Circadian Disruptions in the Myshkin Mouse Model of Mania Are Independent of Deficits in Suprachiasmatic Molecular Clock Function

Joseph W.S. Timothy, Natasza Klas, Harshmeena R. Sanghani, Taghreed Al-Mansouri, Alun T.L. Hughes, Greer S. Kirshenbaum, Vincent Brienza, Mino D.C. Belle, Martin R. Ralph, Steven J. Clapcote, Hugh D. Piggins*

*Corresponding author for this work

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Abstract

Background: Alterations in environmental light and intrinsic circadian function have strong associations with mood disorders. The neural origins underpinning these changes remain unclear, although genetic deficits in the molecular clock regularly render mice with altered mood-associated phenotypes. Methods: A detailed circadian and light-associated behavioral characterization of the Na+/K+-ATPase α3 Myshkin (Myk/+) mouse model of mania was performed. Na+/K+-ATPase α3 does not reside within the core circadian molecular clockwork, but Myk/+ mice exhibit concomitant disruption in circadian rhythms and mood. The neural basis of this phenotype was investigated through molecular and electrophysiological dissection of the master circadian pacemaker, the suprachiasmatic nuclei (SCN). Light input and glutamatergic signaling to the SCN were concomitantly assessed through behavioral assays and calcium imaging. Results: In vivo assays revealed several circadian abnormalities including lengthened period and instability of behavioral rhythms, and elevated metabolic rate. Grossly aberrant responses to light included accentuated resetting, accelerated re-entrainment, and an absence of locomotor suppression. Bioluminescent recording of circadian clock protein (PERIOD2) output from ex vivo SCN revealed no deficits in Myk/+ molecular clock function. Optic nerve crush rescued the circadian period of Myk/+ behavior, highlighting that afferent inputs are critical upstream mediators. Electrophysiological and calcium imaging SCN recordings demonstrated changes in the response to glutamatergic stimulation as well as the electrical output indicative of altered retinal input processing. Conclusions: The Myshkin model demonstrates profound circadian and light-responsive behavioral alterations independent of molecular clock disruption. Afferent light signaling drives behavioral changes and raises new mechanistic implications for circadian disruption in affective disorders.

Original languageEnglish
Pages (from-to)827-837
Number of pages11
JournalBiological Psychiatry
Volume84
Issue number11
Early online date20 May 2017
DOIs
Publication statusPublished - 1 Dec 2018

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Keywords

  • Bipolar
  • Circadian
  • Light
  • Mania
  • Mood
  • Suprachiasmatic

Cite this

Timothy, J. W. S., Klas, N., Sanghani, H. R., Al-Mansouri, T., Hughes, A. T. L., Kirshenbaum, G. S., Brienza, V., Belle, M. D. C., Ralph, M. R., Clapcote, S. J., & Piggins, H. D. (2018). Circadian Disruptions in the Myshkin Mouse Model of Mania Are Independent of Deficits in Suprachiasmatic Molecular Clock Function. Biological Psychiatry, 84(11), 827-837. https://doi.org/10.1016/j.biopsych.2017.04.018