Journal Article

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

Warden, M R, Enwright, J F, Parekh, P K, McClung, C A, Tye, K M, Dzirasa, K, Deisseroth, K, Spencer, S M, Arey, R N, Kumar, S, Jacobsen, J P R, Remillard, E M, Sidor, M M, Caron, M G

2015

Overview

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 ( Clock Δ19) 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 behaviors in Clock Δ19 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 behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/77 / 64/60 / 692/699/476/1333 / Action Potentials - drug effects / Action Potentials - genetics / Adaptation, Ocular - drug effects / Adaptation, Ocular - genetics / Affect - physiology / Animal models / Animals / Anxiety / Behavior / Behavioral Sciences / Biological Psychology / Bipolar disorder / Cell Line, Transformed / Circadian rhythm / Circadian Rhythm - genetics / Circadian rhythms / Clock gene / CLOCK Proteins - genetics / Daytime / Dopamine / Dopamine Agents - pharmacology / Dopamine receptors / Dopaminergic mechanisms / Dopaminergic Neurons - drug effects / Dopaminergic Neurons - physiology / Emotions / Firing pattern / Food Preferences - drug effects / Food Preferences - physiology / Gene disruption / Gene Expression Regulation - drug effects / Gene Expression Regulation - genetics / Genes / Genetic aspects / Hydroxylase / Male / Maze Learning - drug effects / Maze Learning - physiology / Medicine / Medicine & Public Health / Mental depression / Mice / Mice, Inbred C57BL / Mice, Transgenic / Motor Activity - drug effects / Motor Activity - genetics / Mutation - genetics / Neurosciences / original-article / Pharmacotherapy / Phenotypes / Physiological aspects / Psychiatry / Rats / Risk factors / Swimming / Time Factors / Transcription / Tyrosine 3-monooxygenase / Tyrosine 3-Monooxygenase - genetics / Tyrosine 3-Monooxygenase - metabolism / Ventral Tegmental Area - cytology / Ventral tegmentum