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

基本信息

批准号：
10053529
负责人：
Jan Drugowitsch
金额：
$ 326.48万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053529
关键词：
Acute Address Affective Afferent Neurons Analgesics Anatomy Animals Anterolateral Behavior Behavioral Brain Brain Stem 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 dorsal horn glucocorticoid-induced orphan receptor in vivo inflammatory neuropathic pain midbrain central gray substance mouse genetics novel novel therapeutic intervention novel therapeutics pain behavior pain perception parabrachial nucleus predictive modeling prevent response sensory input superior colliculus Corpora quadrigemina tool

项目摘要

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脊髓伤害感受回路的预测模型，该回路是启动疼痛感知和行为。伤害性信号从外周传递到脊髓背侧角通过高度专业化的初级感觉神经元亚型。这些感觉神经元以及下行调节神经元在一系列形态和生理上不同的类别上形成突触背角中间神经元和投射神经元。来自浅表背角的上升输出信号到大脑的信息是由投射到丘脑的前外侧束（ALT）的神经元传递的，导水管周围灰质、上丘、外侧臂旁核和腹侧脑干。此举的目标该项目的目的是定义这些背角如何实现关键的感觉转换和计算伤害感受电路以及 ALT 电路输出如何以空间和上下文精度传达给接收者驱动疼痛和行为变化的大脑区域，以及了解其机制负责急性疼痛向慢性疼痛的转变。这项工作背后的前提是预测模型引发疼痛感知和行为的脊髓伤害感受回路需要：1）定义电路输出神经元及其特定的调谐特性； 2）理解初级感觉神经元的逻辑输入到这些 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，并确定这种反应在疾病状况中如何变化； 4）定义背角伤害性电路输出群体的大脑目标。该项目将使用新颖的 ALT 小鼠体内用于识别、记录、沉默和激活特定 ALT 亚群的途径遗传工具，以及生理学、解剖学和新颖的定量行为方法来定义关键输出通道不同的背角伤害性回路构成疼痛感知及其相关的情感和行为反应。拟议工作的结果将建立背角伤害性的核心逻辑电路为定义新的治疗机会奠定基础，以破坏该电路来治疗和治疗预防慢性疼痛。