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

摘要 多模式感觉信息通过多突触通路汇聚到 海马体形成完整的表示和编码世界的记忆，这在 反过来，通过多个多突触下游通路指导我们未来的行为。这很好 已知此回路中的每个脑区由不同类型的神经细胞或 在连通性和功能上截然不同的群体。然而，我们不能建造一个远程的 这些特定神经元群之间的多突触扭曲图没有有效的工具来 以受控和定向的方式连续跟踪突触连接的多个顺序 举止。同样，目前还不清楚这条通路的布线是否受到动态修改 由于缺乏持续监测的工具而导致的学习、记忆或大脑障碍 随着时间的推移神经元的连接性。在这里，我们建议开发新的方法来拥抱 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 可以以可控的、循序渐进的方式跨越突触传播。使用新工具，我们将测试 假设海马区CA1或CA3区不同的神经元群 接收不同的多突触输入，并发出不同的多突触输出。在第二个 我们将对特定的CA1或CA3进行功能成像和功能操作 神经元组来测试这些神经元组的假设，这些神经元组由其特定的 多突触输入和/或输出，接收不同的感觉信息，进而调整 行为的不同方面。在第三部分中，我们将开发新的技术来追踪 同一动物在两个时间点上感兴趣的神经元的连接性--在 学习过程--检查学习和记忆是否改变了神经元的连接。一起， 这些研究将证明，大脑中每个区域的不同神经元组 记忆回路选择性地与其他脑区的特定神经元组相连，以 形成功能性“通道”，将不同的感觉信息连接到不同的方面 行为。这项研究将开发/优化的新工具将在 神经科学研究帮助我们绘制出大脑中的功能网络。

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.