Korean J Schizophr Res.  2014 Apr;17(1):12-26. 10.16946/kjsr.2014.17.1.12.

Use of Behavioral Analysis in Animal Models for Schizophrenia Research

• Woo Y
• Lee S
• Jeong J
• Park SK

• KMID: 2288295
• DOI: http://doi.org/10.16946/kjsr.2014.17.1.12

Abstract

Animal models are useful tools to study the molecular basis of schizophrenia pathophysiology and efficacy of potential therapeutic agents. Schizophrenia animal models can be subdivided into three classes ; drug-induced models, genetic models, and environmental models and each model is designed based on specific traits corresponding to the characteristic symptoms of human schizophrenia patients. Psychomotor agitation and sensitivity to psychotomimetic drugs are often thought to reflect positive symptoms. Social interaction deficits and affective impairments are known to correspond to negative symptoms. Also, cognitive symptoms have been linked to the working memory impairments, attention deficits and related cognitive deficits in animals. To analyze such components in quantifiable manners, various behavioral paradigms have been developed and utilized. Here, we overview these animal models, focusing on underlying rationales for their use in the context of schizophrenia research.

Keyword

Schizophrenia; Animal models; Animal behaviors; Behavioral tests

MeSH Terms

Animals
Behavior, Animal
Humans
Interpersonal Relations
Memory, Short-Term
Models, Animal*
Models, Genetic
Neurobehavioral Manifestations
Psychomotor Agitation
Schizophrenia*

Reference

References

1. Tamminga CA. The neurobiology of cognition in schizophrenia. J Clin Psychiatry. 2006; 67(Suppl 9):9–13. ; discussion 36–42.

2. Lipska BK and Weinberger DR. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology. 2000; 23:223–239.

3. Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001; 25:455–467.

4. Tamminga CA, Holcomb HH. Phenotype of schizophrenia: a review and formulation. Mol Psychiatry. 2005; 10:27–39.

5. Carpenter WT Jr, Heinrichs DW, Wagman AM. Deficit and non-deficit forms of schizophrenia: the concept. Am J Psychiatry. 1988; 145:578–583.

6. Planansky K, Johnston R. Depressive syndrome in schizophrenia. Acta Psychiatr Scand. 1978; 57:207–218.

7. Goodwin RD, Amador XF, Malaspina D, Yale SA, Goetz RR, Gorman JM. Anxiety and substance use comorbidity among inpatients with schizophrenia. Schizophr Res. 2003; 61:89–95.

8. Chapman J. The early symptoms of schizophrenia. Br J Psychiatry. 1966; 112:225–251.

9. Kuroda K, Yamada S, Tanaka M, Iizuka M, Yano H, Mori D, et al. Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet. 2011; 20:4666–4683.

10. Elvevag B, Goldberg TE. Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol. 2000; 14:1–21.

11. Hoff AL, Svetina C, Maurizio AM, Crow TJ, Spokes K, DeLisi LE. Familial cognitive deficits in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2005; 133B:43–49.

12. Ranganath C, Minzenberg MJ, Ragland JD. The cognitive neuroscience of memory function and dysfunction in schizophrenia. Biol Psychiatry. 2008; 64:18–25.

13. Henry JD, Crawford JR. A meta-analytic review of verbal fluency deficits in schizophrenia relative to other neurocognitive deficits. Cogn Neuropsychiatry. 2005; 10:1–33.

14. Barch DM, Smith E. The cognitive neuroscience of working memory: relevance to CNTRICS and schizophrenia. Biol Psychiatry. 2008; 64:11–17.

15. Saykin AJ, Gur RC, Gur RE, Mozley PD, Mozley LH, Resnick SM, et al. Neuropsychological function in schizophrenia. Selective impairment in memory and learning. Arch Gen Psychiatry. 1991; 48:618–624.

16. Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 1998; 281:1349–1352.

17. Lubow RE. Construct validity of the animal latent inhibition model of selective attention deficits in schizophrenia. Schizophr Bull. 2005; 31:139–153.

18. Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, et al. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci U S A. 2003; 100:8987–8992.

19. Braff DL, Geyer MA. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry. 1990; 47:181–188.

20. Lodge DJ, Grace AA. Gestational methylazoxymethanol acetate administration: a developmental disruption model of schizophrenia. Behav Brain Res. 2009; 204:306–312.

21. Hradetzky E, Sanderson TM, Tsang TM, Sherwood JL, Fitzjohn SM, Lakics V, et al. The methylazoxymethanol acetate (MAM-E17) rat model: molecular and functional effects in the hippocampus. Neuropsychopharmacology. 2012; 37:364–377.

22. Jones CA, Watson DJ, Fone KC. Animal models of schizophrenia. Br J Pharmacol. 2011; 164:1162–1194.

23. Kapur S, Seeman P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D and serotonin 5-HT-receptors-implications for models of schizophrenia. Mol Psychiatry. 2002; 7:837–844.

24. Egerton A, Reid L, McKerchar CE, Morris BJ, Pratt JA. Impairment in perceptual attentional set-shifting following PCP administration: a rodent model of set-shifting deficits in schizophrenia. Psychopharmacology (Berl). 2005; 179:77–84.

25. Sams-Dodd F. Distinct effects of d-amphetamine and phencyclidine on the social behaviour of rats. Behav Pharmacol. 1995; 6:55–65.

26. Kalinichev M, Robbins MJ, Hartfield EM, Maycox PR, Moore SH, Savage KM, et al. Comparison between intraperitoneal and subcutaneous phencyclidine administration in Sprague-Dawley rats: a locomotor activity and gene induction study. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32:414–422.

27. Mansbach RS, Geyer MA. Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology. 1989; 2:299–308.

28. Sams-Dodd F. A test of the predictive validity of animal models of schizophrenia based on phencyclidine and D-amphetamine. Neuropsychopharmacology. 1998; 18:293–304.

29. Phillips M, Wang C, Johnson KM. Pharmacological characterization of locomotor sensitization induced by chronic phencyclidine administration. J Pharmacol Exp Ther. 2001; 296:905–913.

30. Berman S, O'Neill J, Fears S, Bartzokis G, London ED. Abuse of amphetamines and structural abnormalities in the brain. Ann N Y Acad Sci. 2008; 1141:195–220.

31. Fletcher PJ, Tenn CC, Sinyard J, Rizos Z, Kapur S. A sensitizing regimen of amphetamine impairs visual attention in the 5-choice serial reaction time test: reversal by a D1 receptor agonist injected into the medial prefrontal cortex. Neuropsychopharmacology. 2007; 32:1122–1132.

32. Featherstone RE, Rizos Z, Kapur S, Fletcher PJ. A sensitizing regimen of amphetamine that disrupts attentional set-shifting does not disrupt working or longterm memory. Behav Brain Res. 2008; 189:170–179.

33. Peleg-Raibstein D, Sydekum E, Russig H, Feldon J. Withdrawal from repeated amphetamine administration leads to disruption of prepulse inhibition but not to disruption of latent inhibition. J Neural Transm. 2006; 113:1323–1336.

34. Fletcher PJ, Tenn CC, Rizos Z, Lovic V, Kapur S. Sensitization to amphetamine, but not PCP, impairs attentional set shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex. Psychopharmacology (Berl). 2005; 183:190–200.

35. Tenn CC, Kapur S, Fletcher PJ. Sensitization to amphetamine, but not phencyclidine, disrupts prepulse inhibition and latent inhibition. Psychopharmacology (Berl). 2005; 180:366–376.

36. Ayhan Y, Sawa A, Ross CA, Pletnikov MV. Animal models of gene-environment interactions in schizophrenia. Behav Brain Res. 2009; 204:274–281.

37. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005; 10:40–68. ; image 45.

38. Gogos JA, Gerber DJ. Schizophrenia susceptibility genes: emergence of positional candidates and future directions. Trends Pharmacol Sci. 2006; 27:226–233.

39. International Schizophrenia C. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature. 2008; 455:237–241.

40. Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S, et al. Large recurrent microdeletions associated with schizophrenia. Nature. 2008; 455:232–236.

41. Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008; 320:539–543.

42. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000; 9:1415–1423.

43. Jaaro-Peled H. Gene models of schizophrenia: DISC1 mouse models. Prog Brain Res. 2009; 179:75–86.

44. Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, et al. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A. 2007; 104:14501–14506.

45. Shen S, Lang B, Nakamoto C, Zhang F, Pu J, Kuan SL, et al. Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1. J Neurosci. 2008; 28:10893–10904.

46. Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, et al. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron. 2007; 54:387–402.

47. Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, et al. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2008; 13:173–186. 115.

48. Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, Ehninger D, et al. Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A. 2007; 104:18280–18285.

49. Desbonnet L, Waddington JL, O'Tuathaigh CM. Mutant models for genes associated with schizophrenia. Biochem Soc Trans. 2009; 37(Pt 1):308–312.

50. Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R, et al. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5'SNPs associated with the disease. Proc Natl Acad Sci U S A. 2006; 103:6747–6752.

51. Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008; 9:437–452.

52. Gerlai R, Pisacane P, Erickson S. Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity in multiple behavioral tasks. Behav Brain Res. 2000; 109:219–227.

53. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. Common variants conferring risk of schizophrenia. Nature. 2009; 460:744–747.

54. Harrison PJ, Law AJ. Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry. 2006; 60:132–140.

55. Talbot K. The sandy (sdy) mouse: a dysbindin-1 mutant relevant to schizophrenia research. Prog Brain Res. 2009; 179:87–94.

56. Schwab SG, Knapp M, Mondabon S, Hallmayer J, Borrmann-Hassenbach M, Albus M, et al. Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. Am J Hum Genet. 2003; 72:185–190.

57. Morris DW, Murphy K, Kenny N, Purcell SM, McGhee KA, Schwaiger S, et al. Dysbindin (DTNBP1) and the biogenesis of lysosome-related organelles complex 1 (BLOC-1): main and epistatic gene effects are potential contributors to schizophrenia susceptibility. Biol Psychiatry. 2008; 63:2431.

58. Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV, et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet. 2002; 71:337–348.

59. Talbot K, Eidem WL, Tinsley CL, Benson MA, Thompson EW, Smith RJ, et al. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest. 2004; 113:1353–1363.

60. Tang J, LeGros RP, Louneva N, Yeh L, Cohen JW, Hahn CG, et al. Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbin-din-1 mRNA expression. Hum Mol Genet. 2009; 18:3851–3863.

61. Weickert CS, Straub RE, McClintock BW, Matsumoto M, Hashimoto R, Hyde TM, et al. Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry. 2004; 61:544–555.

62. Weickert CS, Rothmond DA, Hyde TM, Kleinman JE, Straub RE. Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophr Res. 2008; 98:105–110.

63. Iizuka Y, Sei Y, Weinberger DR, Straub RE. Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. J Neurosci. 2007; 27:12390–12395.

64. Ji Y, Yang F, Papaleo F, Wang HX, Gao WJ, Weinberger DR, et al. Role of dysbindin in dopamine receptor trafficking and cortical GABA function. Proc Natl Acad Sci U S A. 2009; 106:19593–19598.

65. Dickman DK, Davis GW. The schizophrenia susceptibility gene dysbindin controls synaptic homeostasis. Science. 2009; 326:1127–1130.

66. Jenzsch A, Eick S, Rassoul F, Purschwitz R, Jentsch H. Nutritional intervention in patients with periodontal disease: clinical, immunological and microbiological variables during 12 months. Br J Nutr. 2009; 101:879–885.

67. Papaleo E, Russo L, Shaikh N, Cipolla L, Fantucci P, De Gioia L. Molecular dynamics investigation of cyclic natriuretic peptides: dynamic properties reflect peptide activity. J Mol Graph Model. 2010; 28:834–841.

68. Karlsgodt KH, Robleto K, Trantham-Davidson H, Jairl C, Cannon TD, Lavin A, et al. Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance. Biol Psychiatry. 2011; 69:28–34.

69. Papaleo F, Yang F, Garcia S, Chen J, Lu B, Crawley JN, et al. Dys-bindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry. 2012; 17:85–98.

70. Cassidy AW, Mulvany SK, Pangalos MN, Murphy KJ. Regan CM, Developmental emergence of reelin deficits in the prefrontal cortex of Wistar rats reared in social isolation. Neuroscience. 2010; 166:377–385.

71. Liu Y, Chen PL, McGrath J, Wolyniec P, Fallin D, Nestadt G, et al. Replication of an association of a common variant in the Reelin gene (RELN) with schizophrenia in Ashkenazi Jewish women. Psychiatr Genet. 2010; 20:184–186.

72. Wedenoja J, Tuulio-Henriksson A, Suvisaari J, Loukola A, Paunio T, Partonen T, et al. Replication of association between working memory and Reelin, a potential modifier gene in schizophrenia. Biol Psychiatry. 2010; 67:983–991.

73. Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, et al. Decrease in reelin and glutamic acid decarbox-ylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry. 2000; 57:1061–1069.

74. Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U S A. 1998; 95:15718–15723.

75. Bellon A, Le Pen G, Matricon J, Jay TM, Krebs MO. Potential application as screening and drug designing tools of cytoarchitectural deficiencies present in three animal models of schizophrenia. Expert Opin Drug Discov. 2009; 4:257–278.

76. O'Tuathaigh CM, Kirby BP, Moran PM, Waddington JL. Mutant mouse models: genotype-phenotype relationships to negative symptoms in schizophrenia. Schizophr Bull. 2010; 36:271–288.

77. Tueting P, Doueiri MS, Guidotti A, Davis JM, Costa E. Reelin down-regulation in mice and psychosis endophenotypes. Neurosci Biobehav Rev. 2006; 30:1065–1077.

78. Krueger DD, Howell JL, Hebert BF, Olausson P, Taylor JR, Nairn AC. Assessment of cognitive function in the heterozygous reeler mouse. Psychopharmacology (Berl). 2006; 189:95–104.

79. Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, et al. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol. 2002; 22:25–33.

80. Fatemi SH, Reutiman TJ, Folsom TD, Huang H, Oishi K, Mori S, et al. Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders. Schizophr Res. 2008; 99:56–70.

81. Vyas A, Kim SK, Giacomini N, Boothroyd JC, Sapolsky RM. Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors. Proc Natl Acad Sci U S A. 2007; 104:6442–6447.

82. Nyffeler M, Meyer U, Yee BK, Feldon J, Knuesel I. Maternal immune activation during pregnancy increases limbic GABAA receptor immunoreactivity in the adult offspring: implications for schizophrenia. Neuroscience. 2006; 143:51–62.

83. Makinodan M, Tatsumi K, Manabe T, Yamauchi T, Makinodan E, Matsuyoshi H, et al. Maternal immune activation in mice delays myelination and axonal development in the hippocampus of the offspring. J Neurosci Res. 2008; 86:2190–2200.

84. Baharnoori M, Brake WG, Srivastava LK. Prenatal immune challenge induces developmental changes in the morphology of pyramidal neurons of the prefrontal cortex and hippocampus in rats. Schizophr Res. 2009; 107:99–109.

85. Miyazaki S, Ishikawa F, Fujikawa T, Nagata S, Yamaguchi K. Intraperitoneal injection of lipopolysaccharide induces dynamic migration of Gr-1high polymorphonuclear neutrophils in the murine abdominal cavity. Clin Diagn Lab Immunol. 2004; 11:452–457.

86. Nogai A, Siffrin V, Bonhagen K, Pfueller CF, Hohnstein T, Volk-mer-Engert R, et al. Lipopolysaccharide injection induces relapses of experimental autoimmune encephalomyelitis in nontrans-genic mice via bystander activation of autoreactive CD4+ cells. J Immunol. 2005; 175:959–966.

87. Meyer U, Feldon J. To poly (I:C) or not to poly (I:C): advancing preclinical schizophrenia research through the use of prenatal immune activation models. Neuropharmacology. 2012; 62:1308–1321.

88. Silva-Gomez AB, Rojas D, Juarez I, Flores G. Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats. Brain Res. 2003; 983:128–136.

89. Day-Wilson KM, Jones DN, Southam E, Cilia J, Totterdell S.Medial prefrontal cortex volume loss in rats with isolation rearing-induced deficits in prepulse inhibition of acoustic startle. Neuroscience. 2006; 141:1113–1121.

90. Fone KC, Porkess MV. Behavioural and neurochemical effects of postweaning social isolation in rodents-relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev. 2008; 32:1087–1102.

91. Niwa M, Matsumoto Y, Mouri A, Ozaki N, Nabeshima T. Vulnerability in early life to changes in the rearing environment plays a crucial role in the aetiopathology of psychiatric disorders. Int J Neuropsychopharmacol. 2011; 14:459–477.

92. Pascual R, Zamora-Leon SP, Valero-Cabre A. Effects of postweaning social isolation and re-socialization on the expression of vasoactive intestinal peptide (VIP) and dendritic development in the medial prefrontal cortex of the rat. Acta Neurobiol Exp (Wars). 2006.

93. Marsden CA, King MV, Fone KC. Influence of social isolation in the rat on serotonergic function and memory–relevance to models of schizophrenia and the role of 5-HT receptors. Neuropharmacology. 2011; 61:400–407.

94. McLean S, Grayson B, Harris M, Protheroe C, Woolley M, Neill J. Isolation rearing impairs novel object recognition and attentional set shifting performance in female rats. J Psychopharmacol. 2010; 24:57–63.

95. King MV, Seeman P, Marsden CA, Fone KC. Increased dopamine D2High receptors in rats reared in social isolation. Synapse. 2009; 63:476–483.

96. Bianchi M, Fone KF, Azmi N, Heidbreder CA, Hagan JJ, Marsden CA. Isolation rearing induces recognition memory deficits accompanied by cytoskeletal alterations in rat hippocampus. Eur J Neurosci. 2006; 24:2894–2902.

97. Schubert MI, Porkess MV, Dashdorj N, Fone KC, Auer DP. Effects of social isolation rearing on the limbic brain: a combined behavioral and magnetic resonance imaging volumetry study in rats. Neuroscience. 2009; 159:21–30.

98. Cash-Padgett T. Jaaro-Peled H, DISC1 mouse models as a tool to decipher gene-environment interactions in psychiatric disorders. Front Behav Neurosci. 2013; 7:113.

99. Kudryavtseva NN, Bakshtanovskaya IV, Koryakina LA. Social model of depression in mice of C57BL/6J strain. Pharmacol Biochem Behav. 1991; 38:315–320.

100. Venzala E, Garcia-Garcia AL, Elizalde N, Delagrange P, Tordera RM. Chronic social defeat stress model: behavioral features, antidepressant action, and interaction with biological risk factors. Psychopharmacology (Berl). 2012; 224:313–325.

101. Kannan G, Sawa A, Pletnikov MV. Mouse models of gene-environment interactions in schizophrenia. Neurobiol Dis. 2013; 57:5–11.

102. Niwa M, Jaaro-Peled H, Tankou S, Seshadri S, Hikida T, Matsumoto Y, et al. Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids. Science. 2013; 339:335–339.

103. Caspi A, Moffitt TE. Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci. 2006; 7:583–590.

104. Rutter M, Moffitt TE, Caspi A. Gene-environment interplay and psychopathology: multiple varieties but real effects. J Child Psychol Psychiatry. 2006; 47:226–261.

105. Rutter M. Biological implications of gene-environment interaction. J Abnorm Child Psychol. 2008; 36:969–975.

106. Denenberg VH. Open-field bheavior in the rat: what does it mean? Ann N Y Acad Sci. 1969; 159:852–859.

107. File SE, Hyde JR. Can social interaction be used to measure anxiety? Br J Pharmacol. 1978; 62:19–24.

108. Sams-Dodd F. Automation of the social interaction test by a video-tracking system: behavioural effects of repeated phencyclidine treatment. J Neurosci Methods. 1995; 59:157–167.

109. Nadler JJ, Moy SS, Dold G, Trang D, Simmons N, Perez A, et al. Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav. 2004; 3:303–314.

110. Braff DL, Geyer MA, Swerdlow NR. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl). 2001; 156:234–258.

111. Swerdlow NR, Weber M, Qu Y, Light GA, Braff DL. Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology (Berl). 2008; 199:331–388.

112. Kim JJ, Fanselow MS. Modality-specific retrograde amnesia of fear. Science. 1992; 256:675–677.

113. Fanselow MS, Poulos AM. The neuroscience of mammalian associative learning. Annu Rev Psychol. 2005; 56:207–234.

114. Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984; 11:47–60.

115. D'Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 2001; 36:60–90.

116. Freeman JH Jr, Stanton ME. Fimbria-fornix transections disrupt the ontogeny of delayed alternation but not position discrimination in the rat. Behav Neurosci. 1991; 105:386–395.

117. Robbins TW. The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology (Berl). 2002; 163:362–380.

118. Bari A, Dalley JW, Robbins TW. The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats. Nat Protoc. 2008; 3:759–767.

119. Monchi O, Petrides M, Petre V, Worsley K, Dagher A. Wisconsin Card Sorting revisited: distinct neural circuits participating in different stages of the task identified by event-related functional magnetic resonance imaging. J Neurosci. 2001; 21:7733–7741.

120. Birrell JM, Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci. 2000; 20:4320–4324.

121. Colacicco G, Welzl H, Lipp HP, Wurbel H. Attentional set-shifting in mice: modification of a rat paradigm, and evidence for strain-dependent variation. Behav Brain Res. 2002; 132:95–102.

122. Swerdlow NR, Geyer MA, Braff DL. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl). 2001; 156:194–215.