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New Frontiers in Animal Research of Psychiatric Illness

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Psychiatric Disorders

Part of the book series: Methods in Molecular Biology ((MIMB,volume 829))

Abstract

Alterations in neurodevelopment are thought to modify risk of numerous psychiatric disorders, including schizophrenia, autism, ADHD, mood and anxiety disorders, and substance abuse. However, little is known about the cellular and molecular changes that guide these neurodevelopmental changes and how they contribute to mental illness. In this review, we suggest that elucidating this process in humans requires the use of model organisms. Furthermore, we advocate that such translational work should focus on the role that genes and/or environmental factors play in the development of circuits that regulate specific physiological and behavioral outcomes in adulthood. This emphasis on circuit development, as a fundamental unit for understanding behavior, is distinct from current approaches of modeling psychiatric illnesses in animals in two important ways. First, it proposes to replace the diagnostic and statistical manual of mental disorders (DSM) diagnostic system with measurable endophenotypes as the basis for modeling human psychopathology in animals. We argue that a major difficulty in establishing valid animal models lies in their reliance on the DSM/International Classification of Diseases conceptual framework, and suggest that the Research Domain Criteria project, recently proposed by the NIMH, provides a more suitable system to model human psychopathology in animals. Second, this proposal emphasizes the developmental origin of many (though clearly not all) psychiatric illnesses, an issue that is often glossed over in current animal models of mental illness. We suggest that animal models are essential to elucidate the mechanisms by which neurodevelopmental changes program complex behavior in adulthood. A better understanding of this issue, in animals, is the key for defining human psychopathology, and the development of earlier and more effective interventions for mental illness.

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-1-61779-458-2_38

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-1-61779-458-2_38

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References

  1. Willner, P. (1984) The validity of animal models of depression, Psychopharmacology (Berl) 83, 1–16.

    Article  CAS  Google Scholar 

  2. Kellendonk, C., Simpson, E. H., and Kandel, E. R. (2009) Modeling cognitive endophenotypes of schizophrenia in mice, Trends Neurosci 32, 347–358.

    Article  PubMed  CAS  Google Scholar 

  3. Chadman, K. K., Yang, M., and Crawley, J. N. (2009) Criteria for validating mouse models of psychiatric diseases, Am J Med Genet B Neuropsychiatr Genet 150B, 1–11.

    Article  PubMed  Google Scholar 

  4. Nestler, E. J., and Hyman, S. E. Animal models of neuropsychiatric disorders, Nat Neurosci 13, 1161–1169.

    Google Scholar 

  5. Hikida, T., Jaaro-Peled, H., Seshadri, S., Oishi, K., Hookway, C., Kong, S., Wu, D., Xue, R., Andrade, M., Tankou, S., Mori, S., Gallagher, M., Ishizuka, K., Pletnikov, M., Kida, S., and Sawa, A. (2007) Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans, Proc Natl Acad Sci USA 104, 14501–14506.

    Article  PubMed  CAS  Google Scholar 

  6. Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., Belzung, C., and Hen, R. (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants, Science 301, 805–809.

    Article  PubMed  CAS  Google Scholar 

  7. Shahbazian, M., Young, J., Yuva-Paylor, L., Spencer, C., Antalffy, B., Noebels, J., Armstrong, D., Paylor, R., and Zoghbi, H. (2002) Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3, Neuron 35, 243–254.

    Article  PubMed  CAS  Google Scholar 

  8. Reboldi, A., Coisne, C., Baumjohann, D., Benvenuto, F., Bottinelli, D., Lira, S., Uccelli, A., Lanzavecchia, A., Engelhardt, B., and Sallusto, F. (2009) C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE, Nat Immunol 10, 514–523.

    Article  PubMed  CAS  Google Scholar 

  9. Berry-Kravis, E., Hessl, D., Coffey, S., Hervey, C., Schneider, A., Yuhas, J., Hutchison, J., Snape, M., Tranfaglia, M., Nguyen, D. V., and Hagerman, R. (2009) A pilot open label, single dose trial of fenobam in adults with fragile X syndrome, J Med Genet 46, 266–271.

    Article  PubMed  CAS  Google Scholar 

  10. Sanacora, G., Zarate, C. A., Krystal, J. H., and Manji, H. K. (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders, Nat Rev Drug Discov 7, 426–437.

    Article  PubMed  CAS  Google Scholar 

  11. Grillon, C. (2009) D-cycloserine facilitation of fear extinction and exposure-based therapy might rely on lower-level, automatic mechanisms, Biol Psychiatry 66, 636–641.

    Article  PubMed  CAS  Google Scholar 

  12. State, M. W. (2010) Another piece of the autism puzzle, Nat Genet 42, 478–479.

    Google Scholar 

  13. Sebat, J., Levy, D. L., and McCarthy, S. E. (2009) Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders, Trends Genet 25, 528–535.

    Article  PubMed  CAS  Google Scholar 

  14. Lai, C. S., Fisher, S. E., Hurst, J. A., Vargha-Khadem, F., and Monaco, A. P. (2001) A forkhead-domain gene is mutated in a severe speech and language disorder, Nature 413, 519–523.

    Article  PubMed  CAS  Google Scholar 

  15. Hurst, J. A., Baraitser, M., Auger, E., Graham, F., and Norell, S. (1990) An extended family with a dominantly inherited speech disorder, Dev Med Child Neurol 32, 352–355.

    Article  PubMed  CAS  Google Scholar 

  16. Enard, W., Gehre, S., Hammerschmidt, K., Holter, S. M., Blass, T., Somel, M., Bruckner, M. K., Schreiweis, C., Winter, C., Sohr, R., Becker, L., Wiebe, V., Nickel, B., Giger, T., Muller, U., Groszer, M., Adler, T., Aguilar, A., Bolle, I., Calzada-Wack, J., Dalke, C., Ehrhardt, N., Favor, J., Fuchs, H., Gailus-Durner, V., Hans, W., Holzlwimmer, G., Javaheri, A., Kalaydjiev, S., Kallnik, M., Kling, E., Kunder, S., Mossbrugger, I., Naton, B., Racz, I., Rathkolb, B., Rozman, J., Schrewe, A., Busch, D. H., Graw, J., Ivandic, B., Klingenspor, M., Klopstock, T., Ollert, M., Quintanilla-Martinez, L., Schulz, H., Wolf, E., Wurst, W., Zimmer, A., Fisher, S. E., Morgenstern, R., Arendt, T., de Angelis, M. H., Fischer, J., Schwarz, J., and Paabo, S. (2009) A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice, Cell 137, 961–971.

    Article  PubMed  CAS  Google Scholar 

  17. Hyman, S. E. The diagnosis of mental disorders: the problem of reification, Annu Rev Clin Psychol 6, 155–179.

    Google Scholar 

  18. Helzer, J. E., Clayton, P. J., Pambakian, R., Reich, T., Woodruff, R. A., Jr., and Reveley, M. A. (1977) Reliability of psychiatric diagnosis. II. The test/retest reliability of diagnostic classification, Arch Gen Psychiatry 34, 136–141.

    Article  PubMed  CAS  Google Scholar 

  19. Helzer, J. E., Robins, L. N., Taibleson, M., Woodruff, R. A., Jr., Reich, T., and Wish, E. D. (1977) Reliability of psychiatric diagnosis. I. A methodological review, Arch Gen Psychiatry 34, 129–133.

    Article  PubMed  CAS  Google Scholar 

  20. Feighner, J. P., Robins, E., Guze, S. B., Woodruff, R. A., Jr., Winokur, G., and Munoz, R. (1972) Diagnostic criteria for use in psychiatric research, Arch Gen Psychiatry 26, 57–63.

    Article  PubMed  CAS  Google Scholar 

  21. Pies, R. (2007) How “objective” are psychiatric diagnoses?: (guess again), Psychiatry (Edgmont) 4, 18–22.

    Google Scholar 

  22. Widiger, T. A., and Clark, L. A. (2000) Toward DSM-V and the classification of psychopathology, Psychol Bull 126, 946–963.

    Article  PubMed  CAS  Google Scholar 

  23. Thompson, B. L., and Levitt, P. (2010) The clinical-basic interface in defining pathogenesis in disorders of neurodevelopmental origin, Neuron 67, 702–712.

    Google Scholar 

  24. Green, J. G., McLaughlin, K. A., Berglund, P. A., Gruber, M. J., Sampson, N. A., Zaslavsky, A. M., and Kessler, R. C. Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders, Arch Gen Psychiatry 67, 113–123.

    Google Scholar 

  25. Muenzenmaier, K., Meyer, I., Struening, E., and Ferber, J. (1993) Childhood abuse and neglect among women outpatients with chronic mental illness, Hosp Community Psychiatry 44, 666–670.

    PubMed  CAS  Google Scholar 

  26. Bryer, J. B., Nelson, B. A., Miller, J. B., and Krol, P. A. (1987) Childhood sexual and physical abuse as factors in adult psychiatric illness, Am J Psychiatry 144, 1426–1430.

    PubMed  CAS  Google Scholar 

  27. Olds, D., Henderson, C. R., Jr., Cole, R., Eckenrode, J., Kitzman, H., Luckey, D., Pettitt, L., Sidora, K., Morris, P., and Powers, J. (1998) Long-term effects of nurse home visitation on children’s criminal and antisocial behavior: 15-year follow-up of a randomized controlled trial, Jama 280, 1238–1244.

    Article  PubMed  CAS  Google Scholar 

  28. Olds, D. L., Kitzman, H., Cole, R., Robinson, J., Sidora, K., Luckey, D. W., Henderson, C. R., Jr., Hanks, C., Bondy, J., and Holmberg, J. (2004) Effects of nurse home-visiting on maternal life course and child development: age 6 follow-up results of a randomized trial, Pediatrics 114, 1550–1559.

    Article  PubMed  Google Scholar 

  29. Olds, D. L., Robinson, J., Pettitt, L., Luckey, D. W., Holmberg, J., Ng, R. K., Isacks, K., Sheff, K., and Henderson, C. R., Jr. (2004) Effects of home visits by paraprofessionals and by nurses: age 4 follow-up results of a randomized trial, Pediatrics 114, 1560–1568.

    Article  PubMed  Google Scholar 

  30. Kaffman, A. (2009) The silent epidemic of neurodevelopmental injuries, Biol Psychiatry 66, 624–626.

    Article  PubMed  Google Scholar 

  31. Kaffman, A., and Meaney, M. J. (2007) Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights, J Child Psychol Psychiatry 48, 224–244.

    Article  PubMed  Google Scholar 

  32. Schurov, I. L., Handford, E. J., Brandon, N. J., and Whiting, P. J. (2004) Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment, Mol Psychiatry 9, 1100–1110.

    Article  PubMed  CAS  Google Scholar 

  33. Duan, X., Chang, J. H., Ge, S., Faulkner, R. L., Kim, J. Y., Kitabatake, Y., Liu, X. B., Yang, C. H., Jordan, J. D., Ma, D. K., Liu, C. Y., Ganesan, S., Cheng, H. J., Ming, G. L., Lu, B., and Song, H. (2007) Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain, Cell 130, 1146–1158.

    Article  PubMed  CAS  Google Scholar 

  34. Mao, Y., Ge, X., Frank, C. L., Madison, J. M., Koehler, A. N., Doud, M. K., Tassa, C., Berry, E. M., Soda, T., Singh, K. K., Biechele, T., Petryshen, T. L., Moon, R. T., Haggarty, S. J., and Tsai, L. H. (2009) Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling, Cell 136, 1017–1031.

    Article  PubMed  CAS  Google Scholar 

  35. Berkel, S., Marshall, C. R., Weiss, B., Howe, J., Roeth, R., Moog, U., Endris, V., Roberts, W., Szatmari, P., Pinto, D., Bonin, M., Riess, A., Engels, H., Sprengel, R., Scherer, S. W., and Rappold, G. A. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation, Nat Genet 42, 489–491.

    Google Scholar 

  36. Jamain, S., Quach, H., Betancur, C., Rastam, M., Colineaux, C., Gillberg, I. C., Soderstrom, H., Giros, B., Leboyer, M., Gillberg, C., and Bourgeron, T. (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism, Nat Genet 34, 27–29.

    Article  PubMed  CAS  Google Scholar 

  37. Laumonnier, F., Bonnet-Brilhault, F., Gomot, M., Blanc, R., David, A., Moizard, M. P., Raynaud, M., Ronce, N., Lemonnier, E., Calvas, P., Laudier, B., Chelly, J., Fryns, J. P., Ropers, H. H., Hamel, B. C., Andres, C., Barthelemy, C., Moraine, C., and Briault, S. (2004) X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family, Am J Hum Genet 74, 552–557.

    Article  PubMed  CAS  Google Scholar 

  38. Correll, C. U., Hauser, M., Auther, A. M., and Cornblatt, B. A. (2010) Research in people with psychosis risk syndrome: a review of the current evidence and future directions, J Child Psychol Psychiatry 51, 390–431.

    Google Scholar 

  39. Gotlib, I. H., Hamilton, J. P., Cooney, R. E., Singh, M. K., Henry, M. L., and Joormann, J. Neural processing of reward and loss in girls at risk for major depression, Arch Gen Psychiatry 67, 380–387.

    Google Scholar 

  40. Pantelis, C., Velakoulis, D., Wood, S. J., Yucel, M., Yung, A. R., Phillips, L. J., Sun, D. Q., and McGorry, P. D. (2007) Neuroimaging and emerging psychotic disorders: the Melbourne ultra-high risk studies, Int Rev Psychiatry 19, 371–381.

    Article  PubMed  CAS  Google Scholar 

  41. Yung, A. R., Phillips, L. J., McGorry, P. D., McFarlane, C. A., Francey, S., Harrigan, S., Patton, G. C., and Jackson, H. J. (1998) Prediction of psychosis. A step towards indicated prevention of schizophrenia, Br J Psychiatry Suppl 172, 14–20.

    CAS  Google Scholar 

  42. Walterfang, M., Yung, A., Wood, A. G., Reutens, D. C., Phillips, L., Wood, S. J., Chen, J., Velakoulis, D., McGorry, P. D., and Pantelis, C. (2008) Corpus callosum shape alterations in individuals prior to the onset of psychosis, Schizophr Res 103, 1–10.

    Article  PubMed  Google Scholar 

  43. Walterfang, M., McGuire, P. K., Yung, A. R., Phillips, L. J., Velakoulis, D., Wood, S. J., Suckling, J., Bullmore, E. T., Brewer, W., Soulsby, B., Desmond, P., McGorry, P. D., and Pantelis, C. (2008) White matter volume changes in people who develop psychosis, Br J Psychiatry 193, 210–215.

    Article  PubMed  Google Scholar 

  44. Woodruff, P. W., McManus, I. C., and David, A. S. (1995) Meta-analysis of corpus callosum size in schizophrenia, J Neurol Neurosurg Psychiatry 58, 457–461.

    Article  PubMed  CAS  Google Scholar 

  45. Ferdinand, R. F., and Verhulst, F. C. (1995) Psychopathology from adolescence into young adulthood: an 8-year follow-up study, Am J Psychiatry 152, 1586–1594.

    PubMed  CAS  Google Scholar 

  46. Ferdinand, R. F., Verhulst, F. C., and Wiznitzer, M. (1995) Continuity and change of self-reported problem behaviors from adolescence into young adulthood, J Am Acad Child Adolesc Psychiatry 34, 680–690.

    Article  PubMed  CAS  Google Scholar 

  47. Hofstra, M. B., Van der Ende, J., and Verhulst, F. C. (2002) Pathways of self-reported problem behaviors from adolescence into adulthood, Am J Psychiatry 159, 401–407.

    Article  PubMed  Google Scholar 

  48. Hofstra, M. B., van der Ende, J., and Verhulst, F. C. (2002) Child and adolescent problems predict DSM-IV disorders in adulthood: a 14-year follow-up of a Dutch epidemiological sample, J Am Acad Child Adolesc Psychiatry 41, 182–189.

    Article  PubMed  Google Scholar 

  49. Hofstra, M. B., Van der Ende, J., and Verhulst, F. C. (2000) Continuity and change of psychopathology from childhood into adulthood: a 14-year follow-up study, J Am Acad Child Adolesc Psychiatry 39, 850–858.

    Article  PubMed  CAS  Google Scholar 

  50. Kim-Cohen, J., Caspi, A., Moffitt, T. E., Harrington, H., Milne, B. J., and Poulton, R. (2003) Prior juvenile diagnoses in adults with mental disorder: developmental follow-back of a prospective-longitudinal cohort, Arch Gen Psychiatry 60, 709–717.

    Article  PubMed  Google Scholar 

  51. Biro, F. M., and Wien, M. Childhood obesity and adult morbidities, Am J Clin Nutr 91, 1499S–1505S.

    Google Scholar 

  52. Deshmukh-Taskar, P., Nicklas, T. A., Morales, M., Yang, S. J., Zakeri, I., and Berenson, G. S. (2006) Tracking of overweight status from childhood to young adulthood: the Bogalusa Heart Study, Eur J Clin Nutr 60, 48–57.

    Article  PubMed  CAS  Google Scholar 

  53. Guo, S. S., and Chumlea, W. C. (1999) Tracking of body mass index in children in relation to overweight in adulthood, Am J Clin Nutr 70, 145S-148S.

    CAS  Google Scholar 

  54. Whitaker, R. C., Wright, J. A., Pepe, M. S., Seidel, K. D., and Dietz, W. H. (1997) Predicting obesity in young adulthood from childhood and parental obesity, N Engl J Med 337, 869–873.

    Article  PubMed  CAS  Google Scholar 

  55. Reilly, J. J., Armstrong, J., Dorosty, A. R., Emmett, P. M., Ness, A., Rogers, I., Steer, C., and Sherriff, A. (2005) Early life risk factors for obesity in childhood: cohort study, BMJ 330, 1357.

    Article  PubMed  Google Scholar 

  56. Krishnan, V., Han, M. H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., Laplant, Q., Graham, A., Lutter, M., Lagace, D. C., Ghose, S., Reister, R., Tannous, P., Green, T. A., Neve, R. L., Chakravarty, S., Kumar, A., Eisch, A. J., Self, D. W., Lee, F. S., Tamminga, C. A., Cooper, D. C., Gershenfeld, H. K., and Nestler, E. J. (2007) Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions, Cell 131, 391–404.

    Article  PubMed  CAS  Google Scholar 

  57. Belin, D., Mar, A. C., Dalley, J. W., Robbins, T. W., and Everitt, B. J. (2008) High impulsivity predicts the switch to compulsive cocaine-taking, Science 320, 1352–1355.

    Article  PubMed  CAS  Google Scholar 

  58. Gorwood, P. (2008) Neurobiological mechanisms of anhedonia, Dialogues Clin Neurosci 10, 291–299.

    PubMed  Google Scholar 

  59. Kessler, R. C., McGonagle, K. A., Zhao, S., Nelson, C. B., Hughes, M., Eshleman, S., Wittchen, H. U., and Kendler, K. S. (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey, Arch Gen Psychiatry 51, 8–19.

    CAS  Google Scholar 

  60. Kessler, R. C., DuPont, R. L., Berglund, P., and Wittchen, H. U. (1999) Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys, Am J Psychiatry 156, 1915–1923.

    PubMed  CAS  Google Scholar 

  61. Moffitt, T. E., Caspi, A., Harrington, H., Milne, B. J., Melchior, M., Goldberg, D., and Poulton, R. (2007) Generalized anxiety disorder and depression: childhood risk factors in a birth cohort followed to age 32, Psychol Med 37, 441–452.

    Article  PubMed  Google Scholar 

  62. Ormel, J., VonKorff, M., Ustun, T. B., Pini, S., Korten, A., and Oldehinkel, T. (1994) Common mental disorders and disability across cultures. Results from the WHO Collaborative Study on Psychological Problems in General Health Care, Jama 272, 1741–1748.

    CAS  Google Scholar 

  63. Olfson, M., Fireman, B., Weissman, M. M., Leon, A. C., Sheehan, D. V., Kathol, R. G., Hoven, C., and Farber, L. (1997) Mental disorders and disability among patients in a primary care group practice, Am J Psychiatry 154, 1734–1740.

    PubMed  CAS  Google Scholar 

  64. Mullen, P. E., Martin, J. L., Anderson, J. C., Romans, S. E., and Herbison, G. P. (1996) The long-term impact of the physical, emotional, and sexual abuse of children: a community study, Child Abuse Negl 20, 7–21.

    Article  PubMed  CAS  Google Scholar 

  65. Bebbington, P. E., Bhugra, D., Brugha, T., Singleton, N., Farrell, M., Jenkins, R., Lewis, G., and Meltzer, H. (2004) Psychosis, victimisation and childhood disadvantage: evidence from the second British National Survey of Psychiatric Morbidity, Br J Psychiatry 185, 220–226.

    Article  PubMed  Google Scholar 

  66. Insel, T., Cuthbert, B., Garvey, M., Heinssen, R., Pine, D. S., Quinn, K., Sanislow, C., and Wang, P. (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders, Am J Psychiatry 167, 748–751.

    Google Scholar 

  67. Delgado, M. R., Nearing, K. I., Ledoux, J. E., and Phelps, E. A. (2008) Neural circuitry underlying the regulation of conditioned fear and its relation to extinction, Neuron 59, 829–838.

    Article  PubMed  CAS  Google Scholar 

  68. LeDoux, J. E. (2000) Emotion circuits in the brain, Annu Rev Neurosci 23, 155–184.

    Article  PubMed  CAS  Google Scholar 

  69. Berridge, K. C., and Robinson, T. E. (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?, Brain Res Brain Res Rev 28, 309–369.

    Article  PubMed  CAS  Google Scholar 

  70. O’Doherty, J., Kringelbach, M. L., Rolls, E. T., Hornak, J., and Andrews, C. (2001) Abstract reward and punishment representations in the human orbitofrontal cortex, Nat Neurosci 4, 95–102.

    Article  PubMed  Google Scholar 

  71. Roesch, M. R., and Olson, C. R. (2004) Neuronal activity related to reward value and motivation in primate frontal cortex, Science 304, 307–310.

    Article  PubMed  CAS  Google Scholar 

  72. Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., and Monteggia, L. M. (2002) Neurobiology of depression, Neuron 34, 13–25.

    Article  PubMed  CAS  Google Scholar 

  73. Squire, L. R. (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans, Psychol Rev 99, 195–231.

    Article  PubMed  CAS  Google Scholar 

  74. Fanselow, M. S., and Dong, H. W. Are the dorsal and ventral hippocampus functionally distinct structures?, Neuron 65, 7–19.

    Google Scholar 

  75. Strauss, G. P., Frank, M. J., Waltz, J. A., Kasanova, Z., Herbener, E. S., and Gold, J. M. (2011) Deficits in Positive Reinforcement Learning and Uncertainty-Driven Exploration Are Associated with Distinct Aspects of Negative Symptoms in Schizophrenia, Biol Psychiatry.

    Google Scholar 

  76. Blackwood, D. H., Fordyce, A., Walker, M. T., St Clair, D. M., Porteous, D. J., and Muir, W. J. (2001) Schizophrenia and affective disorders – cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family, Am J Hum Genet 69, 428–433.

    Article  PubMed  CAS  Google Scholar 

  77. Bray, N. J. (2008) Gene expression in the etiology of schizophrenia, Schizophr Bull 34, 412–418.

    Article  PubMed  Google Scholar 

  78. Karssen, A. M., Li, J. Z., Her, S., Patel, P. D., Meng, F., Evans, S. J., Vawter, M. P., Tomita, H., Choudary, P. V., Bunney, W. E., Jr., Jones, E. G., Watson, S. J., Akil, H., Myers, R. M., Schatzberg, A. F., and Lyons, D. M. (2006) Application of microarray technology in primate behavioral neuroscience research, Methods 38, 227–234.

    Article  PubMed  CAS  Google Scholar 

  79. Newton, S. S., Bennett, A., and Duman, R. S. (2005) Production of custom microarrays for neuroscience research, Methods 37, 238–246.

    Article  PubMed  CAS  Google Scholar 

  80. Uranova, N. A., Vostrikov, V. M., Vikhreva, O. V., Zimina, I. S., Kolomeets, N. S., and Orlovskaya, D. D. (2007) The role of oligodendrocyte pathology in schizophrenia, Int J Neuropsychopharmacol 10, 537–545.

    Article  PubMed  CAS  Google Scholar 

  81. Hakak, Y., Walker, J. R., Li, C., Wong, W. H., Davis, K. L., Buxbaum, J. D., Haroutunian, V., and Fienberg, A. A. (2001) Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia, Proc Natl Acad Sci USA 98, 4746–4751.

    Article  PubMed  CAS  Google Scholar 

  82. Sugai, T., Kawamura, M., Iritani, S., Araki, K., Makifuchi, T., Imai, C., Nakamura, R., Kakita, A., Takahashi, H., and Nawa, H. (2004) Prefrontal abnormality of schizophrenia revealed by DNA microarray: impact on glial and neurotrophic gene expression, Ann N Y Acad Sci 1025, 84–91.

    Article  PubMed  CAS  Google Scholar 

  83. Tkachev, D., Mimmack, M. L., Ryan, M. M., Wayland, M., Freeman, T., Jones, P. B., Starkey, M., Webster, M. J., Yolken, R. H., and Bahn, S. (2003) Oligodendrocyte dysfunction in schizophrenia and bipolar disorder, Lancet 362, 798–805.

    Article  PubMed  CAS  Google Scholar 

  84. Coplan, J. D., Abdallah, C. G., Tang, C. Y., Mathew, S. J., Martinez, J., Hof, P. R., Smith, E. L., Dwork, A. J., Perera, T. D., Pantol, G., Carpenter, D., Rosenblum, L. A., Shungu, D. C., Gelernter, J., Kaffman, A., Jackowski, A., Kaufman, J., and Gorman, J. M. (2010) The role of early life stress in development of the anterior limb of the internal capsule in nonhuman primates, Neurosci Lett 480, 93–96.

    Article  PubMed  CAS  Google Scholar 

  85. Cotter, D., Mackay, D., Chana, G., Beasley, C., Landau, S., and Everall, I. P. (2002) Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder, Cereb Cortex 12, 386–394.

    Article  PubMed  Google Scholar 

  86. De Bellis, M. D., Keshavan, M. S., Beers, S. R., Hall, J., Frustaci, K., Masalehdan, A., Noll, J., and Boring, A. M. (2001) Sex differences in brain maturation during childhood and adolescence, Cereb Cortex 11, 552–557.

    Article  PubMed  Google Scholar 

  87. De Bellis, M. D., Keshavan, M. S., Shifflett, H., Iyengar, S., Beers, S. R., Hall, J., and Moritz, G. (2002) Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a sociodemographically matched study, Biol Psychiatry 52, 1066–1078.

    Article  PubMed  Google Scholar 

  88. Vataja, R., Pohjasvaara, T., Leppavuori, A., Mantyla, R., Aronen, H. J., Salonen, O., Kaste, M., and Erkinjuntti, T. (2001) Magnetic resonance imaging correlates of depression after ischemic stroke, Arch Gen Psychiatry 58, 925–931.

    Article  PubMed  CAS  Google Scholar 

  89. Walterfang, M., Yucel, M., Barton, S., Reutens, D. C., Wood, A. G., Chen, J., Lorenzetti, V., Velakoulis, D., Pantelis, C., and Allen, N. B. (2009) Corpus callosum size and shape in individuals with current and past depression, J Affect Disord 115, 411–420.

    Article  PubMed  Google Scholar 

  90. Aston, C., Jiang, L., and Sokolov, B. P. (2005) Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder, Mol Psychiatry 10, 309–322.

    Article  PubMed  CAS  Google Scholar 

  91. Fisher, S. E., Lai, C. S., and Monaco, A. P. (2003) Deciphering the genetic basis of speech and language disorders, Annu Rev Neurosci 26, 57–80.

    Article  PubMed  CAS  Google Scholar 

  92. Enard, W., Przeworski, M., Fisher, S. E., Lai, C. S., Wiebe, V., Kitano, T., Monaco, A. P., and Paabo, S. (2002) Molecular evolution of FOXP2, a gene involved in speech and language, Nature 418, 869–872.

    Article  PubMed  CAS  Google Scholar 

  93. Konopka, G., Bomar, J. M., Winden, K., Coppola, G., Jonsson, Z. O., Gao, F., Peng, S., Preuss, T. M., Wohlschlegel, J. A., and Geschwind, D. H. (2009) Human-specific transcriptional regulation of CNS development genes by FOXP2, Nature 462, 213–217.

    Article  PubMed  CAS  Google Scholar 

  94. Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Maner, S., Massa, H., Walker, M., Chi, M., Navin, N., Lucito, R., Healy, J., Hicks, J., Ye, K., Reiner, A., Gilliam, T. C., Trask, B., Patterson, N., Zetterberg, A., and Wigler, M. (2004) Large-scale copy number polymorphism in the human genome, Science 305, 525–528.

    Article  PubMed  CAS  Google Scholar 

  95. Iafrate, A. J., Feuk, L., Rivera, M. N., Listewnik, M. L., Donahoe, P. K., Qi, Y., Scherer, S. W., and Lee, C. (2004) Detection of large-scale variation in the human genome, Nat Genet 36, 949–951.

    Article  PubMed  CAS  Google Scholar 

  96. Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia, Nature 455, 237–241.

    Google Scholar 

  97. Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., Nord, A. S., Kusenda, M., Malhotra, D., Bhandari, A., Stray, S. M., Rippey, C. F., Roccanova, P., Makarov, V., Lakshmi, B., Findling, R. L., Sikich, L., Stromberg, T., Merriman, B., Gogtay, N., Butler, P., Eckstrand, K., Noory, L., Gochman, P., Long, R., Chen, Z., Davis, S., Baker, C., Eichler, E. E., Meltzer, P. S., Nelson, S. F., Singleton, A. B., Lee, M. K., Rapoport, J. L., King, M. C., and Sebat, J. (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia, Science 320, 539–543.

    Article  PubMed  CAS  Google Scholar 

  98. Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O. P., Barnes, M. R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A., Olason, P. I., Hardarsson, G., Jonsdottir, G. A., Gustafsson, O., Fossdal, R., Giegling, I., Moller, H. J., Hartmann, A. M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O. A., Hansen, T., Werge, T., Kiemeney, L. A., Franke, B., Veltman, J., Buizer-Voskamp, J. E., Sabatti, C., Ophoff, R. A., Rietschel, M., Nothen, M. M., Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., and Collier, D. A. (2009) Disruption of the neurexin 1 gene is associated with schizophrenia, Hum Mol Genet 18, 988–996.

    PubMed  CAS  Google Scholar 

  99. Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O. P., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J. E., Hansen, T., Jakobsen, K. D., Muglia, P., Francks, C., Matthews, P. M., Gylfason, A., Halldorsson, B. V., Gudbjartsson, D., Thorgeirsson, T. E., Sigurdsson, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B. B., Giegling, I., Moller, H. J., Hartmann, A., Shianna, K. V., Ge, D., Need, A. C., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Di Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T. W., Wang, A. G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, L. A., Franke, B., Sabatti, C., Freimer, N. B., Gulcher, J. R., Thorsteinsdottir, U., Kong, A., Andreassen, O. A., Ophoff, R. A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D. B., Nothen, M. M., Peltonen, L., Collier, D. A., St Clair, D., and Stefansson, K. (2008) Large recurrent microdeletions associated with schizophrenia, Nature 455, 232–236.

    Article  PubMed  CAS  Google Scholar 

  100. Muir, W. J., Pickard, B. S., and Blackwood, D. H. (2008) Disrupted-in-Schizophrenia-1, Curr Psychiatry Rep 10, 140–147.

    Article  PubMed  Google Scholar 

  101. Lifton, R. P. (2010) Individual genomes on the horizon, N Engl J Med 362, 1235–1236.

    Google Scholar 

  102. Kircher, M., and Kelso, J. High-throughput DNA sequencing – concepts and limitations, Bioessays 32, 524–536.

    Google Scholar 

  103. Bilguvar, K., Ozturk, A. K., Louvi, A., Kwan, K. Y., Choi, M., Tatli, B., Yalnizoglu, D., Tuysuz, B., Caglayan, A. O., Gokben, S., Kaymakcalan, H., Barak, T., Bakircioglu, M., Yasuno, K., Ho, W., Sanders, S., Zhu, Y., Yilmaz, S., Dincer, A., Johnson, M. H., Bronen, R. A., Kocer, N., Per, H., Mane, S., Pamir, M. N., Yalcinkaya, C., Kumandas, S., Topcu, M., Ozmen, M., Sestan, N., Lifton, R. P., State, M. W., and Gunel, M. (2010) Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations, Nature 467, 207–210.

    Google Scholar 

  104. Choi, M., Scholl, U. I., Ji, W., Liu, T., Tikhonova, I. R., Zumbo, P., Nayir, A., Bakkaloglu, A., Ozen, S., Sanjad, S., Nelson-Williams, C., Farhi, A., Mane, S., and Lifton, R. P. (2009) Genetic diagnosis by whole exome capture and massively parallel DNA sequencing, Proc Natl Acad Sci USA 106, 19096–19101.

    Article  PubMed  CAS  Google Scholar 

  105. Ng, S. B., Bigham, A. W., Buckingham, K. J., Hannibal, M. C., McMillin, M. J., Gildersleeve, H. I., Beck, A. E., Tabor, H. K., Cooper, G. M., Mefford, H. C., Lee, C., Turner, E. H., Smith, J. D., Rieder, M. J., Yoshiura, K., Matsumoto, N., Ohta, T., Niikawa, N., Nickerson, D. A., Bamshad, M. J., and Shendure, J. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome, Nat Genet 42, 790–793.

    Google Scholar 

  106. Ng, S. B., Buckingham, K. J., Lee, C., Bigham, A. W., Tabor, H. K., Dent, K. M., Huff, C. D., Shannon, P. T., Jabs, E. W., Nickerson, D. A., Shendure, J., and Bamshad, M. J. Exome sequencing identifies the cause of a mendelian disorder, Nat Genet 42, 30–35.

    Google Scholar 

  107. Ng, S. B., Turner, E. H., Robertson, P. D., Flygare, S. D., Bigham, A. W., Lee, C., Shaffer, T., Wong, M., Bhattacharjee, A., Eichler, E. E., Bamshad, M., Nickerson, D. A., and Shendure, J. (2009) Targeted capture and massively parallel sequencing of 12 human exomes, Nature 461, 272–276.

    Article  PubMed  CAS  Google Scholar 

  108. Brunetti-Pierri, N., Berg, J. S., Scaglia, F., Belmont, J., Bacino, C. A., Sahoo, T., Lalani, S. R., Graham, B., Lee, B., Shinawi, M., Shen, J., Kang, S. H., Pursley, A., Lotze, T., Kennedy, G., Lansky-Shafer, S., Weaver, C., Roeder, E. R., Grebe, T. A., Arnold, G. L., Hutchison, T., Reimschisel, T., Amato, S., Geragthy, M. T., Innis, J. W., Obersztyn, E., Nowakowska, B., Rosengren, S. S., Bader, P. I., Grange, D. K., Naqvi, S., Garnica, A. D., Bernes, S. M., Fong, C. T., Summers, A., Walters, W. D., Lupski, J. R., Stankiewicz, P., Cheung, S. W., and Patel, A. (2008) Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities, Nat Genet 40, 1466–1471.

    Article  PubMed  CAS  Google Scholar 

  109. Kwon, I., and Schaffer, D. V. (2008) Designer gene delivery vectors: molecular engineering and evolution of adeno-associated viral vectors for enhanced gene transfer, Pharm Res 25, 489–499.

    Article  PubMed  CAS  Google Scholar 

  110. Hommel, J. D., Sears, R. M., Georgescu, D., Simmons, D. L., and DiLeone, R. J. (2003) Local gene knockdown in the brain using viral-mediated RNA interference, Nat Med 9, 1539–1544.

    Article  PubMed  CAS  Google Scholar 

  111. McCown, T. J. (2010) The future of epilepsy treatment: focus on adeno-associated virus vector gene therapy, Drug News Perspect 23, 281–286.

    Google Scholar 

  112. Chen, G., Twyman, R., and Manji, H. K. (2010) p11 and gene therapy for severe psychiatric disorders: a practical goal?, Sci Transl Med 2, 54ps51.

    Google Scholar 

  113. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors, Cell 131, 861–872.

    Article  PubMed  CAS  Google Scholar 

  114. Hotta, A., Cheung, A. Y., Farra, N., Vijayaragavan, K., Seguin, C. A., Draper, J. S., Pasceri, P., Maksakova, I. A., Mager, D. L., Rossant, J., Bhatia, M., and Ellis, J. (2009) Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency, Nat Methods 6, 370–376.

    Article  PubMed  CAS  Google Scholar 

  115. Jacobs, P. A., Aitken, J., Frackiewicz, A., Law, P., Newton, M. S., and Smith, P. G. (1970) The inheritance of translocations in man: data from families ascertained through a balanced heterozygote, Ann Hum Genet 34, 119–136.

    Article  PubMed  CAS  Google Scholar 

  116. St Clair, D., Blackwood, D., Muir, W., Carothers, A., Walker, M., Spowart, G., Gosden, C., and Evans, H. J. (1990) Association within a family of a balanced autosomal translocation with major mental illness, Lancet 336, 13–16.

    Article  PubMed  CAS  Google Scholar 

  117. Millar, J. K., Christie, S., Anderson, S., Lawson, D., Hsiao-Wei Loh, D., Devon, R. S., Arveiler, B., Muir, W. J., Blackwood, D. H., and Porteous, D. J. (2001) Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia, Mol Psychiatry 6, 173–178.

    Article  PubMed  CAS  Google Scholar 

  118. Brandon, N. J., Handford, E. J., Schurov, I., Rain, J. C., Pelling, M., Duran-Jimeniz, B., Camargo, L. M., Oliver, K. R., Beher, D., Shearman, M. S., and Whiting, P. J. (2004) Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders, Mol Cell Neurosci 25, 42–55.

    Article  PubMed  CAS  Google Scholar 

  119. Brandon, N. J., Millar, J. K., Korth, C., Sive, H., Singh, K. K., and Sawa, A. (2009) Understanding the role of DISC1 in psychiatric disease and during normal development, J Neurosci 29, 12768–12775.

    Article  PubMed  CAS  Google Scholar 

  120. Blackwood, D. H., Glabus, M. F., Dunan, J., O’Carroll, R. E., Muir, W. J., and Ebmeier, K. P. (1999) Altered cerebral perfusion measured by SPECT in relatives of patients with schizophrenia. Correlations with memory and P300, Br J Psychiatry 175, 357–366.

    Article  PubMed  CAS  Google Scholar 

  121. O’Donnell, B. F., McCarley, R. W., Potts, G. F., Salisbury, D. F., Nestor, P. G., Hirayasu, Y., Niznikiewicz, M. A., Barnard, J., Shen, Z. J., Weinstein, D. M., Bookstein, F. L., and Shenton, M. E. (1999) Identification of neural circuits underlying P300 abnormalities in schizophrenia, Psychophysiology 36, 388–398.

    Article  PubMed  Google Scholar 

  122. Turetsky, B. I., Cannon, T. D., and Gur, R. E. (2000) P300 subcomponent abnormalities in schizophrenia: III. Deficits In unaffected ­siblings of schizophrenic probands, Biol Psychiatry 47, 380–390.

    CAS  Google Scholar 

  123. Clapcote, S. J., Lipina, T. V., Millar, J. K., Mackie, S., Christie, S., Ogawa, F., Lerch, J. P., Trimble, K., Uchiyama, M., Sakuraba, Y., Kaneda, H., Shiroishi, T., Houslay, M. D., Henkelman, R. M., Sled, J. G., Gondo, Y., Porteous, D. J., and Roder, J. C. (2007) Behavioral phenotypes of Disc1 missense mutations in mice, Neuron 54, 387–402.

    Article  PubMed  CAS  Google Scholar 

  124. Niwa, M., Kamiya, A., Murai, R., Kubo, K., Gruber, A. J., Tomita, K., Lu, L., Tomisato, S., Jaaro-Peled, H., Seshadri, S., Hiyama, H., Huang, B., Kohda, K., Noda, Y., O’Donnell, P., Nakajima, K., Sawa, A., and Nabeshima, T. (2010) Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits, Neuron 65, 480–489.

    Google Scholar 

  125. Kamiya, A., Kubo, K., Tomoda, T., Takaki, M., Youn, R., Ozeki, Y., Sawamura, N., Park, U., Kudo, C., Okawa, M., Ross, C. A., Hatten, M. E., Nakajima, K., and Sawa, A. (2005) A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development, Nat Cell Biol 7, 1167–1178.

    Article  PubMed  CAS  Google Scholar 

  126. Morris, J. A., Kandpal, G., Ma, L., and Austin, C. P. (2003) DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation, Hum Mol Genet 12, 1591–1608.

    Article  PubMed  CAS  Google Scholar 

  127. Koike, H., Arguello, P. A., Kvajo, M., Karayiorgou, M., and Gogos, J. A. (2006) Disc1 is mutated in the 129 S6/SvEv strain and modulates working memory in mice, Proc Natl Acad Sci USA 103, 3693–3697.

    Article  PubMed  CAS  Google Scholar 

  128. Benes, F. M., Taylor, J. B., and Cunningham, M. C. (2000) Convergence and plasticity of monoaminergic systems in the medial prefrontal cortex during the postnatal period: implications for the development of psychopathology, Cereb Cortex 10, 1014–1027.

    Article  PubMed  CAS  Google Scholar 

  129. National Research Council (US) and Institute of Medicine (US) Committee on the Prevention of Mental Disorders and Substance Abuse Among Children, Y., and Young Adults: Research Advances and Promising Interventions (2009) Preventing mental, emotional and behavioral disorders among young people: progress and possibilities, National Academies Press (US, Washington (DC).

    Google Scholar 

  130. Gilbert, R., Widom, C. S., Browne, K., Fergusson, D., Webb, E., and Janson, S. (2009) Burden and consequences of child maltreatment in high-income countries, Lancet 373, 68–81.

    Article  PubMed  Google Scholar 

  131. Kaffman, A., and Meaney, M. (2007) Neurodevelopmental Sequelae of Postnatal Maternal Care in Rodents: Clinical and Research Implications of Molecular Insights, J Child Psychol Psychiatry 48, 224–244.

    Article  PubMed  Google Scholar 

  132. Nemeroff, C. B., Heim, C. M., Thase, M. E., Klein, D. N., Rush, A. J., Schatzberg, A. F., Ninan, P. T., McCullough, J. P., Jr., Weiss, P. M., Dunner, D. L., Rothbaum, B. O., Kornstein, S., Keitner, G., and Keller, M. B. (2003) Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma, Proc Natl Acad Sci U S A 100, 14293–14296.

    Article  PubMed  CAS  Google Scholar 

  133. Zeanah, C. H., Egger, H. L., Smyke, A. T., Nelson, C. A., Fox, N. A., Marshall, P. J., and Guthrie, D. (2009) Institutional rearing and psychiatric disorders in romanian preschool children, Am J Psychiatry 166, 777–785.

    Article  PubMed  Google Scholar 

  134. Champagne, F. A., Francis, D. D., Mar, A., and Meaney, M. J. (2003) Variations in maternal care in the rat as a mediating influence for the effects of environment on development, Physiol Behav 79, 359–371.

    Article  PubMed  CAS  Google Scholar 

  135. Meaney, M. J. (2001) Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations, Annu Rev Neurosci 24, 1161–1192.

    Article  PubMed  CAS  Google Scholar 

  136. Szyf, M., McGowan, P., and Meaney, M. J. (2008) The social environment and the epigenome, Environ Mol Mutagen 49, 46–60.

    Article  PubMed  CAS  Google Scholar 

  137. Weaver, I. C., Cervoni, N., Champagne, F. A., D’Alessio, A. C., Sharma, S., Seckl, J. R., Dymov, S., Szyf, M., and Meaney, M. J. (2004) Epigenetic programming by maternal behavior, Nat Neurosci 7, 847–854.

    Article  PubMed  CAS  Google Scholar 

  138. Weaver, I. C., D’Alessio, A. C., Brown, S. E., Hellstrom, I. C., Dymov, S., Sharma, S., Szyf, M., and Meaney, M. J. (2007) The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes, J Neurosci 27, 1756–1768.

    Article  PubMed  CAS  Google Scholar 

  139. Weaver, I. C., Champagne, F. A., Brown, S. E., Dymov, S., Sharma, S., Meaney, M. J., and Szyf, M. (2005) Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life, J Neurosci 25, 11045–11054.

    Article  PubMed  CAS  Google Scholar 

  140. McGowan, P. O., Sasaki, A., D’Alessio, A. C., Dymov, S., Labonte, B., Szyf, M., Turecki, G., and Meaney, M. J. (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse, Nat Neurosci 12, 342–348.

    Article  PubMed  CAS  Google Scholar 

  141. Moffitt, T. E., Harrington, H., Caspi, A., Kim-Cohen, J., Goldberg, D., Gregory, A. M., and Poulton, R. (2007) Depression and generalized anxiety disorder: cumulative and sequential comorbidity in a birth cohort followed prospectively to age 32 years, Arch Gen Psychiatry 64, 651–660.

    Article  PubMed  Google Scholar 

  142. Caldji, C., Diorio, J., and Meaney, M. J. (2003) Variations in maternal care alter GABA(A) receptor subunit expression in brain regions associated with fear, Neuropsychopharmacology 28, 1950–1959.

    Article  PubMed  CAS  Google Scholar 

  143. Caldji, C., Francis, D., Sharma, S., Plotsky, P. M., and Meaney, M. J. (2000) The effects of early rearing environment on the development of GABAA and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat, Neuropsychopharmacology 22, 219–229.

    Article  PubMed  CAS  Google Scholar 

  144. Caldji, C., Tannenbaum, B., Sharma, S., Francis, D., Plotsky, P. M., and Meaney, M. J. (1998) Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat, Proc Natl Acad Sci USA 95, 5335–5340.

    Article  PubMed  CAS  Google Scholar 

  145. Francis, D. D., Caldji, C., Champagne, F., Plotsky, P. M., and Meaney, M. J. (1999) The role of corticotropin-releasing factor – norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress, Biol Psychiatry 46, 1153–1166.

    Article  PubMed  CAS  Google Scholar 

  146. Francis, D. D., and Meaney, M. J. (1999) Maternal care and the development of stress responses, Curr Opin Neurobiol 9, 128–134.

    Article  PubMed  CAS  Google Scholar 

  147. Meaney, M. J., Bhatnagar, S., Larocque, S., McCormick, C., Shanks, N., Sharma, S., Smythe, J., Viau, V., and Plotsky, P. M. (1993) Individual differences in the hypothalamic-pituitary-adrenal stress response and the hypothalamic CRF system, Ann N Y Acad Sci 697, 70–85.

    Article  PubMed  CAS  Google Scholar 

  148. Anisman, H., Zaharia, M. D., Meaney, M. J., and Merali, Z. (1998) Do early-life events permanently alter behavioral and hormonal responses to stressors?, Int J Dev Neurosci 16, 149–164.

    Article  PubMed  CAS  Google Scholar 

  149. Champagne, F., Diorio, J., Sharma, S., and Meaney, M. J. (2001) Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors, Proc Natl Acad Sci USA 98, 12736–12741.

    Article  PubMed  CAS  Google Scholar 

  150. Champagne, F. A., Chretien, P., Stevenson, C. W., Zhang, T. Y., Gratton, A., and Meaney, M. J. (2004) Variations in nucleus accumbens dopamine associated with individual differences in maternal behavior in the rat, J Neurosci 24, 4113–4123.

    Article  PubMed  CAS  Google Scholar 

  151. Champagne, F. A., Weaver, I. C., Diorio, J., Dymov, S., Szyf, M., and Meaney, M. J. (2006) Maternal Care Associated with Methylation of the Estrogen Receptor-{alpha}1b Promoter and Estrogen Receptor-{alpha} Expression in the Medial Preoptic Area of Female Offspring, Endocrinology 147, 2909–2915.

    Article  PubMed  CAS  Google Scholar 

  152. Champagne, F. A., Weaver, I. C., Diorio, J., Sharma, S., and Meaney, M. J. (2003) Natural variations in maternal care are associated with estrogen receptor alpha expression and estrogen sensitivity in the medial preoptic area, Endocrinology 144, 4720–4724.

    Article  PubMed  CAS  Google Scholar 

  153. Parent, C. I., and Meaney, M. J. (2008) The influence of natural variations in maternal care on play fighting in the rat, Dev Psychobiol 50, 767–776.

    Article  PubMed  Google Scholar 

  154. Bredy, T. W., Grant, R. J., Champagne, D. L., and Meaney, M. J. (2003) Maternal care influences neuronal survival in the hippocampus of the rat, Eur J Neurosci 18, 2903–2909.

    Article  PubMed  Google Scholar 

  155. Bredy, T. W., Humpartzoomian, R. A., Cain, D. P., and Meaney, M. J. (2003) Partial reversal of the effect of maternal care on cognitive function through environmental enrichment, Neuroscience 118, 571–576.

    Article  PubMed  CAS  Google Scholar 

  156. Bredy, T. W., Zhang, T. Y., Grant, R. J., Diorio, J., and Meaney, M. J. (2004) Peripubertal environmental enrichment reverses the effects of maternal care on hippocampal development and glutamate receptor subunit expression, Eur J Neurosci 20, 1355–1362.

    Article  PubMed  Google Scholar 

  157. Champagne, D. L., Bagot, R. C., van Hasselt, F., Ramakers, G., Meaney, M. J., de Kloet, E. R., Joels, M., and Krugers, H. (2008) Maternal care and hippocampal plasticity: evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress, J Neurosci 28, 6037–6045.

    Article  PubMed  CAS  Google Scholar 

  158. Liu, D., Diorio, J., Day, J. C., Francis, D. D., and Meaney, M. J. (2000) Maternal care, hippocampal synaptogenesis and cognitive development in rats, Nat Neurosci 3, 799–806.

    Article  PubMed  CAS  Google Scholar 

  159. Caldji, C., Diorio, J., and Meaney, M. J. (2000) Variations in maternal care in infancy regulate the development of stress reactivity, Biol Psychiatry 48, 1164–1174.

    Article  PubMed  CAS  Google Scholar 

  160. Francis, D., Diorio, J., Liu, D., and Meaney, M. J. (1999) Nongenomic transmission across generations of maternal behavior and stress responses in the rat, Science 286, 1155–1158.

    Article  PubMed  CAS  Google Scholar 

  161. Laplante, P., Diorio, J., and Meaney, M. J. (2002) Serotonin regulates hippocampal glucocorticoid receptor expression via a 5-HT7 receptor, Brain Res Dev Brain Res 139, 199–203.

    Article  PubMed  CAS  Google Scholar 

  162. Liu, D., Caldji, C., Sharma, S., Plotsky, P. M., and Meaney, M. J. (2000) Influence of ­neonatal rearing conditions on stress-induced adrenocorticotropin responses and norepinepherine release in the hypothalamic paraventricular nucleus, J Neuroendocrinol 12, 5–12.

    Article  PubMed  Google Scholar 

  163. Liu, D., Diorio, J., Tannenbaum, B., Caldji, C., Francis, D., Freedman, A., Sharma, S., Pearson, D., Plotsky, P. M., and Meaney, M. J. (1997) Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress, Science 277, 1659–1662.

    Article  PubMed  CAS  Google Scholar 

  164. Meaney, M. J., and Aitken, D. H. (1985) The effects of early postnatal handling on hippocampal glucocorticoid receptor concentrations: temporal parameters, Brain Res 354, 301–304.

    PubMed  CAS  Google Scholar 

  165. Weaver, I. C., La Plante, P., Weaver, S., Parent, A., Sharma, S., Diorio, J., Chapman, K. E., Seckl, J. R., Szyf, M., and Meaney, M. J. (2001) Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites, Mol Cell Endocrinol 185, 205–218.

    Article  PubMed  CAS  Google Scholar 

  166. Zhang, T. Y., Chretien, P., Meaney, M. J., and Gratton, A. (2005) Influence of naturally occurring variations in maternal care on prepulse inhibition of acoustic startle and the medial prefrontal cortical dopamine response to stress in adult rats, J Neurosci 25, 1493–1502.

    Article  PubMed  CAS  Google Scholar 

  167. Zhang, T. Y., Hellstrom, I. C., Bagot, R. C., Wen, X., Diorio, J., and Meaney, M. J. Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus, J Neurosci 30, 13130–13137.

    Google Scholar 

  168. Huot, R. L., Thrivikraman, K. V., Meaney, M. J., and Plotsky, P. M. (2001) Development of adult ethanol preference and anxiety as a consequence of neonatal maternal separation in Long Evans rats and reversal with antidepressant treatment, Psychopharmacology (Berl) 158, 366–373.

    Article  CAS  Google Scholar 

  169. Meaney, M. J., Brake, W., and Gratton, A. (2002) Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse?, Psychoneuroendocrinology 27, 127–138.

    Article  PubMed  CAS  Google Scholar 

  170. Francis, D. D., and Kuhar, M. J. (2008) Frequency of maternal licking and grooming correlates negatively with vulnerability to cocaine and alcohol use in rats, Pharmacol Biochem Behav 90, 497–500.

    Article  PubMed  CAS  Google Scholar 

  171. Brake, W. G., Zhang, T. Y., Diorio, J., Meaney, M. J., and Gratton, A. (2004) Influence of early postnatal rearing conditions on mesocorticolimbic dopamine and behavioural responses to psychostimulants and stressors in adult rats, Eur J Neurosci 19, 1863–1874.

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by NIMH 1KO8MH074856, DANA foundation Program in Brain and Immuno-imagine 2011, the Clinical Neuroscience Division of the VA National Center for PTSD, the NIAAA Center for the Translational Neuroscience of Alcoholism (P50- AA012870-09), and CTSA Grant Number UL1 RR024139 from the National Center for Research Resources.

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  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Arie Kaffman & John J. Krystal

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  1. Arie Kaffman
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  2. John J. Krystal
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Correspondence to Arie Kaffman .

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  1. McKnight Brain Institute, Department of Psychiatry, University of Florida, S. Newell Dr. 100, Gainesville, 32610, Florida, USA

    Firas H. Kobeissy

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Kaffman, A., Krystal, J.J. (2012). New Frontiers in Animal Research of Psychiatric Illness. In: Kobeissy, F. (eds) Psychiatric Disorders. Methods in Molecular Biology, vol 829. Humana Press. https://doi.org/10.1007/978-1-61779-458-2_1

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  • DOI: https://doi.org/10.1007/978-1-61779-458-2_1

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