Scientific Papers

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

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Hippocampome.org, through its continuous updates and conspicuous usage, has established itself prominently amongst other readily accessible, evidence-based, expert-curated bioscience public resources of note, such as FlyBase for Drosophila molecular biology (The FlyBase Consortium, 1994; dos Santos et al., 2015), WormBase for nematode genomics (Stein et al., 2001), the Blue Brain Project for somatosensory cortex (Markram, 2006), SynGO for synaptic functions (Koopmans et al., 2019), and RegenBase for spinal cord injury biology (Callahan et al., 2016). Hippocampome.org has evolved from being a storehouse of information in v1.0–1.12, along the lines of FlyBase, WormBase, SynGO, and RegenBase, to a platform in v2.0 for launching detailed simulations of the hippocampal formation, in the vein of the Blue Brain Project. However, Hippocampome.org distinguishes itself in its reliance wholly on already published data and the more tailored focus on a single portion of the brain.

The foundation for Hippocampome.org has always been the data that are published in the literature. Although a certain level of interpretation is always necessary to make the data machine readable and suitable for database incorporation, data inclusion does not depend on how the data are modeled. Nevertheless, 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; Izhikevich, 2003) and the unitary synaptic values (Tsodyks-Pawelzik-Markram model; Tsodyks et al., 1998). 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).

The growth of Hippocampome.org since the initial release of v1.0 (Wheeler et al., 2015) has been prodigious. To date, the site has been visited over 136,000 times with over 33,000 unique visits, and the original publication has been cited more than hundred times. Each successive release of Hippocampome.org v1.X has added new dimensions of knowledge and/or functionality and has been building toward assembling all the components necessary to produce real-scale computational models of the rodent hippocampal formation. The culmination of all this work is the release of Hippocampome.org v2.0, which introduces a framework for launching computer simulations directly from the accumulated knowledge. However, achieving simulations does not mark the end point for this project, because Hippocampome.org will continue to aggregate new knowledge as it is published in the peer-reviewed literature. Gradually, the focus of this resource will shift from development to exploitation through the in silico emulation of complex dynamics observed in vivo and in vitro, with the goal of shedding light on the underlying synaptic-level computational mechanisms.

The creation of real-scale spiking neural network models of the hippocampal formation and its subregions can foster biologically realistic, data-driven, mesoscopic simulations of cognitive function and dysfunction (Sutton and Ascoli, 2021). For instance, simulations with Hippocampome.org’s real-scale model of the dentate gyrus can build on previous network models of epileptogenesis (Dyhrfjeld-Johnsen et al., 2007) by providing further clarity to the roles of all documented neuron types and their corresponding potential connections in seizure initiation and propagation. A real-scale model of CA1 can aim to further the insights into the spatiotemporal dynamics of the circuit during theta oscillations (Bezaire et al., 2016; Navas-Olive et al., 2020; Romani et al., 2023). Furthermore, network models involving multiple subregions can open new vistas on unexplored territories, such as the use of real-scale models of the entorhinal cortex and CA2 to simulate the neuron- and connection-type specific mechanisms of social memory (Lopez-Rojas et al., 2022). Moreover, open source sharing of the real-scale models replicating those functions (Gleeson et al., 2017) will facilitate cross-talk within the systems neuroscience community to better understand the role of distinct neuron types in hippocampal function.

A notable aspect of Hippocampome.org is that all freely downloadable model parameters are directly linked to the specific peer-reviewed empirical evidence from which they were derived. Thus, if users disagree with a specific interpretation, or are not fully convinced by an individual experimental measurement, they maintain control in selecting the information sources. Conversely, researchers can choose to reuse the collated experimental data to constrain different computational models they may prefer, such as adopting the Hodgkin-Huxley formalism instead of Izhikevich dynamics. At the same time, Hippocampome.org is not only a collection of model parameters and corresponding empirical evidence, but it also provides an opportunity to unearth knowledge gaps, as facilitated by an intuitive search functionality (hippocampome.org/find-neuron). Missing data can serve to guide the design of targeted ‘low hanging fruit’ experiments or to generate new hypotheses.

Another important element of Hippocampome.org is the careful annotation of the experimental metadata for each piece of evidence, including the species (rat or mouse), sex (male or female), age (young or adult) as well as any and all reported details that could affect the recorded neuronal property. Examples of these confounding factors abound especially for in vitro electrophysiological data, such as the exact chemical composition of the solution in the electrode and in the bath, slice thickness and orientation, clamping configuration, recording temperature, and animal weight. Because these covariates, when reported by the original investigators, are also stored in the database, it is possible to account for them in subsequent analyses and simulations. Hippocampome.org therefore constitutes a considerably rich one-stop resource to compare and ‘translate’ key parameters, such as the amplitude and duration of a synaptic signal between two specifically identified neuron types, for instance, from 14-day-old male rat at 22 °C in voltage clamp to a 56-day-old female mouse at 32 °C in current clamp. When fed into spiking neural network simulations, these differential parameter values can foster intuition while attempting to reconcile neuroscience theories and observations.

Hippocampome.org is yet poised for the onset of an information deluge from current and future big science projects, which will need to be integrated into a complete cohesive picture (de la Prida and Ascoli, 2021). Although morphological identification will continue to play a fundamental role in defining neuron types and circuit connectivity, the manner in which knowledge is cross-referenced in this resource will allow its effective linkage to rapidly accumulating molecular and imaging data. The ongoing spatial transcriptomics revolution is already transforming the frontiers of cellular neuroscience, often using the hippocampus as its favorite sandbox (Lein et al., 2017; Yao et al., 2021; Zeisel et al., 2015). Single-cell transcriptomics via scRNAseq can bolster the current morphological information by offering distinct transcription factor codes for existing neuron types and assist in defining new ones (Cembrowski and Spruston, 2019; Winnubst et al., 2020; Yuste et al., 2020). From the functional side, optical imaging via genetically encoded voltage indicators (Knöpfel and Song, 2019) will provide in vivo voltage traces for defined neuron types that can greatly enhance the repertoire of firing pattern phenotypes to utilize in simulations (Adam et al., 2019). Data-driven computational models can provide a useful conceptual bridge between molecular sequencing and activity imaging by investigating the effects of specific subcellular distributions of voltage- and ligand-gated conductances on neuronal excitability (Migliore et al., 2018). With the converging maturation of these young techniques and the advent of others yet on the horizon, Hippocampome.org will be able to integrate multidimensional knowledge on the solid foundation of neuronal classification.

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