Retrosplenial Cortex Circuit Interactions Supporting Spatial Cognition and Memory

该项目建议研究支持空间认知和情景记忆的神经生理回路机制。脾后皮质(RSC)在这些认知过程中至关重要，因为RSC功能障碍与空间定向障碍、学习和记忆障碍以及阿尔茨海默病的病理有关。一个突出的想法是，RSC促进了坐标系之间的空间转换，其中相对于动物本身编码的自我中心空间信息与相对于外部世界编码的异地中心空间信息相关。这种计算是导航和情景记忆所必需的，因为两者都需要通过感官体验的信息相对于更广泛的环境进行表征。RSC拥有促进空间转换所需的解剖和活动模式，但还没有直接证据表明计算发生在该区域内。这种差距至少部分是由于普遍缺乏关于RSC基本功能的知识；尚不清楚该区域是否作为持续行为的结果而被灵活招募，功能定义的RSC子群体投射在哪里，或者传入输入如何对该区域内的已知形式的空间编码做出贡献。我将学习高密度细胞外记录、活体神经成像和投射特定光遗传学的技术，以测试脾后回路动力学在空间转换中的作用。首先，我将提供空间编码差异的第一个表征，以及基于任务的不同RSC子区域的招募，这些RSC子区域具有对自我中心和分配中心空间加工流的偏向投影。从这些同时记录的大量神经元中，我将测试反映空间转换计算的区域内和区域外内部网络状态。接下来，我将利用大量RSC群体的活体成像，纵向检查神经元是否预先连接或学习其空间感受野作为任务需求的函数。我将利用特定于投影的成像来测试特定的空间信号是否被传输到特定的传出目标以支持空间转换。最后，我将把上述观察大型神经元群体活动的方法与投影特定的光遗传电路操作配对，以测试不同传入输入对不同形式的RSC空间编码的作用。通过利用创新的实验方法，这些项目将提供关于RSC在空间导航和情节记忆基础上的空间转换功能的重要见解。这些研究的结果将建立RSC电路机制，在健康和病理状态下调节这些认知过程。在这个奖项的指导阶段，我将开发的科学专业知识和职业/实验室管理工具将对我的成功至关重要，因为我将过渡到教员职位，并从事自己的独立研究计划。

This project proposes to investigate neurophysiological circuit mechanisms supporting spatial cognition and episodic memory. The retrosplenial cortex (RSC) is critical in these cognitive processes as RSC dysfunction is associated with spatial disorientation and learning and memory deficits, as well as Alzheimer’s disease pathology. One prominent idea is that RSC facilitates spatial transformations between coordinate systems, wherein egocentric spatial information encoded relative to the animal itself is related to allocentric spatial information encoded relative to the external world. This computation is required for navigation and episodic memory, as both require information experienced via sensory organs to be represented relative to the broader environment. RSC possesses the requisite anatomy and activity patterns to facilitate spatial transformations, but there has been no direct evidence of the computation occurring within the region. This gap at least partly arises from a general lack of knowledge regarding RSC base function; it is unknown if the region is flexibly recruited as a consequence of ongoing behavior, where functionally-defined RSC sub-populations project, or how afferent inputs contribute to known forms of spatial coding within the area. I will learn techniques for high-density extracellular recordings, in vivo neuroimaging, and projection- specific optogenetics to test the role of retrosplenial circuit dynamics in spatial transformations. First, I will provide the first characterization of spatial coding differences and task-based recruitment of distinct RSC sub-regions that have biased projections to egocentric and allocentric spatial processing streams. From these large populations of simultaneously recorded neurons, I will test for intra- and extra-regional internal network states that reflect computation of spatial transformations. Next, I will utilize in vivo imaging of large RSC populations longitudinally to examine if neurons are prewired or learn their spatial receptive fields as a function of task demands. I will utilize projection-specific imaging to test if specific spatial signals are transmitted to specific efferent targets in support of spatial transformations. Finally, I will pair the aforementioned methods for observing activity of large neuronal populations with projection-specific optogenetic circuit manipulations to test the role of different afferent inputs on different forms of RSC spatial coding. By utilizing innovative experimental approaches, these projects will provide important insights regarding the function of RSC in spatial transformations underlying spatial navigation and episodic memory. Results from these studies will establish RSC circuit mechanisms that mediate these cognitive processes in both healthy and pathological states. The scientific expertise and career/laboratory management tools that I will develop during the mentored phase of this award will be vital for my success as I transition into a faculty position and pursue my own independent research program.