May 10, 2012

BSSR Lecture Series: Regulation of the dopaminergic reward circuit and manic-like behavior

Speaker-McClung, Colleen A., National Institutes of Health (U.S.)

Multiple studies have suggested that disruptions in circadian rhythms are central to the development of mood and addiction disorders. However, the mechanisms by which circadian genes regulate mood and reward-related circuitry remains unclear.

Our laboratory has found that mice with a mutation in the Clock gene (Clock∆19) have a complete behavioral profile that bears a striking resemblance to human mania (including hyperactivity, lowered levels of anxiety, increased preference and self-administration of drugs, and lowered levels of depression-related behavior) which can be reversed with chronic lithium treatment. Furthermore, the ClockΔ19 mice have an increase in dopaminergic activity in the ventral tegmental area (VTA) which is also normalized with lithium treatment. We have taken multiple approaches including RNA interference and optogenetics to better understand how CLOCK regulates dopaminergic activity and how this regulation is involved in the control of behavior.

Moreover, in collaboration with Kafui Dzirasa and Miguel Nicolelis at Duke University, we found that the ClockΔ19 mice not only have increased dopaminergic activity, but also have a defect in the ability of neurons in the cortico-limbic circuit to synchronize firing while animals are exploring specific tasks. Thus the CLOCK protein is not only involved in controlling rhythms over the course of 24 hrs, but is also involved in the synchronization of activity between brain regions over short periods of time.

CLOCK functions as a transcription factor and we have identified direct target genes that control dopaminergic activity which appear to be important in the reversal of phenotypes by lithium. Taken together, these results begin to show the mechanisms by which circadian genes regulate mood and reward, and suggest novel therapeutic targets for the treatment of mania and addictive disorders.