Understanding the mechanisms of synapse formation using trans-synaptic labeling

调节大脑连接发育的基本机制被高度探索，但仍然未知。神经连接，被称为突触，是调节神经细胞（神经元）之间交流的专门结构。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基础。尽管有先进的工具使科学家能够评估突触的功能，但突触的形成仍然没有得到很好的理解。目前对突触形成的了解是基于提供一个横断面时间窗口的方法来研究发育过程或评估突触的功能。然而，突触的形成并不是在神经元之间随机发生的，而是一个随时间发生的受调节的动态过程，这是不可能用现有的工具观察到的。我实验室的主要重点是研究突触形成的机制，包括它们的发育速度和特异性，通过使用新型遗传工具和高分辨率显微镜的组合来克服限制。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饰的狂犬病毒，用荧光实时标记形成突触的神经元。使用这种方法，我们现在能够询问哪些神经元彼此形成突触（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，所有这些都是不可能的。为了我们的长期目标，我们将建立在这些新开发的分析和检查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有益于神经发育领域，因为我们的工作将提供突触形成的新知识和机制。这将最终导致更好地理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.