Understanding the mechanisms of synapse formation using trans-synaptic labeling

调控大脑连接发展的基本机制得到了高度探索，但仍不清楚。神经连接，称为突触，是调节神经细胞(神经元)之间通信的特殊结构。这些结构对研究很重要，因为它们是产生学习和记忆等过程的基本底物。尽管科学家们已经开发出复杂的工具来评估突触的功能，但对突触的形成仍然没有很好的了解。目前对突触形成的认识是基于提供横截面时间窗的方法来研究突触的发育过程或评估突触的功能。然而，突触的形成不是在神经元之间随机发生的，而是随着时间的推移而发生的一个受调控的动态过程，这是目前可用的工具无法观察到的。我的实验室的主要重点是通过结合使用新的遗传工具和高分辨率显微镜来克服限制，研究突触形成的机制，包括它们的发育速度和特异性。我们的短期目标是使用一种名为跨突触标记的创新技术，该技术利用一种安全修改的狂犬病病毒，用荧光实时标记产生突触的神经元。使用这种方法，我们现在将能够询问哪些神经元相互形成突触(特异性)，以什么时间尺度(速率)，并确定单个神经元的完整连接图，所有这些都是永远不可能的。为了我们的长期目标，我们将在这些新开发的检测方法的基础上，研究调节这些过程的分子信号通路。从这些研究中获得的知识将直接惠及神经发育领域，因为我们的工作将提供新的知识和突触形成的机制。这最终将使我们更好地了解大脑是如何发育的。

The fundamental mechanisms regulating the development of brain connections are highly explored but remain unknown. Neural connections, known as synapses, are specialized structures that mediate communication between nerve cells (neurons). These structures are important to study because they are the basic substrates from which process such as learning and memory is generated. Synapse formation is still not well understood despite the generation of sophisticated tools that allow scientists to assess their function. Current knowledge of synapse formation is based upon methods that provide a cross-sectional time window to study the developmental process or assess the functionality of synapses. However, synapse formation does not occur randomly between neurons and is a regulated, dynamic process that occurs over time, which is not possible to observe using currently available tools. The main focus of my lab is to study mechanisms of synapse formation including their rate of development and specificity, by overcoming limitations using a combination of novel genetic tools and high-resolution microscopy. Our short-term goals are to use an innovative technique named TRANS-SYNAPTIC LABELING, which makes use of a safely modified Rabies virus that labels neurons making synapses in real time with fluorescence. Using this method, we will now be able to ask which neurons form synapses with each other (specificity), at what time scale (rate), and determine the complete connectivity map of an individual neuron, all of which has never been possible. For our long-term goals, we will build upon these newly developed assays and examine molecular signaling pathways that regulate these processes. The knowledge gained from these studies will directly benefit the neurodevelopment field since our work will provide new knowledge and mechanisms by which synapse formation occurs. This will ultimately lead to a better understanding of how the brain develops.