Identification of the central pathological substrate of bipolar disorder as paraventricular thalamic nucleus

Bipolar disorder (BD) is a major mental disorder, affecting 1% of the global population. Patients suffering from BD frequently experience manic and depressive episodes, which disrupt interpersonal relationships and social confidence. While conventional therapies can mitigate the symptoms for some patients, they are also associated with adverse effects and treatment resistance in many, highlighting the urgent need for pathology-driven diagnosis and therapeutic intervention.

The thalamus, especially the paraventricular thalamic nucleus (PVT), has been previously associated with emotional processing and mood regulation. Magnetic resonance imaging (MRI) studies have shown volume reduction in certain regions of the brain, including the thalamus and cortex, in patients with BD. Current research utilizes single-nucleus ribonucleic acid (RNA) sequencing technology to elucidate the cellular pathology for different mental disorders. The changes in cellular and molecular mechanisms in the subcortical region, particularly the PVT, in patients with BD also warrant further investigation.

In an innovative study published online in the journal Nature Communications on January 07, 2026, a team of researchers led by Associate Professor Masaki Nishioka from the Department of Psychiatry and Behavioral Science, Juntendo University Graduate School of Medicine, Japan, along with Dr. Mie Sakashita-Kubota and Professor Tadafumi Kato, also from Juntendo University Graduate School of Medicine, used single-nucleus RNA sequencing to explore gene expression changes in the PVT of patients with BD.

“While mood stabilizers like lithium and lamotrigine, as well as atypical antipsychotics such as quetiapine, are commonly used for treatment, many patients continue to experience manic or depressive episodes due to low medication response or medication discontinuation caused by side effects. Developing diagnostic tests to determine the necessity of prophylactic medication, as well as creating more effective drugs with fewer side effects, could significantly improve the lives of those with BD and alter societal perceptions of the illness,” explains Dr. Nishioka.

The researchers used postmortem brain samples for single-nucleus RNA sequencing. The comparative analysis of transcriptional changes was conducted between normal brain samples and those obtained from patients with BD. Neurons from the cortical and thalamic regions were utilized for the study.

The PVT region in patients with BD showed notable alteration, with around 50% reduction in the number of cells. There was also downregulation of genes associated with synaptic function and ion channels, which may be associated with altered neural communication, excitability, and synaptic plasticity. Disrupted interactions were also noted between thalamic excitatory neurons and microglia. Interestingly, even though a reduction in cortical volume is observed by brain MRI of patients with BD, alterations in this region were modest compared to those in the PVT.

The dopamine signaling and monoamine receptor enrichment in PVT underscore the relevance of using antipsychotic drugs in the treatment. Focusing on these neurons as a therapeutic target might also restore the regulation of calcium and ion channel functions, leading to the alleviation of symptoms.

“This study highlights the need to extend research to the subcortical regions of the brain, which may harbor critical yet underexplored components of BD pathophysiology. There is also an increasing need for integrating multi-modal methodologies to advance BD pathology-related research. Various cellular, molecular, neuroimaging techniques can help to bridge research gaps and lead up advanced diagnostic and therapeutic strategies, aimed at improving patient outcomes,” said Dr. Nishioka.

“We have been studying the mitochondrial dysfunction of BD, and finally came to be aware that the fact that mitochondrial dysfunction is related to this disorder means that some specific brain region should be affected. We finally identified that PVT is the brain region causative for BD. This discovery will lead to the paradigm shift of BD research,” said Professor Kato.

Despite some limitations, the findings of this study highlight the relevance of PVT neurons in BD pathology, prioritizing them as a diagnostic and therapeutic target.

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Reference

Authors: Masaki Nishioka^1,2, Mie Sakashita-Kubota^1,2, Kouichirou Iijima¹, Yukako Hasegawa¹, Mizuho Ishiwata¹, Kaito Takase¹, Ryuya Ichikawa¹, Naguib Mechawar³, Gustavo Turecki³, and Tadafumi Kato^1,2                                                

Affiliations

¹Department of Psychiatry and Behavioral Science, Juntendo University Graduate School of Medicine, Japan

²Department of Molecular Pathology of Mood Disorders, Juntendo University Graduate School of Medicine, Japan

³McGill Group for Suicide Studies, Douglas Institute, Department of Psychiatry, McGill University, Canada

About Associate Professor Masaki Nishioka from Juntendo University Graduate School of Medicine, Japan

Dr. Masaki Nishioka is an Associate Professor at the Department of Psychiatry and Behavioral Science at Juntendo University Graduate School of Medicine, Japan. He completed his doctoral research in Medicine at The University of Tokyo. He has over 20 publications to his credit. He specializes in neurogenetics and his work focuses on somatic mutations in the brain and their link to mental health disorders. He is also a member of the Japan Neuroscience Society and a Councilor of the Japanese Society of Schizophrenia.

About Professor Tadafumi Kato from Juntendo University Graduate School of Medicine, Japan

Dr. Tadafumi Kato is a Professor at the Department of Psychiatry and Behavioral Science at Juntendo University Graduate School of Medicine, Japan. He graduated from The University of Tokyo. He has over 400 publications to his credit with an H-index of 73 and is dedicated to bridging basic neuroscience and clinical psychiatry. He proposed mitochondrial dysfunction hypothesis of bipolar disorder. He received Colvin Prize from the Brain and Behavior Foundation.