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Dissection of the Organizational Differences Between Paw and Trunk Pain Circuits

爪子和躯干疼痛回路之间组织差异的剖析

基本信息

批准号：
9264439
负责人：
William Paul Olson
金额：
$ 3.09万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2018-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Chronic pain is a costly and complex human health problem. While many chronic pain conditions are region specific (chronic back pain, for instance), we currently know very little about regional differences in pain circuit organization. I was recently discovered that the human fingertips have the best acuity (i.e. can detect fine spatial detail) for pain stimuli compared to other body regions. However, the human fingertips have a lower density of nociceptive fibers compared to other skin areas, raising the question of how a skin area with a low innervation density displays high sensory acuity. My lab recently generated a new inducible Cre mouse line (MrgDCreERT2) that allows for genetic tracing of individual non-peptidergic nociceptors. While paw skin and trunk skin nociceptors have similar peripheral receptive field sizes, after sparse nociceptor labeling, I found that their spinal cord projections display a different morphology (paw nociceptors have rounded central terminals while trunk nociceptors have long and thin central terminals). This finding suggests that nociceptors innervating the hand form different neural circuits from those innervating the proximal limb/trunk skin. I propose to determine if, and how, pain circuits representing the paw and trunk of mice are differently organized. While my preliminary experiments suggest that spinal cord terminal morphologies (round and long) are segregated based on body position (paw-vs.-trunk), these experiments have not excluded the possibility that these morphologies instead belong to different functional subtypes. In Aim 1, I will further test the hypothesis that paw and trunk nociceptors have different morphologies by performing higher density nociceptor labeling to determine if these terminal types remain segregated. Further, to exclude the possibility that these terminal morphologies belong to functionally distinct subpopulations, I will test if a major distinguisher of non-peptidergic nociceptor subtypes (sensitivity to itch-causing beta-alanine) correlates with terminal morphology by combining genetic tracing with calcium imaging. In Aim 2, I will test the hypothesis that paw and trunk nociceptor circuits have different rates of overlap between neighboring nociceptor skin and/or spinal cord terminals. I will use a combination of genetic and viral vector tools to label neighboring nociceptors with different fluorescent proteins. I will then measure overlap rates between neighboring nociceptor terminals and compare these rates between paw and trunk circuits. In summary, these experiments will be the first to elucidate key circuit differences between paw and trunk nociceptors and could provide a likely mechanism to explain the high spatial acuity of the fingertips for pain.

描述(申请人提供)：慢性疼痛是一个昂贵而复杂的人类健康问题。虽然许多慢性疼痛情况是地区性的(例如慢性背痛)，但我们目前对疼痛回路组织的地区性差异知之甚少。我最近发现，与身体的其他区域相比，人类的指尖对疼痛刺激具有最好的敏锐度(即可以检测到细微的空间细节)。然而，与其他皮肤区域相比，人类指尖的伤害性纤维密度较低，这引发了一个问题，即神经密度较低的皮肤区域如何显示出高感官敏锐度。我的实验室最近培育了一种新的可诱导Cre小鼠品系(MRGDCreERT2)，该品系可以对单个非肽能伤害性感受器进行遗传追踪。虽然爪状皮肤和躯干皮肤伤害性感受器具有相似的外周感受野大小，但稀疏的伤害性感受器标记后，我发现它们的脊髓投射呈现不同的形态(爪状伤害性感受器具有圆形的中央终末，而躯干伤害性感受器具有细长的中央终末)。这一发现表明，支配手部的伤害性感受器与支配近端肢体/躯干皮肤的伤害性感受器形成不同的神经回路。我建议确定代表老鼠爪子和躯干的痛觉回路是否以及如何以不同的方式组织起来。虽然我的初步实验表明，脊髓末端的形态(圆形和长形)是根据身体位置(爪状和躯干)分开的，但这些实验并没有排除这些形态属于不同功能亚型的可能性。在目标1中，我将通过执行更高密度的伤害性感受器标记来确定这些终末类型是否保持分离，从而进一步检验爪子和躯干伤害性感受器具有不同形态的假设。此外，为了排除这些末端形态属于功能上不同的亚群的可能性，我将通过结合遗传追踪和钙成像，测试非肽能伤害性感受器亚型的主要区分因素(对引起瘙痒的β-丙氨酸的敏感性)是否与末端形态相关。在目标2中，我将测试爪子和躯干伤害性感受器回路不同的假设邻近伤害性感受器皮肤和/或脊髓终末之间的重叠率。我将使用基因和病毒载体工具的组合来标记邻近的伤害性感受器，并使用不同的荧光蛋白。然后，我将测量相邻伤害性感受器端子之间的重叠率，并比较PAW和干线电路之间的重叠率。综上所述，这些实验将首次阐明爪子和躯干伤害性感受器之间的关键回路差异，并可能提供一种可能的机制来解释指尖对疼痛的高空间敏锐度。