先驱神经元在大脑皮层神经网络发育中的作用

Neural circuits are the physiological basis for study and memory in cerebral cortex, and play an important role in the formation of animal behavior. As the earliest division and maturity neurons in the cortical development, pioneer neurons (PNs) are really involved in the development of neural network, and may be served as hub neurons to connect with large numbers of neurons. However, it is remains unclear what the role PNs play in the development of neural network. In this study, by using transgenic mice and retrovirus to label the PNs and non- pioneer neurons (nPNs), we mainly studied the function of PNs on the regulation mechanism underlying the construction of cortical networks. Through the research, we will clarify systematically the following questions. First, we will elaborate the features of primitive established cortical circuits by studying the microcircuits of PNs. Second, through “silence” or “activation” of PNs in vivo, the influences of PNs on the mature and network formation of nPNs will be revealed. Furthermore, through the large-scale imaging of cortical network activity, we will unfold the role of PNs in shaping developing and mature networks. Meanwhile, in vivo studies will reveal the role of PNs in learning and memory . These findings will hope to unravel the blueprint of template of neocortical neurons arranged and the mechanism underlying the construction of cortical networks.

在大脑皮层中，大量神经元之间所形成的神经网络不仅是大脑学习和记忆的生理基础，而且在各种动物行为的形成中起到重要作用。先驱神经元作为脑皮层最先分裂和成熟的神经元处于神经网络发育的“顶端”，有可能在神经环路发育中与更多的神经元形成环路，并在神经网络中处于中心地位，但先驱神经元在大脑皮层神经网络发育中的作用目前还不清楚。在本项目中利用转基因小鼠和逆转录病毒标记皮层中先驱神经元和较晚成熟的神经元（非先驱神经元），研究先驱神经元对脑皮层神经网络建立的影响和调控机制。通过本项研究我们拟系统阐明：（1）先驱神经元之间形成的最早的皮层神经环路的特点；（2）在体“沉默”或“兴奋”先驱神经元对非先驱神经元成熟以及脑皮层建立神经环路的影响；（3）分析先驱神经元在成熟皮层网络中的作用；（4）先驱神经元在学习记忆行为中的作用。这些研究结果对揭示脑皮层神经元如何装配成功能性网络有重要的参考价值。

在本项研究中，我们主要取得了如下研究成果：（1）先驱中间神经元主要是表达Somatostatin的中间神经元，并位于脑皮层的深层；（2）在发育早期（P5-7）先驱中间神经元较非先驱中间神经元具有更成熟的电生理特性，同时先驱中间神经元突触后膜电流的频率显著高于非先驱中间神经元；（3）先驱中间神经元与非先驱中间神经元在局部微环路连接上并没有显著差异；（4）先驱中间神经元在发育早期具有显著的“枢纽神经元”的特性；（5）先驱中间神经元在发育早期主要参与调控脑皮层大规模同步化放电活动；（6）先驱中间神经元具有投射中间神经元的特性，表达nNos蛋白，并主要参与远距离神经调控；（7）先驱神经元的缺失可显著影响脑皮层兴奋性神经元的形态学和环路发育；（8）先驱神经元的缺失可显著影响小鼠睡眠。这些研究结果对揭示脑皮层神经元如何装配成功能性网络有重要的参考价值。