Determine Functions of Mammalian Touch-sensing Neurons in Chronic Pain

哺乳动物的触觉传入，Aβ低阈值机械感受器（LTMR），长期以来一直是前， 被认为是调节伤害性通路的重要参与者。然而，Aβ LTMRs在 慢性疼痛仍在争论中。旨在结合Aβ LTMR的已知解剖结构和现有的结构 我们推测，在慢性疼痛状态下，Aβ LTMRs的外周激活支配着 受影响的区域通过去抑制前馈回路触发疼痛，而背柱激活 募集Aβ LTMR，支配受累和非受累区域，可阻断受累区域的活动。 Aβ LTMR和/或通过侧抑制的疼痛通路。为了具体测试这一想法，我们将产生转基因小鼠，其中通道视紫红质将在Aβ LTMR中特异性表达，并在基线和慢性疼痛条件下检查其组织学（目的1a）和生理学特性（目的1b）。然后，我们将利用光遗传学的空间和时间精度，在基线和各种慢性疼痛条件下刺激皮肤外周或脊髓背柱中央的Aβ LTMR，以比较其行为结果（目的2）。最后，我们将使用脊髓切片记录来阐明潜在的电路机制（目的3）。我们将联合收割机电刺激和光刺激结合起来，从一定的水平局部或广泛地激活Aβ LTMR，以确定 在基线和慢性疼痛条件下，Aβ LTMR之间存在侧抑制。我们还将确定 这种侧抑制是否可以调节受慢性炎症影响的局部伤害感受回路， 伤/伤。总的来说，我们的研究结果有望建立一个新的模型，如何串扰之间的方式 （触觉和伤害性通路）和一种方式（来自不同脊髓节段的Aβ LTMR） 共同调节痛觉。该模型不仅可以解释Aβ的复杂功能， 慢性疼痛中的LTMR也为未来的疼痛通路干预提供了新的见解。我们的组件- 流血的团队非常适合完成这些目标，利用小鼠遗传学和Aβ LTMR的综合专业知识 (PI罗）和生理学和计算神经科学与哺乳动物体感系统（合作， 调查员奥康纳）。

The mammalian touch-sensing afferents, Aβ low-threshold mechanoreceptors (LTMRs), have long been pro- posed to be important players in modulating nociceptive pathways. However, the exact roles of Aβ LTMRs in chronic pain are still under debate. Aiming to incorporating the known anatomy of Aβ LTMRs and existing con- flicting results, we hypothesize that in chronic pain conditions, peripheral activation of Aβ LTMRs innervating the affected region triggers pain through dis-inhibited feedforward circuits, whereas dorsal column activation recruits Aβ LTMRs innervating both affected and non-affected regions, which could block activities of affected Aβ LTMRs and/or pain pathways through lateral inhibition. To specifically test this idea, we will generate transgenic mice in which channelrhodopsin will be specifically expressed in Aβ LTMRs and examine their histology (Aim 1a) and physiological properties (Aims 1b) at base-line and chronic pain conditions. We will then take advantage of the spatial and temporal precision of optogenetics and stimulate Aβ LTMRs peripherally in the skin or centrally in the spinal cord dorsal column at baseline and various chronic pain conditions to compare their behavioral outcomes (Aim 2). Finally, we will use spinal cord slice recordings to elucidate the underlying circuit mechanisms (Aim 3). We will combine dorsal root electrical stimulation and optical stimulation to activate Aβ LTMRs locally from a given level or broadly to determine lateral inhibition existing among Aβ LTMRs at baseline and chronic pain conditions. We will also determine whether this lateral inhibition could modulate the local nociceptive circuits affected by chronic inflamma- tion/injury. Collectively, our results are expected to establish a new model of how crosstalk between modalities (touch and nociceptive pathways) and within one modality (Aβ LTMRs from different spinal cord segments) work together to modulate pain sensation. This model would not only explain the complicated functions of Aβ LTMRs in chronic pain but also provide novel insights for pain pathway intervention in the future. Our assem- bled team is well suited to complete these aims, utilizing combined expertise in mouse genetics and Aβ LTMRs (PI Luo) and physiology and computational neuroscience with the mammalian somatosensory system (co- investigator O’Connor).