Transcriptomic divergence of network hubs in the fetal human brain
Poster No:
1012
Submission Type:
Abstract Submission
Authors:
Stuart Oldham1, Gareth Ball1
Institutions:
1Murdoch Children's Research Institute, Melbourne, VIC
First Author:
Co-Author:
Introduction:
Connections between brain regions are unevenly distributed. In the human brain, a disproportionate number of connections converge on select hub nodes, located in transmodal, paralimbic and association areas[1,2]. Connections between hubs form a central nexus, or 'rich club', that facilitates long-distance communication and integration across functional sub-systems[3]. This structural core of the human connectome is assembled prior to the time of normal birth[2,4]. These observations, coupled with evidence that genetic influences on brain connectivity are concentrated on hubs and their respective connections, support a role of genes in shaping the network core[5], potentially through guidance of neuronal circuitry via spatiotemporal molecular cues. However, little is known about how neuronal connections converge upon putative hub regions during human gestation. To address this, we combined high-resolution whole-brain tractography in a large neonatal cohort with µBrain, a recently developed 3D atlas of fetal gene expression[6] to examine the molecular identities of cortical hub regions in mid-gestation.
Methods:
We constructed a group consensus structural connectome from whole-brain tractography in 238 term neonates (122 female, median birth age [range]=40 [37-42] weeks; median scan age [range]=40.86 [37-44] weeks) from the Developing Human Connectome Project. Using a high-resolution subdivision of the µBrain cortical atlas (512 nodes; Fig. 1A), we identified network hubs based on node degree (Fig. 1B) and confirmed the presence of rich club architecture in the neonatal brain (Fig. 1C-D). Rich club nodes (degree≥125) were assigned to their corresponding µBrain parcellation to identify areal "richness" (n=29 cortical regions; Fig. 1E).
We analysed microarray data from four prenatal brain specimens aligned to the µBrain atlas to assess spatial associations with prenatal gene expression across 29 cortical regions and five developmental tissue zones (Fig. 2A). After data cleaning (Fig. 2B), we retained 6,843 genes and modelled gene expression as a function of areal "richness" in each tissue zone using a general linear model (Fig. 2C).
We analysed microarray data from four prenatal brain specimens aligned to the µBrain atlas to assess spatial associations with prenatal gene expression across 29 cortical regions and five developmental tissue zones (Fig. 2A). After data cleaning (Fig. 2B), we retained 6,843 genes and modelled gene expression as a function of areal "richness" in each tissue zone using a general linear model (Fig. 2C).
Results:
Rich club hubs were located in areas previously reported in both neonatal[4] and adult brain networks[5] (Fig. 1E). Over 500 genes were differentially expressed in hub regions compared to non-hub regions in mid-gestation (n=528, pFDR<0.05; Fig. 2D) with most associations in post-mitotic tissue (cortical plate, subplate and intermediate zone). In cortical regions containing multiple hubs at birth, upregulated genes (n=209) were enriched for fundamental neurodevelopmental processes (pFDR<0.05; Fig 2E), and included genes involved in neuronal guidance (e.g., BMP7, EFNA5), synaptic organisation (LRRN3, MEF2C) and transmission (GRIK2, CACNG3). No significant enrichments were found in downregulated genes (n=320) in hub regions.
Taking advantage of a recent single cell survey of pre- and postnatal brain development[7], we tested specific developmental cell lineages for enrichment of hub genes. We found significant enrichment of early neuronal (subplate neurons: p<0.001, subplate and intermediate zone) and glial cell lineages (protoplasmic astrocytes: p<0.001, cortical plate and subplate), populations critical establishing early neuronal circuitry[8,9]. Using a MAGMA gene set analysis we found that genetic risk for neuropsychiatric disease[10] converged on genes associated with increased hub connectivity in the postmitotic subplate (neuropsychiatric risk, p=0.016) and intermediate (mood disorders, p=0.0008) zones.
Taking advantage of a recent single cell survey of pre- and postnatal brain development[7], we tested specific developmental cell lineages for enrichment of hub genes. We found significant enrichment of early neuronal (subplate neurons: p<0.001, subplate and intermediate zone) and glial cell lineages (protoplasmic astrocytes: p<0.001, cortical plate and subplate), populations critical establishing early neuronal circuitry[8,9]. Using a MAGMA gene set analysis we found that genetic risk for neuropsychiatric disease[10] converged on genes associated with increased hub connectivity in the postmitotic subplate (neuropsychiatric risk, p=0.016) and intermediate (mood disorders, p=0.0008) zones.
Conclusions:
Our study identifies prenatal transcriptomic signatures of network hubs in the neonatal human brain. In line with prior experimental data, we establish the importance of astrocytic cell populations in the organisation and maintenance of early cortical circuitry, and identify potential pathways through which developing network structure may be impacted in common neuropsychiatric disorders.
Genetics:
Transcriptomics 2
Lifespan Development:
Normal Brain Development: Fetus to Adolescence 1
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping
Normal Development
Keywords:
Development
Tractography
Other - connectome; network; hubs; rich-club; genes; neonates
1|2Indicates the priority used for review
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Provide references using APA citation style.
2. Oldham, S., Ball, G. & Fornito, A. Early and late development of hub connectivity in the human brain. Current Opinion in Psychology 44, 321–329 (2022).
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4. Ball, G. et al. Rich-club organization of the newborn human brain. Proceedings of the National Academy of Sciences 111, 7456–7461 (2014).
5. Arnatkevičiūtė, A. et al. Genetic influences on hub connectivity of the human connectome. Nature Communications 12, 4237 (2021).
6. Ball, G. et al. Molecular signatures of cortical expansion in the human foetal brain. Nat Commun 15, 9685 (2024).
7. Velmeshev, D. et al. Single-cell analysis of prenatal and postnatal human cortical development. Science 382, eadf0834 (2023).
8. Clarke, L. E. & Barres, B. A. Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 14, 311–321 (2013).
9. Molnár, Z., Luhmann, H. J. & Kanold, P. O. Transient cortical circuits match spontaneous and sensory-driven activity during development. Science 370, eabb2153 (2020).
10. Mallard, T. T. et al. Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities. Cell Genomics 2, 100140 (2022).