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Spatial Transcriptomics Study Refines View Across Layers of Human Brain Region

NEW YORK – A team led by investigators at the Lieber Institute for Brain Development (LIBD) has collected spatially-defined gene expression profiles on samples from the human dorsolateral prefrontal cortex (DLPFC), uncovering disease-related genes that appear to have higher-than-usual expression in specific layers of this brain region. 

For a paper published in Nature Neuroscience on Monday, the researchers profiled gene expression across six layers of the DLPFC in two postmortem brain samples from each of three neurotypical adults. When they analyzed those data in combination with available single-nucleus RNA sequencing profiles and differential expression data from prior neuropsychiatric disease studies, the investigators saw expression signatures that were overrepresented in specific DLPFC layers, along with layers with particularly pronounced expression of genes previously implicated in conditions such as autism spectrum disorder (ASD) and schizophrenia.

"By integrating our data with clinical gene sets and [differentially expressed genes] in the brains of individuals with various neuropsychiatric disorders, we demonstrated preferentially layer-enriched expression of the genes implicated in ASD and [schizophrenia]," co-senior authors Andrew Jaffe and Keri Martinowich, investigators at LIBD who also hold affiliations at Johns Hopkins, and their colleagues wrote.

The investigators used the commercially available 10x Genomics Visium platform and a growing collection of related analytical tools to assess the DLPFC tissue blocks, making it possible to conduct spatial transcriptomic analyses of six cortical layers per sample that would otherwise require specialized microscopes.

The strategy offered advantages over such prior approaches, which tended to have "high barriers to entry" and were infrequently applied to human brain samples, the study's senior authors noted in an email.

In addition to these clinical insights, the spatial transcriptome data also made it possible to get a closer look at the so-called laminar topography of the brain region, pointing to laminar markers that were decidedly different than those found in past studies of the mouse brain.

"We were surprised that many commonly used laminar markers, which were previously identified in rodent models, did not show clear laminar signals in the adult human cortex," Jaffe and Martinowich explained in an email. "This is important because many of these layer marker genes have been used to interpret human studies."

The duo noted that it remains to be seen whether this disparity is due to authentic species differences or whether it may have stemmed from differences related to developmental timing in mice and humans, particularly since relatively few genome-wide expression analyses have been done in each species so far.

More broadly, the authors used data from the current analysis to come up with a framework for placing spatial transcriptomic data from other brain regions or tissue types into informative clusters. Data from the DLPFC, meanwhile, is available online through a spatialLIBD site.

"Using this application, researchers can visualize the spot-level Visium data, manually annotate spots to layers, visualize the layer-level results, assess the enrichment of gene sets among layer-enriched genes, and perform spatial registration," the authors concluded.

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