Skip to main content
Open Access Publications from the University of California

UC San Diego

UC San Diego Electronic Theses and Dissertations bannerUC San Diego

Modelling Neuronal Circadian Rhythms in Bipolar Disorder Using Human Induced Pluripotent Stem Cells


Bipolar Disorder (BD) is a lifelong mental disorder characterized by recurrent episodes of mania and depression. Manic episodes involve elevated mood and reduced need for sleep, while depressive episodes are associated with low energy, increased/decreased sleep, and anhedonia. As such, clinical studies have shown that BD patients experience disturbed circadian rhythms. BD is heritable, as is clinical response to the first-line mood stabilizer lithium, suggesting that a biological approach to the etiology of the disorder may provide insight to BD diagnosis and treatment. Previous research in BD patient-derived fibroblasts indicates that circadian rhythm disturbances extend to the molecular level, but the relationship between BD and the cell-autonomous molecular circadian clock remains to be clarified in the most disease-relevant cell type, neurons.

Using human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) and cortex-like glutamatergic neurons, we measured the oscillatory activity of the molecular circadian clock using a lentiviral Period2-luciferase (Per2-luc) reporter. We found that BD-associated dysregulation of the molecular clock affects NPCs. In differentiated neurons, BD Li Non-Responder (Li-NR)-derived cells were found to have circadian rhythms not modulated by lithium treatment, and were more phase-dispersed and more resistant to external entrainment factors than were BD Li Responder (Li-R) and healthy control cells. We developed a temperature-entrainment protocol that successfully induced high-amplitude, 24-hour circadian rhythms in neurons from all diagnosis groups, reversing the low-amplitude phenotype in Li-NR neurons. Further characterization of the molecular circadian rhythms of BD hiPSC-derived neurons has the potential to reveal clinically-relevant indicators of BD lithium response.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View