Study On The Gene Transcriptional Expression Pattern Of Cortical Thickness Development In Children And Adolescents

In the whole life development,the childhood and adolescent period is the most rapid stage of physical and psychological development,and is of great importance to the individual’s future development.The brain is the most complex structure in the central nervous system.It is not only an organ to regulate the functions of each body,but also the material basis of cognitive,emotional,behavioral and other high-level neural activities.Understanding how the brain changes with age is of great importance to understanding ourselves.Thanks to magnetic resonance imaging,the study of brain structure has improved dramatically in the last two decades.On the other hand,twin and family studies have found that different structural indicators of the cortex include a variety of genetic traits.However,the biological mechanism of cortical development is not yet clear.In recent years,the published database of human brain transcriptional atlases has made it possible to answer this question.Using this database,researchers can explore the relationship between the spatial pattern of gene transcriptional expression and the brain structural or functional characteristics.In addition,there is a common problem in most current brain imaging studies:either the number of subjects is small,thus the results lack statistical power;either the number of subjects is large,but comes from multiple sites,thus the results can be affected by site-effects.Therefore,this study aims to explore the biological mechanism related to the development pattern of cortical thickness in children and adolescents by combining MRI data from a single site with a large sample and human brain transcriptional atlases database.Study 1 attempts to explore the developmental patterns of cortical morphology in children and adolescents.In this study,MRI structural data was collected from 516 normally developing children and adolescents aged 6 to 17 years at the same site.Through a series of processes,the mean thickness and surface area of each cortical area of 308 brain regions were obtained for each participant.The general linear model was used to establish the relationship between age and cortical thickness or cortical surface area.We found that:1).Consistent with the results of previous studies,the mean cortical thickness of the whole brain in children and adolescents showed a significant trend of decline with age(r=-0.576,p<0.001);2).In the development of the cerebral cortex,compared to surface area,the thickness of the cortex is greater regularity.There is no region whose surface area significantly changes with age,however,a wide range of brain regions whose cortical thickness changes significantly with age.Compared to other brain regions,the left and right orbito-frontal cortex thickness shrink faster(the beta norm of the left lateral orbitofrontal lobe:-1～-0.48;the left medial orbitofrontal lobe:-0.94～-0.72;the right lateral orbitofrontal lobe:-0.99～-0.53;the right medial orbitofrontal lobe:-0.85～-0.55);3).Compared with the primary cortex,the cortical thickness of the association cortex,especially in default mode network,changed at a faster rate during childhood and adolescence;4).There was a large consistency in the variation of local cortical thickness with age.Study 2 aims to reveal the underlying biological mechanism of cortical thickness development in children and adolescents.Partial least-squares regression analysis was conducted on the gene transcriptional expression data after quality control and the cortical thickness development pattern of children and adolescents.We found that the first component of partial least-squares regression explained 30.67%of the variance of the cortical thickness development pattern of children and adolescents using the permutation test(Pspin=0.009).Using Bootstrap analysis,we found 1,728(Z>1.96)and 1,885(Z<-1.96)positively(or negatively)weighted gene expressions in the first component of partial least-squares regression were over-expressed(or under-expressed)as cortical thickness changes with age.Gene enrichment analysis based on Gene Ontology showed that over-expressed genes were enriched in biological processes such as oxidation-reduction process(pFDR=3.95e-29),mitochondrion organization(pFDR=3.43e-27)and so on,while under-expressed genes were enriched in biological processes such as negative regulation of cell cycle(pFDR=3.67e-14),synapse organization(pFDR=1.30e-7)and so on.A number of genes in the positive gene list of the first component(PLS1+)significantly involved in astrocytes(n=117,PFDR=0.011),microglia(n=142,PFDR<0.001);and a number of genes in the negative gene list of the first component(PLS1-)significantly involved in excitatory neurons(n=239,PFDR<0.001),inhibitory neurons(n=174,PFDR<0.001).Confirmatory analysis with independent samples showed a very high correlation between the first principal component score of discovery set and the validation set(r=0.713,p<0.001).There is a high overlapping rate of PLS1+(PLS1-)between two sets(55.70%;56.64%,respectively).The results of cell-type analysis were also consistent.Specific analysis with another independent samples showed no significant association between gene transcription and cortical thickness development in late adulthood.In conclusion,this paper found the shrinkage of cortex thickness in children and adolescents in which different brain regions with different rates.This spatial pattern is closely related to the expression of gene transcription.The interaction between different biological processes jointly promotes the development of cortex thickness in children and adolescents.Astrocytes,microglia,excitatory and inhibitory neurons play an important role in the development of the cortex in children and adolescents.Further confirmatory analysis and specific analysis provided strong support for the results of this study and ensured the validity and reliability of the results.The study reveals the underlying neurobiological mechanisms of cortical development in early life,which contributes to a better understanding of the development of human cerebral cortex,and provides a reference for future research on neurodevelopmental disorders.