Multimodal gradients across mouse cortex

Abstract

The primate cerebral cortex displays a hierarchy that extends from primary sensorimotor to association areas, supporting increasingly integrated function underpinned by a gradient of heterogeneity in the brain's microcircuits. The extent to which these hierarchical gradients are unique to primate or may reflect a conserved mammalian principle of brain organization remains unknown. Here we report the topographic similarity of large-scale gradients in cytoarchitecture, gene expression, interneuron cell densities, and long-range axonal connectivity, which vary from primary sensory to prefrontal areas of mouse cortex, highlighting an underappreciated spatial dimension of mouse cortical specialization. Using the T1-weighted:T2-weighted (T1w:T2w) magnetic resonance imaging map as a common spatial reference for comparison across species, we report interspecies agreement in a range of large-scale cortical gradients, including a significant correspondence between gene transcriptional maps in mouse cortex with their human orthologs in human cortex, as well as notable interspecies differences. Our results support the view of systematic structural variation across cortical areas as a core organizational principle that may underlie hierarchical specialization in mammalian brains.

Keywords: cortical gradients; cortical hierarchy; gene expression; interspecies comparison.

Fig. 1.

The spatial map of the MRI measurement, T1w:T2w, is correlated with spatial maps of other structural properties. (A) Variation in T1w:T2w across mouse cortical areas (visualization through medial sections is in SI Appendix, Fig. S3). (B) T1w:T2w broadly decreases across families of connectivity-based groupings of cortical areas (30), from somatomotor areas to anterolateral and prefrontal areas. Groups are ordered by decreasing T1w:T2w, as are areas within each group. (C–F) Scatter plots are shown for T1w:T2w (horizontal axis) vs. (C) cytoarchitecture type (37), (D) relative density of PV(PV + SST) cells in L2/3 (29), (E) sum of incoming interareal axonal projection weight (33), and (F) hierarchical level inferred from feedforward–feedback laminar projection patterns (30). Circles are colored according to the connectivity modules in B and have sizes scaled by T1w:T2w. A small amount of vertical noise has been added to points in C to aid visualization (cytoarchitecture type takes discrete values, indicated as dotted horizontal lines). Abbreviations for cortical areas are defined in SI Appendix.

Fig. 2.

Transcriptional maps of glutamate receptor subunit and interneuron marker genes covary with the T1w:T2w map, and a principal components projection of cortical areas using their gene expression profiles organizes them into meaningful processing streams. (A) Spearman correlation coefficients, $\rho$, between T1w:T2w and the transcriptional maps of genes coding glutamate receptor subunits and interneuron cell-type markers. (B) Scatter plot of T1w:T2w vs. $z$-score normalized levels of Grin3a transcription, $\rho =-0.63$ ($P_{\mathrm{c}\mathrm{o}\mathrm{r}\mathrm{r}}=5\times 10^{-4}$). (C) Projection of brain areas into the space of the two leading principal components of 1,055 brain-expressed genes (52) places cortical areas with similar transcriptional profiles close in the space, yielding a functionally informative organization of cortical areas. Brain areas are shown as circles with radii scaled by T1w:T2w and (symmetrized) axonal projections (33) are annotated where possible. Background shading has been added manually to guide the eye. Abbreviations for cortical areas are defined in SI Appendix.

Fig. 3.

Cell densities and gene expression exhibit distinctive laminar patterns of covariation with T1w:T2w across the mouse cortex. (A and B) Spearman correlation coefficients, $\rho$, of T1w:T2w are plotted as colors for (A) cell density of three types of interneurons (29) and (B) transcriptional level of a given gene (column) in a given cortical layer (row). Overall correlations, obtained from combining all layers of each area, are shown in the bottom row of each plot. Transcriptional levels (32) are shown for the 24 genes with significant overall correlations to T1w:T2w, ordered by their overall correlation to T1w:T2w (results for all 86 brain-related genes are in SI Appendix, Fig. S7).

Fig. 4.

Diverse measurements of cortical areas share a common gradient of variation. Cortical areas form rows, and measurements form columns, with different color maps used to code different datasets (from low values, light colors, to high values, dark colors), as labeled: density of PV neurons (29) (green); T1w:T2w (53) (yellow/red); cytoarchitecture (37) (red); weighted in-degree, $k^w$, of normalized axonal projection density (33) (orange); expression of three selected genes Grin3a, Grik2, and Pvalb (32) (blue); and the first principal component of brain-related genes (green-blue) and estimated hierarchical level (30) (purple). Areas (rows) are ordered according to the first principal component of this multimodal matrix of cortical properties and are colored according to their membership in one of six connectivity-based groupings (30) (compare with Fig. 1B). Measurements (columns) are ordered according to average linkage clustering on correlation distances according to the annotated dendrogram. Measurements cluster into two groups that either increase (Left cluster) or decrease (Right cluster) along a candidate functional hierarchy, from primary somatosensory to transmodal prefrontal areas. Missing data are shown as black rectangles.

Fig. 5.

Mouse–human consistency of T1w:T2w and transcriptional gradients of brain-related genes. We plot the correlation between T1w:T2w and transcription levels in mice, ${\rho }_{\mathrm{m}\mathrm{o}\mathrm{u}\mathrm{s}\mathrm{e}}^{\mathrm{T}\mathrm{1}\mathrm{w}:\mathrm{T}\mathrm{2}\mathrm{w}}$ (horizontal axis), and humans, ${\rho }_{\mathrm{h}\mathrm{u}\mathrm{m}\mathrm{a}\mathrm{n}}^{\mathrm{T}\mathrm{1}\mathrm{w}:\mathrm{T}\mathrm{2}\mathrm{w}}$ (vertical axis), for 70 brain-related genes. The equality line is shown as a dashed blue line. Transcriptional maps of key brain-related genes vary similarly with T1w:T2w in mouse and human cortex, ${\rho }_{mh}=0.44$ ($P=1\times 10^{-4}$).