Hippocampome.org 2.0 is a knowledge base enabling data-driven spiking neural network simulations of rodent hippocampal circuits

  1. Diek W Wheeler
  2. Jeffrey D Kopsick
  3. Nate Sutton
  4. Carolina Tecuatl
  5. Alexander O Komendantov
  6. Kasturi Nadella
  7. Giorgio A Ascoli

  • Curated by eLife

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    eLife assessment

    The authors have greatly expanded their important hippocampome.org resource about rodent hippocampal cell types, their physiological properties, and their interactions. With version 2.0, they make a significant advance in providing a user-friendly means to make computer models of hippocampal circuits. The work is convincing, and there are only minor reservations that the figures may be too complex.

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Abstract

Hippocampome.org is a mature open-access knowledge base of the rodent hippocampal formation focusing on neuron types and their properties. Previously, Hippocampome.org v1.0 established a foundational classification system identifying 122 hippocampal neuron types based on their axonal and dendritic morphologies, main neurotransmitter, membrane biophysics, and molecular expression (Wheeler et al., 2015). Releases v1.1 through v1.12 furthered the aggregation of literature-mined data, including among others neuron counts, spiking patterns, synaptic physiology, in vivo firing phases, and connection probabilities. Those additional properties increased the online information content of this public resource over 100-fold, enabling numerous independent discoveries by the scientific community. Hippocampome.org v2.0, introduced here, besides incorporating over 50 new neuron types, now recenters its focus on extending the functionality to build real-scale, biologically detailed, data-driven computational simulations. In all cases, the freely downloadable model parameters are directly linked to the specific peer-reviewed empirical evidence from which they were derived. Possible research applications include quantitative, multiscale analyses of circuit connectivity and spiking neural network simulations of activity dynamics. These advances can help generate precise, experimentally testable hypotheses and shed light on the neural mechanisms underlying associative memory and spatial navigation.

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  1. Version published to 10.7554/elife.90597.3 on eLife
  2. Version published to 10.7554/elife.90597 on eLife
  3. Version published to 10.7554/elife.90597.2 on eLife
  4. eLife

    Author Response

    The following is the authors’ response to the original reviews.

    Reviewer #2 (Recommendations For The Authors):

    While the details are mostly well-explained, I think that the authors could better bring forth the goals and potential usages of hippocampome.org overall.

    I think that this is a great and helpful tool that can leverage various and detailed cellular experimental studies that are out there in the literature to garner potential insights, direct future experimental studies, observe/classify experimental 'differences' (e.g., the deep and superficial pyramidal studies they mention) and so on. Say that one gets some mechanistic insight from more abstract theoretical models, hippocampome can be used to determine whether the experimental data where available is supportive of the theory. They also describe CA3 model and grid cells. While I am not suggesting that the authors completely re-organize the manuscript, I did feel that the last section 'potential applications...' could have perhaps been brought forth earlier (in a summarized form) for the reader/user to better appreciate hippocampome - indeed it is line 288 that should be near the beginning of the paper I thought.

    We thank the Reviewer for the suggestion. We have now included a summary of the simulation readiness of Hippocampome.org in the Introduction.

    I thought the 'application' paragraph (starting line 288) needed expansion to appreciate - I did not have a chance to look at the cited papers in that section - but maybe 2 paragraphs, one on CA3 and the other on grid cells, with a few more sentences of goal/context and tool usage details could be provided?

    We thank the Reviewer for the suggestion. We have added expanded paragraphs describing the simulation work on CA3 and grid cells.

    The authors start their Discussion by mentioning other resources (e.g. blue brain) in comparison. I thought that this was not too helpful without a bit more expansion about these other resources and what in particular is comparable. For example, the blue brain project is different in that it does not mine the literature per se (I think)? But then I am not sure of the extent of the comparison that the authors intend with blue brain and the other mentioned resources.

    Thank you for the helpful suggestion. We have now expanded upon the paragraph to draw more explicit parallels and contrasts among the various projects, in particular between the Blue Brain Project and Hippocampome.org.

    Minor comments

    • Fig 3D caption missing

    Thank you for pointing this out. We have now amended the figure caption.

    • Fig 5A line 211-12 refers to v2.0 but Fig 5 caption says v1.0?

    We apologize for the confusion. We have now added text clarifying the V1.X relevant descriptions around Figure 5.

    • Fig 6A confusing with thin and thick arrows and direction?

    We apologize for the confusion. We have re-colored the thick arrows orange to emphasize the fact that they are feeding directly into the spiking neural simulations.

    • Line 260 - not sure what this means - how is importance defined?

    We apologize for the confusion. We have now added text clarifying that “importance” refers to the role the neuron type plays in the functioning circuitry of the hippocampal formation.

    • CARLsim vs Brian/NEST in choosing - maybe a sentence or two for rationale

    Thank you for the suggestion. We have now added a sentence explaining the selection of CARLsim. CARLsim was selected due to its ability to run on collections of GPUs. CARLsim was the only simulator with this capability at the time the simulation work was being planned, and the power of a GPU supercomputer was needed to simulate the millions of neurons that comprise a full simulation of the complete hippocampal formation.

    • Fig 9 mv should be mV, and the voltage values specified there refer to which dash?

    Thank you for pointing these situations out. We have amended the millivolts label and have made changes to the figure to help clarify which specific tick marks are being labeled.

    Reviewer #3 (Recommendations For The Authors):

    Compliments to the authors on this nicely organized and structured presentation of V 2.0 of hippocampome.org. The paper is well prepared giving a useful short summary of the history of hippocampome for the newcomers and refreshing the memory of users, switching to highlighting the new data additions, why these are relevant and how these complement the existing database, and opening up to new applications. The added potential is well illustrated and in addition, the authors provide numerical information on the usage of this amazing resource. I enjoyed roaming around in the new version, which was made available for reviewers, and although it has been a while since I worked with the system, the new version is easy to work with. I have not had the time to use it extensively so cannot comment in detail but based on the long experience of the authors and their support team, I trust that version 2 will be almost not completely flawless; however that will for sure become clear when it is released.

    One could always wish for more, disagree, or even criticize choices made to cluster neurons, divide areas, and so forth, though in my view that does not contribute to what the resource has to offer. Having said this, the authors might consider addressing briefly issues about differences in the nomenclature used in original descriptions and how they handled the translation into their nomenclature. To mention one that is constantly being debated: how does one define the border between SMo and SMi.

    Thank you for the suggestion. We have added text to the Introduction that addresses the nomenclature issue, as presented in Hamilton et al. (2017), and provide a definition for SMo and SMi.

    Another confusing issue is presented by layers in the entorhinal cortex or its subdivisions (how many and how are these defined). So, some remarks for newcomers in the field who might use the database without spending too much energy to read the original data, might be useful.

    Thank you for the suggestion to clarify this situation pertaining to the entorhinal cortex. Often, we have assumed the authors’ own definitions of the layers and subdivisions (medial and lateral), when naming neuron types. When our name is a hybrid of two published names that include both medial and lateral neurons, our name is prefixed by a simple EC, rather than by MEC or LEC.

    As noted, the authors present version 2 nicely and comprehensibly and I have only a few additional comments, meant to further improve the already high quality of the paper.

    1. The figures, nice as they are, are incredibly information-dense, so they require serious study to get the details; the legends do help, but the many abbreviations coming from totally different fields make it challenging to keep track of them while reading. This is a pity since there is a lot of new information in this version of the dataset, compared to previous versions and the authors overall succeed in emphasizing what is new and why this might be of use/importance.

    So a few suggestions: i) add relevant/most important abbreviations to the legends of the individual figures; ii) introduce all abbreviations upon first use and do not simply refer to the table in the methods. Interestingly, even the authors lose track in the introduction where they use BICCN in line 43 and refer to the abbreviation list, though the full name is given two lines below.

    We apologize for the confusion. We have amended the main text to clarify abbreviations. We have added the abbreviation definitions to the captions of the figures, and in some instances, removed the abbreviations from the figures altogether where space allowed.

    1. Figure 3 and even more so figure 5 depend strongly on the color differences red/green; please change since generally red/green is no longer used for obvious reasons.

    Thank you for pointing this out. We have switched the fonts in Figure 3 to black (excitatory) and gray (inhibitory) to match our previous publication. We have also changed the color schemes in Figure 5 to avoid red and green.

    Reviewer #3 commented on the complexity of our figures and how the figures are information dense. To partially address this, we have decided to remove panel A2 of Figure 3. It was originally meant to emphasize where the information came from to add new axonal projections to two v1.0 neuron types; however, it is not necessary to make the point in the illustration. Thus, we have removed the panel and amended the caption for Figure 3A to include the cited reference.

  5. eLife

    eLife assessment

    The authors have greatly expanded their important hippocampome.org resource about rodent hippocampal cell types, their physiological properties, and their interactions. With version 2.0, they make a significant advance in providing a user-friendly means to make computer models of hippocampal circuits. The work is convincing, and there are only minor reservations that the figures may be too complex.

  6. eLife

    Reviewer #2 (Public Review):

    The authors have greatly expanded their helpful hippocampome.org resource for the community regarding hippocampal cell types and their interactions from many perspectives. The many updates from v1.0 to v1.12 are nicely summarized in Table 1.

    With v2.0, they now achieve the original vision of their project - to enable data-driven spiking neural network simulations of rodent hippocampal circuits. This work thus moves hippocampome.org from not only being a useful resource but also being able to launch simulations in which the models have direct links to the experimental literature. This will not only be of interest to the vast hippocampal community, but also to the diverse computational neuroscience community as theoretical models can potentially be "experimentally tested" with v2.0 to allow theoretical insights to be more biologically applicable.

  7. eLife

    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 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 exiting 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. The database itself is easy to navigate and to access relevant information, allowing to do further research on the available data.

    Weaknesses:

    The figures are complex, containing a heavy information load. One needs some general knowlegde of the system in order to grasp the enormous potential of what is provided.

  8. Version published to 10.1101/2023.05.12.540597v4 on bioRxiv
  9. Version published to 10.1101/2023.05.12.540597v3 on bioRxiv
  10. Version published to 10.7554/elife.90597.1 on eLife
  11. eLife

    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.

  12. eLife

    eLife assessment

    The authors have updated a helpful resource for the neuroscience community regarding hippocampal cell types and their interactions, called the "hippocampome." The updates expand content, tools, and potential applications, and therefore the significance is important. The strong presentation makes the paper compelling.

  13. eLife

    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.

    Properties are often a result of modeling and not biological data, and caveats to this approach, and other assumptions are unclear.

    Several interneuron subtypes in the dentate gyrus do not appear to be listed, such as neurogliaform cells.

    The nomenclature HIPROM should be distinguished or made synonymous with HIPP. Same for MOCAP and MOPP/HICAP.

    Dorsal ventral and sex differences are not mentioned.

  14. eLife

    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?

  15. eLife

    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.

  16. Version published to 10.1101/2023.05.12.540597v2 on bioRxiv
  17. Version published to 10.1101/2023.05.12.540597v1 on bioRxiv