Timothy, JWS, Klas, N, Sanghani, H, Al-Mansouri, T, Hughes, ATL, Kirshenbaum, GS, Brienza, V, Belle, MDC, Ralph, MR, Clapcote, SJ and Piggins, HD (2017) Circadian Disruptions in the Myshkin Mouse Model of Mania are Independent of Deficits in Suprachiasmatic Molecular Clock Function. Biological Psychiatry. ISSN 1873-2402

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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 (NKA) α3 Myshkin (Myk/+) mouse model of mania was performed. NKA 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 signalling 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 (PER2) 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 response to glutamatergic stimulation as well as 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.

Item Type:	Article
Uncontrolled Keywords:	06 Biological Sciences, 17 Psychology And Cognitive Sciences, 11 Medical And Health Sciences
Subjects:	B Philosophy. Psychology. Religion > BF Psychology Q Science > QH Natural history > QH301 Biology
Divisions:	Natural Sciences & Psychology (closed 31 Aug 19)
Publisher:	Elsevier
Date Deposited:	19 Sep 2018 08:49
Last Modified:	04 Sep 2021 10:06
URI:	https://researchonline.ljmu.ac.uk/id/eprint/9253

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