Human Neocortical Glutamatergic Neurons Revealed Through Multimodal Profiling

The human neocortex underlies higher cognition and is the engine of complex thought. Yet our understanding of its neuronal diversity is limited by sparse access to tissue, inconsistent sampling across studies, and a lack of multiple modality data. Although single-cell transcriptomic taxonomies are an important framework for characterizing cell type diversity, transcriptomic information alone cannot reveal the cellular properties that define neuronal computations. To address this, we performed Patch-seq, a method for collecting Morphology, Electrophysiology, and Transcriptomic data from a single neuron. We focused on glutamatergic, neocortical, excitatory neurons, the principal long-range projecting neurons of the cortex, and systematically integrated their morphoelectric features with transcriptomic identity. In combination with spatial transcriptomic data, we interrogated 39 of 42 transcriptomically-defined neuron types with a layer-centric perspective. Morphoelectric properties, such as cortical depth, apical dendrite structure, and excitability clearly distinguish transcriptomic subclasses and support many finer transcriptomic types. Morphoelectric properties are influenced by spatial location in supragranular layers, while deeper layers exhibit greater heterogeneity. Cross-species comparisons reveal conserved subclass organization but pronounced differences in apical dendrite arborization between mouse and human, and surprising similarities between human and macaque. Together, these datasets provide a unified multimodal reference that advances our understanding of human cortical circuitry and establishes a foundation for experimental and computational studies of human brain function and disease.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-01-08
DOI
https://doi.org/10.64898/2026.01.08.698257
Citations
1
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
22.24
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article

Human Neocortical Glutamatergic Neurons Revealed Through Multimodal Profiling

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1 citations
bioRxiv (Cold Spring Harbor Laboratory)
Single-cell and spatial transcriptomics
22.24
article

Human Neocortical Glutamatergic Neurons Revealed Through Multimodal Profiling

Delissa McMillen, Lauren Kruse, Gabriela León, Eline Jasmijn Mertens, Jacob Ruzevick, Jeremy A. Miller, Gábor Tamás, Daniel Carey, David E. Sandman, Rebecca de Frates, Éva Csordás Tóth, Trangthanh Pham, Lauren Ellingwood, Jason S. Hauptman, Charles Cobbs, Agata Budzillo, Rachel Enstrom, Jazmin Campos, Tim Jarsky, Nathan W. Gouwens, María Camila Vergara, Sara Kebede, Michelle Maxwell, Jessica Gloe, Julian Thijssen, Ramkumar Rajanbabu, Nikolai Dembrow, Jasmine Bomben, Dan Silbergeld, Lindsay Ng, Tung Herman, Christina Alice Pom, Kyla Berry, David P. Noske, Sander Idema, Sara Vargas, Lauren Alfiler, Jocelin Malone, Emily Gelfand, Tim S. Heistek, Niels Verburg, Tom V. Coopmans, Eliza Barkan, Jeanelle Ariza, Laurens Witter, Katherine Baker, Ayoub J. Khalil, Alice Mukora, Benjamin C. Grannan, Grace Williams, Julia Wilson, Sarah Walling-Bell, Katherine Wadhwani, Mean-Hwan Kim, Cristina Radaelli, Verjinia D. Metodieva, Rusty Mann, Stan L.W. Driessens, Anna A. Galakhova, Elliot J Phillips, Jessica Trinh, Samantha D. Hastings, Kirsten Crichton, 弘 西谷, INGRID K. REDFORD, Zoe Juneau, Daniel Park, Xiao-Ping Liu, Manuel Ferreira, Brian Long, Lisa Kim, Scott Sawchuk, Andrew L Ko, Staci A Sorensen, Ed S Lein, Anubhav G. Amin, HongKui Zeng, Tim Fliss, Alex Tran, Ryder P Gwinn, Brian R Lee, Rachel Dalley, Marshall VanNess, Matthew Jungert, Huibert D Mansvelder, Alvin Huang, Madeline Bixby, Nick Dee, Darren Bertagnolli, Aaron Oldre, Madhav Kannan, Kris Bickley, Shea T. Ransford, Aditi Kumar, Boudewijn Lelieveldt, Natia Shamugia, Anoop Patel, Megan Koch, Agnes Katalin Kocsis, Tjerk P. Swinkels, Daan C. Jol, Femke Waleboer, Kristen Hadley, Krista Blake, Matt Mallory, Miranda R. Moore, Angela Ayala, Medea McGraw, Amanda Gary, Matthew Kroll, Anish Bhaswanth Chakka, Natalia A. Goriounova, Josef Sulc, Windy Ho, Christine Rimorin, Dijon Hill, Samuel Emerson, Chris English, Kamiliam Nasirova, Jeffrey G. Ojemann, Audrey McCutcheon, Dana Rocha, Ana Rios Sigler, Kimberly A. Smith, Christiaan P.J. de Kock, Atlas Jordan, Stuard Barta
article en
1 citations

Abstract

The human neocortex underlies higher cognition and is the engine of complex thought. Yet our understanding of its neuronal diversity is limited by sparse access to tissue, inconsistent sampling across studies, and a lack of multiple modality data. Although single-cell transcriptomic taxonomies are an important framework for characterizing cell type diversity, transcriptomic information alone cannot reveal the cellular properties that define neuronal computations. To address this, we performed Patch-seq, a method for collecting Morphology, Electrophysiology, and Transcriptomic data from a single neuron. We focused on glutamatergic, neocortical, excitatory neurons, the principal long-range projecting neurons of the cortex, and systematically integrated their morphoelectric features with transcriptomic identity. In combination with spatial transcriptomic data, we interrogated 39 of 42 transcriptomically-defined neuron types with a layer-centric perspective. Morphoelectric properties, such as cortical depth, apical dendrite structure, and excitability clearly distinguish transcriptomic subclasses and support many finer transcriptomic types. Morphoelectric properties are influenced by spatial location in supragranular layers, while deeper layers exhibit greater heterogeneity. Cross-species comparisons reveal conserved subclass organization but pronounced differences in apical dendrite arborization between mouse and human, and surprising similarities between human and macaque. Together, these datasets provide a unified multimodal reference that advances our understanding of human cortical circuitry and establishes a foundation for experimental and computational studies of human brain function and disease.

bioRxiv (Cold Spring Harbor Laboratory)
University of Washington (US), University of Szeged (HU), Veterans Health Administration (US), Leiden University Medical Center (NL), Swedish Medical Center (US), Amsterdam Neuroscience (NL), Seattle Children's Hospital (US), Allen Institute (US), Amsterdam University Medical Centers (NL), Neurological Surgery (US), Cognitive Research (United States) (US), Vrije Universiteit Amsterdam (NL), Delft University of Technology (NL)
Openalex Percentile: Top 3%
Single-cell and spatial transcriptomics
22.24
DOIOpen Access PDFOpenAlex
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