High Resolution of Mapping of Pain Ciruity in the Dorsal Horn

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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.