Genetic Mapping of Somatosensory Neural Networks

描述（由申请人提供）：在哺乳动物中，化学、机械或热性质的刺激的检测通过构成我们的躯体感觉系统的初级和高级感觉神经元的复杂网络发生。我们在分子水平上对躯体感觉的理解的一个重大进展来自于瞬时受体电位（TRP）通道家族成员的鉴定，这些成员是外周神经中热刺激的主要检测器。这些“热传感器”在不同的温度范围内是敏感的，并且在大多数情况下，定义了感觉神经元的离散群体。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，以及用于传达这些刺激的神经网络的架构仍然不清楚。本申请的目的是开发遗传模型系统，这将使映射的体感神经网络参与检测特定的刺激方式。这些探索性研究将集中在最近克隆的冷和薄荷醇受体，CMR 1或TRPM 8。我们打算使用TRPM8转录启动子在TRPM8+外周传入神经中特异性表达跨神经元示踪剂，以映射这些神经元用于集中传达温度的神经网络和突触连接。在建立这种动物模型后，我们将评估TRPM 8神经网络的脊髓组织的变化，这些变化可能在诱导炎症性或神经性疼痛后产生。我们还将通过开发一种小鼠模型来评估这一群体的感觉神经的生理相关性，在该模型中这些细胞可以被有条件地消融。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，并将扩大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.