Paradoxical effect of exercise on the long-term stability of hippocampal place code

In addition to maintaining a healthy body, physical activity benefits the brain, improving memory and cognition. While some of the physiological effects of voluntary exercise on the brain are known (e.g., increased hippocampal neurogenesis), little is known about its effects on the neural code. Using longitudinal Ca2+ imaging in freely behaving mice and tracking the same neurons over weeks, we studied how voluntary exercise affects the quality and long-term stability of hippocampal place codes. In addition to increasing neurogenesis, we found that running accelerated the emergence of spatial code in novel environments, increased the amount of information that neurons carried about the mouse’s position, and increased code stability over timescales of days-weeks. Paradoxically, although running mice demonstrated an overall more stable place code than their sedentary peers, when controlling for code quality, their place code was in fact less stable for any given code quality level. This result suggests that the seemingly increased stability for runners is mediated by the difference in the code quality between the two groups (known as the “Simpson’s paradox”). A model-based simulation showed that the combination of both improved code quality and faster representational drift in runners, but neither of these effects alone, could account for our results. Thus, exercise may benefit hippocampal function by inducing faster learning and promoting long-term memory via a more informative place code.