Paraventricular thalamic nucleus rather than cerebral cortex identified as causative brain region for bipolar disorder

Bipolar disorder (bipolar affective disorder) is a psychiatric condition characterized by recurring manic and depressive states, affecting approximately 1% of the world's population. Although it is a disorder with high suicide risk and substantial social burden, its brain pathology has not been fully elucidated. An international collaborative research group consisting of Associate Professor Masaki Nishioka, Professor Tadafumi Kato, and Project Associate Professor Mie Sakashita (Kubota) from the Department of Psychiatry and Behavioral Science at Juntendo University Graduate School of Medicine, together with Professor Gustavo Turecki from McGill University in Canada, has revealed through postmortem brain research that neurons in the paraventricular thalamic nucleus (PVT), a part of the epithalamus, are particularly severely impaired.

Kato stated, "I have been conducting research on bipolar disorder for 37 years, and we have finally achieved the result of identifying the causative brain region. Elucidating the causative region is the starting point for developing diagnostic and therapeutic methods, and if this discovery is replicated overseas and recognized worldwide, we can expect bipolar disorder research to advance dramatically." Their findings were published in Nature Communications .

Until now, postmortem brain research has focused almost exclusively on the frontal lobe. This is because in humans the frontal lobe is highly developed and large, allowing distribution to many researchers, and it appears to be involved in human mental function. Kato said, "When we began postmortem brain research 25 years ago, we analyzed the frontal lobe first but did not obtain sufficient results." He reflected, "In 2006, we created a model mouse based on the mitochondrial hypothesis of bipolar disorder. When that mouse showed behavioral changes similar to bipolar disorder, I temporarily felt we had proven the mitochondrial hypothesis."

However, mitochondrial dysfunction is said to be related to diabetes and Parkinson's disease as well, so it is not specific to bipolar disorder. Therefore, the researchers posed the question of which cells are affected by mitochondrial dysfunction. As a result of searching for where mitochondrial dysfunction occurs in the model mouse, they arrived at the PVT. "When the data came out (around the early 2010s), I didn't even know the name 'paraventricular thalamic nucleus.' However, when we investigated, we found it had connections to all the brain regions that had been said to be involved in the causes of bipolar disorder, and it seemed like this was the only possible answer. After that, from around 2015 onward, several reports demonstrated that the paraventricular thalamic nucleus plays an important role in emotional regulation, and that impression turned into conviction," he said.

Therefore, the researchers conducted single-nucleus RNA sequencing analysis using a total of 82 samples of postmortem brains from 21 patients with bipolar disorder and 20 controls, including the thalamus and cerebral cortex (prefrontal cortex). Through this single-nucleus RNA sequencing analysis, they identified a cell population believed to be from the PVT, and confirmed that these were PVT neurons by comparing them with results from single-cell RNA analysis of the mouse PVT. Furthermore, they confirmed through spatial transcriptome analysis that the cell population they had identified exists in the paraventricular region of the thalamus. Analysis of approximately 380,000 cell nuclei revealed that in bipolar disorder, thalamic excitatory neurons, especially PVT neurons, were reduced by approximately half.

Throughout the thalamus and cerebral cortex, the PVT showed the largest changes in gene expression. In PVT neurons, gene groups related to synaptic transmission and ion channel function were markedly reduced, with genes associated with genetic risk for bipolar disorder such as CACNA1C, KCNQ3, and SHISA9 serving as central nodes. Additionally, gene networks suggesting interactions between PVT neurons and microglia were also impaired, indicating that disruption of neuron-microglia interactions may be involved in the pathology. These changes were also more pronounced in the thalamus than in the cerebral cortex.

This demonstrates that the PVT plays a major role in the pathology of bipolar disorder, where pathology centered on the cerebral cortex had been vaguely assumed until now. The PVT receives strong projections from serotonergic neurons, while its axons branch and project to the amygdala, which is involved in fear, and the nucleus accumbens, which is involved in reward. When the PVT is manipulated in mice, they exhibit repetitive depression-like behavior whether it is inhibited or stimulated, suggesting that the changes in the PVT found this time are not a result of bipolar disorder but rather its cause.

Nishioka commented: "Research on bipolar disorder has long focused on the cerebral cortex, but this time we were able to demonstrate that more pronounced pathology exists in the PVT, a center that has tended to be overlooked. We believe these are results that emerged because of single-cell analysis of the human brain. We hope this achievement will lead to new breakthroughs in diagnosis and treatment."

Journal Information
Publication: Nature Communications
Title: Disturbances of paraventricular thalamic nucleus neurons in bipolar disorder revealed by single-nucleus analysis
DOI: 10.1038/s41467-025-68094-5