The emerging role of the paraventricular thalamic nucleus in bipolar disorder: Lessons from mitochondrial dysfunction

regulation. Recent work highlights the paraventricular thalamic nucleus (PVT) as a critical site of pathology. The PVT integrates serotonergic and limbic circuits, regulates salience, and exhibits the highest burden of mtDNA deletions in mutant Polg (mtDNA polymerase) mice. In humans, single-nucleus RNA sequencing reveals a ~50% reduction of PVT neurons in bipolar disorder, with marked transcriptional dysregulation enriched for bipolar disorder risk loci in PVT, with additional changes in microglia. Neuropathological studies further suggest neurodegenerative changes in PVT, particularly in late-onset bipolar disorder. Collectively, these findings position PVT pathology at the core of bipolar disorder pathophysiology, offering a framework that integrates genetic risk, neuronal hyperexcitability, and circuit-level dysregulation and guiding future therapeutic strategies.