Fos ensembles encode and shape stable spatial maps in the hippocampus

In the hippocampus, spatial maps are formed by place cells while contextual memories are thought to be encoded as engrams(1–6). Engrams are typically identified by expression of the immediate early gene Fos, but little is known about the neural activity patterns that drive, and are shaped by, Fos expression in behaving animals(7–10). Thus, it is unclear whether Fos-expressing hippocampal neurons also encode spatial maps and whether Fos expression correlates with and affects specific features of the place code(11). Here we measured the activity of CA1 neurons with calcium imaging while 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, exhibit reliable place fields that evenly tile the environment and have more stable tuning across days than nearby non-Fos-induced cells. Comparing neighbouring cells with and without Fos function using a sparse genetic loss-of-function approach, we find that neurons with disrupted Fos function have less reliable activity, decreased spatial selectivity and lower across-day stability. Our results demonstrate that Fos-induced cells contribute to hippocampal place codes by encoding accurate, stable and spatially uniform maps and that Fos itself has a causal role in shaping these place codes. Fos ensembles may therefore link two key aspects of hippocampal function: engrams for contextual memories and place codes that underlie cognitive maps.