Retrosplenial Cortex Circuit Interactions Supporting Spatial Cognition and Memory

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.

Grant Number: 5R00NS119665-05
NIH Institute/Center: NIH
Principal Investigator: Andrew Alexander