Author Response:
Reviewer #1 (Public Review):
Summary:
The authors made significant updates to Hippacampome.org including 50 new cell types.
Strengths:
The authors have been thorough in basing their views on peer-reviewed literature. They have made the data highly accessible and the user has the ability to control what is included.
Weaknesses:
There are many inconsistencies in the literature regarding cell types and how these are incorporated into hippocampome.org is not clear.
We agree with the Reviewer that there can be inconsistencies in the literature, especially when it comes to nomenclature. This is why for Hippocampome.org v1.0 we decided to focus on the morphologies, the distributions of axons and dendrites across the layers and parcels of the hippocampal formation, rather than the names authors have applied to the neurons they are studying. We have also clarified our stance on nomenclature in our Brain Informatics manuscript that accompanied v1.1. We will revise the manuscript to make these points explicit.
Properties are often a result of modeling and not biological data, and caveats to this approach, and other assumptions are unclear.
The foundation for Hippocampome.org has always been the data that are published in the literature. Those include, among others, the axonal and dendritic spans in each layer and subregion, the molecular expression patterns, the total neuron count by layer and subregion, the membrane properties, firing patterns, and experimental synaptic signals and corresponding covariates. For all of those, we do not depend on how the data are modeled, although there is always some level of interpretation of the data to make them machine readable and ready for incorporation into our database. However, some of the simulation-ready parameters now also included in Hippocampome.org are indeed the result of modeling, such as the neuronal input/output functions (Izhikevich model) and the unitary synaptic values (Tsodyks-Markram model). Other simulation-ready parameters are the result of specific analysis approaches, including the connection probabilities (axonal-dendritic spatial overlaps) and the neuron type census (numerical optimization of all constraints). We plan to explicitly distinguish among these various cases in the revised manuscript.
Several interneuron subtypes in the dentate gyrus do not appear to be listed, such as neurogliaform cells.
The neuron types listed in Figure 2 of the current manuscript are only the new additions to the catalog of neuron types at Hippocampome.org v2.0. DG Neurogliaform cells were included in our original eLife manuscript, which described the deployment of v1.0 of the website. We will clarify this in the revisions.
The nomenclature HIPROM should be distinguished or made synonymous with HIPP. Same for MOCAP and MOPP/HICAP.
The Reviewer has referred to 5 separate neuron types in Hippocampome.org. Each neuron type has a unique distribution of axonal and dendritic invasions of the 26 layers and parcels of the hippocampal formation. For example, HIPROM cells have dendrites in the inner one-third of stratum moleculare, stratum granulosum, and hilus and axons in all four layers of the dentate gyrus in addition to axonal projections into CA3 stratum radiatum, stratum lucidum, stratum pyramidale, and stratum oriens. HIPP cells in contrast have dendrites only in the hilus and axons only in the outer two-thirds of stratum moleculare with no cross-subregional projections. Similar considerations distinguish MOPP, MOCAP, and HICAP cells in Hippocampome.org. In expanding the nomenclature to include the neuron types we first described at Hippocampome.org, we attempted to mimic the styling of the already established neuron types of the DG: HIPROM (Hilar Interneuron with PRojections to the Outer Molecular layer), HIPP (HIlar Perforant Path-associated), MOCAP (MOlecular Commissural-Associational Pathway-related axons and dendrites), MOPP (MOlecular layer Perforant Path-associated), and HICAP (HIlar Commissural-Associational Pathway-related). We intend to insert a paragraph in the revised version to clarify these issues.
Dorsal ventral and sex differences are not mentioned.
We thank the Reviewer for pointing this out. As a result of the dearth of literature describing differences between dorsal and ventral hippocampus when we first assembled Hippocampome.org v1.0, we made the decision to focus solely on the distributions of the axons and dendrites along the depth, or layers, of the hippocampal formation. As the amount of literature concerning relating to the other axes of the hippocampus continues to grow, we will gradually incorporate information along the added dimensions into our knowledge base. In the revised manuscript we intend to note this, and also stress the fact that Hippocampome.org contains knowledge from a mixture of sexes, and that whenever the original papers report the animal sex, so does our knowledge base. The revised manuscript will also mention that, whenever possible (e.g. synaptic physiology parameters), values are reported separately for males and females.
Reviewer #2 (Public Review):
Summary and strengths:
The authors have developed a helpful resource for the community regarding hippocampal cell types and their interactions from many perspectives. There have been many updates to hippocampome v1.0 to v1.12, that are nicely summarized and explained (e.g., Table 1). The content and impact are also presented (Fig. 4).
Weaknesses:
My main comment is that it is not completely clear and/or it is a bit buried as to what makes this v2.0 (rather than v1.13). The title would seem to encompass it ('... enabling data-driven spiking neural network simulations...), but in the introduction, the authors seem to emphasize "50 newly identified neuron types...". Is it the case that launching network simulations (using CARLsim) was not possible up to v1.12? I don't think so? I think that this research advance is to announce and summarize the various updates and to demonstrate how network simulations can be easily done? If so, this should and could be made more clear so that the reader does not necessarily have to go through all the previous versions to understand what is 'special' or different about v2.0. This could perhaps be achieved by situating their tool and its goals relative to other efforts (e.g., blue brain project) that are mentioned in the Discussion?
We thank the Reviewer for their helpful suggestions. Hippocampome.org v1.12 included the final piece needed, the synaptic physiology parameter values, to start fully simulating the hippocampal formation. In the revised manuscript, we will endeavor to emphasize more the specialness of v2.0 over the various v1.X in the Abstract, Introduction, and Discussion, in part by more fully describing the differences between our work and that of other efforts, such as the Blue Brain Project.
Reviewer #3 (Public Review):
Summary:
The authors aim to provide a multidisciplinary resource on the structural and physiological organization of the hippocampal system and make the available experimental data available for further theoretical work, providing tools to do so in a very flexible and user-friendly way. Since this is a new version of an already existing data-resource, the authors certainly reach their aim and fulfil expectations that the reader might have. The content of the database is as good as the original data, collected from the published knowledge-database, sometimes with the help of the original authors, and the overall quality depends further on how the data are curated by the team of authors and many others who helped them. That process is briefly described and more details are available in descriptions of previous versions and on the website. The data extraction, examples of how data can be used, and the part on attempts to model the hippocampus are exciting and open doors to new and exciting research opportunities.
Strengths:
Excellent description with many outlined opportunities. Nicely illustrated and inviting to explore the online database.
Weaknesses:
The figures are complex, containing a heavy information load with many abbreviations. You need some general knowledge of the system in order to grasp the enormous potential of what is provided.
We agree with the Reviewer that we generously used abbreviations throughout our figures as a means of conserving limited space. We have attempted to balance that by providing a complete glossary of all the abbreviations used throughout the manuscript. However, we will make an effort to supply definitions of the abbreviations in the figure captions and at their first use in the manuscript, or even replacing the abbreviations altogether in key places in the figures.
