Molecular mechanisms of human synapse formation induced by secreted bloodborne factors

突触是神经元之间的单一连接，使大脑中的信息能够快速传输和处理。突触的形成由两种类型的组织者分子指导：一种是在神经细胞表面表达的黏附分子，另一种是大脑内部或外部由其他器官产生的分泌因子。特别令人感兴趣的是在血液中循环的“系统性因素”，已被证明可以增强小鼠的学习和记忆。这项研究的目的是了解这些系统性因素是否以及如何作用于人类神经元来调节突触的形成。首先，我们将使用来自干细胞的人类神经元来筛选结构蛋白、生长因子和激素，以确定它们对突触数量和活性的直接影响。这将通过用每个系统因子处理人类神经元，并测量神经元网络活动和单个神经元对电刺激的突触反应的变化来实现。其次，我们将结合生化和基因编辑方法，识别与系统因子结合的神经元受体蛋白，并引发内部细胞反应，以触发突触组装和活动。最后，我们将产生具有特殊组织层的人类“迷你大脑”有机化合物，该组织层在内部有机物质液体和外部环境之间形成选择性屏障。我们将测试系统因素是否可以越过这一选择性障碍，并使用高分辨率显微镜和全球电网络活动测量来检查对有机类突触形成的潜在影响。我们的机械洞察力将在系统环境和大脑功能之间建立因果联系，并最终可能为突触丢失驱动的神经退行性疾病的治疗策略提供参考。

Synapses are unitary connections between neurons that enable rapid transfer and processing of information in the brain. Synapse formation is guided by two types of organizer molecules: adhesion molecules expressed at the neuronal cell surface and secreted factors produced inside the brain or externally by other organs. Of particular interest are "systemic factors" circulating in the bloodstream that have been shown to enhance learning and memory in mice. The goal of this research is to understand whether and how these systemic factors act on human neurons to regulate synapse formation. First, we will use human neurons derived from stem cells to screen structural proteins, growth factors and hormones for direct effects on synapse number and activity. This will be accomplished by treating the human neurons with each systemic factor and measuring changes in the activity of neuronal networks and in the synaptic responses of individual neurons to electrical stimulation. Second, we will combine biochemical and gene editing approaches to identify neuronal receptor proteins that bind to the systemic factors and elicit internal cellular responses to trigger synapse assembly and activity. Finally, we will generate human "mini-brain" organoids with a specialized tissue layer that forms a selective barrier between the internal organoid fluid and the external environment. We will test whether systemic factors can cross this selective barrier and examine potential effects on organoid synapse formation using high-resolution microscopy and global measurements of electrical network activity. Our mechanistic insights will establish a causal link between the systemic environment and brain function and may ultimately inform therapeutic strategies for neurodegenerative diseases driven by synapse loss.