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Time and experience dependent evolution of hippocampal memory codes

Final Report Summary - MEMORYCODES (Time and experience dependent evolution of hippocampal memory codes)

Project MemoryCodes aimed to characterize how time and experience interact to drive changes in hippocampal memory codes. To study neural coding of long-term memory we combined miniature fluorescence microscopes, microendoscope lenses, and genetically encoded indicators of neuronal activity to perform chronic Ca2+-imaging in the hippocampus of a freely behaving mice. We recently developed CellReg, a probabilistic method that automatically registers cells across multiple sessions and estimates the registration confidence for each registered cell (Sheintuch et al, Cell Reports 2017). Using large-scale Ca2+ imaging data recorded over weeks from the hippocampus and cortex of freely behaving mice, we showed that CellReg performs more accurate registration than previously used routines, yielding estimated error rates <5%, and that the registration is scalable for many sessions. Thus, our method allows reliable longitudinal analysis of the same neurons over long time periods, which is essential for studying neural coding of long-term memory. In another study (Rubin et al, eLife 2015), we performed time-lapse imaging of thousands of neurons over weeks in the hippocampal CA1 of mice as they repeatedly visited two distinct environments. Longitudinal analysis exposed ongoing environment independent evolution of episodic representations, despite stable place field locations and constant remapping between the two environments. These dynamics time-stamped experienced events via neuronal ensembles that had cellular composition and activity patterns unique to specific points in time. Temporally close episodes shared a common timestamp regardless of the spatial context in which they occurred. Temporally remote episodes had distinct timestamps, even if they occurred within the same spatial context. Our results suggest that days-scale hippocampal ensemble dynamics could support the formation of a mental timeline in which experienced events could be mnemonically associated or dissociated based on their temporal distance.