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Real world memories are formed in a particular context and are not acquired or recalled in isolation. Time is a key variable in the organization of memories, since events experienced close in time are more likely to be meaningfully associated, while those experienced with a longer interval are not. How does the brain segregate events that are temporally distinct? Here, we report that a delayed (12-24h) increase in the expression of the C-C chemokine receptor type 5 (CCR5), an immune receptor well known as a co-receptor for HIV infection, following the formation of a contextual memory, determines the duration of the temporal window for associating or linking that memory with subsequent memories. This delayed CCR5 expression in mouse dorsal CA1 (dCA1) neurons results in a decrease in neuronal excitability, which in turn negatively regulates neuronal memory allocation, thus reducing the overlap between dCA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, thus closing the temporal window for memory linking. Remarkably, our findings also show that an age-related increase in CCL5/CCR5 expression leads to impairments in memory linking in aged mice, which could be reversed with a CCR5 knockout and an FDA approved drug that inhibits this receptor, a result with significant clinical implications. All together the findings reported here provide the first insights into the molecular and cellular mechanisms that shape the temporal window for memory linking.

Events occurring close in time are often linked in memory, providing an episodic timeline and a framework for those memories. Recent studies suggest that memories acquired close in time are encoded by overlapping neuronal ensembles, and that this overlap is necessary for memory linking. Transient increases in neuronal excitability drive this ensemble overlap, but whether dendritic plasticity plays a role in linking memories is unknown. Here, we show that contextual memory linking is not only dependent on ensemble overlap in the retrosplenial cortex (RSC), but also on RSC branch-specific dendritic allocation mechanisms. Using longitudinal two-photon calcium imaging of RSC dendrites, we show that the same dendritic segments are preferentially activated by two linked (but not independent) contextual memories, and that spine clusters added after each of two linked (but not independent) contextual memories are allocated to the same dendritic segments. Importantly, with a novel optogenetic tool, selectively targeted to activated dendritic segments following learning, we show that reactivation of dendrites tagged during the first context exploration is sufficient to link two contextual memories. These results demonstrate a causal role for dendritic mechanisms in memory linking and reveal a novel set of rules that govern how linked, and independent memories are allocated to dendritic compartments.

SummaryIndividual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on temporary increase in excitability that drive the overlap between dorsal CA1 (dCA1) hippocampal ensembles encoding the linked memories. Here, we show that the Locus Coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine and not by noradrenaline. Additionally, we found that LC to dCA1 projecting neurons modulate the excitability of dCA1 neurons, and the extent of overlap between dCA1 memory ensembles, as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation, reveals a fundamental separation between the brain mechanisms that modulate these two distinct processes.

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