Determine Functions of Mammalian Touch-sensing Neurons in Chronic Pain

哺乳动物的触觉传入，β低阈值机械感受器(LTMR)，长期以来一直是支持的。 被认为是调节伤害感受通路的重要角色。然而，AβLTM在 慢性疼痛仍在争论中。目的是结合已知的βLTMR解剖结构和现有的 根据筛选结果，我们假设在慢性疼痛条件下，神经支配的AβLTMR的外周激活 受影响的区域通过去抑制的前馈电路触发疼痛，而背柱激活 招募同时支配受影响和非受影响区域的AβLTMR，这可能会阻止受影响的活动 AβLTMR和/或通过侧向抑制的疼痛通路。为了具体测试这一想法，我们将产生转基因小鼠，在其中通道视紫红质将在AβLTMR中特异性表达，并检测它们在基线和慢性疼痛条件下的组织学(目标1a)和生理特性(目标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，在皮肤周围或脊髓背柱中央刺激AβLTMR，以比较他们的行为结果(目标2)。最后，我们将使用脊髓切片记录来阐明潜在的电路机制(目标3)。我们将结合背根电刺激和光刺激从给定的水平局部或广泛地激活AβLTMR，以确定 在基线和慢性疼痛条件下，AβLTM之间存在侧向抑制。我们还将确定 这种侧向抑制是否可以调节慢性炎症影响的局部伤害性环路- 受伤/受伤。总而言之，我们的结果有望建立一个新的模型，研究不同模式之间的串扰 (触摸和伤害性通路)和在一个通道内(来自不同脊髓节段的βLTMR) 共同努力调节痛感。该模型不仅可以解释β的复杂功能 LTMR不仅为慢性疼痛的治疗提供了新的见解，也为未来的疼痛通路干预提供了新的见解。我们的Assem- Bleed团队非常适合完成这些目标，利用小鼠遗传学和AβLTMR的组合专业知识 (皮罗)与哺乳动物躯体感觉系统的生理学和计算神经科学(共同- 调查员O‘Connor)。

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).