title: Anhedonic behavior in cryptochrome 2-deficient mice is paralleled by altered diurnal patterns of amygdala gene expression.
abstract: Mood disorders are frequently paralleled by disturbances in circadian rhythm-related physiological and behavioral states and genetic variants of clock genes have been associated with depression. Cryptochrome 2 (Cry2) is one of the core components of the molecular circadian machinery which has been linked to depression, both, in patients suffering from the disease and animal models of the disorder. Despite this circumstantial evidence, a direct causal relationship between Cry2 expression and depression has not been established. Here, a genetic mouse model of Cry2 deficiency (Cry2 (-/-) mice) was employed to test the direct relevance of Cry2 for depression-like behavior. Augmented anhedonic behavior in the sucrose preference test, without alterations in behavioral despair, was observed in Cry2 (-/-) mice. The novelty suppressed feeding paradigm revealed reduced hyponeophagia in Cry2 (-/-) mice compared to wild-type littermates. Given the importance of the amygdala in the regulation of emotion and their relevance for the pathophysiology of depression, potential alterations in diurnal patterns of basolateral amygdala gene expression in Cry2 (-/-) mice were investigated focusing on core clock genes and neurotrophic factor systems implicated in the pathophysiology of depression. Differential expression of the clock gene Bhlhe40 and the neurotrophic factor Vegfb were found in the beginning of the active (dark) phase in Cry2 (-/-) compared to wild-type animals. Furthermore, amygdala tissue of Cry2 (-/-) mice contained lower levels of Bdnf-III. Collectively, these results indicate that Cry2 exerts a critical role in the control of depression-related emotional states and modulates the chronobiological gene expression profile in the mouse amygdala.
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse, 17, 1090, Vienna, Austria.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Savalli
authors.forename: Weifei
authors.initials: W
authors.lastname: Diao
authors.forename: Stefanie
authors.initials: S
authors.lastname: Berger
authors.forename: Marianne
authors.initials: M
authors.lastname: Ronovsky
authors.forename: Timo
authors.initials: T
authors.lastname: Partonen
authors.forename: Daniela D
authors.initials: DD
authors.lastname: Pollak
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm; D056931:Cryptochromes / Q000172:deficiency / Q000235:genetics*; D003863:Depression / Q000378:metabolism; D005518:Food Preferences; D015870:Gene Expression; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D042561:Vascular Endothelial Growth Factor B; C467482:vascular endothelial growth factor B, mouse
references.citation: Neuropsychobiology. 1982;8(5):225-32
references.pmid: 7133371
references.citation: Acta Pharmacol Sin. 2011 Jan;32(1):3-11
references.pmid: 21131999
references.citation: Cell. 2002 Dec 13;111(6):905-18
references.pmid: 12526815
references.citation: Biol Psychiatry. 2003 Sep 1;54(5):552-65
references.pmid: 12946884
references.citation: PLoS One. 2013;8(2):e57115
references.pmid: 23437327
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4180-4
references.pmid: 15746242
references.citation: Learn Mem. 2001 Jul-Aug;8(4):209-19
references.pmid: 11533224
references.citation: Biol Psychiatry. 2007 Jan 15;61(2):250-2
references.pmid: 16860779
references.citation: Tissue Eng. 2005 Sep-Oct;11(9-10):1618-29
references.pmid: 16259615
references.citation: Physiol Behav. 2001 Aug;73(5):705-17
references.pmid: 11566205
references.citation: Dev Biol. 2006 Jan 15;289(2):329-35
references.pmid: 16337622
references.citation: J Psychiatr Res. 2013 Aug;47(8):1080-7
references.pmid: 23684549
references.citation: J Biol Chem. 2011 Jul 22;286(29):25891-902
references.pmid: 21613214
references.citation: Nature. 2012 Jul 12;487(7406):183-9
references.pmid: 22785313
references.citation: Cell. 1999 Jul 23;98(2):193-205
references.pmid: 10428031
references.citation: J Neurosci. 2005 Feb 9;25(6):1514-22
references.pmid: 15703405
references.citation: Science. 1998 Jun 5;280(5369):1564-9
references.pmid: 9616112
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9950-5
references.pmid: 23671070
references.citation: J Neurosci. 2011 Jun 22;31(25):9075-83
references.pmid: 21697358
references.citation: Nature. 2011 Dec 22;480(7378):552-6
references.pmid: 22170608
references.citation: Transl Psychiatry. 2012;2:e171
references.pmid: 23047242
references.citation: Cell. 2005 Jul 29;122(2):275-87
references.pmid: 16051151
references.citation: Am J Psychiatry. 1971 Jul;128(1):31-40
references.pmid: 4949651
references.citation: Psychopharmacology (Berl). 1989;97(2):277-9
references.pmid: 2567028
references.citation: Front Behav Neurosci. 2013 Oct 24;7:152
references.pmid: 24187535
references.citation: Proc Natl Acad Sci U S A. 2011 May 31;108(22):9262-7
references.pmid: 21518864
references.citation: Science. 1998 Nov 20;282(5393):1490-4
references.pmid: 9822380
references.citation: Neuron. 2002 Nov 14;36(4):727-38
references.pmid: 12441060
references.citation: Biochemistry. 1996 Nov 5;35(44):13871-7
references.pmid: 8909283
references.citation: Mol Cell Neurosci. 1997;10(3-4):460-75
references.pmid: 9532582
references.citation: Nat Neurosci. 2007 Sep;10(9):1116-24
references.pmid: 17726478
references.citation: Pediatr Res. 2011 Sep;70(3):229-35
references.pmid: 21587098
references.citation: Am J Psychiatry. 1988 Sep;145(9):1133-7
references.pmid: 3414857
references.citation: PLoS One. 2010;5(2):e9407
references.pmid: 20195522
references.citation: Ann Med. 2014 May;46(3):148-54
references.pmid: 24405329
references.citation: Nature. 1999 Apr 15;398(6728):627-30
references.pmid: 10217146
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12114-9
references.pmid: 10518585
references.citation: Arch Gen Psychiatry. 1992 Aug;49(8):651-68; discussion 669-70
references.pmid: 1386215
references.citation: Neuron. 2012 Apr 26;74(2):246-60
references.pmid: 22542179
references.citation: Psychopharmacologia. 1968 Sep 20;13(3):222-57
references.pmid: 5679627
references.citation: PLoS One. 2010;5(9):e12632
references.pmid: 20856823
references.citation: Science. 1999 Oct 22;286(5440):768-71
references.pmid: 10531061
references.citation: Nat Neurosci. 2006 Apr;9(4):519-25
references.pmid: 16501568
references.citation: Transl Psychiatry. 2014;4:e363
references.pmid: 24548878
references.citation: PLoS One. 2013;8(8):e71450
references.pmid: 23951166
references.citation: Psychiatry Res. 1989 Jun;28(3):263-78
references.pmid: 2762432
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12662-7
references.pmid: 22778400
references.citation: Biochem J. 2007 Mar 15;402(3):525-36
references.pmid: 17115977
references.citation: Neurosci Biobehav Rev. 1992 Winter;16(4):525-34
references.pmid: 1480349
references.citation: Neuropsychopharmacology. 2004 Jul;29(7):1321-30
references.pmid: 15085085
references.citation: Neuroscience. 2012 Feb 17;203:135-43
references.pmid: 22206943
references.citation: Neuron. 2009 May 28;62(4):479-93
references.pmid: 19477151
references.citation: J Neurosci. 2013 Apr 24;33(17):7145-53
references.pmid: 23616524
references.citation: Nat Med. 2010 Oct;16(10):1152-6
references.pmid: 20852621
references.citation: Hippocampus. 2010 Mar;20(3):377-88
references.pmid: 19437502
references.citation: Ann Med. 2011 Aug;43(5):389-402
references.pmid: 21254899
references.citation: J Pharmacol Exp Ther. 2009 Apr;329(1):377-86
references.pmid: 19164465
references.citation: Int J Neuropsychopharmacol. 2015 Mar;18(5). pii: pyu095. doi: 10.1093/ijnp/pyu095
references.pmid: 25522426
references.citation: Eur Arch Psychiatry Neurol Sci. 1987;237(1):36-45
references.pmid: 3428315
references.citation: Psychoneuroendocrinology. 2006 Nov;31(10):1266-77
references.pmid: 17098367