Genetic Mapping of Somatosensory Neural Networks

描述（由申请人提供）：在哺乳动物中，对化学、机械或热性质的刺激的检测通过构成我们体感觉系统的初级和高阶感觉神经元的复杂网络发生。我们在分子水平上对体感觉的理解取得了重大进展，因为我们发现了瞬时受体电位（TRP）通道家族成员是外周神经热刺激的主要探测器。这些“热传感器”对不同的温度范围敏感，在大多数情况下，定义了离散的感觉神经元群。然而，热刺激诱发的信号如何在高于外周传入的水平上被解释和处理，以及用于传递这些刺激的神经网络的结构仍不清楚。本应用程序的目的是开发遗传模型系统，使参与特定刺激模式检测的体感神经网络的映射成为可能。这些探索性研究将集中在最近克隆的感冒和薄荷醇受体CMR1或TRPM8上。我们打算利用TRPM8转录启动子在TRPM8+外周传入神经中特异性表达一种跨神经元示踪剂，以便绘制这些神经元用于中枢温度交流的神经网络和突触连接。在该动物模型建立后，我们将评估炎症性或神经性疼痛诱导后TRPM8神经网络脊柱组织的变化。我们还将通过开发一种小鼠模型来评估这些感觉神经的生理相关性，在这种模型中，这些细胞可以有条件地消融。从这些探索性研究中获得的经验将用于其他热传感器的未来研究，并将扩展我们对如何检测和区分感官刺激的理解。

DESCRIPTION (provided by applicant): In mammals, the detection of stimuli of a chemical, mechanical, or thermal nature occurs through a complex network of primary and higher-order sensory neurons that make up our somatosensory system. A significant advance in our understanding of somatosensation at the molecular level came from the identification of members of the transient receptor potential (TRP) channel family as the primary detectors of thermal stimuli in peripheral nerves. These "thermosensors" are sensitive over distinct temperature ranges and, in most cases, define discrete populations of sensory neurons. However, how signals evoked by thermal stimuli are interpreted and processed at levels higher than the peripheral afferents, as well as the architecture of the neural networks used to communicate these stimuli is still unclear. The aims of this application are to develop genetic model systems that will enable the mapping of somatosensory neural networks involved in the detection of specific stimulus modalities. These exploratory studies will focus on the recently cloned cold and menthol receptor, CMR1 or TRPM8. We intend to use the TRPM8 transcriptional promoter to specifically express a transneuronal tracer in TRPM8+ peripheral afferent nerves in order to map the neural networks and synaptic connections used by these neurons to communicate temperature centrally. After this animal model has been established, we will then assess for changes in spinal organization of TRPM8 neural networks that may result after the induction of inflammatory or neuropathic pain. We will also assess the physiological relevance of this population of sensory nerves by developing a mouse model in which these cells can be conditionally ablated. The experienced gained from these exploratory studies will be used for future investigations of other thermosensors and will expand our understanding of how we detect and discriminate sensory stimuli.