Lithium Impacts on the Amplitude and Period of the Molecular Circadian Clockwork

The findings of the study presented below are in line with the data recorded in the study conducted by JBRF researchers: Sleep, Activity Patterns and Temperature Study. JBRF will continue to explore the role of thermoregulation in the biological basis of the Fear-of-Harm type of juvenile bipolar disorder.

Lithium salt has been widely used in treatment of Bipolar Disorder, a mental disturbance associated with circadian rhythm disruptions. Lithium mildly but consistently lengthens circadian period of behavioural rhythms in multiple organisms. To systematically address the impacts of lithium on circadian pacemaking and the underlying mechanisms, we measured locomotor activity in mice in vivo following chronic lithium treatment, and also tracked clock protein dynamics (PER2::Luciferase) in vitro in lithium-treated tissue slices/cells. Lithium lengthens period of both the locomotor activity rhythms, as well as the molecular oscillations in the suprachiasmatic nucleus, lung tissues and fibroblast cells. In addition, we also identified significantly elevated PER2::LUC expression and oscillation amplitude in both central and peripheral pacemakers. Elevation of PER2::LUC by lithium was not associated with changes in protein stabilities of PER2, but instead with increased transcription of Per2 gene. Although lithium and GSK3 inhibition showed opposing effects on clock period, they acted in a similar fashion to up-regulate PER2 expression and oscillation amplitude. Collectively, our data have identified a novel amplitude-enhancing effect of lithium on the PER2 protein rhythms in the central and peripheral circadian clockwork, which may involve a GSK3-mediated signalling pathway. These findings may advance our understanding of the therapeutic actions of lithium in Bipolar Disorder or other psychiatric diseases that involve circadian rhythm disruptions.

Lithium lengthens period for behavioral rhythms and alters molecular oscillations in the suprachiasmatic nucleus

Click here to read the peer-reviewed research article in its entirety.

Jian Li1, Wei-Qun Lu2, Stephen Beesley1, Andrew S. I. Loudon1*, Qing-Jun Meng1*
1 Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom,   2Faculty of Fisheries and Life Sciences, Shanghai Ocean University, Shanghai, China

 

What is the suprachiasmatic nucleus?

In mammals, the controlling clock component that generates a 24-hour rhythm is the suprachiasmatic nucleus (SCN), located in a part of the brain called the hypothalamus. The SCN produces a signal that can keep the rest of the body on an approximately 24-hour schedule.  Click here to watch an animated illustration of the human SCN created by the Howard Hughes Medical Institute1.

1Human SCN Anatomy Credits – Director: Dennis Liu, Ph.D. ~ Scientific Direction: Joseph Takahashi, Ph.D. ~ Scientific Content: Donna Messersmith, Ph.D. ~ Animator: Eric Keller