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.

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Alterations in the levels of synaptic proteins affect synaptic transmission and synaptic plasticity. However, the precise effects on neuronal network activity are still enigmatic. Here, we utilized microelectrode array (MEA) to elucidate how manipulation of the presynaptic release process affects the activity of neuronal networks. By combining pharmacological tools and genetic manipulation of synaptic proteins, we show that overexpression of DOC2B and Munc13-1, proteins known to promote vesicular maturation and release, elicits opposite effects on the activity of the neuronal network. Although both cause an increase in the overall number of spikes, the distribution of spikes is different. While DOC2B enhances, Munc13-1 reduces the firing rate within bursts of spikes throughout the network; however, Munc13-1 increases the rate of network bursts. DOC2B's effects were mimicked by Strontium that elevates asynchronous release but not by a DOC2B mutant that enhances spontaneous release rate. This suggests for the first time that increased asynchronous release on the single-neuron level promotes bursting activity in the network level. This innovative study demonstrates the complementary role of the network level in explaining the physiological relevance of the cellular activity of presynaptic proteins and the transformation of synaptic release manipulation from the neuron to the network level.

Memories are dynamic in nature. A cohesive representation of the world requires memories to be altered over time, linked with other memories and eventually integrated into a larger framework of sematic knowledge. Although there is a considerable literature on how single memories are encoded, retrieved and updated, little is known about the mechanisms that govern memory linking, e.g., linking and integration of various memories across hours or days. In this review, we present evidence that specific memory allocation mechanisms, such as changes in CREB and intrinsic excitability, ensure memory storage in ways that facilitate effective recall and linking at a later time. Beyond CREB and intrinsic excitability, we also review a number of other phenomena with potential roles in memory linking.