A transcriptional signature of hub connectivity in the mouse connectome

Abstract

Connectivity is not distributed evenly throughout the brain. Instead, it is concentrated on a small number of highly connected neural elements that act as network hubs. Across different species and measurement scales, these hubs show dense interconnectivity, forming a core or "rich club" that integrates information across anatomically distributed neural systems. Here, we show that projections between connectivity hubs of the mouse brain are both central (i.e., they play an important role in neural communication) and costly (i.e., they extend over long anatomical distances) aspects of network organization that carry a distinctive genetic signature. Analyzing the neuronal connectivity of 213 brain regions and the transcriptional coupling, across 17,642 genes, between each pair of regions, we find that coupling is highest for pairs of connected hubs, intermediate for links between hubs and nonhubs, and lowest for connected pairs of nonhubs. The high transcriptional coupling associated with hub connectivity is driven by genes regulating the oxidative synthesis and metabolism of ATP-the primary energetic currency of neuronal communication. This genetic signature contrasts that identified for neuronal connectivity in general, which is driven by genes regulating neuronal, synaptic, and axonal structure and function. Our findings establish a direct link between molecular function and the large-scale topology of neuronal connectivity, showing that brain hubs display a tight coordination of gene expression, often over long anatomical distances, that is intimately related to the metabolic requirements of these highly active network elements.connectome | complex networks | hub | rich club | metabolism C ertain neural elements possess an unusually high degree of connectivity, designating them as putative network hubs (1). Analyses of microscale, mesoscale, and macroscale connectomes of multiple species, constructed using a variety of methods, indicate that these hubs are strongly interconnected with each other, forming a so-called "rich club" of connectivity that mediates a large fraction of communication traffic in the brain and supports the efficient integration of otherwise segregated neural systems (2-8).Hub connectivity is functionally advantageous, but it is also costly. Hub regions make more connections with other areas, and these connections often extend over long anatomical distances, thus requiring greater physical space, cellular material, and metabolic resources (3, 9). Accordingly, human neuroimaging studies have indicated that topologically central hub regions have a higher energetic demand than other brain areas (9-12), which may render them particularly vulnerable to the effects of damage or disease (10, 13). This hypothesis is supported by evidence that pathology in a broad range of disorders preferentially accumulates within highly connected brain regions (14).Hub connectivity is thus a topologically central and costly aspect of brain network organization that is conserved across species and spatial scales....

Regional expression of the MAPT gene is associated with loss of hubs in brain networks and cognitive impairment in Parkinson disease and progressive supranuclear palsy

“…Global network properties have been found to mirror patterns in gene expression (Fulcher and Fornito, 2016, Rubinov et al., 2015, Vértes et al., 2016), and more specifically, the association between MAPT expression and connection strength reflects the importance of the tau protein in maintaining axonal integrity by stabilizing microtubules (Lindwall and Cole, 1984). In humans, previous imaging studies have linked single gene variants with patterns of change in brain imaging (Filippini et al., 2009, Mata et al., 2014, Whitwell et al., 2011).…”

Network neuroscience

“…Transcriptional profiles also exhibit relationships with the topological roles of brain areas in the macroscale connectome. In the mouse brain, highly connected and highly central areas exhibit a common and distinct topological profile, specifically involving genes regulating oxidative metabolism, suggestive of links between network topology and metabolic demand 128 . A separate study found evidence of elevated expression of genes associated with cognition, learning and memory in hub nodes of the mouse brain 129 .…”

373. Adolescence is Associated with Genomically Patterned Consolidation of the Hubs of the Human Brain Connectome

“…26) but not previously related to measures of cortical shrinkage or myelination. Recently, several studies have linked brain regional gene expression to axonal connectivity in the mouse (27,28) and functional MRI networks in humans (29,30), but there have been no previous efforts to investigate genetic mechanisms of adolescent myelination of human cortex.…”