title: Adaptation to experimental jet-lag in R6/2 mice despite circadian dysrhythmia.
abstract: The R6/2 transgenic mouse model of Huntington's disease (HD) shows a disintegration of circadian rhythms that can be delayed by pharmacological and non-pharmacological means. Since the molecular machinery underlying the circadian clocks is intact, albeit progressively dysfunctional, we wondered if light phase shifts could modulate the deterioration in daily rhythms in R6/2 mice. Mice were subjected to four x 4 hour advances in light onset. R6/2 mice adapted to phase advances, although angles of entrainment increased with age. A second cohort was subjected to a jet-lag paradigm (6 hour delay or advance in light onset, then reversal after 2 weeks). R6/2 mice adapted to the original shift, but could not adjust accurately to the reversal. Interestingly, phase shifts ameliorated the circadian rhythm breakdown seen in R6/2 mice under normal LD conditions. Our previous finding that the circadian period (tau) of 16 week old R6/2 mice shortens to approximately 23 hours may explain how they adapt to phase advances and maintain regular circadian rhythms. We tested this using a 23 hour period light/dark cycle. R6/2 mice entrained to this cycle, but onsets of activity continued to advance, and circadian rhythms still disintegrated. Therefore, the beneficial effects of phase-shifting are not due solely to the light cycle being closer to the tau of the mice. Our data show that R6/2 mice can adapt to changes in the LD schedule, even beyond the age when their circadian rhythms would normally disintegrate. Nevertheless, they show abnormal responses to changes in light cycles. These might be caused by a shortened tau, impaired photic re-synchronization, impaired light detection and/or reduced masking by evening light. If similar abnormalities are present in HD patients, they may suffer exaggerated jet-lag. Since the underlying molecular clock mechanism remains intact, light may be a useful treatment for circadian dysfunction in HD.
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
authors: Nigel I
authors: NI
authors: Wood
authors: Catherine J
authors: CJ
authors: McAllister
authors: Marc
authors: M
authors: Cuesta
authors: Juliet
authors: J
authors: Aungier
authors: Eloise
authors: E
authors: Fraenkel
authors: A Jennifer
authors: AJ
authors: Morton
mesh_terms: D000222:Adaptation, Physiological / Q000528:radiation effects*; D000367:Age Factors; D000818:Animals; D057906:Circadian Clocks / Q000502:physiology; D002940:Circadian Rhythm / Q000528:radiation effects*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology*; D020179:Jet Lag Syndrome / Q000235:genetics / Q000503:physiopathology*; D008027:Light; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology / Q000528:radiation effects; D017440:Photoperiod
references: J Immunol. 2010 Nov 15;185(10):5796-805
references: 20944004
references: Cancer Res. 2004 Nov 1;64(21):7879-85
references: 15520194
references: J Neurosci. 2005 Jan 5;25(1):157-63
references: 15634777
references: Neurobiol Dis. 2009 Mar;33(3):331-41
references: 19130884
references: J Neurosci. 1999 Dec 1;19(23):10428-37
references: 10575040
references: J Neurochem. 2006 May;97(4):1078-88
references: 16573644
references: J Neurosci. 2002 Sep 1;22(17):7326-30
references: 12196553
references: J Neurosci. 1999 Apr 15;19(8):3248-57
references: 10191337
references: Trials. 2010 Feb 23;11:19
references: 20178604
references: Chronobiol Int. 1999 Jul;16(4):415-29
references: 10442236
references: Arch Ophthalmol. 2009 Jun;127(6):737-41
references: 19506190
references: Nat Neurosci. 2001 Jun;4(6):567-8
references: 11369936
references: J Neurosci. 2007 Jul 18;27(29):7869-78
references: 17634381
references: Exp Neurol. 2011 Mar;228(1):80-90
references: 21184755
references: J Clin Invest. 2010 Jul;120(7):2600-9
references: 20577050
references: J Neurol. 2009 Dec;256(12):1961-5
references: 19562249
references: J Neurosci. 2010 Jul 28;30(30):10199-204
references: 20668203
references: Curr Biol. 2006 Nov 7;16(21):R914-6
references: 17084685
references: Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6412-7
references: 20308563
references: Cell. 1996 Nov 1;87(3):493-506
references: 8898202
references: J Clin Invest. 2010 Jul;120(7):2265-7
references: 20577055
references: Sleep Med Clin. 2010 Dec;5(4):701-715
references: 21243069
references: Science. 2002 Dec 13;298(5601):2211-3
references: 12481140
references: CNS Drugs. 2001;15(10):777-96
references: 11602004
references: Am J Physiol. 1998 Dec;275(6):H2334-7
references: 9843836
references: Ann N Y Acad Sci. 1984;423:442-68
references: 6588808
references: Neurobiol Learn Mem. 2008 May;89(4):533-44
references: 18069020
references: J Comp Neurol. 2004 Nov 8;479(2):181-97
references: 15452853
references: Neurobiol Dis. 2012 Jan;45(1):145-55
references: 21820053
references: Science. 1969 Jun 13;164(3885):1249-55
references: 5770615