Brain wiring and supragranular-enriched genes linked to protracted human frontal cortex development

Abstract

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

Closing the gap from transcription to the structural connectome enhances the study of connections in the human brain

“…Because neuronal populations have a tendency to project stereotypically, variation in subpopulation of neuron numbers can be used to make inferences about variation in connectivity patterns across species. 14,17,[100][101][102][103] Neuronal populations can be quantified with stereological methods as well as from sequencing of RNA, methylation, or open chromatin regions at the single cell level. [104][105][106][107][108][109][110] The use of classical stereological approaches coupled with RNA or DNA sequencing can provide rigorous approaches to compare cell populations across species.…”

“…Single cell methylome and RNA sequencing data set from frontal cortices of humans and mice show that frontal cortex excitatory pyramidal layer III neuron numbers are expanded in humans relative to mice (Figure 1). 14,17,107,110 The amplification of layer II-IV neuronal populations, which may be specific to layer III, coupled with knowledge of stereotypical projection patterns across the depth of the cortex suggest an amplification of neurons projecting crosscortically is a shared and distinguishing feature of many primates.…”

“…Primates possess an expanded layer III, an increase in excitatory layer III neuron numbers, and a concomitant increase in the expression of genes linked to long-range cortical projections (eg, NEFH). 14,17,69,107 Because layer III neurons have a tendency to form cortico-cortical projections, the expansion of layer III and suite of differentially expressed genes across layers suggest an expansion in cortico-cortical projections in humans vs mice. In two recent studies, we used diffusion MR tractography to confirm that primates possess an expansion in cross-cortically projecting pathways relative to rodents.…”

“…In two recent studies, we used diffusion MR tractography to confirm that primates possess an expansion in cross-cortically projecting pathways relative to rodents. 14,17 We compared the relative proportion of cortico-cortical pathways coursing through the cortical white matter of human and non-human primates relative to rodents. We randomly selected voxels though the white matter of the frontal cortex of humans and mice and quantified the relative percentage of cortico-cortical pathways in humans relative to mice.…”

“…I illustrate how these approaches enhance our understanding of the developmental mechanisms underlying variation in connectivity in humans relative to model organisms (Figure 1). [13][14][15][16][17][18] I also discuss our recent efforts capturing temporal variation in transcription to find corresponding time points across humans and model organisms ( Figure 2). Developing appropriate norming procedures to compare development permits identifying sources of conservation and variation in developmental programs across species.…”