High Resolution of Mapping of Pain Ciruity in the Dorsal Horn

描述(申请人提供)：近年来，疼痛研究在从基因到行为的水平上取得了革命性的进展。然而，已被证明特别抵抗分析的一个基本组织水平是第一中央中继区脊髓背角内潜在的痛传递和调制的内在电路。有许多证据表明，内源性背角中间神经元的变化有助于炎症和神经病理性疼痛的可塑性，但由于缺乏研究这一内在回路的方法，进一步的了解受到限制。近年来，一种新的技术被开发出来，这使得第一次有可能剖析紧密排列的神经元件的突触连接的组织。利用激光扫描光刺激(LSPs)技术，在单个神经元中记录突触反应，而激光诱导的谷氨酸去除产生的焦点刺激被传递到记录的神经元周围的组织中的多个位置。结果图显示了局部兴奋性和抑制性突触前神经元的位置，这些神经元向记录的神经元提供单突触输入。LSP已经改变了我们对中枢神经系统许多区域电路的认识，但尚未用于疼痛系统。我们现在建议使用这项技术来研究背角疼痛(伤害性)回路的组织。建议的实验将定位引起局部兴奋性和抑制性突触输入到板层I投射神经元和板层中间神经元(胰岛、中央、垂直和放射状细胞)的背角神经元的位置。这种方法是基于这样的假设，即背角的内在连接模式是在空间上组织的，并且这种空间组织是背角功能的基本决定因素。我们进一步假设，这种空间组织对于兴奋性和抑制性输入是不同的，并且是细胞类型特有的。将这一技术应用于背角，将促进我们对最近对背角的研究中提出的模块化组织的新概念的理解，并开辟一个完整的领域来研究背角回路的组织和可塑性。

DESCRIPTION (provided by applicant): In recent years, pain research has made revolutionary advances at levels ranging from genes to behavior. However, one basic level of organization that has proved particularly resistant to analysis is the intrinsic circuitry underlying pain transmission and modulation within the first central relay area, the spinal dorsal horn. There is much evidence that changes in intrinsic dorsal horn interneurons contribute to plasticity underlying inflammatory and neuropathic pain, but further understanding has been limited by a dearth of methods for studying this intrinsic circuitry. In recent years a novel technique was developed that has made it possible for the first time to dissect the organization of the synaptic connectivity of closely spaced neural elements. With this technique, laser scanning photostimulation (LSPS), synaptic responses are recorded in a single neuron while focal stimulation produced by laser-induced glutamate uncaging is delivered to multiple sites in the tissue surrounding the recorded neuron. The resulting map reveals the location of local excitatory and inhibitory pre-synaptic neurons that give monosynaptic input to the recorded neuron. LSPS has transformed our knowledge of circuitry in a many areas of the central nervous system, but has not yet been used in the pain system. We now propose to use this technique to study the organization of pain (nociceptive) circuitry in the dorsal horn. The proposed experiments will map the locations of dorsal horn neurons that give rise to local excitatory and inhibitory synaptic input to lamina I projection neurons and lamina II interneurons (islet, central, vertical, and radial cells). This approach is based on the hypothesis that the pattern of intrinsic connectivity in the dorsal horn is spatially organized, and that this spatial organization is a fundamental determinant of dorsal horn function. We further hypothesize that this spatial organization differs for excitatory and inhibitory inputs, and is cell-type specific. The application of this technique to the dorsal horn will advance our understanding of the new concept of a modular organization that has been proposed from recent studies of the dorsal horn, and open up an entire field of investigation into the organization and plasticity of dorsal horn circuitry.