Retrosplenial Cortex Circuit Interactions Supporting Spatial Cognition and Memory

本计画旨在探讨空间认知与情景记忆的神经生理回路机制。压后皮质（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和学习记忆缺陷以及阿尔茨海默病病理学相关。一个突出的想法是，RSC促进坐标系之间的空间变换，其中相对于动物本身编码的自我中心的空间信息与相对于外部世界编码的非自我中心的空间信息相关。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觉器官体验到的信息相对于更广泛的环境来表示。RSC拥有必要的解剖结构和活动模式，以促进空间转换，但一直没有直接的证据表明，计算发生在该地区。这种差距至少部分源于对RSC基本功能的普遍缺乏了解;目前尚不清楚该区域是否因持续行为而灵活招募，功能定义的RSC亚群投射在哪里，或者传入输入如何有助于该区域内已知形式的空间编码。 我将学习高密度细胞外记录，体内神经成像和投射特异性光遗传学技术，以测试空间转换中压后电路动态的作用。首先，我将提供的第一个表征的空间编码差异和基于任务的招聘不同的RSC子区域，有偏见的预测自我中心和allocentric空间处理流。从这些大量同时记录的神经元中，我将测试区域内和区域外的内部网络状态，这些状态反映了空间变换的计算。接下来，我将利用大型RSC群体的纵向体内成像来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。我将利用投影特异性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变换。最后，我将把上述观察大型神经元群体活动的方法与投射特异性光遗传学回路操作配对，以测试不同传入输入对不同形式RSC空间编码的作用。 通过利用创新的实验方法，这些项目将提供有关RSC在空间导航和情景记忆基础的空间转换中的功能的重要见解。这些研究的结果将建立RSC电路机制，在健康和病理状态下介导这些认知过程。我将在这个奖项的指导阶段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，因为我过渡到教师职位并追求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.