal of this project is to define how critical sensory transformations and computations are achieved by these dorsal horn nociceptive circuits and how ALT circuit outputs are conveyed with spatial and contextual precision to recipient brain regions to drive pain and changes in behavior, as well as gain an understanding of the mechanisms responsible for the transition of acute to chronic pain. The premise behind this work is that predictive models of spinal cord nociceptive circuits that underlie the initiation of pain perception and behavior require: 1) defining circuit output neurons and their specific tuning properties; 2) understanding the logic of primary sensory neuron input onto these ALT output neurons; 3) determining the contributions of ALT output neuron classes to reactions to noxious and innocuous stimuli and determining how this changes in disease conditions, and; 4) defining the brain targets of dorsal horn nociceptive circuit output populations. This project will use novel ALT pathway genetic tools in mice to identify, record from, silence and activate specific ALT subpopulations, and physiological, anatomical, and novel, quantitative behavioral approaches to define the pivotal output channels of distinct dorsal horn nociceptive circuits that underlie the perception of pain and its associated affective and behavioral responses. Findings of the proposed work will establish the core logic of dorsal horn nociceptive circuitry to lay a foundation for defining novel therapeutic opportunities for disrupting this circuitry to treat and prevent chronic pain.

抽象的 我们的目标是生成一个脊髓伤害性电路的预测模型，该电路是启动的基础 痛苦的感知和行为。伤害性信号从外围传达到脊髓背侧 喇叭通过高度专业的主感觉神经元亚型。这些感觉神经元以及下降 调节神经元，形成在形态和生理上不同类别的一系列突触 背角中间神经元和投影神经元。从表面角的上升输出信号 向大脑的神经元（ALT）的神经元传达，该神经元向丘脑投射， 周期灰色，上丘，侧侧核和腹脑干。目标的目标 项目是定义这些背角如何实现关键的感觉转换和计算 伤害性电路以及如何用空间和上下文精确到接收者传达ALT电路输出 大脑区域驱动疼痛和行为变化，并了解机制 负责急性向慢性疼痛的过渡。这项工作的前提是 疼痛感知和行为启动的基础的脊髓伤害性电路需要：1）定义 电路输出神经元及其特定的调整特性； 2）了解主要感觉神经元的逻辑 输入这些ALT输出神经元； 3）确定ALT输出神经元类别对 对有害和无害刺激的反应，并确定这种疾病状况如何变化，并且； 4） 定义背角伤害感受电路输出种群的大脑靶标。这个项目将使用小说Alt 小鼠中的途径遗传工具，以识别，记录，沉默和激活特定的ALT亚群，以及 生理，解剖学和新颖的定量行为方法来定义关键输出通道 疼痛感知及其相关的情感和 行为反应。拟议工作的发现将建立背角伤害感的核心逻辑 电路为定义新的治疗机会奠定基础，以破坏该电路以治疗和 防止慢性疼痛。