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. 2023 Mar;33(3):150-160.
doi: 10.1002/hipo.23508. Epub 2023 Feb 14.

Further refining the boundaries of the hippocampus CA2 with gene expression and connectivity: Potential subregions and heterogeneous cell types

Michael S Bienkowski  1   2   3
Affiliations

Further refining the boundaries of the hippocampus CA2 with gene expression and connectivity: Potential subregions and heterogeneous cell types

Michael S Bienkowski. Hippocampus. 2023 Mar.

Abstract

Over the last two decades, the definition of hippocampal area CA2 has evolved from Lorente de Nó's original Golgi-based morphological description with the discovery of specific CA2 gene expression markers. Exploiting the specificity of these molecules has allowed for the genetic dissection of CA2 structure and function in transgenic mice. With this change in criteria, the anatomical boundaries of the CA2 have expanded across the hippocampal axis but the CA2's full rostrocaudal extent is not consistently delineated across atlases. The Hippocampus Gene Expression Atlas (HGEA) provides a comprehensive map of 20 gene expression domains across the entire mouse hippocampus including the CA2. In this commentary, I will review the consensus gene expression patterns that demarcate the expanded CA2 boundaries in the HGEA. Using DropViz single-cell transcriptomics and Mouse Connectome Project connectomics data, I will then suggest potential differences in CA2 cell type heterogeneity and connectivity that may identify and characterize further CA2 subregions.

Keywords: CA2; cell types; connectivity; gene expression.

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Conflict of interest statement

Competing Financial Interests

The author declares no competing financial interests.

Figures

Figure 1.
Figure 1.. 3D organization of the CA2 within the Hippocampus Gene Expression Atlas.
The 3D atlas model of the CA2 can be visualized using a smartphone with the Schol-AR app (Ard et al., 2022).
Figure 2.
Figure 2.. Comparative cytoarchitecture of the CA2 across species.
Nissl-stained coronal tissue sections from www.brainmap.org showing the cytoarchitecture of the hippocampus in rat (rattus norvegicus), opossum (monodelphis domestica), echidna (Tachyglossidae), cat (felis cattus), and callicebus and rhesus macaque primates (callicebus moloch and macaca mulatta). In some species a small bump in the pyramidal layer is found at the CA2 region, but this is not always consistent across sections and in all species.
Figure 3.
Figure 3.. Marker gene expression patterns at the classic level of the CA2.
Mouse coronal in situ hybridization of six different CA2 marker genes at HGEA level 72 demonstrate the consistent anatomical boundaries of the CA2 despite varying levels of expression intensity. Small variations in distribution are mainly attributed to the histological sectioning differences across multiple brains, but cell type heterogeneity within CA2 could also produce differences. (Top right) Zoom in of labeled cells at the pyramidal layer ‘bump’ shows CA2 labeling primarily within the proximal 2/3rd area. All in situ hybridization images are available online from Allen Brain Atlas website.
Figure 4.
Figure 4.. Comparison of the rostral extension of the CA2 boundary within the HGEA, ARAv2, and CCFv3.
Rostral levels of the HGEA atlas showing CA2 (orange area) in comparison to corresponding levels of the ARAv2 (2011 atlas) and coronal slices of the CCFv3 (2015) atlas. ARAv2 and CCFv3 images from www.brain-map.org. Additional documentation and technical white papers regarding ARAv2 and CCFv3 can be found at help.brain-map.org/display/mousebrain/Documentation. Abbreviations: CA1, Field CA1; CA1d, CA1 dorsal; CA2, Field CA2; CA3, Field CA3; CA3dd, CA3 dorsal, dorsal part, CA3i, CA3 intermediate
Figure 5.
Figure 5.. Comparison of the caudal and ventral extension of the CA2 boundary within the HGEA, ARAv2, and CCFv3.
Rostral levels of the HGEA atlas showing CA2 (orange area) in comparison to corresponding levels of the ARAv2 (2011 atlas) and coronal slices of the CCFv3 (2015) atlas. ARAv2 and CCFv3 images from www.brain-map.org. Additional documentation and technical white papers regarding ARAv2 and CCFv3 can be found at help.brain-map.org/display/mousebrain/Documentation. Abbreviations: CA1, Field CA1; CA1d, CA1 dorsal; CA1i, CA1 intermediate; CA1v, CA1 ventral; CA1vv, CA1 ventral, ventral part; CA2, Field CA2; CA3, Field CA3; CA3d, CA3 dorsal; CA3dd, CA3 dorsal, dorsal part; CA3i, CA3 intermediate; CA3v, CA3 ventral; CA3vv, CA3 ventral, ventral part; DG, Dentate gyrus; DGd, Dentate gyrus granule cell layer, dorsal part; DGi, Dentate gyrus intermediate granule, intermediate part; DGv, Dentate gyrus granule cell layer, ventral part; DGpo, Dentate gyrus polymorph layer; DGpod, Dentate gyrus polymorph layer, dorsal part; Dgpov, Dentate gyrus polymorph layer, ventral part; SUB, subiculum
Figure 6.
Figure 6.. Caudal and ventral extension of the CA2.
Mouse sagittal in situ hybridization sections of seven different CA2 marker genes at HGEA sagittal level 4. Amigo2, Rgs14, Pcp4, and 1700024P16Rik are robustly expressed in both a dorsal and ventral CA2 region, whereas Map3k15 is weakly expressed in both and Tiam2 and Cacng5 are only expressed in the dorsal CA2 region. Abbreviations: CA1, Field CA1; CA1d, CA1 dorsal; CA1i, CA1 intermediate; CA1v, CA1 ventral; CA2, Field CA2; CA2d, CA2 dorsal; CA2v, CA2 ventral; CA3.
Figure 7.
Figure 7.. CA2 input/output wiring diagram.
CA2 outputs and bidirectional connections in black/yellow, all other colors are CA2 inputs. HGEA interactive wiring diagram available at www.MouseConnectome.org.
Figure 8.
Figure 8.. CA2 connectivity across the longitudinal axis.
A) CA2 input/output connectivity from the HGEA interactive wiring diagram at www.MouseConnectome.org. B) Mouse Connectome Project anterograde tracer labeling (AAV in green or red, PHAL in magenta) comparison of the CA1 and septum terminal field distribution of CA3dd and CA3d (case SW151029-03A) vs. rostral, classic, and caudal CA2 (case SW160909-02A). CA1 images show contralateral side to avoid injection sites but distribution is similar bilaterally.
See this image and copyright information in PMC

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