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Transcriptomic Characterization of the Human Insular Cortex and Claustrum

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Transcriptomic Characterization of the Human Insular Cortex and Claustrum

Christine Ibrahim et al. Front Neuroanat.

Abstract

The insular cortex has been linked to a multitude of functions. In contrast, the nearby claustrum is a densely connected subcortical region with unclear function. To view the insula-claustrum region from the molecular perspective we analyzed the transcriptomic profile of these areas in six adult and four fetal human brains. We identified marker genes with specific expression and performed transcriptome-wide tests for enrichment of biological processes, molecular functions, and cellular components. In addition, specific insular and claustral expression of genes pertaining to diseases, addiction, and depression was tested. At the anatomical level, we used brain-wide analyses to determine the specificity of our results and to determine the transcriptomic similarity of the insula-claustrum region. We found UCMA to be the most significantly enriched gene in the insular cortex and confirmed specific expression of NR4A2, NTNG2, and LXN in the claustrum. Furthermore, the insula was found to have enriched expression of genes associated with mood disorders, learning, cardiac muscle contraction, oxygen transport, glutamate and dopamine signaling. Specific expression in the claustrum was enriched for genes pertaining to human immunodeficiency virus (HIV), severe intellectual disability, epileptic encephalopathy, intracellular transport, spine development, and macroautophagy. We tested for enrichment of genes related to addiction and depression, but they were generally not highly specific to the insula-claustrum region. Exceptions include high insular expression of genes linked to cocaine abuse and genes associated with ever smoking in the claustrum. Brain-wide, we find that markers of the adult claustrum are most specifically expressed in the fetal and adult insula. Altogether, our results provide a novel molecular perspective on the unique properties of the insula and claustrum.

Keywords: addiction; claustrum; depression; dopamine; epilepsy; insula; macroautophagy; transcriptomics.

Figures

FIGURE 1
FIGURE 1
Plots of UCMA expression in the adult (A) and fetal (B) brains. Expression (log2 intensity) is plotted on the y-axis for each of the two probes for UCMA. Donor identification numbers are marked on the x-axis. Expression in the short insular gyri and dysgranular insular cortex is marked in black with orange marking the long and granular divisions. Expression across the remaining brain regions is shown in blue violin plots.
FIGURE 2
FIGURE 2
Euler diagram demonstrating gene overlaps between the significantly enriched GO groups in the adult long insular gyri that are also validated in the fetal granular insular cortex.
FIGURE 3
FIGURE 3
Associations between cocaine-related disorder genes and insular specific expression. (A) ROC curves showing the proportion of cocaine-related disorder genes that overlap (y-axis, true positive fraction) in varying lengths of the insular specific gene rankings (approximated by the x-axis, false positive fraction). (B) Distributions of the cocaine-related disorder genes across the insular specific gene rankings with each gene representing a single colored line. Color marks the short/dysgranular (black) and long/granular (orange) rankings. Dashed lines are used for the fetal datasets.
FIGURE 4
FIGURE 4
Plots of NR4A2 expression in the adult (A) and fetal (B) brains. Expression (log2 intensity) is plotted on the y-axis for each of the three probes for NR4A2. Donor identification numbers are marked on the x-axis. Expression in the claustrum is marked in black, expression across the remaining brain regions is shown in blue violin plots.
FIGURE 5
FIGURE 5
UMAP projection of the insular and clastral samples. Complete transcriptome profiles are reduced to a two-dimensional space (UMAP1 and 2) for visualization. Each dot represents a sample with color marking the sampled region (claustrum: red; long insular gyri: green; long insular gyri: blue).

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