Understanding the spinal circuitry of cold

皮肤温度感觉对于检测和避免潜在的有害环境温度是至关重要的， 以及体温调节。这种机制在神经性疼痛条件下经常出错， 表现为冷超敏反应，一种通常冷的输入被感知为冷得痛苦的状况。一 对冷刺激如何在神经系统中编码的有限理解使得这种使人衰弱的情况 管理不善。最近的研究表明，冷输入是从外周传递到中枢神经的 系统由表达温度敏感性阳离子通道TRPM 8的初级传入的群体。 然而，这些信息在脊髓中处理并传递到脊髓的神经回路 大脑仍然几乎完全未知。为了弥补这一根本性的知识差距，本提案将 通过行为、电生理和神经网络的结合， 和形态学方法。根据我们的初步研究，我们认为冷输入是从 通过表达神经激肽1受体（NK 1 R）的脊髓臂旁投射将脊髓连接到大脑 神经元为了研究这种可能性，我们的实验室最近产生了一个NK 1 R-CreER等位基因，从而为我们提供了 用基因来标记和操纵NK 1 R神经元的活动。这项提案将检验这一假设 冷输入由一组形态上不同的NK 1 R神经元从脊髓传递到大脑， 其从冷感、TRPM 8初级感觉传入接收突触输入（直接或间接）。目标1将 研究是否NK 1 R脊髓投射神经元所需的恶寒使用行为分析。 目的2将解剖TRPM 8初级传入和NK 1 R脊髓投射神经元之间的回路， 使用电生理学和光遗传学方法结合我们的离体方法对冷刺激做出反应。 体感准备目的3将确定冷选择性脊髓投射神经元的形态， 使用组织学重建脊髓背角内的细胞结构。这些实验将建立 介导冷输入的基本脊髓回路，从而提供了一个研究框架 在未来的研究中，电路的变化是冷过敏的基础。这种多方面的成功 研究金培训计划包括科学和职业发展活动，将得到 匹兹堡疼痛中心提供的科学专业知识、合作和教育机会 Research.

Cutaneous thermosensation is critical for detecting and avoiding potentially harmful environmental temperatures, as well as thermoregulation. This mechanism frequently goes awry under neuropathic pain conditions, manifesting as cold hypersensitivity, a condition in which normally cool input is perceived as painfully cold. A limited understanding of how cold stimuli are encoded in the nervous system has left this debilitating condition poorly managed. Recent studies suggest that cold input is conveyed from the periphery to the central nervous system by a population of primary afferents that express the temperature-sensitive cation channel TRPM8. However, the neural circuits through which this information is processed in the spinal cord and conveyed to the brain remain almost completely unknown. To address this fundamental gap in knowledge, this proposal will dissect the neural circuitry that encodes cold stimuli through a combination of behavioral, electrophysiological and morphological approaches. Based on our preliminary studies, we believe that cold input is conveyed from the spinal cord to the brain by a subset of neurokinin 1 receptor (NK1R)-expressing spinoparabrachial projection neurons. To investigate this possibility, our lab recently generated a NK1R-CreER allele, thereby providing us with genetic access to label and manipulate the activity of NK1R neurons. This proposal will test the hypothesis that cold input is conveyed from the spinal cord to the brain by a subset of morphologically distinct NK1R neurons that receive synaptic input (direct or indirect) from cold-sensing, TRPM8 primary sensory afferents. Aim 1 will investigate whether NK1R spinal projection neurons are required for aversion to cold using behavioral assays. Aim 2 will dissect the circuitry between TRPM8 primary afferents and NK1R spinal projection neurons that respond to cold stimuli using electrophysiology and optogenetic approaches in combination with our ex vivo somatosensory preparation. Aim 3 will determine the morphology of cold-selective spinal projection neurons by using histology to reconstruct cell architecture within the spinal cord dorsal horn. These experiments will establish the basic spinal circuitry that mediates cold input, thereby providing a framework from which to investigate changes in circuitry that underlie cold hypersensitivity in future studies. The success of this multifaceted fellowship training plan, which includes activities for scientific and career development, will be aided by the scientific expertise, collaboration, and educational opportunities offered by the Pittsburgh Center for Pain Research.