Transcriptional Substrates Underlying Functional Connectivity Profiles Of Subregions Within The Human Sensorimotor Cortex

Background and objective: The human sensorimotor cortex has multiple subregions showing functional commonalities and differences,likely attributable to their connectivity profiles.However,the molecular substrates underlying such connectivity profiles are unclear.We aimed to test the hypothesis of commonalities and differences in the identified genes and their functional characteristics across sensorimotor subregions.Methods: We utilized a newly proposed standardized pipeline to process brain transcriptomic data from the Allen Human Brain Atlas.Combining a large discovery dataset and two validation datasets,we performed the seed-based resting-state functional connectivity(rs FC)analysis of cross-scanner and cross-race data.24fine-grained sensorimotor subregions were defined as the seeds according to the Human Brainnetome Atlas,and genes associated with the homotopic subregions were pooled for subsequent analysisResults: After excluding subregions that failed the spatially constrained permutation tests and were not specifically enriched in brain tissue,the rs FC of six subregions were associated with expression measures of six gene sets that were specifically expressed in brain tissue among the 12 pooled sensorimotor subregions.The hundreds of genes related to rs FC of A4 hf,A4ul,A1/2/3ulhf and A1/2/3tru were specifically expressed in multiple types of neurons and immune cells and were preferentially expressed during late fetal,neonatal and early infancy,early childhood,middle and late childhood,adolescence,and young adulthood.Furthermore,they were enriched for MFs including transporter activity and channel activity,BPs including synaptic signaling and cell–cell signaling,and CCs including neuron projection,synapse and axon;for pathways including neuronal system,phase 0-rapid depolarization,voltage gated potassium channels,and calcium signaling pathway.Also,these subregions were enriched for neuropsychiatric disorders such as absence seizures and were associated with additional behavioral terms including vision and dementia besides the general sensorimotor behavioral processes including sensorimotor,movements and motor.The other two subregions(A6cdl and A4ll)whose rs FC were related to dozens of genes were not specifically expressed in any cortical cell types and only the A6 cdl were preferentially expressed during young adulthood.For functional enrichment,they were enriched for MFs including voltage-gated calcium channel activity,BPs including neurofilament bundle assembly and neurofilament cytoskeleton organization,and CCs including neurofilament and postsynaptic intermediate filament cytoskeleton.The identified genes in these two subregions were associated with normal sensorimotor behavioral processes.Conclusion: The sensorimotor cortex can be conceptualized as the polygenic-modulated subregions(A4hf,A4 ul,A1/2/3ulhf and A1/2/3tru)and oligogenic-modulated subregions(A6cdl and A4ll),whose rs FC were related to gene sets diverging on their numbers and functional characteristics.These findings may advance our understanding of the functional homogeneity and heterogeneity of the human sensorimotor cortex from the perspective of underlying genetic architecture.