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Hippocampome.org: A Knowledge Base of Neuron Types in the Rodent Hippocampus

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Hippocampome.org: A Knowledge Base of Neuron Types in the Rodent Hippocampus

Diek W Wheeler et al. Elife.

Abstract

Hippocampome.org is a comprehensive knowledge base of neuron types in the rodent hippocampal formation (dentate gyrus, CA3, CA2, CA1, subiculum, and entorhinal cortex). Although the hippocampal literature is remarkably information-rich, neuron properties are often reported with incompletely defined and notoriously inconsistent terminology, creating a formidable challenge for data integration. Our extensive literature mining and data reconciliation identified 122 neuron types based on neurotransmitter, axonal and dendritic patterns, synaptic specificity, electrophysiology, and molecular biomarkers. All ∼3700 annotated properties are individually supported by specific evidence (∼14,000 pieces) in peer-reviewed publications. Systematic analysis of this unprecedented amount of machine-readable information reveals novel correlations among neuron types and properties, the potential connectivity of the full hippocampal circuitry, and outstanding knowledge gaps. User-friendly browsing and online querying of Hippocampome.org may aid design and interpretation of both experiments and simulations. This powerful, simple, and extensible neuron classification endeavor is unique in its detail, utility, and completeness.

Keywords: dentate gyrus; entorhinal cortex; literature mining; mouse; neural circuit; neuronal classification; neuroscience; potential connectome; rat.

Conflict of interest statement

The authors declare that no competing interests exist.

Figures

Figure 1.
Figure 1.. Defining neuron types with anatomical parcels and morphological patterns.
(A, B) Nissl staining of a P56 mouse (coronal sections 74 and 85 from the Allen Brain Atlas) overlaid by color-coded parcels (in accord with Temporal-Lobe.com) of (A) the hippocampus proper and (B) the rest of the hippocampal formation. See main text for abbreviations. (CE) Example morphological reconstructions from NeuroMorpho.Org (left) with red axons and blue dendrites; their estimated axonal and dendritic breakdown by layers (middle); and Hippocampome.org representation (right) with blue square and vertical line (|) indicating dendritic presence, red square and horizontal line (−) indicating axonal presence, purple square and cross (+) indicating both axonal and dendritic presence, and a black dot (•) indicating soma location. (C) Dentate gyrus (DG) Outer Molecular Layer cell with axons in SMo and dendrites in all layers (NMO_00179; [Mott et al., 1997]). (D) CA1 O-LM cell with axons in SLM and dendrites in SO (NMO_02347; [Cossart et al., 2003]). (E) MEC LII Pyramidal-Multiform cell with axons in layers II–VI and dendrites in layers I-III (NMO_07252; (Quilichini et al., 2010]). (F) Axon and dendrite locations for 100 representative neuron types (glutamatergic: black; GABAergic: gray; full matrix: hippocampome.org/morphology or hippocampome.org/php/images/morphology/Morphology_Matrix.jpg). DOI: http://dx.doi.org/10.7554/eLife.09960.003
Figure 2.
Figure 2.. Expression of 20 common biomarkers for 100 representative neuron types (full matrix: hippocampome.org/markers or hippocampome.org/php/images/marker/Marker_Matrix.jpg; complete list of abbreviations: hippocampome.org/help).
Positive expression: left green flags; negative expression: right blue; mixed expression (possible subtypes): left/right green blue; mixed expression (different experimental protocols, species, or sub-cellular localization): top orange; unresolved mixed expression: bottom red; empty gray boxes indicate that morphologically linkable information was not found. The right summary column reports the number of additional biomarkers with known expression for each neuron type. Bottom values are counts of neuron types with available information for each biomarker. DOI: http://dx.doi.org/10.7554/eLife.09960.004
Figure 3.
Figure 3.. Flow chart of inclusion criteria for neuron types.
Beginning with a reconstruction, schematic, or text description of a neuron morphology, the flow chart ends with either a new ‘on hold’ neuron type, supplemental information for an existing active neuron type, or a new active neuron type. Intermediate decision points evaluate the presence of both axons and dendrites, the determination of the main neurotransmitter, the uniqueness of the new type, and whether information is sufficient to create a new active type. DOI: http://dx.doi.org/10.7554/eLife.09960.006
Figure 4.
Figure 4.. Quantifying knowledge in Hippocampome.org about morphology, biomarkers, and electrophysiology of hippocampal neuron types.
(A) Histograms comparing the sum of pieces of knowledge (PoK) in relevant journal articles or book chapters, in reviews, and in Hippocampome.org. (B) Interconnected knowledge graph of neuron type properties mined from two typical journal articles. (C) Balloon plot of collated knowledge for a majority of GABAergic neuron types. The balloon size indicates the sum of PoK for that type across all three dimensions; balloon color denotes the subregion (as in Figure 1). Note the dearth of biomarker information in entorhinal cortex (EC) and the uneven distribution of data between CA3 and CA1. DOI: http://dx.doi.org/10.7554/eLife.09960.007
Figure 5.
Figure 5.. Hippocampome.org enables searching neuron types by neurotransmitter; axon, dendrite, and soma locations; molecular expression; electrophysiological parameters; and input/output connectivity.
(A) Sample query for parvalbumin-negative neuron types with axons in DG and firing threshold >20 mV. (B) The knowledge base may also be queried for a specific PubMed ID or author name (e.g., ‘Fuentealba P’). (C, D) Returned results link to (C) neuron type summary pages (Figure 1A from Price et al., 2005, J. Neurosci. 25:6775–6786 [permission to reuse granted by SfN]) and (D) evidence from published figures, tables, and text quotes supporting all reported properties (Figure 6B from Fuentealba et al., 2010, J. Neurosci. 30:1595–1609; Table 2 and Figure 3A from Price et al., 2005, J. Neurosci. 25:6775–6786 [permission to reuse granted by SfN]). DOI: http://dx.doi.org/10.7554/eLife.09960.008
Figure 6.
Figure 6.. Neuron type connectivity (area color coding and numbering as in Figure 1).
(A) Known and potential connections for 100 neuron types (full matrix: hippocampome.org/connectivity or hippocampome.org/php/images/connectivity/Connectivity_Matrix.jpg), with pre-synaptic types in rows and post-synaptic types in columns. Black squares indicate potential glutamatergic connections and gray squares GABAergic. Pairs of neuron types with experimentally established and refuted synapses are shown using green and red squares, respectively. Colored boundaries demarcate intra-area connections. (B) Regional pathways with 33 glutamatergic connections (full lines ending in arrows) and 20 GABAergic connections (dashed lines ending in open circles); line thickness represents the numbers of connected neuron types between areas. DOI: http://dx.doi.org/10.7554/eLife.09960.010
Figure 7.
Figure 7.. Neuron type circuitry.
(A) Circuit diagram of selected neuron types in DG (full diagram: hippocampome.org/php/images/connectivity/DG_Circuit_Diagram.jpg or hippocampome.org/php/images/connectivity/DG_Circuit_Diagram.graffle.zip). Axonal connections from pre-synaptic somata (orange glutamatergic, green GABAergic) to post-synaptic somata or dendrites (blue) have unique line colors for each pre-synaptic type for clarity. Lines ending in arrows and open circles indicate, respectively, glutamatergic and GABAergic connections; 22 known (thick lines) and 231 potential (thin) connections are depicted. 1: Granule. 2: Semilunar Granule. 3: Mossy. 4: AIPRIM. 5: Axo-axonic. 6: Basket. 7: Basket CCK+. 8: HICAP. 9: HIPP. 10: HIPROM. 11: MOCAP. 12: MOLAX. 13: MOPP. 14: Neurogliaform. 15: Outer Molecular Layer. (B) Pre- and post-synaptic connections for DG Granule and CA3 Basket cells. Red lines ending in arrows indicate glutamatergic connections, and blue lines ending in open circles indicate GABAergic connections. Thick and thin lines indicate, respectively, known and potential connections. Neuron types are color coded by area of origin (as in Figure 1). DOI: http://dx.doi.org/10.7554/eLife.09960.011

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References

    1. Ali AB, Thomson AM. Facilitating pyramid to horizontal oriens-alveus interneurone inputs: dual intracellular recordings in slices of rat hippocampus. The Journal of Physiology. 1998;507:185–199. doi: 10.1111/j.1469-7793.1998.185bu.x. - DOI - PMC - PubMed
    1. Amaral D, Lavenex P. Hippocampal neuroanatomy. In: Andersen P, Morris R, Amaral D, Bliss T, O'Keefe J, editors. The hippocampus book. Oxford: Oxford University Press; 2007. pp. 37–114.
    1. Amaral DG, Scharfman HE, Lavenex P. The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies) Progress in Brain Research. 2007;163:3–22. doi: 10.1016/S0079-6123(07)63001-5. - DOI - PMC - PubMed
    1. Armañanzas R, Ascoli GA. Towards the automatic classification of neurons. Trends in Neurosciences. 2015;38:307–318. doi: 10.1016/j.tins.2015.02.004. - DOI - PMC - PubMed
    1. Armstrong C, Szabadics J, Tamás G, Soltesz I. Neurogliaform cells in the molecular layer of the dentate gyrus as feed-forward γ-aminobutyric acidergic modulators of entorhinal-hippocampal interplay. The Journal of Comparative Neurology. 2011;519:1476–1491. doi: 10.1002/cne.22577. - DOI - PMC - PubMed

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