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

摘要 我们的目标是生成一个脊髓伤害性回路的预测性模型，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 角通过高度专门化的初级感觉神经元亚型。这些感觉神经元，以及下行的 调制神经元在一系列形态和生理上截然不同的神经元上形成突触 背角中间神经元和投射神经元。浅背角的上行输出信号 通过投射到丘脑的前外侧束(ALT)神经元传递到大脑， 中脑导水管周围灰质、上丘、臂旁外侧核和脑干腹侧。这样做的目的是 项目是定义关键的感觉转换和计算是如何通过这些后角实现的 伤害性感受电路以及ALT电路输出如何以空间和上下文的精确度传达给接受者 驱动疼痛和行为变化的大脑区域，以及了解其机制 负责从急性疼痛到慢性疼痛的过渡。这项工作背后的前提是， 作为痛觉和行为基础的脊髓伤害性环路需要：1)定义 电路输出神经元及其特定的调谐特性；2)了解初级感觉神经元的逻辑 输入到这些ALT输出神经元上；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条件下是如何变化的；以及 确定背角伤害性环路输出群体的脑靶点。该项目将使用新颖的替代方案 小鼠识别、记录、沉默和激活特定ALT亚群的途径遗传工具，以及 生理、解剖和新的量化行为方法来定义关键的输出通道 具有独特的背角伤害性环路，是感知疼痛及其相关情感和 行为反应。拟议工作的发现将建立背角伤害性感受器的核心逻辑 为定义新的治疗机会奠定基础，以扰乱这一电路以治疗和 预防慢性疼痛。

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.