Knockdown of clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior

Shibani Mukherjee, Laurent Coque, Jun Li Cao, Jaswinder Kumar, Sumana Chakravarty, Aroumougame Asaithamby, Ami Graham, Elizabeth Gordon, John F. Enwright, Ralph J. Dileone, Shari G. Birnbaum, Donald C. Cooper, Colleen A. McClung

Research output: Contribution to journalArticle

131 Citations (Scopus)

Abstract

Background: Circadian rhythm abnormalities are strongly associated with bipolar disorder; however the role of circadian genes in mood regulation is unclear. Previously, we reported that mice with a mutation in the Clock gene (ClockΔ19) display a behavioral profile that is strikingly similar to bipolar patients in the manic state. Methods: Here, we used RNA interference and viral-mediated gene transfer to knock down Clock expression specifically in the ventral tegmental area (VTA) of mice. We then performed a variety of behavioral, molecular, and physiological measures. Results: We found that knockdown of Clock, specifically in the VTA, results in hyperactivity and a reduction in anxiety-related behavior, which is similar to the phenotype of the ClockΔ19 mice. However, VTA-specific knockdown also results in a substantial increase in depression-like behavior, creating an overall mixed manic state. Surprisingly, VTA knockdown of Clock also altered circadian period and amplitude, suggesting a role for Clock in the VTA in the regulation of circadian rhythms. Furthermore, VTA dopaminergic neurons expressing the Clock short hairpin RNA have increased activity compared with control neurons, and this knockdown alters the expression of multiple ion channels and dopamine-related genes in the VTA that could be responsible for the physiological and behavioral changes in these mice. Conclusions: Taken together, these results suggest an important role for Clock in the VTA in the regulation of dopaminergic activity, manic and depressive-like behavior, and circadian rhythms.

Original languageEnglish (US)
Pages (from-to)503-511
Number of pages9
JournalBiological Psychiatry
Volume68
Issue number6
DOIs
StatePublished - Sep 15 2010

Fingerprint

Ventral Tegmental Area
RNA Interference
Bipolar Disorder
Depression
Circadian Rhythm
Genes
Viral Genes
Dopaminergic Neurons
Ion Channels
Small Interfering RNA
Dopamine
Anxiety
Phenotype
Neurons
Mutation

Keywords

  • Anxiety
  • bipolar disorder
  • depression
  • dopamine
  • RNAi
  • VTA

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Knockdown of clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. / Mukherjee, Shibani; Coque, Laurent; Cao, Jun Li; Kumar, Jaswinder; Chakravarty, Sumana; Asaithamby, Aroumougame; Graham, Ami; Gordon, Elizabeth; Enwright, John F.; Dileone, Ralph J.; Birnbaum, Shari G.; Cooper, Donald C.; McClung, Colleen A.

In: Biological Psychiatry, Vol. 68, No. 6, 15.09.2010, p. 503-511.

Research output: Contribution to journalArticle

Mukherjee, Shibani ; Coque, Laurent ; Cao, Jun Li ; Kumar, Jaswinder ; Chakravarty, Sumana ; Asaithamby, Aroumougame ; Graham, Ami ; Gordon, Elizabeth ; Enwright, John F. ; Dileone, Ralph J. ; Birnbaum, Shari G. ; Cooper, Donald C. ; McClung, Colleen A. / Knockdown of clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. In: Biological Psychiatry. 2010 ; Vol. 68, No. 6. pp. 503-511.
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AU - Chakravarty, Sumana

AU - Asaithamby, Aroumougame

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AU - Gordon, Elizabeth

AU - Enwright, John F.

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AB - Background: Circadian rhythm abnormalities are strongly associated with bipolar disorder; however the role of circadian genes in mood regulation is unclear. Previously, we reported that mice with a mutation in the Clock gene (ClockΔ19) display a behavioral profile that is strikingly similar to bipolar patients in the manic state. Methods: Here, we used RNA interference and viral-mediated gene transfer to knock down Clock expression specifically in the ventral tegmental area (VTA) of mice. We then performed a variety of behavioral, molecular, and physiological measures. Results: We found that knockdown of Clock, specifically in the VTA, results in hyperactivity and a reduction in anxiety-related behavior, which is similar to the phenotype of the ClockΔ19 mice. However, VTA-specific knockdown also results in a substantial increase in depression-like behavior, creating an overall mixed manic state. Surprisingly, VTA knockdown of Clock also altered circadian period and amplitude, suggesting a role for Clock in the VTA in the regulation of circadian rhythms. Furthermore, VTA dopaminergic neurons expressing the Clock short hairpin RNA have increased activity compared with control neurons, and this knockdown alters the expression of multiple ion channels and dopamine-related genes in the VTA that could be responsible for the physiological and behavioral changes in these mice. Conclusions: Taken together, these results suggest an important role for Clock in the VTA in the regulation of dopaminergic activity, manic and depressive-like behavior, and circadian rhythms.

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