Elucidating the Wiring and Rewiring of Poly-synaptic Memory Circuits by Directed Stepwise Trans-neuronal Tracing

总结 多模态感觉信息通过多突触通路会聚到 海马体形成整合的表征和编码世界的记忆， 反过来通过多突触下游通路引导我们未来的行为。公 已知该回路中的每个大脑区域由各种神经元细胞类型组成，或者 在连接性和功能上不同的组。然而，我们不能建立一个长期的 在这些特定的神经元组之间的多突触扭曲图，没有有效的工具， 连续跟踪突触连接的多个顺序， 方式同样，这条通路的连线是否会受到动态修改也不清楚 学习、记忆或大脑障碍，因为缺乏持续监测大脑活动的工具。 神经元的连接在这里，我们建议开发新的方法， 这些挑战。在第一部分中，我们将修改用于跨神经元追踪的病毒载体， 能以一种可控的、逐步的方式在突触间传播。我们将使用新工具进行测试 假设海马CA 1或CA 3区的不同神经元群 接收不同的多突触输入并发出不同的多突触输出。在第二 部分我们将对特定的CA 1或CA 3进行功能成像和功能操作， 神经元组，以测试这些神经元组的假设，由其特定的 多突触输入和/或输出接收不同的感觉信息，并依次调节 行为的不同方面。在第三部分中，我们将开发新的技术来跟踪 同一只动物在两个时间点的感兴趣的神经元的连接-之前和之后， 学习过程--检查学习和记忆是否改变了神经元的连接。在一起， 这些研究将证明是否在每个大脑区域的不同的神经元群， 记忆回路选择性地与其他大脑区域的特定神经元群连接， 形成功能性的“通道”，将不同的感官信息连接到不同的方面， 行为在这项研究中开发/优化的新工具将在以下方面得到广泛使用： 神经科学研究帮助我们绘制出大脑的功能网络。

Summary Multimodal sensory information is converged through poly-synaptic pathways to the hippocampus to form integrated representations and encode memories of the world, which in turn guide our future behavior through multiple poly-synaptic downstream pathways. It is well known that each of the brain regions in this circuit consists of various neuronal cell types or groups which are distinct in connectivity and functions. Yet we cannot construct a long-range poly-synaptic wring diagram among these specific neuronal groups without efficient tools to continuously track the multiple orders of synaptic connections in a controlled and directed manner. Similarly, it is not clear if the wiring of this pathway is subject to dynamic modifications by learning, memory or brain disorders due to a lack of tools to continuously monitor the neuronal connectivity over time. Here we propose to develop novel methodology to embrace these challenges. In the first part we will modify viral vectors for trans-neuronal tracing which can spread across synapses in a controlled, stepwise manner. With the new tool we will test the hypothesis that distinct neuronal groups in the CA1 or CA3 regions of the hippocampus receive distinct poly-synaptic inputs and send out distinct poly-synaptic outputs. In the second part we will conduct functional imaging and functional manipulations of the specific CA1 or CA3 neuronal groups to test the hypothesis that these neuronal groups, defined by their specific poly-synaptic inputs and/or outputs, receive distinct sensory information and in turn adjust different aspects of behavior. In the third part we will develop novel technology to trace in the same animal the connectivity of neurons of interest at two time points--before and after a learning process--to examine if learning and memory alters neuronal connectivity. Together, these studies will demonstrate whether the distinct neuronal groups at each brain region in the memory circuit are selectively connected with specific neuronal groups in other brain regions to form functional “channels” which bridge different sensory information to the different aspects of behavior. The novel tools to be developed/optimized in this study will find wide use in neuroscience research helping us to map out the functional network in the brain.