Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice

Abstract

Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels, and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviours in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behaviour. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

Neuronal correlates of depression

“…A more recent study extended the role of Clock gene and the regulation of anxiety related behaviours. Clock mutant mice were found to exhibit rapid mood cycling across the light-dark cycle such that the Clock mutants exhibited robust manic-like behaviour compared to wild-type controls when tested in an open field-, forced swim- and sucrose-preference test during the day [294]. Furthermore Clock mutant mice exhibited robust increases in both daytime tyrosine hydroxylase expression and VTA DA neuron activity [294].…”

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

“…Although the master circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus synchronizes rhythms throughout the brain and body, the genes that control circadian rhythms are expressed in nearly every cell (6). In recent years, it has become apparent that these genes serve important functions in specific brain regions, including the control of daily rhythms in neuronal activity and the response to environmental stimuli (7)(8)(9).…”

Circadian Rhythms and Psychopathology: From Models of Depression to Rhythms in Clock Gene Expression and Back Again

“…Investigators in McClung's laboratory have demonstrated that clock mutant mice (ClockΔ19) also exhibit changes in moodrelated behaviors, but the region specificity of this effect was impossible to elucidate in these constitutive mutants (10). The observation that region-specific rhythms of clock gene expression correlate with depression-like behaviors by Logan et al (1) is an important step forward toward identifying brain areas where clock genes are associated with mood-related and depression-related behaviors and vice versa.…”