Transcriptomic Characterization of the Human Habenula Highlights Drug Metabolism and the Neuroimmune System

Abstract

Due to size and accessibility, most information about the habenula is derived from rodent studies. To better understand the molecular signature of the habenula we characterized the genes that have high expression in the habenula. We compared anatomical expression profiles of three normal adult human brains and four fetal brains. We used gene set enrichment analyses to determine if genes annotated to specific molecular functions, cellular components, and biological processes are enriched in the habenula. We also tested gene sets related to depression and addiction to determine if they uniquely involve the habenula. As expected, we observed high habenular expression of GPR151, nicotinic cholinergic receptors, and cilia-associated genes (medial division). Genes identified in genetic studies of smoking and associated with nicotine response were enriched in the habenula. Genes associated with major depressive disorder did not have enriched expression in the habenula but genes negatively correlated with hedonic well-being were, providing a link to anhedonia. We observed enrichment of genes associated with diseases that are comorbid with addictions (hematopoiesis, thrombosis, liver cirrhosis, pneumonia, and pulmonary fibrosis) and depression (rheumatoid arthritis, multiple sclerosis, and kidney disease). These inflammatory diseases mark a neuroimmune signature that is supported by genes associated with mast cells, acute inflammatory response, and leukocyte migration. We also found enrichment of cytochrome p450 genes suggesting the habenula is uniquely sensitive to endogenous and xenobiotic compounds. Our results suggest the habenula receives negative reward signals from immune and drug processing molecules. This is consistent with the habenular role in the "anti-reward" system and suggests it may be a key bridge between autoimmune disorders, drug use, and psychiatric diseases.

Keywords: addiction; cannabis; depression; drug metabolism; habenula; mast cell; neuroimmune; transcriptomics.

FIGURE 1

Violin plots of GPR151 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 GPR151. Donor identification numbers are marked in the x-axis. Expression in the lateral habenula is marked in black with orange marking the medial division. The distribution of expression across the remaining sampled regions is shown in blue.

FIGURE 2

Violin plots of CYP3A4 and CYP3A5 expression in the adult (A) and fetal (B) brains. Expression (log₂ intensity) is plotted individually for each probe on the y-axis (gene symbols in parenthesis). Donor identification numbers are marked in the x-axis. Expression in the lateral habenula is marked in black with orange marking the medial division. The distribution of expression across the remaining brain regions is shown in blue.

FIGURE 3

Associations between genes that are down-regulated in the blood of people with high levels of hedonic well-being and habenular specific expression. (A) ROC curves showing the proportion of hedonia down-regulated genes that overlap (y-axis, true positive fraction) in varying lengths of the habenula specific gene rankings (approximated by the x-axis, false positive fraction). (B) Distributions of the hedonia down-regulated genes across the habenular specific gene rankings with each gene representing a single colored line. Color marks the lateral (black) and medial (orange) habenula rankings. Dashed lines are used for the fetal datasets.