Populations of inhibitory interneurons in the dorsal horn of the spinal cord

脊髓背角的抑制性中间神经元群

• 批准号: BB/J001082/1
• 负责人: Andrew Todd
• 金额: $ 99.62万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ001082%2F1
• 关键词: Populations; inhibitory; interneurons; dorsal; horn

Nerve fibres that enter the spinal cord carry various types of sensory information. Some of these fibres (nociceptors) respond selectively to tissue damaging stimuli. The signals conveyed by nociceptors are transmitted to local nerve circuits in the spinal cord that are responsible for withdrawal reflexes, and also to a group of nerve cells (projection neurons) that carry the information to the brain, where it is perceived as pain. The great majority of nerve cells in the spinal cord are only involved in local circuits, and these are defined as interneurons. Many of these cells release chemical messengers that reduce the activity of other nerve cells, and therefore have an inhibitory function. There are complex nerve circuits within the spinal cord that connect incoming sensory fibres with interneurons and projection neurons. These circuits play an important part in modulating the flow of sensory information and regulating the intensity of pain. For example it has been shown that blocking the function of inhibitory interneurons in the spinal cord causes excessive pain, and disorders affecting these cells can lead to chronic pain states. However, despite their great importance, we still know little about the organisation of the nerve circuits that process pain signals within the spinal cord. A major reason for this has been that spinal cord interneurons are very diverse in their appearance, and it has therefore been difficult to classify them into distinct functional populations. Until we can do this, it will not be possible to unravel the complex connections between the different types of nerve cell, and therefore to understand their roles in pain processing. We have found that several groups of inhibitory interneurons in the spinal cord can be recognised on the basis of different substances that they contain. The main aim of this project is to test whether these groups differ in their connections with other nerve cells, and therefore in their function. We will perform experiments on genetically altered mice in which a naturally fluorescent protein is present in these different groups of inhibitory interneurons. This will allow us to record the activity of these cells and to label them with another fluorescent dye, so that the structure and connections of each cell can be investigated. We have preliminary evidence that cells belonging to one of these groups are not activated by painful stimuli, and we will therefore test whether cells in this group receive fewer connections from nociceptors. We will use a powerful technique known as 'cluster analysis' to look at a large sample of cells pooled from each of these groups. Cluster analysis compares a wide range of measures obtained for each cell, and uses these to provide an objective assessment of the number of different populations within the sample. This technique has been used to define different functional populations of interneurons in several brain regions, but has not yet been applied to pain pathways in the spinal cord. We have also found that cells belonging to two of these chemically-defined groups provide a powerful inhibitory input to two different types of pain-activated projection neuron. We will therefore test whether these cells are activated by nociceptors, and whether they correspond to populations identified by the cluster analysis. The project will provide important information about the different types of inhibitory interneuron that are involved in regulating pain. By revealing their connections with incoming sensory fibres and projection neurons, it will add a great deal to our knowledge of how the nerve circuits in the spinal cord are organised. Identifying the interneurons that directly inhibit projection neurons may reveal new targets for the development of drugs designed to treat pain.

进入脊髓的神经纤维携带着各种感觉信息。其中一些纤维（痛觉感受器）选择性地对组织损伤刺激作出反应。痛觉感受器传递的信号被传递到脊髓中负责退缩反射的局部神经回路，以及一组神经细胞（投射神经元），这些神经细胞将信息传递到大脑，在那里它被感知为疼痛。脊髓中的绝大多数神经细胞只参与局部回路，这些被定义为中间神经元。许多这些细胞释放化学信使，减少其他神经细胞的活动，因此具有抑制功能。脊髓内有复杂的神经回路，将传入的感觉纤维与中间神经元和投射神经元连接起来。这些回路在调节感觉信息流和调节疼痛强度方面起着重要作用。例如，研究表明，阻断脊髓中抑制性中间神经元的功能会导致过度疼痛，影响这些细胞的疾病会导致慢性疼痛状态。然而，尽管它们非常重要，我们仍然对脊髓内处理疼痛信号的神经回路的组织知之甚少。造成这一现象的一个主要原因是脊髓中间神经元在外观上非常多样化，因此很难将它们划分为不同的功能群体。在我们能做到这一点之前，我们不可能解开不同类型的神经细胞之间的复杂联系，从而理解它们在疼痛处理中的作用。我们发现脊髓中的几组抑制性中间神经元可以根据它们所含的不同物质来识别。该项目的主要目的是测试这些细胞群与其他神经细胞的连接是否不同，从而测试它们的功能是否不同。我们将对转基因小鼠进行实验，其中天然荧光蛋白存在于这些不同组的抑制性中间神经元中。这将使我们能够记录这些细胞的活动，并用另一种荧光染料标记它们，以便研究每个细胞的结构和连接。我们有初步证据表明，属于其中一组的细胞不会被疼痛刺激激活，因此我们将测试这一组的细胞是否从伤害感受器接收到较少的连接。我们将使用一种被称为“聚类分析”的强大技术来观察从这些群体中收集的大量细胞样本。聚类分析比较每个细胞获得的广泛测量值，并使用这些测量值对样本内不同种群的数量进行客观评估。这项技术已被用于确定几个大脑区域的中间神经元的不同功能群，但尚未应用于脊髓的疼痛通路。我们还发现，属于这两种化学定义组的细胞为两种不同类型的疼痛激活投射神经元提供了强大的抑制输入。因此，我们将测试这些细胞是否被伤害感受器激活，以及它们是否与聚类分析确定的群体相对应。该项目将提供有关参与调节疼痛的不同类型的抑制性中间神经元的重要信息。通过揭示它们与传入的感觉纤维和投射神经元的联系，它将大大增加我们对脊髓中神经回路如何组织的认识。确定直接抑制投射神经元的中间神经元可能为开发治疗疼痛的药物提供新的靶点。

项目成果

Neurochemical characterisation of lamina II inhibitory interneurons that express GFP in the PrP-GFP mouse.

• DOI: 10.1186/1744-8069-9-56
• 发表时间: 2013-10-31
• 期刊: Molecular pain
• 影响因子: 3.3
• 作者: Iwagaki N;Garzillo F;Polgár E;Riddell JS;Todd AJ
• 通讯作者: Todd AJ

A putative relay circuit providing low-threshold mechanoreceptive input to lamina I projection neurons via vertical cells in lamina II of the rat dorsal horn.

• DOI: 10.1186/1744-8069-10-3
• 发表时间: 2014-01-17
• 期刊: Molecular pain
• 影响因子: 3.3
• 作者: Yasaka T;Tiong SY;Polgár E;Watanabe M;Kumamoto E;Riddell JS;Todd AJ
• 通讯作者: Todd AJ

A quantitative study of inhibitory interneurons in laminae I-III of the mouse spinal dorsal horn.

• DOI: 10.1371/journal.pone.0078309
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Polgár E;Durrieux C;Hughes DI;Todd AJ
• 通讯作者: Todd AJ

Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord.

• DOI: 10.1016/j.neuron.2014.02.046
• 发表时间: 2014-05-07
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Kardon AP;Polgár E;Hachisuka J;Snyder LM;Cameron D;Savage S;Cai X;Karnup S;Fan CR;Hemenway GM;Bernard CS;Schwartz ES;Nagase H;Schwarzer C;Watanabe M;Furuta T;Kaneko T;Koerber HR;Todd AJ;Ross SE
• 通讯作者: Ross SE

Identifying functional populations among the interneurons in laminae I-III of the spinal dorsal horn.

• DOI: 10.1177/1744806917693003
• 发表时间: 2017-01
• 期刊: Molecular pain
• 影响因子: 3.3
• 作者: Todd AJ