Hippocampal CA3 connectomics reveals a gradient of mossy fiber inputs and selective feedforward inhibition onto pyramidal cells
10 affiliations
- 1Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA. [email protected]
- 2Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA
- 3Drosophila Connectomics Group, Department of Zoology, University of Cambridge, Cambridge, UK
- 4Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK
- 5Allen Institute for Brain Science, Seattle, WA, USA
- 6Computer Science Department, Princeton University, Princeton, NJ, USA. [email protected]
- 7Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA. [email protected]
- 8Bezos Center for Neural Circuit Dynamics, Princeton University, Princeton, NJ, USA. [email protected]
- 9Department of Molecular Biology, Princeton University, Princeton, NJ, USA. [email protected]
- 10Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA. [email protected]
Abstract
The mossy fiber (MF) connections to pyramidal cells in hippocampal CA3 are hypothesized to participate in pattern separation and memory encoding, yet no large-scale neuronal wiring diagram exists for these connections. We assembled a 3D electron microscopy volume (∼1×1×0.1mm 3 ) from mouse hippocampal CA3. By proofreading and automated segmentation, we reconstructed and classified all soma-containing neurons—including 1,815 pyramidal cells and 229 inhibitory cells—and over 55,000 MFs. Pyramidal cells receive more numerous MF inputs along a proximodistal gradient. Some distal cells show surprisingly high convergence via relatively small terminals with fewer vesicles. Pyramidal cells share significantly more MF inputs than networks randomized by degree-preserving swap, and are better approximated by networks randomized by proximity-preserving swap. We identify a feedforward inhibitory circuit from MFs via perisomatic interneurons that selectively target a pyramidal subtype. We demonstrated large-scale mapping across levels in the hippocampus—from circuits to cell types to vesicles. The dataset is shared through Pyr, an online platform for hippocampal connectomics.
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BibTeX
@article{zheng2026hippocampal,
title = {{Hippocampal CA3 connectomics reveals a gradient of mossy fiber inputs and selective feedforward inhibition onto pyramidal cells}},
author = {Zhihao Zheng and Changjoo Park and Eric W. Hammerschmith and Ran Lu and Szi-chieh Yu and Marissa Sorek and Ben Silverman and Chris S. Jordan and Amy Robinson Sterling and William Silversmith and Philipp Schlegel and Gregory S.X.E. Jefferis and Forrest Collman and H. Sebastian Seung and David W. Tank},
journal = {Nature Neuroscience},
year = {2026},
month = aug,
doi = {10.1038/s41593-026-02388-9},
url = {https://doi.org/10.1038/s41593-026-02388-9},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Hippocampal CA3 connectomics reveals a gradient of mossy fiber inputs and selective feedforward inhibition onto pyramidal cells
AU - Zhihao Zheng
AU - Changjoo Park
AU - Eric W. Hammerschmith
AU - Ran Lu
AU - Szi-chieh Yu
AU - Marissa Sorek
AU - Ben Silverman
AU - Chris S. Jordan
AU - Amy Robinson Sterling
AU - William Silversmith
AU - Philipp Schlegel
AU - Gregory S.X.E. Jefferis
AU - Forrest Collman
AU - H. Sebastian Seung
AU - David W. Tank
PY - 2026
DA - 2026/08/05
JO - Nature Neuroscience
DO - 10.1038/s41593-026-02388-9
UR - https://doi.org/10.1038/s41593-026-02388-9
AB - The mossy fiber (MF) connections to pyramidal cells in hippocampal CA3 are hypothesized to participate in pattern separation and memory encoding, yet no large-scale neuronal wiring diagram exists for these connections. We assembled a 3D electron microscopy volume (∼1×1×0.1mm 3 ) from mouse hippocampal CA3. By proofreading and automated segmentation, we reconstructed and classified all soma-containing neurons—including 1,815 pyramidal cells and 229 inhibitory cells—and over 55,000 MFs. Pyramidal cells receive more numerous MF inputs along a proximodistal gradient. Some distal cells show surprisingly high convergence via relatively small terminals with fewer vesicles. Pyramidal cells share significantly more MF inputs than networks randomized by degree-preserving swap, and are better approximated by networks randomized by proximity-preserving swap. We identify a feedforward inhibitory circuit from MFs via perisomatic interneurons that selectively target a pyramidal subtype. We demonstrated large-scale mapping across levels in the hippocampus—from circuits to cell types to vesicles. The dataset is shared through Pyr, an online platform for hippocampal connectomics.
SN - 1097-6256
SN - 1546-1726
ER -