Hippocampal integration and separation processes with different temporal and spatial dynamics during learning for associative memory

The hippocampus is known to be critically involved in associative memory formation. However, the role of the hippocampus during the learning of associative memory is still controversial; while the hippocampus is considered to play a critical role in the integration of related stimuli, numerous studies also suggest a role of the hippocampus in the separation of different memory traces for rapid learning. Here, we employed an associative learning paradigm consisting of repeated learning cycles. By tracking the changes in the hippocampal representations of associated stimuli on a cycle-by-cycle basis as learning progressed, we show that both integration and separation processes occur in the hippocampus with different temporal dynamics. We found that the degree of shared representations for associated stimuli decreased significantly during the early phase of learning, whereas it increased during the later phase of learning. Remarkably, these dynamic temporal changes were observed only for stimulus pairs remembered 1 day or 4 weeks after learning, but not for forgotten pairs. Further, the integration process during learning was prominent in the anterior hippocampus, while the separation process was obvious in the posterior hippocampus. These results demonstrate temporally and spatially dynamic hippocampal processing during learning that can lead to the maintenance of associative memory.