Attention and Working Memory: Animal Models for Cognitive Symptoms of Schizophrenia – Studies on D2-Like Receptor Knockout Mice

  • Claudia SchmaussEmail author

The ability of humans and other higher vertebrates to implement and orchestrate behavioral strategies that are geared towards defined goals is governed by fundamental cognitive functions of attentional control and working memory that control lower-level sensory, memory, and motor operations for the purpose of achieving these goals. Studies on patients with distinct brain lesions have provided the foundation to delineate a structure–function relationship of such cognitive functions. Moreover, recent advances in brain imaging using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have added a new dimension to the study of this structure–function relationship, namely the potential of investigating functional interactions among various brain regions in subjects performing defined cognitive tasks. Hence, the last decade of research on higher cognitive functions yielded a wealth of new knowledge about the multiplicity of brain regions that are activated at different stages of information processing.


Attentional Control Sustained Attention High Cognitive Function Behavioural Brain Research Compound Discrimination 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arnsten, A. F.,&Goldman-Rakic, P. S. (1998). Noise stress impairs prefrontal cortical cognitive function in monkeys: Evidence for a hyperdopaminergic mechanism. Archives of General Psychiatry, 55, 362–368.PubMedCrossRefGoogle Scholar
  2. Awh, E., Vogel, E. K.,&Oh, S.-H. (2006). Interactions between attention and working memory. Neuroscience, 139, 201–208.PubMedCrossRefGoogle Scholar
  3. Baddeley, A. (2003). Working memory: Looking back and looking forward. Nature Reviews. Neuroscience, 4, 829–839.PubMedCrossRefGoogle Scholar
  4. Barch, D. M. (2006). What can research on schizophrenia tell us about the cognitive neuroscience of working memory? Neuroscience, 139, 73–84.PubMedCrossRefGoogle Scholar
  5. Beane, M.,&Marrocco, R. T. (2004). Norepinephrine and acetylcholine mediation of the components of reflexive attention: Implications for attention deficit disorders. Progress in Neurobiology, 74, 167–181.PubMedCrossRefGoogle Scholar
  6. Bertolino, A., Blasi, G., Latorre, V., Rubino, V., Rampino, A., Sinibaldi, L., et al. (2006). Additive effects of genetic variation in dopamine regulating genes on working memory cortical activity in human brain. Journal of Neuroscience, 26, 3918–3922.PubMedCrossRefGoogle Scholar
  7. Birrell, J. M.,&Brown, V. J. (2000). Medial frontal cortex mediates perceptual attention set shifting in the rat. Journal of Neuroscience, 20, 4320–4324.PubMedGoogle Scholar
  8. Blasi, G., Mattay, V. S., Bertolino, A., Elverv\g, B., Callicott, J. H., Das, S., et al. (2005). Effect of catechol-O-methyltransferase val 158met genotype on attentional control. Journal of Neuroscience, 25, 5038–5045.PubMedCrossRefGoogle Scholar
  9. Botvinick, M. M., Braverm T. S., Barch, D. M., Carter, C. S.,&Cohen, J. D. (2001). Conflict monitoring and cognitive control. Psychological Review, 108, 624–652.PubMedCrossRefGoogle Scholar
  10. Brozoski, T. J., Brown, R. M., Rosvold, H. E.,&Goldman-Rakic, P. S. (1979). Cognitive deficits caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science, 205, 929–932.PubMedCrossRefGoogle Scholar
  11. Caldarone, B. J., Duman, C. H.,&Piccioto, M. R. (2000). Fear conditioning and latent inhibition in mice lacking the high affinity subclass of nicotinic acetylcholine receptors in the brain. Neuropharmacology, 39, 2779–2784.PubMedCrossRefGoogle Scholar
  12. Carli, M., Robbins, T. W., Evenden, J. L.,&Everitt, B. J. (1983). Effects of lesions to ascending noradrenergic neurons on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behavioural Brain Research, 9, 361–380.PubMedCrossRefGoogle Scholar
  13. Castner, S. A., Williams, G. V.,&Goldman-Rakic, P. S. (2000). Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1-receptor stimulation. Science, 287, 2020–2022.PubMedCrossRefGoogle Scholar
  14. Collins, P., Wilkinson, L. S., Everitt, B. J., Robbins, T. W.,&Roberts, A. C. (2000). The effect of dopamine depletion from the caudate nucleus of the common marmoset (Callithrix jacchus) on tests of prefrontal cognitive function. Behavioural Neuroscience, 114, 3–17.CrossRefGoogle Scholar
  15. Dalley, J. W., Cardinal, R. N.,&Robbins, T. W. (2004). Prefrontal executive and cognitive functions in rodents: Neural and neurochemical substrates. Neuroscience and Biobehavioural Reviews, 28, 771–784.CrossRefGoogle Scholar
  16. Egan, M. F., Goldberg, T. E., Kolachana, B. S., Callicott, J. H., Mazzanti, C. M., Straub, R. E., et al. (2001). Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 98, 6917–6922.PubMedCrossRefGoogle Scholar
  17. Erlenmeyer-Kimling, L. (2000). Neurobiological deficits in offspring of schizophrenic parents: Liability indicators and predictors of illness. American Journal of Medical Genetics, 97, 65–71.PubMedCrossRefGoogle Scholar
  18. Etchepareborda, M. C.,&Abas-Mas, L. (2005). Working memory in basic learning processes. Reviews of Neurology, 15(Suppl. 1), S79–S83.Google Scholar
  19. Fan, J., Fossella, J., Sommer, T., Wu, Y.,&Posner, M. I. (2003). Mapping the genetic variation of executive attention onto brain activation. Proceedings of the National Academy of Sciences of the United States of America, 100, 7406–7411.PubMedCrossRefGoogle Scholar
  20. Friedman, H. R.,&Goldman-Rakic, P. S. (1994). Coactivation of prefrontal cortex and inferior parietal cortex in working memory tasks revealed by 2DG functional mapping in the rhesus monkey. Journal of Neuroscience, 14, 2775–2788.PubMedGoogle Scholar
  21. Glickstein, S. B., DeSteno, D. A., Hof, P. R.,&Schmauss, C. (2005). Mice lacking dopamine D 2 and D 3 receptors exhibit different differential activation of prefrontal cortical neurons during tasks requiring attention. Cerebral Cortex, 15, 1016–1024.PubMedCrossRefGoogle Scholar
  22. Glickstein, S. B., Hof, P. R.,&Schmauss, C. (2002). Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits. Journal of Neuroscience, 22, 5619–5629.PubMedGoogle Scholar
  23. Glickstein, S. B.,&Schmauss, C. (2004). Focused motor stereotypies do not require enhanced activation of neurons in striosomes. Journal of Comparative Neurology, 469, 227–238.PubMedCrossRefGoogle Scholar
  24. Goldman-Rakic, P. S. (1995). Cellular basis of working memory. Neuron, 14, 477–485.PubMedCrossRefGoogle Scholar
  25. Goldman-Rakic, P. S., Castner, S. A., Svensson, T. H., Siever, L. J.,&Williams, G. V. (2004). Targeting the dopamine D1 receptor in schizophrenia: Insights for cognitive dysfunctions. Psychopharmacology, 174, 3–16.PubMedCrossRefGoogle Scholar
  26. Granon, S., Passatti, F., Thomas, K. L., Dalley, J. W., Everitt, B. J.,&Robbins, T. W. (2000). Enhanced and impaired attentional performance after infusion of D1 dopaminergic agents into rat prefrontal cortex. Journal of Neuroscience, 20, 1208–1215.PubMedGoogle Scholar
  27. Humby, T., Laird, F. M., Davies, W.,&Wilkinson, L. S. (1999). Visuospatial attentional functioning in mice: Interactions between cholinergic manipulations and genotype. European Journal of Neuroscience, 11, 2813–2823.PubMedCrossRefGoogle Scholar
  28. Kerns, J. G., Cohen, J. D., MacDonald, A. W., III, Cho, R. Y., Stenger, V. A.,&Carter, C. S. (2004). Anterior cingulate conflict monitoring and adjustments in control. Science, 303, 1023–1026.PubMedCrossRefGoogle Scholar
  29. Kindlon, D. J. (1998). The measurements of attention. Child Psychology and Psychiatry Review, 3, 72–78.CrossRefGoogle Scholar
  30. Lubow, R. E. (2005). Construct validity of the animal latent inhibition model of selective attention deficits in schizophrenia. Schizophrenia Bulletin, 31, 139–153.PubMedCrossRefGoogle Scholar
  31. MacDonald, A. W., III, Cohen, J. D., Stenger, V. A.,&Carter, C. S. (2000). Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science, 288, 1835–1838.PubMedCrossRefGoogle Scholar
  32. Markowitsch, H. J.,&Pritzel, M. (1977). Comparative analysis of prefrontal learning functions in rats, cats, and monkeys. Psychological Bulletin, 84, 817–837.PubMedCrossRefGoogle Scholar
  33. Martinussen, R., Hayden, J., Hogg-Johnson, S.,&Tannock, R. (2005). A meta-analysis of working memory impairments in children with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 44, 377–384.PubMedCrossRefGoogle Scholar
  34. Mattay, V. S., Callicott, J. H., Bertolino, A., Heaton, I., Frank, J. A., Coppola, R., et al. (2000). Effects of dextroamphetamine on cognitive performance and cortical activation. Neuroimage, 12, 268–275.PubMedCrossRefGoogle Scholar
  35. McAlonan, K.,&Brown, V. J. (2003). Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat. Behavioural Brain Research, 146, 97–103.PubMedCrossRefGoogle Scholar
  36. Mcgaughy, J.,&Sarter, M. (1995). Behavioral vigilance in rats: Task validation and effects of age, amphetamine, and benzodiazepine receptor ligands. Psychopharmacology, 117, 340–357.PubMedCrossRefGoogle Scholar
  37. Miyakawa, T., Leiter, L. M., Gerber, D. J., Gainetdinov, R. R., Sotnikova, T. D., Zeng, H., et al. (2003). Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 100, 8987–8992.PubMedCrossRefGoogle Scholar
  38. Moran, P. M. (1993). Differential effects of scopolamine and mecamylamine on working and reference memory in the rat. Neuroscience Letters, 138, 157–160.Google Scholar
  39. Nuechterlein, K. H., Barch, D. M., Gold, J. M., Goldberg, J. M., Green, M. F.,&Heaton, R. K. (2004). Identification of separable cognitive factors in schizophrenia. Schizophrenia Research, 15, 29–39.CrossRefGoogle Scholar
  40. Owens, A. M., James, M., Leigh, P. N., Summers, B. A., Marsden, C. D., Quinn, N. P., et al. (1992.) Fronto-striatal cognitive deficits at different stages of Parkinson’s disease. Brain, 115, 1727–1751.CrossRefGoogle Scholar
  41. Park, S.,&Holzman, P. S. (1992). Schizophrenics show spatial working memory deficits. Archives of General Psychiatry, 49, 975–982.PubMedGoogle Scholar
  42. Peuskens, J., Demily, C.,&Thibaut, F. (2005). Treatment of cognitive dysfunctions in schizophrenia. Clinical Therapeutics, 27, S25–S37.PubMedCrossRefGoogle Scholar
  43. Posner, M. I. (1980). Orienting of attention. Quarterly Journal of Experimental Psychology, 32, 3–25.PubMedCrossRefGoogle Scholar
  44. Posner, M. I.,&Petersen, S. E. (1990). The attention system of the human brain. Annual Review of Neuroscience, 13, 25–42.PubMedCrossRefGoogle Scholar
  45. Raz, A. (2004). Anatomy of attentional networks. The American Record (Part B: New Anat), 281B, 21–26.Google Scholar
  46. Raz, A.,&Buhle, J. (2006). Typologies of attentional networks. Nature Reviews. Neuroscience, 7, 367–379.PubMedCrossRefGoogle Scholar
  47. Robbins, T. W. (2002). The 5-choice serial reaction time task: Behavioral pharmacology and functional neurochemistry. Psychopharmacology, 163, 362–380.PubMedCrossRefGoogle Scholar
  48. Robbins, T. W. (2005). Chemistry of the mind: Neurochemical modulation of prefrontal cortical function. Journal of Comparative Neurology, 493, 140–146.PubMedCrossRefGoogle Scholar
  49. Sarter, M., Givens, B.,&Bruno, J. P. (2001). The cognitive neuroscience of sustained attention: Where top-down meets bottom-up. Brain Research Reviews, 35, 146–160.PubMedCrossRefGoogle Scholar
  50. Sawaguchi, T.,&Goldman-Rakic, P. S. (1991). D1 dopamine receptors in prefrontal cortex: Involvement in working memory. Science, 251, 947–950.PubMedCrossRefGoogle Scholar
  51. Schmauss, C. (2000). A single dose of methamphetamine leads to a long-term reversal of the blunted dopamine D 1-receptor-mediated neocortical c-fos responses in mice deficient for D 2 and D 3 receptors. Journal of Biological Chemistry, 275, 38944–38948.PubMedCrossRefGoogle Scholar
  52. Shalev, U.,&Weiner, I. (2001). Gender-dependent differences in latent inhibition following prenatal stress and corticosterone administration. Behavioural Brain Research, 126, 57–63.PubMedCrossRefGoogle Scholar
  53. Stewart, C., Burke, S.,&Marrocco, R. (2001). Cholinergic modulation of covert attention in the rat. Psychopharmacology, 155, 210–218.PubMedCrossRefGoogle Scholar
  54. Uylings, H. B. M., Groenewegen, H. J.,&Kolb, B. (2003). Do rats have a prefrontal cortex? Behavioural Brain Research, 146, 3–17.PubMedCrossRefGoogle Scholar
  55. Van Haaren, F., De Bruin, J. P., Heinsbroek, R. P.,&Van de Poll, N. E. (1985). Delayed spatial response alternation: Effects of delayed-interval duration and lesions of the medial prefrontal cortex on response accuracy of male and female Wistar rats. Behavioural Brain Research, 18, 41–49.PubMedCrossRefGoogle Scholar
  56. Weinberger, D. R., Berman, K. F.,&Zec, R. F. (1986). Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow (rCBF) evidence. Archives of General Psychiatry, 43, 114–125.PubMedGoogle Scholar
  57. Weiner, I. (2003). The “two-headed” latent inhibition model of schizophrenia: Modeling positive and negative symptoms and their treatment. Psychopharmacology, 169, 257–297.PubMedCrossRefGoogle Scholar
  58. Williams, G. V.,&Goldman-Rakic, P. S. (1995). Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature, 376, 549–550.CrossRefGoogle Scholar
  59. Young, J. W., Finlayson, K., Spratt, C., Marston, H. M., Crawford, N., Kelly, J. S., et al. (2004). Nicotine improves sustained attention in mice: Evidence for involvement of the a7 nicotinic acetylcholine receptor. Neuropsychopharmacology, 29, 891–900.PubMedCrossRefGoogle Scholar
  60. Young, A. M. J., Moran, P. M.,&Joseph, M. H. (2005). The role of dopamine in conditioning and latent inhibition: What, when, where and how? Neuroscience and Biobehavioral Reviews, 29, 963–976.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Psychiatry and Molecular TherapeuticsColumbia University and New York State Psychiatric InstituteNew YorkUSA

Personalised recommendations