Genetic and behavioral state influences on the hippocampal spatial code

Abstract

The hippocampus encodes and recalls contextual memories using engrams and forms spatial memories using place cells. Engrams are typically identified by the expression of the immediate early gene Fos, while place cells are identified by their neural activity patterns during spatial tasks. Surprisingly little is known about the relationship between Fos-expressing engram neurons and place cells, in part because the neural activity patterns that drive, and are shaped by, Fos expression in behaving animals are poorly understood. Here we measured the activity of CA1 neurons with calcium imaging while simultaneously monitoring Fos induction in mice performing a hippocampus-dependent spatial learning task in virtual reality. We find that neurons with high Fos induction form ensembles of cells with highly correlated activity that are organized as sequences of place cells. These Fos-induced cells have reliable place fields that evenly tile the environment and are stable across days, forming an accurate, spatially uniform map, unlike neighboring non-Fos-induced cells. To assess whether Fos expression shapes the place code, we compared neighboring cells with and without Fos function and find that neurons lacking Fos have higher activity levels but decreased reliability, less spatial selectivity, and decreased across-day stability. Our results reveal a major contribution of Fos-induced cells to hippocampal place codes through the formation of neural ensembles that constitute reliable, stable, and spatially unbiased maps. We propose that Fos ensembles link two key functions of the hippocampus: establishing engrams for contextual memories and the place codes that underlie cognitive maps. Finally, in the same hippocampal dependent goal-directed behavior, we examined the influence of behavioral state on place cell activity, taking advantage of naturally occurring changes in task engagement. The hippocampus is thought to automatically form and maintain a place code by combining sensory and self-motion signals. Instead, we observed an extensive degradation of the place code when mice voluntarily disengaged from a virtual-navigation task, remarkably even as they continued to traverse the identical environment. Internal states can therefore strongly gate spatial maps and reorganize hippocampal activity even without sensory and self-motion changes.