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Transgenic and Knockout Models of Psychiatric Disorders

Introduction, History, and Assessment

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Transgenic and Knockout Models of Neuropsychiatric Disorders

Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

Abstract

Humans have long distinguished themselves from infrahuman organisms. Modern notions of humans and infrahuman animals, however, date from the mid-19th century and are essentially derived from Darwin’s The Origin of Species. Although Darwin differentiated between acquired habits in humans and inherited instincts in animals, his theory of evolution embraced the notion of continuity of species. Late-19th and early-20th century animal psychologists debated this issue; particularly, whether animals had minds, and, if so, whether they were capable of the same thought and emotion evinced in humans. To avoid the problems created by mentalism and consciousness in animal behavior, many leading psychologists of the time adopted the mechanistic assumption, as extant among the British associationists. Others, however, subscribed to the belief that animals were capable of problem solving that went beyond the simple conditioning paradigm incorporating the principle of reinforcement. As a formal approach, operant conditioning was instrumental in providing many important results and was an effective epistemological framework in which to view animal and human behavior. For many psychologists, however, behaviorism seemed limited to what could be inferred from bar pressing and key pecking. As enthusiasm for behaviorism ebbed, cognitive psychology began to assert its influence, restoring the concepts of mentalism to and consciousness in animals, and directing its research efforts to intelligence and problem solving. At approximately the same time, other related areas in science—neurobiology, genetics—converged onto issues related to learning and memory, the result of which was the emergence of cognitive neuroscience. The revolution in genetics brought about by the discovery of the structure of DNA, along with the discovery of genetic abnormalities associated with learning disabilities, accelerated research into genetics factors that produced mental retardation and psychopathology. Cognitive psychology and cognitive neuroscience provided the epistemological justification for using animal models to explore various forms of human cognitive impairment. Studies in neuroscience using recently developed behavioral procedures have identified brain structures associated with certain features of learning and emotion. Successful development of knockout and transgenic technologies, followed by the creation of mouse models of genetic disorders, were used to identify many of the neurobiological and neurophysiological functions associated with neurobehavioral disorders. However, mice are not humans and the question regarding whether studies of animal behavior are relevant to human thought, problem solving, intelligence, and emotions has not been resolved.

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References

  1. Royce JE. Man and His Nature. New York: McGraw-Hill, 1961, p. 3.

    Google Scholar 

  2. McDougall W. An experiment for testing the hypothesis by Lamarck. Br J Psychol 1927;17:267–304.

    Google Scholar 

  3. Darwin CR. On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. London: John Murray, 1859.

    Google Scholar 

  4. Darwin C. The Expression of the Emotions in Man and Animals. London: John Murray, 1872.

    Google Scholar 

  5. Darwin C. The Descent of Man. 2 Vols. London: John Murray, 1871.

    Google Scholar 

  6. Spalding DA. Instinct: with original observations oNYoung animals. MacMillan’ Magazine 1873;27:282–293.

    Google Scholar 

  7. Lubbock J. Ants, Bees, and Wasps. New York: D. Appleton, 1884.

    Google Scholar 

  8. Romanes GS. Animal Intelligence. London: Kegan Paul, 1882.

    Google Scholar 

  9. Lloyd Morgan C. An Introduction to Comparative Psychology. London: Walter Scott, 1894.

    Google Scholar 

  10. Wundt W. Lectures on Human and Animal Psychology. Creighton JE, Titchener EB, trans. London: Swan Sonnenshein & Sons, 1894.

    Google Scholar 

  11. Thorndike EL. Animal intelligence: an experimental study of the associative processes in animals. The Psychological Review Monograph Supplements, 1898; 8.

    Google Scholar 

  12. Yerkes RM. The formation of habits in the turtle. The Popular Science Monthly 1901;58:519–529.

    Google Scholar 

  13. Thorndike EL. The Elements of Psychology. New York: Seiler, 1905, 203.

    Google Scholar 

  14. Jennings HS. Behavior of Lower Organisms. New York: Columbia University Press, 1906.

    Google Scholar 

  15. Sherrington C. The Integrative Action of the Nervous System. Reprinted 1947.New Haven: Yale University Press, 1906/1947.

    Google Scholar 

  16. Loeb J. Forced Movements, Tropisms, and Animal Conduct. Reprinted 1973.New York: Dover Publications, 1918/1973.

    Google Scholar 

  17. Holmes SJ. The Evolution of Animal Intelligence. New York: Henry Holt, 1911.

    Google Scholar 

  18. Pavlov IP. Lectures on the Conditioned Reflexes. Gantt WH, trans. New York: Liveright Publishing, 1928.

    Google Scholar 

  19. Washburn MF. The Animal Mind. 3rd ed. New York: MacMillan, 1930.

    Google Scholar 

  20. Watson JB. Psychology as the behaviorist views it. Psychological Review 1913;20:158–177.

    Article  Google Scholar 

  21. Köhler W. The Mentality of Apes. Winter E, trans. New York: Harcourt Brace, 1927.

    Google Scholar 

  22. Skinner BF. The Behavior of Organisms. Reprinted 1966. Englewood Cliffs: Prentice-Hall, 1938.

    Google Scholar 

  23. Maier NRF, Schneirla TC. Principles of Animal Psychology. Reprinted 1964, New York: Dover Publications, 1935.

    Google Scholar 

  24. Hunter WS. The delayed reaction in animals and children. Behavior Monographs 1913;2:86.

    Google Scholar 

  25. Hinde RA. Animal Behaviour: A Synthesis of Ethology and Comparative Psychology. 2nd ed. New York: McGraw-Hill, 1970.

    Google Scholar 

  26. Voronin LG. Some results of comparative-physiological investigations of higher nervous activity. PsycholBull 1962;59:161–195.

    CAS  Google Scholar 

  27. Warren JM. Learning in Vertebrates. In: Dewsbury DA, Rethlingshafer DA, eds. Comparative Psychology: A Modern Survey. New York: McGraw-Hill, 1973.

    Google Scholar 

  28. Tinbergen N. The Study of Instinct. Oxford: Clarendon, 1951.

    Google Scholar 

  29. Lorenz KL. The comparative method in studying innate behaviour patterns. Symp Soc Exp Biol1950;4:221–268.

    Google Scholar 

  30. Shettleworth SJ. Biological Approaches to the Study of Learning. In: Mackintosh NJ, ed. Animal Learning and Cognition. San Diego: Academic, 1994, 185–219.

    Google Scholar 

  31. Ten Cate C. Behavioral development: towards understanding processes. Perspectives in Ethology 1989;8:243–269.

    Google Scholar 

  32. de Vos GJ, van Kampen HS. Effects of primary imprinting on the subsequent development of

    Google Scholar 

  33. Ten Cate C, Los L, Schilperood L. The influence of differences in social experience on the devel

    Google Scholar 

  34. Stoddard PK, Beecher MD, Loesche P, Campbell SE. Memory does not constrain individual recognition in a bird with song repertoires. Behaviour 1992;122:271–284.

    Google Scholar 

  35. Mackintosh NJ. Approaches to the study of animal intelligence. Br J Psychol 1988;79:509–525.

    Google Scholar 

  36. Blackman DE. On the Cognitive Theories of Animal Learning: Extrapolation from Humans to Animals? In: Davey GCL, ed. Animal Models of Human Behavior. London: John Wiley & Sons, 1983, 37–50.

    Google Scholar 

  37. Zeldin RK, Olton DS. Rats acquire spatial learning sets. J Exp Psychol 1986;37B:295–311.

    Google Scholar 

  38. Devine JV. Stimulus attributes and training procedures in learning-set formation of rhesus and cebus monkey. J Comp Physiol Psychol 1970;73:62–67.

    Article  PubMed  CAS  Google Scholar 

  39. Macphail EM. Brain and Intelligence in Vertebrates. Oxford: Oxford University Press, 1982.

    Google Scholar 

  40. Pearce JM. Discrimination and Categorization. In: Mackintosh NJ, ed. Animal Learning and Cognition. San Diego: Academic, 1994, 109–134.

    Google Scholar 

  41. Bluton-Jones NG. Two Investigations of Human Behavior Guided by Evolutionary Theory. In: Davey GCL, ed. Animal Models of Human Behavior, London: John Wiley & Sons Ltd, 1983, 179–204.

    Google Scholar 

  42. Hebb DO. The Organization of Behavior. New York: Wiley, 1949.

    Google Scholar 

  43. Lashley KS. Brain Mechanisms and Intelligence. Chicago: University of Chicago Press, 1929.

    Google Scholar 

  44. Hamilton V, Vernon MD. The Development of Cognitive Processes. London: Academic, 1976.

    Google Scholar 

  45. Watkins MJ. An Experimental Psychologist’s View of Cognitive Science. In: Lister RG, Weingartner HJ, eds. Perspectives in Cognitive Neuroscience. Oxford: Oxford University Press, 1991, 132–144.

    Google Scholar 

  46. Neisser U. Cognitive Psychology. New York: Appleton Century Crofts, 1967.

    Google Scholar 

  47. Newall A, Simon HA. Human Problem Solving. Englewood Cliffs: Prentice-Hall, 1972.

    Google Scholar 

  48. Cowan WM, Harter DH, Kandel ER. The emergence of modern neuroscience: some implications for neurology and psychiatry. Annu Rev Neurosci 2000;23:343–391.

    Article  PubMed  CAS  Google Scholar 

  49. Eccles JC. The Neurophysiological Basis of Mind: The Principle of Neurophysiology. Oxford: Clarendon, 1953.

    Google Scholar 

  50. Evarts EV. Relation of pyramidal tract activity to force exerted during voluntary movement. J Neurophysiol 1968;31:14–27.

    PubMed  CAS  Google Scholar 

  51. Galton F. Inquiries into Human Faculty and its Development. New York: MacMillan, 1883.

    Google Scholar 

  52. Scheerenberger RC. A History of Mental Retardation. Baltimore: Brookes, 1982

    Google Scholar 

  53. Lejeune J, Gautier M, Turpin R. Etudes des chromosomes somatiques de neuf enfants mongoliens. CR Academie de Science 1959;248:1721.

    CAS  Google Scholar 

  54. Lubs HA. A marker X chromosome. Am J Hum Genet, 1969;21:231–244.

    PubMed  CAS  Google Scholar 

  55. Kraepelin E. Compendium der Psychiatrie zum Gebrauche für Studirende und Aerzte. Leipzig: AbelVerlag, 1883.

    Google Scholar 

  56. Kallman FJ. The Genetics of Mental Illness. In: Arieti S, ed. American Handbook of Psychiatry. New York: Basic Books, 1959.

    Google Scholar 

  57. Gottesman II. Schizophrenia Genesis—The Origins of Madness. New York: WH Freeman, 1991.

    Google Scholar 

  58. Cannon TD, Thompson PM, van Erp TG, et al. Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proc Natl Acad Sci USA 2002;99(5):3228–3323.

    Article  PubMed  CAS  Google Scholar 

  59. Anderson B. Role for animal research in the investigation of human mental retardation. Am J Ment Retard 1994;99:50–59.

    PubMed  CAS  Google Scholar 

  60. Thompson R, Crinella FM, Yu J. Brain Mechanisms in Problem Solving and Intelligence. New York: Plenum, 1990.

    Google Scholar 

  61. Morris RGM. Spatial localization does not require the presence of local cues. Learn Motiv 1981;12:239–260.

    Article  Google Scholar 

  62. Morris RGM, Garrud P, Rawlins JNP, O’Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature (London) 1982;297:681–683.

    Article  PubMed  CAS  Google Scholar 

  63. Scoville WB, Milner BJ. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 1957;20:1 1–21. Reprinted in J Neuropsychiatry Clin Neurosci 2000;12:103-113.

    Article  Google Scholar 

  64. Rudy JW, Sutherland RJ. The hippocampal formation is necessary for rats to learn and remember configural discriminations. Behav Brain Res 1989;34:97–109.

    Article  PubMed  CAS  Google Scholar 

  65. Gerlai RT, McNamara A, Williams S, Phillips HS. Hippocampal dysfunction and behavioral deficit in the water maze in mice: an unresolved issue? Brain Res Bull 2002;57:3–9.

    Article  PubMed  Google Scholar 

  66. Morris RGM. The Neural Basis of Learning with Particular Reference to the Role of Synaptic Plasticity. In: Mackintosh NJ, ed. Animal Learning and Cognition. San Diego: Academic, 1994.

    Google Scholar 

  67. Grant SG, O’Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 1992;258(5090): 1903–1910.

    Article  PubMed  CAS  Google Scholar 

  68. Pavlov IP. Lectures on Conditioned Reflexes Volume II. Conditioned Reflexes and Psychiatry. WH Gantt, trans. New York: International Publishing, 1941.

    Google Scholar 

  69. Andy OJ. Psychomotor-psychic seizures treated with bilateral amygdalotomy and orbitotomy. South Med J1976;69:88–93.

    PubMed  CAS  Google Scholar 

  70. Goddard GV. Analysis of avoidance conditioning following cholinergic stimulation of amygdala in rats. J Comp Physiol Psychol 1969;68:1–18.

    Article  PubMed  CAS  Google Scholar 

  71. Slotnick BM. Fear behavior and passive avoidance deficits in mice with amygdala lesions. Physiol Behav 1973;11:717–720.

    Article  PubMed  CAS  Google Scholar 

  72. Maren S. The amygdala, synaptic plasticity, and fear memory. Ann NY Acad Sci 2003;985:106–113.

    Article  PubMed  Google Scholar 

  73. Wilensky AE, Schafe GE, LeDoux JW. The amygdala modulates memory consolidation of fearmotivated inhibitory avoidance learning but not classical fear conditioning. J Neurosci 2000;20:7059–7066.

    Google Scholar 

  74. Crawley JN. Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res 1999;835:18–26.

    Article  PubMed  CAS  Google Scholar 

  75. Dutch-Belgian Fragile X Consortium. Fmr1 knockout mice: a model to study fragile X mental retardation. Cell 1994;15:23–33.

    Google Scholar 

  76. Reeves RH, Irving NG, Moran TH, et al. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nature Genet 1995;11:177–184.

    Article  PubMed  CAS  Google Scholar 

  77. D’Adamo P, Welzl H, Papadimitriou S, et al. Deletion of the mental retardation gene Gdi1 impairs associative memory and alters social behavior in mice. Hum Mol Genet 2002; 11:2567–2580.

    Article  PubMed  CAS  Google Scholar 

  78. Shahbazian M, Young J, Yuva-Paylor L, et al. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 2002;35:243–254.

    Article  PubMed  CAS  Google Scholar 

  79. Muscatelli F, Abrous DN, Massacrier A, et al. Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Hum Mol Genet 2000;9:3101–3110.

    Article  PubMed  CAS  Google Scholar 

  80. Liu H, Abecasis GR, Heath SC, et al. Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc Natl Acad Sci USA 2002;99:16,859–16,864.

    Article  PubMed  CAS  Google Scholar 

  81. DeSilva U, Elnitski L, Idol JR, et al. Generation and comparative analysis of approximately 3.3 Mb of mouse genomic sequence orthologous to the region of human chromosome 7q11.23 implicated in Williams syndrome. Genome Res 2002;12:3–15.

    Article  PubMed  CAS  Google Scholar 

  82. Bayarsaihan D, Dunai J, Greally JM, et al. Genomic organization of the genes Gtf2ird1, Gtf2i, and Ncf1 at the mouse chromosome 5 region syntenic to the human chromosome 7q11.23 Williams syndrome critical region. Genomics 2002;79:137–143.

    Article  PubMed  CAS  Google Scholar 

  83. Seznec H, Agbulut O, Sergeant N, et al. Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities. Hum Mol Genet 2001;10:2717–2726.

    Article  PubMed  CAS  Google Scholar 

  84. Gallagher M, Rapp PR. The use of animal models to study the effects of aging on cognition. Annu Rev Psychol 1997;48:339–370.

    Article  PubMed  CAS  Google Scholar 

  85. Kordower JH, Gash DM. Animal models of age-and disease-related cognitive decline: perspectives on the models and therapeutic strategies. Neurobiol Aging 1988;9:685–689.

    Article  PubMed  CAS  Google Scholar 

  86. Strupp BJ, Levitsky DA, Blumstein L. PKU, learning, and models of mental retardation. Dev Psychobiol 1984;17:109–120.

    Article  PubMed  CAS  Google Scholar 

  87. Paylor R, Hirotsune S, Gambello MJ, Yuva-Paylor L, Crawley JN, Wynshaw-Boris A. Impaired learning and motor behavior in heterozygous Pafah1b1 (Lis1) mutant mice. Learn Mem1999;6:521–537.

    Article  PubMed  CAS  Google Scholar 

  88. Dalvi A, Lucki I. Murine models of depression. Psychopharmacology (Berl) 1999;147:4–6.

    Google Scholar 

  89. Clement Y, Calatayud F, Belzung C. Genetic basis of anxiety-like behaviour: a critical review. Brain Res Bull 2002;57:57–71.

    Article  PubMed  Google Scholar 

  90. Flint J. Genetic effects on an animal model of anxiety. FEBS Lett 2002;529:131–134.

    Article  PubMed  CAS  Google Scholar 

  91. Tremolizzo L, Carboni G, Ruzicka WB, et al. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc Natl Acad Sci USA 2002;99:17,095–17,100.

    Article  PubMed  CAS  Google Scholar 

  92. Ellenbroek BA, Cools AR. Apomorphine susceptibility and animal models for psychopathology: genes and environment. Behav Genet 2002;32:349–361.

    Article  PubMed  Google Scholar 

  93. Wahlsten D. Standardized tests of mouse behavior: reasons, recommendations, and reality. Physiol Behav 2001;73:695–704.

    Article  PubMed  CAS  Google Scholar 

  94. Phillips TJ, Belknap JK, Hitzemann RJ, Buck KJ, Cunningham CL, Crabbe JC. Harnessing the mouse to unravel the genetics of human disease. Genes Brains Behav 2002;1:14–26.

    Article  CAS  Google Scholar 

  95. Crabbe JC, Wahlsten D, Dudek BC. Genetics of mouse behavior: interactions with laboratory environment. Science 1999;284:1670–1672.

    Article  PubMed  CAS  Google Scholar 

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Fisch, G.S. (2006). Transgenic and Knockout Models of Psychiatric Disorders. In: Fisch, G.S., Flint, J. (eds) Transgenic and Knockout Models of Neuropsychiatric Disorders. Contemporary Clinical Neuroscience. Humana Press. https://doi.org/10.1007/978-1-59745-058-4_1

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