High Resolution of Mapping of Pain Ciruity in the Dorsal Horn

描述（由申请人提供）：近年来，疼痛研究在从基因到行为的各个层面上取得了革命性的进展。然而，一个基本的组织水平，已被证明是特别抵抗分析的内在电路的疼痛传输和调制内的第一个中央中继区，脊髓背角。有很多证据表明，内在的背角中间神经元的变化有助于可塑性炎症和神经性疼痛的基础，但进一步的理解已被限制了缺乏的方法来研究这种内在的电路。近年来，一种新的技术被开发出来，这使得第一次有可能解剖紧密间隔的神经元的突触连接的组织。利用这种技术，激光扫描光刺激（LSPS），在单个神经元中记录突触反应，而由激光诱导的谷氨酸释放产生的局灶性刺激被递送到记录的神经元周围的组织中的多个位点。由此产生的地图揭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。LSPS已经改变了我们对中枢神经系统许多领域电路的认识，但尚未用于疼痛系统。我们现在建议使用这种技术来研究组织的疼痛（伤害性）电路在背角。拟议的实验将映射的背角神经元的位置，引起局部兴奋性和抑制性突触输入到板I投射神经元和板II中间神经元（胰岛，中央，垂直，放射状细胞）。这种方法是基于这样的假设，即背角的内在连接的模式是空间组织的，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，这种空间组织不同的兴奋性和抑制性输入，是细胞类型特异性。这项技术的应用，背角将推进我们的理解，一个模块化的组织，已提出了从最近的研究背角的新概念，并开辟了一个完整的领域的调查背角电路的组织和可塑性。

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.