Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - NeurogenesisCode (Deciphering the role of adult neurogenesis in hippocampal memory codes by optically imaging neuronal activity in freely behaving mice)

Teaser

The hippocampal dentate gyrus (DG) is one of the few areas in the adult mammalian brain that exhibits neurogenesis, the continuous generation of new neurons. Much evidence indicates that adult neurogenesis contributes to hippocampal-dependent cognition, but the nature of this...

Summary

The hippocampal dentate gyrus (DG) is one of the few areas in the adult mammalian brain that exhibits neurogenesis, the continuous generation of new neurons. Much evidence indicates that adult neurogenesis contributes to hippocampal-dependent cognition, but the nature of this contribution remains elusive. I envisioned that the clearest path towards understanding the function of adult neurogenesis would be to reveal the changes that occur in the coding properties of DG neurons throughout their development, and the changes that these neurons impose on neural codes generated by the hippocampus. The study of such coding dynamics requires longitudinal recordings of neuronal ensembles in both the DG and CA1 over periods of weeks, since this is the timescale on which new DG neurons mature. Until recently, however, it has been technically impossible to obtain such data. This urgent need drove me to develop a new method, which allows for the optical recording of Ca2+ dynamics from up to 1,200 of the same genetically defined neurons in the hippocampus of freely behaving mice for periods of months. Here, we propose to combine this method with established tools for manipulation of neurogenesis rates or newborn neuron activity, to determine how neurogenesis contributes to coding dynamics in downstream CA1 while mice repeatedly explore familiar environments or preform a long-term memory task. Furthermore, we will establish time-lapse imaging of Ca2+ dynamics in populations of newborn DG neurons while mice perform tasks that engage the DG, and find how newborn neuron coding properties evolve as a function of their maturation. Our work will advance understanding of how the hippocampus supports long-term memory by resolving fundamental questions that pertain to a nearly unexplored facet of memory: how memory codes change with time, while their behavioral manifestations persist.

Work performed

Much of the current ERC project relies on optical imaging in freely behaving mice, and specifically on the ability to chronically record large populations of the same neurons and longitudinally analyze their coding properties. This technological aspect is important to all aims of the ERC project. Therefore, we decided to further develop and validate our own algorithms for tracking the same neurons across days and weeks. This findings and technology from this work were recently published (Sheintuch et al, Cell Reports 2017), and presented at the Society for Neuroscience (SfN) Annual meeting. Summary of the project: Ca2+ imaging techniques permit time-lapse recordings of neuronal activity from large populations over weeks. However, without identifying the same neurons across imaging sessions (cell registration), longitudinal analysis of the neural code is restricted to population-level statistics. Accurate cell registration becomes challenging with increased numbers of cells, sessions, and inter-session intervals. Current cell registration practices, whether manual or automatic, do not quantitatively evaluate registration accuracy, possibly leading to data misinterpretation. We developed a probabilistic method that automatically registers cells across multiple sessions and estimates the registration confidence for each registered cell. Using large-scale Ca2+ imaging data recorded over weeks from the hippocampus and cortex of freely behaving mice, we show that our method 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.

In another project (Rubin et al, eLife 2015) we tested our hypothesis that ongoing changes in the cellular composition and firing patterns of hippocampal ensembles over timescales of days uniquely timestamp experienced episodes in long-term memory. We performed time-lapse imaging of Ca2+ dynamics in large populations of hippocampal neurons in freely behaving mice to record hippocampal neural coding of episodes that occurred in different contexts and at different times over the course of two weeks. Our experiments revealed that CA1 neuronal dynamics carried temporal information via 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, whereas temporally remote episodes had distinct timestamps, even if occurred within the same spatial context. Based on these results, we propose 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.

Final results

To understand the function of adult neurogenesis we would like to reveal the changes that occur in the coding properties of dentate gyrus neurons throughout their development, and the changes that these neurons impose on neural codes generated by the hippocampus. We will do this using a combination of novel optical imaging and genetic targeting techniques for reading out and manipulating the activity of newborn neurons in the hippocampus.