Connecting single-cell transcriptomes to projectomes in mouse visual
cortex
Authors: Sorensen Staci A. , Gouwens Nathan W. , Wang Yun , Mallory Matt , Budzillo Agata , Dalley Rachel , Lee Brian , Gliko Olga , Kuo Hsien-chi , Kuang Xiuli , Mann Rusty , Ahmadinia Leila , Alfiler Lauren , Baftizadeh Fahimeh , Baker Katherine , Bannick Sarah , Bertagnolli Darren , Bickley Kris , Bohn Phil , Brown Dillan , Bomben Jasmine , Brouner Krissy , Chen Chao , Chen Kai , Chvilicek Maggie , Collman Forrest , Daigle Tanya , Dawes Tim , de Frates Rebecca , Dee Nick , DePartee Maxwell , Egdorf Tom , El-Hifnawi Laila , Enstrom Rachel , Esposito Luke , Farrell Colin , Gala Rohan , Glomb Andrew , Gamlin Clare , Gary Amanda , Goldy Jeff , Gu Hong , Hadley Kristen , Hawrylycz Mike , Henry Alex , Hill Dijon , Hirokawa Karla E. , Huang Zili , Johnson Katelyn , Juneau Zoe , Kebede Sara , Kim Lisa , Lee Changkyu , Lesnar Phil , Li Anan , Glomb Andrew , Li Yaoyao , Liang Elizabeth , Link Katie , Maxwell Michelle , McGraw Medea , McMillen Delissa A. , Mukora Alice , Ng Lindsay , Ochoa Thomas , Oldre Aaron , Park Daniel , Pom Christina Alice , Popovich Zoran , Potekhina Lydia , Rajanbabu Ram , Ransford Shea , Reding Melissa , Ruiz Augustin , Sandman David , Siverts La’Akea , Smith Kimberly A. , Stoecklin Michelle , Sulc Josef , Tieu Michael , Ting Jonathan , Trinh Jessica , Vargas Sara , Vumbaco Dave , Walker Miranda , Wang Micheal , Wanner Adrian , Waters Jack , Williams Grace , Wilson Julia , Xiong Wei , Lein Ed , Berg Jim , Kalmbach Brian , Yao Shenqin , Gong Hui , Luo Qingming , Ng Lydia , Sümbül Uygar , Jarsky Tim , Yao Zizhen , Tasic Bosiljka , Zeng Hongkui 
Published: December 2023

The mammalian brain is composed of diverse neuron types that play different
functional roles. Recent single-cell RNA sequencing approaches have led to a
whole brain taxonomy of transcriptomically-defined cell types, yet cell type
definitions that include multiple cellular properties can offer additional
insights into a neuron’s role in brain circuits. While the Patch-seq method can
investigate how transcriptomic properties relate to the local morphological and
electrophysiological properties of cell types, linking transcriptomic identities
to long-range projections is a major unresolved challenge. To address this, we
collected coordinated Patch-seq and whole brain morphology data sets of
excitatory neurons in mouse visual cortex. From the Patch-seq data, we defined
16 integrated morphoelectric-transcriptomic (MET)-types; in parallel, we
reconstructed the complete morphologies of 300 neurons. We unified the two data
sets with a multi-step classifier, to integrate cell type assignments and
interrogate cross-modality relationships. We find that transcriptomic variations
within and across MET-types correspond with morphological and
electrophysiological phenotypes. In addition, this variation, along with the
anatomical location of the cell, can be used to predict the projection targets
of individual neurons. We also shed new light on infragranular cell types and
circuits, including cell-type-specific, interhemispheric projections. With this
approach, we establish a comprehensive, integrated taxonomy of excitatory neuron
types in mouse visual cortex and create a system for integrated,
high-dimensional cell type classification that can be extended to the whole
brain and potentially across species.