Abstract
Anxiety is one of the most fundamental emotions required to survive or to cope with potential threatening stimuli. Under certain circumstances, it can change to excessive or maladaptive response and might manifest in anxious personality or even anxiety disorders. Genetic studies provide a number of promising candidate genes that, however, account for only a few percent of the phenotypic variance. Social and material environmental effects such as stressful life events, drugs or chemicals and particular behavioural influences such as parental care are suggested to interact with gene effects presumably involving epigenetic processes. Such interaction probably modifies an individual’s predisposition, personality and susceptibility to develop normal or low anxiety or even maladaptive or excessive anxiety. Since human anxiety involves complex emotions as well as cognitions, unique experiences and an individual genetic make-up, studies trying to clarify the complex and functionally interwoven pathogenesis of anxious personality or anxiety disorders often adopt a reductionistic, simplifying approach. Therein, mice constitute an invaluable tool for modelling human anxiety in its various forms as they display remarkable similarities on anatomical, physiological, biochemical, molecular and behavioural levels. This review aims to fit observations and results obtained from men and mice on behavioural, genetic and environmental levels in response to different threatening stimuli elucidating different genetic and epigenetic effects.
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References
Bandelow B, Alvarez Tichauer G, Späth C et al (2001) Separation anxiety and actual separation experiences during childhood in patients with panic disorder. Can J Psychiatry 46:948–952
Bandelow B, Späth C, Tichauer GA et al (2002) Early traumatic life events, parental attitudes, family history, and birth risk factors in patients with panic disorder. Compr Psychiatry 43:269–278
Battaglia M, Ogliari A (2005) Anxiety and panic: from human studies to animal research and back. Neurosci Biobehav Rev 29:169–179
Belzung C, Griebel G (2001) Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav Brain Res 125:141–149
Benaroya-Milshtein N, Hollander N, Apter A et al (2004) Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity. Eur J Neurosci 20:1341–1347
Blanchard RJ, Blanchard DC (1972) Effects of hippocampal lesions on the rat’s reaction to a cat. J Comp Physiol Psychol 78:77–82
Blanchard DC, Griebel G, Blanchard RJ (2001) Mouse defensive behaviors: pharmacological and behavioral assays for anxiety and panic. Neurosci Biobehav Rev 25:205–218
Blanchard DC, Griebel G, Blanchard RJ (2003) The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic. Eur J Pharmacol 463(1–3):97–116
Borsini F, Podhorna J, Marazziti D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology 163:121–141
Bourin M, Petit-Demoulière B, Dhonnchadha BN et al (2007) Animal models of anxiety in mice. Fundam Clin Pharmacol 21:567–574
Cases O, Seif I, Grimsby J et al (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268:1763–1766
Cattell RB (1950) Personality: a systematic theoretical and factual study. McGraw-Hill, New York
Chen ZY, Jing D, Bath KG et al (2006) Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314:140–143
Chrousos GP (1998) Stressors, stress, neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture. Ann NY Acad Sci 851:311–335
Cloninger CR (1987) A systematic method for clinical description and classification of personality variants. A proposal. Arch Gen Psychiatry 44:573–588
Cloninger CR (1988) A unified biosocial theory of personality and its role in the development of anxiety states: a reply to commentaries. Psychiatr Dev 6:83–120
Cooper JR, Bloom FE, Roth RH (2003) The biochemical basis of neuropharmacology. Oxford University Press, New York
Coutellier L, Friedrich AC, Failing K et al (2008) Effects of foraging demand on maternal behaviour and adult offspring anxiety and stress response in C57BL/6 mice. Behav Brain Res 4 Sep 2008 [Epub ahead of print]
Crawley JN (2008) Behavioral phenotyping strategies for mutant mice. Neuron 57:809–818
Deckert J, Nothen MM, Franke P et al (1998) Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease. Mol Psychiatry 3:81–85
Deckert J, Catalano M, Syagailo YV et al (1999) Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 8:621–624
Depino AM, Gross C (2007) Simultaneous assessment of autonomic function and anxiety-related behavior in BALB/c and C57BL/6 mice. Behav Brain Res 177:254–260
Ditzen C, Jastorff AM, Kessler MS et al (2006) Protein biomarkers in a mouse model of extremes in trait anxiety. Mol Cell Proteomics 5:1914–1920
Domschke K, Freitag CM, Kuhlenbumer G et al (2004) Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. Int J Neuropsychopharmacol 7:183–188
Domschke K, Hohoff C, Jacob C et al (2008) Chromosome 4q31–34 panic disorder risk locus: association of neuropeptide Y Y5 receptor variants. Am J Med Genet B Neuropsychiatr Genet 147:510–516
Donner J, Pirkola S, Silander K et al (2008) An association analysis of murine anxiety genes in humans implicates novel candidate genes for anxiety disorders. Biol Psychiatry 64:672–680
Endler JA (1986) Defense against predators. In: Feder ME, Lauder GV (eds) Predator–prey relationships. University of Chicago Press, Chicago, pp 109–134
Fanselow MS (1994) Neural organization of the defensive behavior system responsible for fear. Psychonomic Bull Rev 1:429–438
Finn CT, Smoller JW (2001) The genetics of panic disorder. Curr Psychiatry Rep 3:131–137
Finn DA, Rutledge-Gorman MT, Crabbe JC (2003) Genetic animal models of anxiety. Neurogenetics 4:109–135
Flint J (2003a) Analysis of quantitative trait loci that influence animal behavior. J Neurobiol 54:46–77
Flint J (2003b) Animal models of anxiety. In: Plomin R, de Fries JC, Craig IW et al (eds) Behavioral genetics in the postgenomic era. American Psychological Association, Washington, pp 425–442
Flint J, Shifman S (2008) Animal models of psychiatric disease. Curr Opin Genet Dev 18:235–240
Francis D, Diorio J, Liu D et al (1999) Nongenomic transmission across generations of maternal behaviour and stress responses in the rat. Science 286:1155–1158
Francis DD, Szegda K, Campbell G et al (2003) Epigenetic sources of behavioral differences in mice. Nat Neurosci 6:445–446
Freitag CM, Domschke K, Rothe C et al (2006) Interaction of serotonergic and noradrenergic gene variants in panic disorder. Psychiatr Genet 16:59–65
Friske JE, Gammie SC (2005) Environmental enrichment alters plus maze, but not maternal defense performance in mice. Physiol Behav 85:187–194
Fyer AJ, Hamilton SP, Durner M et al (2006) A third-pass genome scan in panic disorder: evidence for multiple susceptibility loci. Biol Psychiatry 60:388–401
Gatt JM, Nemeroff CB, Dobson-Stone C et al (2009) Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry 20 Jan [Epub ahead of print]
Gerlsma C, Emmelkamp PMG, Arrindell WA (1990) Anxiety, depression, and perception of early parenting: a meta-analysis. Clin Psychol Rev 10:251–277
Gluckman PD, Hanson MA (2004) Developmental origins of disease paradigm: a mechanistic and evolutionary perspective. Pediatr Res 56:311–317
Gordon JA, Hen R (2004) Genetic approaches to the study of anxiety. Annu Rev Neurosci 27:193–222
Gray JA (1981) A critique of Eysenck’s theory of personality. In: Eysenck HJ (ed) A model for personality. Springer, Berlin, pp 246–277
Hamilton SP, Slager SL, Heiman GA et al (2002) Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22. Biol Psychiatry 51:591–601
Henderson ND, Turri MG, DeFries JC et al (2004) QTL analysis of multiple behavioral measures of anxiety in mice. Behav Genet 34:267–293
Hettema JM, Neale MC, Kendler KS (2001) A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 158:1568–1578
Hohoff C, Neumann A, Domschke K et al (2008) Association analysis of Rgs7 variants with panic disorder. J Neural Transm 2 Sep 2008 [Epub ahead of print]
Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8:253–262
Keck ME, Kern N, Erhardt A et al (2008) Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder. Am J Med Genet B Neuropsychiatr Genet 147:1196–1204
Kennedy JL, Bradwejn J, Koszycki D et al (1999) Investigation of cholecystokinin system genes in panic disorder. Mol Psychiatry 4:284–285
Kimbrel NA, Cobb AR, Mitchell JT et al (2008) Sensitivity to punishment and low maternal care account for the link between bulimic and social anxiety symptomology. Eat Behav 9:210–217
King SM (1999) Escape-related behaviours in an unstable elevated and exposed environment. I. A new behavioural model of extreme anxiety. Behav Brain Res 98:113–126
Laucht M, Treutlein J, Blomeyer D et al (2009) Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults. Int J Neuropsychopharmacol 20 Jan:1–11 [Epub ahead of print]
Laviola G, Macrì S, Morley-Fletcher S et al (2003) Risk-taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence. Neurosci Biobehav Rev 27:19–31
LeDoux JE (1996) The emotional brain: the mysterious underpinnings of emotional life. Simon and Schuster, New York
Leonardo ED, Hen R (2006) Genetics of affective and anxiety disorders. Annu Rev Psychol 57:14.1–14.21
Leygraf A, Hohoff C, Freitag C et al (2006) RGS 2 gene polymorphisms as modulators of anxiety in humans? J Neural Transm 113:1921–1925
Lindhout IE, Markus MT, Borst SR et al (2009) Childrearing style in families of anxiety-disordered children: between-family and within-family differences. Child Psychiatry Hum Dev 40:197–212
Maier W, Gansicke M, Freyberger HJ et al (2000) Generalized anxiety disorder (ICD–10) in primary care from a cross–cultural perspective: a valid diagnostic entity? Acta Psychiatr Scand 101:29–36
McCrae RR, Costa PT (1990) Personality in adulthood. Guilford, New York
Meyer M, Stiedl O (2003) Self-affine fractal variability of human heartbeat interval dynamics in health and disease. Eur J Appl Physiol 90:305–316
Nieman BJ, Bock NA, Bishop J et al (2005) Magnetic resonance imaging for detection and analysis of mouse phenotypes. NMR Biomed 18:447–468
Nieman BJ, Bishop J, Dazai J et al (2007) MR technology for biological studies in mice. NMR Biomed 20:291–303
Paulus MP (2008) The role of neuroimaging for the diagnosis and treatment of anxiety disorders. Depress Anxiety 25:348–356
Plomin R, Owen MJ, McGuffin P (1994) The genetic basis of complex human behaviors. Science 264:1733–1739
Rothe C, Gutknecht L, Freitag C et al (2004) Association of a functional 1019C>G 5-HT1A receptor gene polymorphism with panic disorder with agoraphobia. Int J Neuropsychopharmacol 7:189–192
Rottman JN, Ni G, Brown M (2007) Echocardiographic evaluation of ventricular function in mice. Echocardiography 24:83–89
Rutter M (2003) Commentary: nature–nurture interplay in emotional disorders. J Child Psychol Psychiatry 44:934–944
Schenberg LC, Bittencourt AS, Murari Sudre¢ EC et al (2001) Modeling panic attacks. Neurosci Biobehav Rev 25:647–659
Shekhar A, McCann UD, Meaney MJ et al (2001) Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders. Psychopharmacology 157:327–339
Singer JB, Hill AE, Nadeau JH et al (2005) Mapping quantitative trait loci for anxiety in chromosome substitution strains of mice. Genetics 169:855–862
Smoller JW, Acierno JS Jr, Rosenbaum JF et al (2001) Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am J Med Genet 105:195–206
Smoller JW, Paulus MP, Fagerness JA et al (2008) Influence of RGS2 on anxiety-related temperament, personality, and brain function. Arch Gen Psychiatry 65:298–308
Stiedl O, Pieneman AW, Youn J et al (2008a) Concomitant assessment of heart rate and behavior in freely moving mice. In: Spink AJ, Ballintijn MR, Bogers ND et al (eds) Proceedings of measuring behaviour, Maastricht, The Netherlands, 26–29 August, 2008
Stiedl O, Jansen RF, Pieneman AW et al (2008b) Assessing aversive emotional states through the heart in mice: Implications for cardiovascular dysregulation in affective disorders. Neurosci Biobehav Rev. 2008 Sep 7. [Epub ahead of print]
Turri MG, DeFries JC, Henderson ND et al (2004) Multivariate analysis of quantitative trait loci influencing variation in anxiety-related behavior in laboratory mice. Mamm Genome 15:69–76
van den Heuvel OA, van de Wetering BJ, Veltman DJ et al (2000) Genetic studies of panic disorder: a review. J Clin Psychiatry 61:756–766
Van West D, Claes S (2004) The genetics of panic disorder: state of the art. Acta Neuropsychiatrica 16:68–78
Vianna DML, Landeira-Fernandez J, Brandão ML (2001) Dorsolateral and ventral regions of the periaqueductal gray matter are involved in distinct types of fear. Neurosci Biobehav Rev 25:711–719
Wang W, Du W, Liu P et al (2002) Five-factor personality measures in Chinese university students: effects of one-child policy? Psychiatry Res 109:37–44
Weaver IC (2007) Epigenetic programming by maternal behavior and pharmacological intervention. Nature versus nurture: let’s call the whole thing off. Epigenetics 2:22–28
Weaver IC, Cervoni N, Champagne FA et al (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854
Weaver IC, Meaney MJ, Szyf M (2006) Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc Natl Acad Sci USA 103:3480–3485
Yalcin B, Willis-Owen SAG, Fullerton J et al (2004) Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nat Genet 36:1197–1202
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Hohoff, C. Anxiety in mice and men: a comparison. J Neural Transm 116, 679–687 (2009). https://doi.org/10.1007/s00702-009-0215-z
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DOI: https://doi.org/10.1007/s00702-009-0215-z