Interleaved Replay of Novel and Familiar Memory Traces During Slow-Wave Sleep Prevents Catastrophic Forgetting

Humans and animals can learn continuously, acquiring new knowledge and integrating it into a pool of lifelong memories. Memory replay during sleep has been proposed as a powerful mechanism contributing to interference-free new learning ^1–5 . In contrast, artificial neural networks suffer from a problem called catastrophic forgetting ^6–9 , where new training damages existing memories. This issue can be mitigated by interleaving training on new tasks with past data ^6,10,11 ; however, whether the brain employs this strategy remains unknown. In this work, we show that slow-wave sleep (SWS) employs an interleaved replay of familiar cortical and novel hippocampal memory traces within individual Up states of the slow oscillation (SO), allowing new memories to be embedded into the existing pool of cortical memories without interference. Using a combination of biophysical modeling and analyses of single-unit activity from the mouse retrosplenial cortex - for a mouse trained first in a highly familiar environment and then in a novel one - we found that hippocampal ripples arriving near the Down-to-Up or Up-to-Down transitions of the sleep SO can entrain novel memory replay, while the middle phase of the Up state tends to replay familiar cortical memories. This strategy ensures the consolidation of novel cortical memory traces into long-term storage while minimizing damage to familiar ones. This study presents a novel framework for how replay of familiar and novel memory traces is organized during SWS to enable continual learning.