脊髓Ucn3+神经元传递痒觉信号的环路机制研究

痒是一种引起机体抓挠欲望的不愉快感觉，包括致痒剂引起的化学痒和毫毛的机械振动引起的机械痒。申请人近期的研究表明，脊髓尿皮质素3阳性(Ucn3+)神经元通过接收外周低阈值机械感受器TLR5-Abeta的信号输入来实现对机械痒信号的传递，同时被神经肽Y阳性(NPY+)抑制性中间神经元所门控；而Ucn3+神经元自身兴奋性的增强和NPY+神经元对其抑制作用的减弱共同导致慢性痒的发生(Neuron,2019)。然而，Ucn3+神经元通过何种神经通路进一步将机械痒信号从脊髓传递至大脑，目前尚不清楚。本项目拟在先前工作的基础上，鉴定Ucn3+神经元的下级神经元，阐明其在机械痒信号传递中的作用；分析其电生理特性和功能，明确其与Ucn3+神经元的关系；分析其在慢性痒发生中的作用及机制；鉴定该下游神经通路是否直接投射至大脑。本项目对阐明痒觉信息传递的中枢神经通路、寻找缓解慢性痒的有效干预靶点具有重要的意义。

Itch is an unpleasant sensation that induces scratching behavior. Itch includes pruritogens-induced chemical itch and vellus vibration-evoked mechanical itch. Our recent study demonstrates that spinal Urocortin 3+ (Ucn3+) neurons transmit mechanical itch by receiving inputs from peripheral toll-like receptor 5-positive (TLR5+) low-threshold mechanoreceptors TLR5-Abeta, and such transmission is gated by spinal inhibitory interneurons expressing neuropeptide Y (NPY+) (Neuron, 2019). Both increased intrinsic excitability of Ucn3+ neurons and decreased inhibition from NPY+ neurons on Ucn3+ neurons contribute to chronic itch. However, it remains unknown how Ucn3+ neurons continue to transmit mechanical itch signals from spinal cord to brain. In the present study, we will identify the downstream neurons of Ucn3+ neurons, determine the role of the downstream neurons in transmitting mechanical itch signals; analyze the electrophysiological properties and function of the downstream neurons, determine the relationship between the downstream neurons with Ucn3+ neurons; analyze the role of the downstream neurons in chronic itch and the underlying mechanism; and identify if such neural pathway directly projects to brain. The present study is of significance for understanding the central circuit mechanism of itch and discovering drug therapy target for chronic itch.