1The human frontal cortex is unusually large compared with many other species. The expansion 2 of the human frontal cortex is accompanied by both connectivity and transcriptional changes. 3 Yet, the developmental origins generating variation in frontal cortex circuitry across species 4 remain unresolved. Nineteen genes, which encode filaments, synapse, and voltage-gated 5 channels (e.g., NEFH, SYT2, VAMP1) are especially enriched in the supragranular layers of 6 the cerebral cortex in humans relative to mice. The increased expression of these genes 7 suggests enhanced cortico-cortical projections emerging from layer III in humans. We confirm 8 that the expression of these supragranular-enriched genes is preferentially expressed in frontal 9 cortex layer III in humans relative to mice. We demonstrate a concomitant expansion in 10 cortico-cortical pathways projecting within the frontal cortex white matter in humans with 11 diffusion MR tractography. To identify developmental sources of such variation, we compare 12 frontal cortical white matter growth and developmental trajectories of transcriptional profiles of 13 supragranular-enriched genes in humans and mice. We also use temporal changes in gene 14 expression during postnatal development to control for variation in developmental schedules 15 across species. The growth of the frontal cortex white matter and transcriptional profiles of 16 supragranular genes are both protracted in humans relative to the timing of other 17 transformations. These findings demonstrate that an expansion of projections emerging from 18 the human frontal cortex is achieved by extending the duration of cortical circuitry 19 development. Integrating RNA sequencing with neuroimaging level phenotypes is an effective 20 strategy to assess deviations in developmental programs leading to variation in connections 21 across species. 22 23 24 25 26 27 28 29
The human frontal cortex is unusually large compared with many other species. The expansion of the human frontal cortex is accompanied by both connectivity and transcriptional changes. Yet, the developmental origins generating variation in frontal cortex circuitry across species remain unresolved. Nineteen genes that encode filaments, synapse, and voltage-gated channels are especially enriched in the supragranular layers of the human cerebral cortex, which suggests enhanced corticocortical projections emerging from layer III. We identify species differences in connections with the use of diffusion MR tractography as well as gene expression in adulthood and in development to identify developmental mechanisms generating variation in frontal cortical circuitry. We demonstrate that increased expression of supragranular-enriched genes in frontal cortex layer III is concomitant with an expansion in corticocortical pathways projecting within the frontal cortex in humans relative to mice. We also demonstrate that the growth of the frontal cortex white matter and transcriptional profiles of supragranular-enriched genes are protracted in humans relative to mice. The expansion of projections emerging from the human frontal cortex arises by extending frontal cortical circuitry development. Integrating gene expression with neuroimaging level phenotypes is an effective strategy to assess deviations in developmental programs leading to species differences in connections.
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