Reproducible and predictable reorganization of place fields driven by grid subfield rate changes

Reviewer #1 (Public review):

This manuscript investigates how chemogenetic depolarization of medial entorhinal cortex layer II stellate cells reshapes spatial coding in downstream hippocampal CA1. Building on the authors' prior work (Kanter et al., Neuron 2017), the study examines changes in grid cell subfield firing rates and CA1 place cell firing patterns after CNO administration. A central advance of the present work is the use of the same manipulation on two consecutive days. The authors show that the induced grid subfield rate changes are highly similar across days and that CA1 place field reorganization is likewise reproducible across days. In addition, they report that CA1 remapping after CNO is not arbitrary. The new main place field often emerges at a location that can be anticipated from the baseline rate map of the same cell, typically corresponding to a weak secondary peak outside the primary field. Finally, the authors demonstrate that these experimental findings can be recapitulated in a feedforward grid to place cell model by selectively redistributing grid subfield firing rates, supporting the interpretation that grid subfield rate changes are sufficient to drive predictable and reproducible place field reorganization.

Overall, this study is positioned as a follow-up to the authors' previous report in which the main phenomenon (grid subfield rate remapping and accompanying CA1 place cell remapping following chemogenetic depolarization of MEC layer II neurons) was already established. While the conceptual novelty is therefore incremental, the present manuscript adds important and convincing evidence about two key properties of this phenomenon, including its reproducibility across days and the extent to which the direction of place field reorganization is predictable from baseline activity. The experimental approach and analyses appear generally appropriate and carefully executed, and the inclusion of modeling strengthens the mechanistic interpretation. These results provide useful new insight into stable input-output relationships within the entorhinal hippocampal system, and the work will be of interest to researchers studying remapping and the grid to place cell transformation.

Reviewer #2 (Public review):

Summary:

Hippocampal remapping - the collective reorganization of neural tuning properties - is thought to be a crucial determinant of memory outcomes. Understanding its mechanistic bases is a fundamental goal of neuroscience and likely to be critical to understanding memory in health and disease. Here, Lykken et al. 2025 leverage a unique empirical manipulation paired with computational modeling to investigate how one mechanism - reorganization of grid cell subfield firing rates - impacts hippocampal remapping. The authors find that repeated chemogenetic excitation of MEC stellate cells induces reliable reorganization of grid cell subfield firing rates, which is in turn coupled with reliable hippocampal remapping. Notably, the authors show that this hippocampal remapping is not random but predictable, with changes in field location that can be predicted based on weak out-of-field firing observed during control sessions. These findings were well-replicated by a simple model of grid-to-place transformation.

Strengths:

This work has many strengths. One key strength of this work is its compelling demonstration that chemogenetic activation of stellate cells induces changes to the grid and place cell representations, which are reliable across repeated activations. This reliability means that the functional changes induced by this manipulation are not merely noise but rather contain a consistent structure that can be investigated to gain insight into the entorhinal-hippocampal transformation. Similarly, the demonstration that hippocampal remapping during this manipulation is not random, but predictable at the single-cell level, is also a strength. This predictability can help us distinguish competing mechanisms of remapping and place field formation more generally. Finally, by reproducing key experimental outcomes with a straightforward grid-to-place computational model, the authors show that this relatively simple model is sufficient to understand their results.

Weaknesses:

This work also has limitations that leave some relevant questions open at this time. One such set of questions which might be addressable with the author's data and modeling concerns population analyses. Do grid fields at similar locations exhibit similar changes in field properties, or do these fields change independently? Are changes in field location consistent or inconsistent among simultaneously recorded place cells? Would we expect or not expect such a structure given the model? These results might help discriminate between different mechanisms possibly at play.

Another limitation of this work is its reliance on a single measure of predictability. While this is a great start, and the various controls and modeling are appreciated, I wonder whether the modeling could be used to generate additional verifiable predictions. For example, perhaps analyzing whether there is or is not structure to unpredictable errors (are these distributed around predictions but further away, or are they random)?

Finally, one limitation comes from the between-group nature of the recordings. Because the MEC and hippocampus are recorded in separate groups of animals, the authors lose the ability to test whether each mouse's particular grid field reorganization predicts its particular pattern of remapping. If the author's model is correct, then one might hope to be able to predict with even higher accuracy the particular patterns of remapping in CA1 given sufficiently well-characterized grid field changes. This ambitious goal would require simultaneous recordings from the hippocampus and entorhinal cortex, which are beyond the scope of the current work, but would ultimately yield even more compelling evidence of the grid-to-place transformation underlying this form of remapping.