Researchers have shown for the first time that ensembles of genes within the brain’s striatum—a part of the basal ganglia responsible for voluntary motor control and believed to contribute to risk and reward decision-making—could be deeply involved in bipolar disorder.
This discovery links a gene-level etiology of bipolar disorder to a specific region of the brain. It also points to the brain region’s signaling pathways as potential targets for novel treatments to manage bipolar disorder, the authors concluded. Their results were published online June 28, 2016 in the journal Molecular Psychiatry.
Until this point, most other gene expression analyses of bipolar disorder have focused on the cerebral cortex—the region associated with higher-level thought, memory, and consciousness.
“This is the first real study of gene expression in the striatum for bipolar disorder,” said study director Ronald L. Davis, PhD, Chair of the Department of Neuroscience at The Scripps Research Institute, in Jupiter, FL. “We now have a snapshot of the genes and proteins expressed in that region.”
For this study, the researchers obtained post-mortem tissue samples from 18 subjects diagnosed with bipolar disorder and 17 non-bipolar control subjects. They sequenced the samples’ total striatal transcriptomes and compared the results of the two groups.
Surprisingly, the number of genes differentially expressed in both groups of tissue samples turned out to be small—just 14 in all. However, co-expression network analysis also revealed two modules of interconnected genes that were particularly rich in genetic variations associated with bipolar disorder, suggestive of a causal role in the disorder.
Of these two modules, the one with the highest genetic association signal for bipolar disorder was especially remarkable because its gene expression was also highly characteristic of the striatum.
“Our finding of a link between bipolar disorder and the striatum at the molecular level complements studies that implicate the same brain region in bipolar disorder at the anatomical level, including functional imaging studies that show altered activity in the striatum of bipolar subjects during tasks that involve balancing reward and risk,” said first author Rodrigo Pacifico, PhD, Research Associate in Dr. Davis’ lab.
Because bipolar patients may act impulsively and engage in high-risk activities during periods of mania, analyzing their reactions to risk is important.
“We speculate that, at least in a subset of bipolar subjects, the presence of a susceptible genetic background affecting signaling in striatal medium spiny neurons, compounded by chronic oxidative and/or inflammatory stress, may disturb striatal circuits and bring about recurring imbalances in the activation of the two pathways that ultimately cause some of the changes in behavior seen in bipolar disorder,” the authors wrote.
Functional pathway analysis also found changes in genes linked to immune and inflammation pathways. “We don’t know if these changes are a cause of the disease or the result of it,” Dr. Davis said. “But they provide additional gene markers in bipolar disorder that could potentially lead to the future development of diagnostics or treatments.”