Mapping Gene Transcription and Neurocognition Across Human Neocortex

Post by Andrew Vo

What's the science?

As neuroscientists, we study the brain at different levels: from genes and neurons at the microscale to cognition and behavior at the macroscale. We know intuitively that these two scales are linked, building from gene expression to protein interactions, to neuronal wiring and firing, to complex psychological processes. However, this link has yet to be demonstrated in a comprehensive, data-driven, and multivariate framework. This week in Nature Human Behaviour, Hansen and colleagues bridge these two scales by spatially mapping gene expression and functional activation patterns across the human cortex.

How did they do it?

The authors began by performing partial least-squares (PLS) analysis on two open source datasets: (1) the Allen Human Brain Atlas (AHBA) that maps the expression of different genes across the brain and (2) Neurosynth that meta-analytically assigns psychological terms to brain regions they are commonly associated with. The resulting latent variable represented a covarying pattern of gene expression and functional activation, which they referred to as a gene-cognition gradient. In other words, they generated a scale that captured how much gene expression was related to functional activation of different brain regions. Next, they determined which specific sets of genes and psychological processes were related to one another by computing their loadings (i.e., the strength of their contributions) on the gene-cognition gradient. They further examined the biological processes and specific cell types associated with the uncovered gene sets.

To test whether their gene-cognition gradient followed the brain’s structural organization—an intermediate step proposed to link gene expression to functional activation—they compared it to several other previously reported brain patterns. These patterns described microstructural, laminar (referring to the brain’s layers) and functional organizations of the brain. Finally, they tested whether the gene-cognition gradient evolves across neurodevelopment by examining this pattern in the BrainSpan dataset, which provides gene expression estimates across varying stages of human development.

What did they find?

Multivariate PLS analysis revealed a pattern of gene expression and functional activation that spatially covaried across the brain in a ventromedial-dorsolateral gradient. This pattern separated gene sets that were related to affective (emotion-related) processes, neurogenesis, and differentiation, and support cell (e.g., astrocytes, microglia) expression from those gene sets associated with perception and attention, synaptic signaling, and inhibitory/excitatory neurons. Taken together, these findings demonstrate a link between gene expression and functional brain processes.

The authors also found that the gene-cognition gradient reflected other previously described brain organizations, hierarchies based on microstructural, laminar, or functional attributes. This suggests that the link between gene expression and functional activation is likely mediated through brain structure. Examining changes in the gene-cognition gradient across different stages of neurodevelopment, they found that the pattern strengthened over time and was most pronounced in adolescence and adulthood.

What's the impact?

In summary, this study identified a gene-cognition gradient that directly couples genetic expression to functional activation across the human cortex. This gradient delineates sets of genes, biological processes, and specific cell types related to emotional versus perceptual processes. The organization of this gene-cognition coupling follows the brain’s structural and functional hierarchies and matures through neurodevelopment. The study builds on previous literature that focused on single genes, brain regions, or cognitive functions by analyzing high-dimensional genetic and psychological data in a multivariate framework to offer a broader, more comprehensive view of the link between genes and cognition. This framework opens doors to new hypotheses about the genes involved in specific psychological processes, and vice-versa. It may also allow thorough characterization of brain alterations related to different psychiatric disorders across multiple scales, from transcription to cognition.

Hansen et al. Mapping gene transcription and neurocognition across human neocortex. Nature Human Behaviour (2021). Access the original scientific publication here.