Subfield-specific interneuron circuits govern the hippocampal response to novelty in male mice

The hippocampus is the brain’s center for episodic memories. Its subregions, the dentate gyrus and CA1-3, are differentially involved in memory encoding and recall. Hippocampal principal cells represent episodic features like movement, space, and context, but less is known about GABAergic interneurons. Here, we performed two-photon calcium imaging of parvalbumin- and somatostatin-expressing interneurons in the dentate gyrus and CA1-3 of male mice exploring virtual environments. Parvalbumin-interneurons increased activity with running-speed and reduced it in novel environments. Somatostatin-interneurons in CA1-3 behaved similar to parvalbumin-expressing cells, but their dentate gyrus counterparts increased activity during rest and in novel environments. Congruently, chemogenetic silencing of dentate parvalbumin-interneurons had prominent effects in familiar contexts, while silencing somatostatin-expressing cells increased similarity of granule cell representations between novel and familiar environments. Our data indicate unique roles for parvalbumin- and somatostatin-positive interneurons in the dentate gyrus that are distinct from those in CA1-3 and may support routing of novel information.

Editorial Note: This manuscript has been previously reviewed at another journal that is not operafing a transparent peer review scheme.This document only contains reviewer comments and rebuftal lefters for versions considered at Nature Communicafions.Menfions of the other journal have been redacted.

REVIEWERS' COMMENTS
Reviewer #1 (Remarks to the Author): The authors have addressed all of my concerns.I support publicafion.

Reviewer #2 (Remarks to the Author):
This manuscript is significantly improved in terms of content from the inifial submission to [redacted].The authors have addressed most of my previous comments by adding new stafisfical tests and new data.
1) Unfortunately, the new addifions have made an already complex and dense paper even more difficult to read and parse out the main points and allow the reader to draw conclusions.The authors do a commendable job of laying out the data and stafisfical tests in detail for readers to see and evaluate.However, it takes a lot of effort to read this paper, as the reader is forced to bounce from main text figures to supplementary figures to supplementary tables to gather all of the informafion required to evaluate the robustness and stafisfical significance of many of the results.I encourage the authors to think about how they can simplify presentafion so that the main informafion needed for readers to evaluate the results is in the main text and figures, with the supplementary figures reserved for supporfing data rather than crifical informafion needed to evaluate the significance of the main results.For example, the direct comparison tests requested in the inifial reviews are necessary to evaluate some of the claims made, yet the data that show these comparisons (both those that show posifive and negafive results) are often placed in the supplementary material and only briefly menfioned in the main text.The informafion is all there, but it is hard to access, and I think few readers will have the pafience and fime to dig it all out.Similar comments are applicable to the control data of Supplementary Figure 7.I leave it to the authors and editors to decide how, or whether, to address this issue, as it is a quesfion of readability of the paper rather than of scienfific validity or impact.
2) I remain unconvinced about the authors' arguments about the magnitude of many of the effects (e.g., that limitafions of the technique "may" underesfimate the true effect sizes is not a strong argument; that they see a strong effect size in their validafion that the DREADDs are actually silencing the neurons in the intended fashion does not address the quesfion of whether the scienfific quesfions under study here show a strong enough effect to be scienfifically meaningful, etc.) and whether their conclusions about different funcfions played by PV and SOM neurons in different regions are supported strongly and cleanly by these relafive weak effects.However, for the intended specialist audience of Nature Communicafions this is less of a concern, as the data are available for readers to draw their own conclusions.I do wonder whether the authors' choice of violin plots, with connecfing lines between individual neurons in the background, contributes to the impression of small magnitudes of effects.The problem is that most of the lines are obscured by the lines occluding each other.I wonder if scafter plots, such as in Figure 4A, are overall a more effecfive way of portraying the data than the violin plots.For example, seeing that almost all of the points are above the diagonal for DG-SOM in Fig 4A is visually more compelling than seeing the small shift in the medians and the highly overlapping distribufions in the violin plots of Fig 4A .I leave it to the authors to decide if they believe that their message will be more effecfively conveyed by presenfing more scafter plots in place of (or in addifion to) the violin plots.
3) For future work (not in the present paper), I recommend that the authors consider the use of mixedeffects models to account for the contribufions of individual animals and cells within an animal, ufilizing these variables as random effects in the models.These techniques are becoming increasingly used in neuroscience to account for the problems that arise by quesfions of whether the individual cell, the individual session, or the individual animal are the proper units of measurement for stafisfical significance tesfing.This is especially problemafic as the number of simultaneously recorded neurons, from both imaging and high-density electrode arrays, increases dramafically with new technologies and magnifies this problem.The use of mixed effects models potenfially eliminates the awkwardness and ambiguity of showing results that are highly significant when using hundreds of cells that are not independent samples, but having the significance disappear when using individual animals or sessions as the unit of analysis.
Reviewer #3 (Remarks to the Author): The authors have done a superb job at addressing my concerns.