title: 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 behaviors 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 behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.
authors.affiliation: Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, USA.|Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Sidor
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Spencer
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Center for Neuroengineering, Duke University Medical Center, Durham, NC, USA.
authors.forename: K
authors.initials: K
authors.lastname: Dzirasa
authors.affiliation: Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Parekh
authors.affiliation: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Tye
authors.affiliation: Department of Neurobiology and Behavior, Cornell University, Ithaca, NY, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Warden
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: R N
authors.initials: RN
authors.lastname: Arey
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.|Department of Biology, Austin College, Sherman, TX, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Enwright
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: J P R
authors.initials: JP
authors.lastname: Jacobsen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Center for Neuroengineering, Duke University Medical Center, Durham, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Biology, Austin College, Sherman, TX, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Remillard
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Center for Neuroengineering, Duke University Medical Center, Durham, NC, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Caron
authors.affiliation: Departments of Bioengineering and Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, USA.|Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: McClung
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics*; D000221:Adaptation, Ocular / Q000187:drug effects / Q000235:genetics; D000339:Affect / Q000502:physiology*; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics*; D002461:Cell Line, Transformed; D002940:Circadian Rhythm / Q000235:genetics*; D015259:Dopamine Agents / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D005518:Food Preferences / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D051381:Rats; D013550:Swimming; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology
chemical_list: D015259:Dopamine Agents; D014446:Tyrosine 3-Monooxygenase; D056926:CLOCK Proteins; C538944:Clock protein, mouse