title: Mammalian rest/activity patterns explained by physiologically based modeling.
abstract: Circadian rhythms are fundamental to life. In mammals, these rhythms are generated by pacemaker neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is remarkably consistent in structure and function between species, yet mammalian rest/activity patterns are extremely diverse, including diurnal, nocturnal, and crepuscular behaviors. Two mechanisms have been proposed to account for this diversity: (i) modulation of SCN output by downstream nuclei, and (ii) direct effects of light on activity. These two mechanisms are difficult to disentangle experimentally and their respective roles remain unknown. To address this, we developed a computational model to simulate the two mechanisms and their influence on temporal niche. In our model, SCN output is relayed via the subparaventricular zone (SPZ) to the dorsomedial hypothalamus (DMH), and thence to ventrolateral preoptic nuclei (VLPO) and lateral hypothalamus (LHA). Using this model, we generated rich phenotypes that closely resemble experimental data. Modulation of SCN output at the SPZ was found to generate a full spectrum of diurnal-to-nocturnal phenotypes. Intriguingly, we also uncovered a novel mechanism for crepuscular behavior: if DMH/VLPO and DMH/LHA projections act cooperatively, daily activity is unimodal, but if they act competitively, activity can become bimodal. In addition, we successfully reproduced diurnal/nocturnal switching in the rodent Octodon degu using coordinated inversions in both masking and circadian modulation. Finally, the model correctly predicted the SCN lesion phenotype in squirrel monkeys: loss of circadian rhythmicity and emergence of ∼4-h sleep/wake cycles. In capturing these diverse phenotypes, the model provides a powerful new framework for understanding rest/activity patterns and relating them to underlying physiology. Given the ubiquitous effects of temporal organization on all aspects of animal behavior and physiology, this study sheds light on the physiological changes required to orchestrate adaptation to various temporal niches.
authors.affiliation: Division of Sleep Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: A J K
authors.initials: AJ
authors.lastname: Phillips
authors.forename: B D
authors.initials: BD
authors.lastname: Fulcher
authors.forename: P A
authors.initials: PA
authors.lastname: Robinson
authors.forename: E B
authors.initials: EB
authors.lastname: Klerman
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D008954:Models, Biological; D009043:Motor Activity; D013493:Suprachiasmatic Nucleus / Q000502:physiology
references.citation: PLoS Comput Biol. 2012;8(11):e1002788
references.pmid: 23209396
references.citation: Am J Physiol. 1983 Dec;245(6):R927-34
references.pmid: 6660335
references.citation: Neuroscience. 1999;93(1):209-14
references.pmid: 10430484
references.citation: Nature. 2012 Apr 04;484(7394):371-5
references.pmid: 22495312
references.citation: Physiol Behav. 2007 Feb 28;90(2-3):325-33
references.pmid: 17084868
references.citation: Brain Res. 1975 Oct 10;96(1):76-81
references.pmid: 1175007
references.citation: Chronobiol Int. 1999 Jul;16(4):415-29
references.pmid: 10442236
references.citation: J Math Biol. 2010 May;60(5):615-44
references.pmid: 19557415
references.citation: Brain Res. 2003 Mar 7;965(1-2):1-8
references.pmid: 12591114
references.citation: Nature. 2004 Oct 14;431(7010):862-8
references.pmid: 15483615
references.citation: J Biol Rhythms. 2011 Oct;26(5):441-53
references.pmid: 21921298
references.citation: Proc Natl Acad Sci U S A. 1972 Jun;69(6):1583-6
references.pmid: 4556464
references.citation: Neuroscience. 2004;127(1):13-23
references.pmid: 15219664
references.citation: Behav Neurosci. 1999 Aug;113(4):755-65
references.pmid: 10495083
references.citation: Nature. 2005 Oct 27;437(7063):1257-63
references.pmid: 16251950
references.citation: Behav Brain Res. 2008 Jun 3;189(2):298-305
references.pmid: 18313152
references.citation: Brain Res. 2002 Nov 15;955(1-2):1-7
references.pmid: 12419515
references.citation: J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2005 Jan;191(1):51-9
references.pmid: 15558289
references.citation: PLoS One. 2012;7(8):e42059
references.pmid: 22905114
references.citation: Science. 2003 Nov 21;302(5649):1408-12
references.pmid: 14631044
references.citation: Philos Trans A Math Phys Eng Sci. 2011 Oct 13;369(1952):3840-54
references.pmid: 21893531
references.citation: J Biol Rhythms. 1999 Oct;14(5):364-77
references.pmid: 10511004
references.citation: Brain Res. 1976 Sep 17;114(2):305-17
references.pmid: 963552
references.citation: Physiol Behav. 1982 Aug;29(2):231-9
references.pmid: 7146128
references.citation: J Comp Physiol A. 1999 Apr;184(4):449-56
references.pmid: 10377979
references.citation: J Biol Rhythms. 1999 Aug;14(4):300-6
references.pmid: 10447310
references.citation: J Theor Biol. 2008 Dec 21;255(4):413-23
references.pmid: 18805427
references.citation: Neuroscience. 2008 Sep 22;156(1):48-58
references.pmid: 18692118
references.citation: J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2005 Jan;191(1):23-30
references.pmid: 15449094
references.citation: Nature. 2005 Oct 27;437(7063):1264-71
references.pmid: 16251951
references.citation: Mol Cell Endocrinol. 1991 Aug;79(1-3):C153-8
references.pmid: 1936532
references.citation: J Biol Rhythms. 2004 Oct;19(5):374-87
references.pmid: 15534318
references.citation: J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2005 Nov;191(11):1011-24
references.pmid: 16163543
references.citation: J Neurosci. 1999 Jan 1;19(1):328-33
references.pmid: 9870962
references.citation: J Biol Rhythms. 2010 Jun;25(3):217-27
references.pmid: 20484693
references.citation: J Comp Physiol A. 1999 Apr;184(4):439-48
references.pmid: 10377978
references.citation: J Exp Zool. 1996 May 1;275(1):67-70
references.pmid: 8708632
references.citation: J Biol Rhythms. 1999 Dec;14(6):500-15
references.pmid: 10643747
references.citation: J Biol Rhythms. 2004 Feb;19(1):58-67
references.pmid: 14964704
references.citation: Science. 2000 Oct 27;290(5492):799-801
references.pmid: 11052942
references.citation: J Biol Rhythms. 2011 Apr;26(2):118-29
references.pmid: 21454292
references.citation: J Theor Biol. 2007 Aug 21;247(4):583-99
references.pmid: 17531270
references.citation: PLoS Comput Biol. 2010 Jun 24;6(6):e1000826
references.pmid: 20585613
references.citation: J Neurophysiol. 2007 Jun;97(6):3828-40
references.pmid: 17409167
references.citation: Curr Biol. 2002 Nov 19;12(22):1919-22
references.pmid: 12445384
references.citation: J Biol Rhythms. 2007 Apr;22(2):167-79
references.pmid: 17440218
references.citation: J Theor Biol. 1998 Jun 21;192(4):455-65
references.pmid: 9680719
references.citation: Am J Physiol. 1985 Mar;248(3 Pt 2):R353-62
references.pmid: 3976909
references.citation: Am Nat. 2012 Jun;179(6):794-804
references.pmid: 22617266
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13133-8
references.pmid: 18695249
references.citation: Brain Res Bull. 1994;35(5-6):607-16
references.pmid: 7859118
references.citation: Am J Physiol. 1981 Nov;241(5):R385-91
references.pmid: 7304784
references.citation: Chronobiol Int. 2009 Feb;26(2):219-41
references.pmid: 19212838
references.citation: Philos Trans A Math Phys Eng Sci. 2011 Oct 13;369(1952):3855-83
references.pmid: 21893532
references.citation: Neuron. 2010 Dec 22;68(6):1023-42
references.pmid: 21172606
references.citation: Neuroscience. 2010 Jan 20;165(2):337-49
references.pmid: 19837140
references.citation: J Neurosci. 1993 Mar;13(3):1065-79
references.pmid: 8441003
references.citation: Brain Behav Evol. 2010;75(1):9-22
references.pmid: 20134153
references.citation: J Theor Biol. 2013 Feb 21;319:75-87
references.pmid: 23220346
references.citation: Neurosci Biobehav Rev. 1994 Summer;18(2):171-95
references.pmid: 8058212
references.citation: Chronobiol Int. 2001 Sep;18(5):737-58
references.pmid: 11763983
references.citation: Chronobiol Int. 2003 Jan;20(1):1-8
references.pmid: 12638686
references.citation: Open Sleep J. 2008;1:11-14
references.pmid: 18978959
references.citation: Brain Res. 1977 Feb 11;122(1):33-47
references.pmid: 837222
references.citation: Electroencephalogr Clin Neurophysiol. 1974 Feb;36(2):201-4
references.pmid: 4129632
references.citation: Brain Res Brain Res Rev. 2005 Nov;49(3):429-54
references.pmid: 16269313
references.citation: Nature. 1978 Mar 23;272(5651):333-6
references.pmid: 634356