Inhibitory specificity from a connectomic census of mouse visual cortex

Casey M. Schneider-Mizell (), Agnes L. Bodor, Derrick Brittain, JoAnn Buchanan, Daniel J. Bumbarger, Leila Elabbady, Clare Gamlin, Daniel Kapner, Sam Kinn, Gayathri Mahalingam, Sharmishtaa Seshamani, Shelby Suckow, Marc Takeno, Russel Torres, Wenjing Yin, Sven Dorkenwald, J. Alexander Bae, Manuel A. Castro, Akhilesh Halageri, Zhen Jia, Chris Jordan, Nico Kemnitz, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, William Silversmith, Nicholas L. Turner, William Wong, Jingpeng Wu, Jacob Reimer, Andreas S. Tolias, H. Sebastian Seung, R. Clay Reid, Forrest Collman and Nuno Maçarico Costa ()
Additional contact information
Casey M. Schneider-Mizell: Allen Institute for Brain Science
Agnes L. Bodor: Allen Institute for Brain Science
Derrick Brittain: Allen Institute for Brain Science
JoAnn Buchanan: Allen Institute for Brain Science
Daniel J. Bumbarger: Allen Institute for Brain Science
Leila Elabbady: Allen Institute for Brain Science
Clare Gamlin: Allen Institute for Brain Science
Daniel Kapner: Allen Institute for Brain Science
Sam Kinn: Allen Institute for Brain Science
Gayathri Mahalingam: Allen Institute for Brain Science
Sharmishtaa Seshamani: Allen Institute for Brain Science
Shelby Suckow: Allen Institute for Brain Science
Marc Takeno: Allen Institute for Brain Science
Russel Torres: Allen Institute for Brain Science
Wenjing Yin: Allen Institute for Brain Science
Sven Dorkenwald: Princeton University
J. Alexander Bae: Princeton University
Manuel A. Castro: Princeton University
Akhilesh Halageri: Princeton University
Zhen Jia: Princeton University
Chris Jordan: Princeton University
Nico Kemnitz: Princeton University
Kisuk Lee: Rice University
Kai Li: Princeton University
Ran Lu: Princeton University
Thomas Macrina: Princeton University
Eric Mitchell: Princeton University
Shanka Subhra Mondal: Princeton University
Shang Mu: Princeton University
Barak Nehoran: Princeton University
Sergiy Popovych: Princeton University
William Silversmith: Princeton University
Nicholas L. Turner: Princeton University
William Wong: Princeton University
Jingpeng Wu: Princeton University
Jacob Reimer: Baylor College of Medicine
Andreas S. Tolias: Baylor College of Medicine
H. Sebastian Seung: Princeton University
R. Clay Reid: Allen Institute for Brain Science
Forrest Collman: Allen Institute for Brain Science
Nuno Maçarico Costa: Allen Institute for Brain Science

Nature, 2025, vol. 640, issue 8058, 448-458

Abstract: Abstract Mammalian cortex features a vast diversity of neuronal cell types, each with characteristic anatomical, molecular and functional properties1. Synaptic connectivity shapes how each cell type participates in the cortical circuit, but mapping connectivity rules at the resolution of distinct cell types remains difficult. Here we used millimetre-scale volumetric electron microscopy2 to investigate the connectivity of all inhibitory neurons across a densely segmented neuronal population of 1,352 cells spanning all layers of mouse visual cortex, producing a wiring diagram of inhibition with more than 70,000 synapses. Inspired by classical neuroanatomy, we classified inhibitory neurons based on targeting of dendritic compartments and developed an excitatory neuron classification based on dendritic reconstructions with whole-cell maps of synaptic input. Single-cell connectivity showed a class of disinhibitory specialist that targets basket cells. Analysis of inhibitory connectivity onto excitatory neurons found widespread specificity, with many interneurons exhibiting differential targeting of spatially intermingled subpopulations. Inhibitory targeting was organized into ‘motif groups’, diverse sets of cells that collectively target both perisomatic and dendritic compartments of the same excitatory targets. Collectively, our analysis identified new organizing principles for cortical inhibition and will serve as a foundation for linking contemporary multimodal neuronal atlases with the cortical wiring diagram.

Date: 2025
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DOI: 10.1038/s41586-024-07780-8

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