Integration of Sensory and Temporal Information in CA3

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ABSTRACT Memories are temporally organized. When we recall an event, we also recall the relative timing it was experienced. How does the brain compute and store this temporal representation of memory? The hippocampus is important to the temporal organization of memories. Hippocampal CA1 or CA3 lesions cause impaired coding of sequential events separated by time. The hippocampus bridges stimuli-free gaps between sequential events through neural ensembles that fire sequentially during the delay. These “time cells” fire sequentially encoding successive moments during the delay. Recent work in our laboratory and other groups have confirmed and furthered these findings. They have found that the CA1 region of the hippocampus contains neurons that display stimulus-specific sequential firing patterns during the delay period of a working memory task. CA1 largely lacks recurrent connectivity, so it is unlikely that it generates these sequential firing patterns on its own. CA3 is an upstream region with direct connections through the Schaffer collaterals to CA1. CA3 has extensive recurrent connections and is a likely candidate that generates these stimulus-specific sequential firing patterns. The recurrent connections in CA3 are well-suited for storing and working with temporary information because they allow for rapid associations. CA3 also receives input from the lateral entorhinal cortex, which processes nonspatial sensory information and receives direct connects from the olfactory bulb. To date, it is unknown where and how sensory and temporal information is integrated. Given the unique attributes of CA3, we propose that CA3 is where sensory and temporal information is integrated and then this code is passed onto CA1. To test this hypothesis, we will use cutting-edge chronic in vivo two-photon calcium imaging to monitor CA3 neuronal populations during a working memory task. Additionally, we will use simultaneous in vivo two-photon imaging and optogenetics to modulate targeted sub-populations within CA3 that are active during stimulus presentation or during the delay period of a working memory task. This will allow us to examine the causal relationships between sensory and temporal information. These experiments will lay the groundwork for understanding how elements of a memory are unified and coded within CA3.