申请人系统研究Synaptotagmin蛋白家族和Complexin蛋白家族重要成员在神经元囊泡转运中的功能，取得一系列创新性研究成果 (Cao et al., Cell, 2011; Cao et al., Journal of Neuroscience, 2013)，揭示出钙离子同时精确控制同一个神经元中两条并行囊泡转运通路的分子机制。这些研究成果发表后被Cell和Nature Reviews Neuroscience杂志发文评述，并获得国际同行的普遍好评。在此基础上，申请人拟应用神经元囊泡转运原理，开发新型“突触遗传学”分子工具；并利用这些分子工具深入研究小鼠嗅觉社交学习的分子神经机制。这些研究有望从囊泡转运这一崭新的角度揭示人类社交学习的分子机理；更重要的是，本项目开发的突触遗传学工具可供广大研究同行使用，从而推动神经科学的整体发展。

The applicant systematically studied how calcium triggers different vesicle trafficking pathways in neurons. He found that, in a single neuron, Syt1 and Syt10, two key members in synaptotagmin family, work differentially as calcium sensors for the neurotransmitter release and the secretion of insulin-like growth factor-1 (IGF1). He further revealed that complexin-1 and -2 are essential for activation of multiple types of calcium-induced exocytosis that are regulated by different synaptotagmin isoforms. Viewed together, these results suggest that different types of regulated exocytosis are mediated by similar synaptotagmin-dependent fusion mechanisms, that particular synaptotagmin isoforms confer specificity onto different types of regulated exocytosis, and that complexins serve as universal synaptotagmin adaptors for all of these types of exocytosis independent of which synaptotagmin isoform is involved. These results also attracted a Leading-Edge Preview from Cell, and Research Highlight from Nature Reviews Neuroscience. On the basis of these results, the applicant will (1) develop "synaptogenetic" tools, a new class of molecular tools that can be used to study synaptic mechanisms underlying behavior and cognition; (2) use these synaptogenetic tools to study molecular and circuit mechanisms underlying olfactory social learning. The outcome of this research project would not only reveal the principles for social learning, but also provide new tools for the colleagues in neuroscience research field.

在博士后期间，申请人系统研究了 Synaptotagmin 蛋白家族重要成员在神经元囊泡转运中的功能（Cao et al., Cell, 2011; Cao et al., Journal of Neuroscience, 2013），揭示了钙离子同时精确控制同一神经元中两条并行的囊泡转运通路的分子机制。在本项目（2015年-2017年）中，申请人进一步深入研究了这两条囊泡转运通路的生理功能。他们发现，在小鼠嗅觉学习过程中，嗅觉刺激可同时激活嗅球僧帽细胞中由Synaptotagmin-1 和 -10 控制的两条钙离子依赖的囊泡转运通路。其中，Synaptotagmin-1 控制僧帽细胞的神经递质 GABA 的释放，负责小鼠的嗅觉感知；Synaptotagmin-10 控制僧帽细胞钙依赖的 IGF1 的释放，负责小鼠嗅觉记忆的维持。被释放的生长因子 IGF1 可以作用于僧帽细胞的 IGF1 受体，引发僧帽细胞 GABA 能突触的可塑性。这些发现揭示出 Synaptotagmin-1 和 -10 的囊泡转运通路的重要生理功能，已于2017年7月在神经科学权威刊物《Neuron》上发表。与此同时，申请人开发了一系列囊泡转运相关蛋白的基因敲除小鼠模型，为进一步深入研究神经元囊泡转运的分子机制和生理功能打下了基础。这些小鼠模型将逐步运送至 Jackson 实验室，为国内外领域同行开展研究提供支持。