Recent studies suggest the hypothesis that a shared neural ensemble may link distinct memories encoded close in time1–13. According to the memory allocation hypothesis1,2, learning triggers a temporary increase in neuronal excitability14–16 that biases the representation of a subsequent memory to the neuronal ensemble encoding the first memory, such that recall of one memory increases the likelihood of recalling the other memory. Accordingly, we report that the overlap between the hippocampal CA1 ensembles activated by two distinct contexts acquired within a day is higher than when they are separated by a week. Multiple convergent findings indicate that this overlap of neuronal ensembles links two contextual memories. First, fear paired with one context is transferred to a neutral context when the two are acquired within a day but not across a week. Second, the first memory strengthens the second memory within a day but not across a week. Older mice, known to have lower CA1 excitability16,17, do not show the overlap between ensembles, the transfer of fear between contexts, or the strengthening of the second memory. Finally, in aged animals, increasing cellular excitability and activating a common ensemble of CA1 neurons during two distinct context exposures rescued the deficit in linking memories. Taken together, these findings demonstrate that contextual memories encoded close in time are linked by directing storage into overlapping ensembles. Alteration of these processes by aging could affect the temporal structure of memories, thus impairing efficient recall of related information.

Summary Declarative memories are thought to be stored within anatomically distributed neuronal networks requiring the hippocampus; however, it is unclear how neocortical areas participate in memory at the time of encoding. Here, we use a c-fos-based genetic tagging system to selectively express the channelrhodopsin variant, ChEF, and optogenetically reactivate a specific neural ensemble in retrosplenial cortex (RSC) engaged by context fear conditioning. Artificial stimulation of RSC was sufficient to produce both context-specific behavior and downstream cellular activity commensurate with natural experience. Moreover, optogenetically, but not contextually-elicited responses were insensitive to hippocampal inactivation, suggesting that although the hippocampus is needed to coordinate activation by sensory cues, a higher-order cortical framework can independently subserve learned behavior, even shortly after learning.

Memories are often classified as hippocampus-dependent or –independent, and sleep has been found to facilitate both, but in different ways. In this Opinion article, we explore the optimal neural state for cellular and systems consolidation of hippocampus-dependent memories that benefit from sleep. We suggest that these two kinds of consolidation, which are ordinarily treated separately, may overlap in time and jointly benefit from a period of reduced interference (during which no new memories are formed). Conditions that result in reduced interference include slow wave sleep (SWS), NMDA receptor antagonists, benzodiazepines, alcohol, and acetylcholine antagonists. We hypothesize that the consolidation of hippocampal-dependent memories may not depend on SWS per se. Instead, the brain opportunistically consolidates previously encoded memories whenever the hippocampus is not otherwise occupied by the task of encoding new memories.