Transcriptomic cytoarchitecture reveals principles of human neocortex organization

Nikolas L. Jorstad, Jennie Close, Nelson Johansen, Anna Marie Yanny, Eliza R. Barkan, Kyle J. Travaglini, Darren Bertagnolli, Jazmin Campos, Tamara Casper, Kirsten Crichton, Nick Dee, Song-Lin Ding, Emily Gelfand, Jeff Goldy, Daniel Hirschstein, Matthew Kroll, Michael Kunst, Kanan Lathia, Brian Long, Naomi Martin, Delissa McMillen, Trangthanh Pham, Christine Rimorin, Augustin Ruiz, Nadiya Shapovalova, Soraya Shehata, Kimberly Siletti, Saroja Somasundaram, Josef Sulc, Michael Tieu, Amy Torkelson, Herman Tung, Katelyn Ward, Edward M. Callaway, Patrick R. Hof, C. Dirk Keene, Boaz P. Levi, Sten Linnarsson, Partha P. Mitra, Kimberly Smith, Rebecca D. Hodge, Trygve E. Bakken, Ed S. Lein
bioRxiv (2022)


Variation in cortical cytoarchitecture is the basis for histology-based definition of cortical areas, such as Brodmann areas. Single cell transcriptomics enables higher-resolution characterization of cell types in human cortex, which we used to revisit the idea of the canonical cortical microcircuit and to understand functional areal specialization. Deeply sampled single nucleus RNA-sequencing of eight cortical areas spanning cortical structural variation showed highly consistent cellular makeup for 24 coarse cell subclasses. However, proportions of excitatory neuron subclasses varied strikingly, reflecting differences in intra- and extracortical connectivity across primary sensorimotor and association cortices. Astrocytes and oligodendrocytes also showed differences in laminar organization across areas. Primary visual cortex showed dramatically different organization, including major differences in the ratios of excitatory to inhibitory neurons, expansion of layer 4 excitatory neuron types and specialized inhibitory neurons. Finally, gene expression variation in conserved neuron subclasses predicts differences in synaptic function across areas. Together these results provide a refined cellular and molecular characterization of human cortical cytoarchitecture that reflects functional connectivity and predicts areal specialization.