Although the involvement of genomic factors in bipolar disorder is clear, its neural basis remains a question. We proposed the mitochondrial dysfunction hypothesis of bipolar disorder in 2000 and have since been testing it. Our results showed that mitochondrial DNA (mtDNA) polymorphisms affected mitochondrial Ca2+ concentration, and mitochondrial Ca2+ uptake and intracellular Ca2+ signaling were altered. Spontaneous repetitive depressive episodes were seen in mice in which mtDNA mutations accumulated in the brain (mutant Polg transgenic mice). We searched for the brain regions with the accumulation of mutant mtDNA in these mice, and found that it was most abundant in the paraventricular nucleus of the thalamus (PVT). Neural circuit manipulation of the PVT caused similar repetitive hypoactive episodes, suggesting that the PVT may be involved in causing bipolar disorder.