Brigman et al. REFERENCES Abdul-Monim, Z., Neill, J. C., and Reynolds, G. P. (2007). Sub-chronic psychotomimetic phencyclidine induces deﬁcits in reversal learning and alterations in parvalbumin- immunoreactive expression in the rat. J. Psychopharmacol. 21, 198–205. Abdul-Monim, Z., Reynolds, G. P., and Neill, J. C. (2003). The atypical antipsy- chotic ziprasidone, but not haloperidol, improvesphencyclidine-inducedcogni- tive deﬁcits in a reversal learning task in the rat. J. Psychopharmacol. 17, 57–65. Abdul-Monim, Z., Reynolds, G. P., and Neill, J. C. (2006). The effect of atypical and classical antipsychotics on sub-chronic PCP-induced cog- nitive deﬁcits in a reversal-learning paradigm. Behav. Brain Res. 169, 263–273. Angelo, M., Plattner, F., Irvine, E. E., and Giese, K. P. (2003). Improved reversal learning and altered fear conditioning in transgenic mice with regionally restricted p25 expression. Eur. J. Neurosci. 18, 423–431. Arguello, P. A., and Gogos, J. A. (2006). Modeling madness in mice: one piece at a time. Neuron 52, 179–196. Balogh, S. A., McDowell, C. S., Tae Kwon, Y., and Denenberg, V. H. (2001). Facilitated stimulus-response associa- tive learning and long-term memory in mice lacking the NTAN1 amidase of the N-end rule pathway. Brain Res. 892, 336–343. Balschun, D., Moechars, D., Callaerts- Vegh, Z.,Vermaercke, B.,Van Acker, N., Andries, L., and D’Hooge, R. (2009). Vesicular glutamate transporter VGLUT1 has a role in hippocampal long-term potentiation and spatial reversal learning. Cereb. Cortex. doi: 10.1093/cercor/bhp133. Bannerman, D. M., Deacon, R. M., Seeburg, P. H., and Rawlins, J. N. (2003). GluR-A-deﬁcient mice display normal acquisition of a hippocampus- dependent spatial reference memory task but are impaired during spa- tial reversal. Behav. Neurosci. 117, 866–870. Barnett, J. H., Sahakian, B. J., Werners, U., Hill, K. E., Brazil, R., Gallagher, O., Bullmore, E. T., and Jones, P. B. 26 | May 2010 | Volume 4 | Issue 1 and, indeed, for other neuropsychiatric dis- orders characterized by cognitive inflexibil- ity and other executive dysfunctions, such as depression (Holmes and Wellman, 2009) and drug addiction (Schoenbaum and Shaham, 2008). In concert with more established assays described above, the system could provide a valuable behavioral platform for elucidating the aberrant neural, molecular and genetic mechanisms underlying cognitive inflexibility in these disorders. ACKNOWLEDGMENTS We are grateful to Dr. Timothy J. Bussey for com- ments on the manuscript. Research supported by the Intramural Research Programs of the National Institute on Alcohol Abuse and Alcoholism (Z01- AA000411). (2005). Visuospatial learning and executive function are independently impaired in ﬁrst-episode psychosis. Psychol. Med. 35, 1031–1041. Birrell, J. M., and Brown, V. J. (2000). Medial frontal cortex mediates per- ceptual attentional set shifting in the rat. J. Neurosci. 20, 4320–4324. Bissonette, G. B., Martins, G. J., Franz, T. M., Harper, E. S., Schoenbaum, G., and Powell, E. M. (2008). Double dis- sociation of the effects of medial and orbital prefrontal cortical lesions on attentional and affective shifts in mice. J. Neurosci. 28, 11124–11130. Bohn, I., Giertler, C., and Hauber, W. (2003a). NMDA receptors in the rat orbital prefrontal cortex are involved in guidance of instrumental behav- iour under reversal conditions. Cereb. Cortex 13, 968–976. Bohn, I., Giertler, C., and Hauber, W. (2003b). Orbital prefrontal cortex and guidance of instrumental behaviour in rats under reversal conditions. Behav. Brain Res. 143, 49–56. Braw, Y., Bloch, Y., Mendelovich, S., Ratzoni, G., Gal, G., Harari, H., Tripto, A., and Levkovitz,Y. (2008). Cognition in young schizophrenia outpatients: comparison of ﬁrst-episode with mul- tiepisode patients. Schizophr. Bull. 34, 544–554. Brigman, J. L., Bussey, T. J., Saksida, L. M., and Rothblat, L. A. (2005). Discrimination of multidimensional visual stimuli by mice: intra- and extradimensional shifts. Behav. Neurosci. 119, 839–842. Brigman, J. L., Feyder, M., Saksida, L. M., Bussey, T. J., Mishina, M., and Holmes, A. (2008). Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit. Learn. Mem. 15, 50–54. Brigman, J. L., Ihne, J., Saksida, L. M., Bussey, T. J., and Holmes, A. (2009). Effects of subchronic phencyclidine (PCP) treatment on social behav- iors, and operant discrimination and reversal learning in C57BL/6J mice. Front. Behav. Neurosci. 3:2. doi:10.3389/neuro.08.002.2009. Brigman, J. L., Padukiewicz, K. E., Sutherland, M. L., and Rothblat, L. A. (2006). Executive functions in the heterozygous reeler mouse model of schizophrenia. Behav. Neurosci. 120, 984–988. Brigman, J. L., and Rothblat, L. A. (2008). Stimulus specific deficit on visual reversal learning after lesions of medial prefrontal cortex in the mouse. Behav. Brain Res. 187, 405–410. Broberg, B. V., Dias, R., Glenthoj, B. Y., and Olsen, C. K. (2008). Evaluation of a neurodevelopmental model of schizophrenia – early postnatal PCP treatment in attentional set-shifting. Behav. Brain Res. 190, 160–163. Brooks, S. P., Betteridge, H., Trueman, R. C., Jones, L., and Dunnett, S. B. (2006). Selective extra-dimensional set shift- ing deﬁcit in a knock-in mouse model of Huntington’s disease. Brain Res. Bull. 69, 452–457. Bussey, T. J., Muir, J. L., Everitt, B. J., and Robbins, T. W. (1997). Triple dissocia- tion of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat. Behav. Neurosci. 111, 920–936. Bussey, T. J., Muir, J. L., and Robbins, T. W. (1994).A novel automated touchscreen procedure for assessing learning in the rat using computer-graphic stimuli. Neurosci. Res. Commun. 15, 103–110. Bussey, T. J., Padain, T. L., Skillings, E. A., Winters, B. D., Morton, A. J., and Saksida, L. M. (2008). The touchscreen cognitive testing method for rodents: how to get the best out of your rat. Learn. Mem. 15, 516–523. Bussey,T.J.,Saksida,L.M.,and Rothblat,L. A. (2001). Discrimination of compu- ter-graphic stimuli by mice: a method for the behavioral characterization of transgenic and gene-knockout mod- els. Behav. Neurosci. 115, 957–960. Capecchi, M. R. (2005). Gene targeting in mice: functional analysis of the mam- malian genome for the twenty-ﬁrst century. Nat. Rev. Genet. 6, 507–512. Carter, C. S., Barch, D. M., Buchanan, R. W., Bullmore, E., Krystal, J. H., Cohen, J., Geyer, M., Green, M., Nuechterlein, K. H., Robbins, T., Silverstein, S., Smith, E. E., Strauss, M., Wykes, T., and Heinssen, R. (2008). Identifying cognitive mechanisms targeted for treatment development in schizophre- nia: an overview of the ﬁrst meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative. Biol. Psychiatry 64, 4–10. Chishti, M. A., Yang, D. S., Janus, C., Phinney, A. L., Horne, P., Pearson, J., Strome, R., Zuker, N., Loukides, J., French, J., Turner, S., Lozza, G., Grilli, M., Kunicki, S., Morissette, C., Paquette, J., Gervais, F., Bergeron, C., Fraser, P. E., Carlson, G. A., George- Hyslop, P. S., and Westaway, D. (2001). Early-onset amyloid deposition and cognitive deﬁcits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J. Biol. Chem. 276, 21562–21570. Choeiri, C., Hewitt, K., Durkin, J., Simard, C. J., Renaud, J. M., and Messier, C. (2005). Longitudinal evaluation of memory performance and periph- eral neuropathy in the Ins2C96Y Akita mice. Behav. Brain Res. 157, 31–38. Chudasama,Y., and Robbins, T.W. (2003). Dissociable contributions of the orbitofrontal and infralimbic cortex to pavlovian autoshaping and dis- crimination reversal learning: further evidence for the functional heteroge- neity of the rodent frontal cortex. J. Neurosci. 23, 8771–8780. Clelland, C. D., Choi, M., Romberg, C., Clemenson, G. D. Jr., Fragniere, A., Tyers, P., Jessberger, S., Saksida, L. M., Barker, R. A., Gage, F. H., and Bussey, T. J. (2009). A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213. Colacicco, G., Welzl, H., Lipp, H. P., and Wurbel, H. (2002). Attentional set- shifting in mice: modiﬁcation of a rat paradigm, and evidence for strain- dependent variation. Behav. Brain Res. 132, 95–102. Corbetta, S., D’Adamo, P., Gualdoni, S., Braschi, C., Berardi, N., and de Curtis, I. (2008). Hyperactivity and novelty-induced hyperreactivity in mice lacking Rac3. Behav. Brain Res. 186, 246–255. Coyle, J. T. (2006). Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell. Mol. Neurobiol. 26, 365–384. www.frontiersin.org