Although formation and stabilization of long-lasting associative memories are thought to require time-dependent coordinated hippocampal-cortical interactions, the underlying mechanisms remain unclear. Here, we present evidence that neurons in the rat cortex must undergo a "tagging process" upon encoding to ensure the progressive hippocampal-driven rewiring of cortical networks that support remote memory storage. This process was AMPA- and N-methyl-D-aspartate receptor-dependent, information-specific, and capable of modulating remote memory persistence by affecting the temporal dynamics of hippocampal-cortical interactions. Post-learning reinforcement of the tagging process via time-limited epigenetic modifications resulted in improved remote memory retrieval. Thus, early tagging of cortical networks is a crucial neurobiological process for remote memory formation whose functional properties fit the requirements imposed by the extended time scale of systems-level memory consolidation.

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.DOI: http://dx.doi.org/10.7554/eLife.14846.001

Training in the active place avoidance task changes hippocampus synaptic function, the dynamics of hippocampus local field potentials, place cell discharge, and active place avoidance memory is maintained by persistent PKMζ activity. The extent to which these changes reflect memory processes and/or stress responses is unknown. We designed a study to assess stress within the active place avoidance task by measuring serum corticosterone (CORT) at different stages of training. CORT levels did not differ between trained mice that learned to avoid the location of the mild foot shock, and untrained no-shock controls exposed to the same environment for the same amount of time. Yoked mice, that received unavoidable shocks in the same time sequence as the trained mice, had significantly higher CORT levels than mice in the trained and no-shock groups after the first trial. This increase in CORT disappeared by the fourth trial the following day, and levels of CORT for all groups matched that of home cage controls. The data demonstrate that place avoidance training is no more stressful than experiencing a familiar environment. We conclude that changes in neural function as a result of active place avoidance training are likely to reflect learning and memory processes rather than stress.

No abstract