Disturbances of paraventricular thalamic nucleus neurons in bipolar disorder revealed by single-nucleus analysis.

Abstract

Bipolar disorder (BD) is a major global health burden, and its treatment challenges highlight the need for pathology-based therapeutic development. Emerging evidence suggests that the thalamus, particularly the paraventricular thalamic nucleus (PVT), is a key region in mood regulation. We performed single-nucleus RNA sequencing on 82 thalamic and cortical samples from 21 patients with BD and 20 controls to compare transcriptional pathology. PVT neurons showed the most striking abnormalities, including the largest number of differentially expressed genes and ~50% fewer cells in BD, whereas cortical alterations were comparatively modest. PVT neurons exhibited marked downregulation of synaptic and ion channel-related genes such as SHISA9, CACNA1C, and KCNQ3, which are linked to BD risk and serve as central nodes in downregulated networks. We also observed disrupted interactions between thalamic excitatory neurons and microglia. Overall, PVT neurons emerge as a central pathological substrate and a promising diagnostic and therapeutic target in BD.