Predictably Irrational: Assaying Cognitive Inflexibility in Mouse Models of Schizophrenia

The development of sophisticated, translatable mouse-based assays modeling the behavioral manifestations of neuropsychiatric diseases, such as schizophrenia, has lagged the advances in molecular and genomic techniques. Our laboratory has made efforts to fill this gap by investing in the development of novel assays, including adapting a touchscreen-based method for measuring cognitive and executive functions for use in mice. As part of these efforts, a recent study by Brigman et al. (2009) investigated the effects of subchronic phencyclidine treatment on mouse touchscreen-based pairwise visual discrimination and reversal learning. Here, we summarize the results of that study, and place them in the larger context of ongoing efforts to develop valid mouse “models” of schizophrenia, with a focus on reversal learning and other measures of cognitive flexibility. Touchscreen-based systems could provide a tractable platform for fully utilizing the mouse to elucidate the pathophysiology of cognitive inflexibility in schizophrenia and other neuropsychiatric disorders.

[1]  R. D'Hooge,et al.  Vesicular glutamate transporter VGLUT1 has a role in hippocampal long-term potentiation and spatial reversal learning. , 2010, Cerebral cortex.

[2]  S. Floresco,et al.  Neural circuits subserving behavioral flexibility and their relevance to schizophrenia , 2009, Behavioural Brain Research.

[3]  Robert Lalonde,et al.  Age-related cognitive decline and nesting behavior in an APPswe/PS1 bigenic model of Alzheimer's disease , 2009, Brain Research.

[4]  Samuel B. Hutton,et al.  Discrimination Learning, Reversal, and Set-Shifting in First-Episode Schizophrenia: Stability Over Six Years and Specific Associations with Medication Type and Disorganization Syndrome , 2009, Biological Psychiatry.

[5]  C. Schmauss,et al.  A role for dopamine D2 receptors in reversal learning , 2009, Neuroscience.

[6]  T. O'Leary,et al.  Visuo-spatial learning and memory deficits on the Barnes maze in the 16-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease , 2009, Behavioural Brain Research.

[7]  L. Saksida,et al.  A Functional Role for Adult Hippocampal Neurogenesis in Spatial Pattern Separation , 2009, Science.

[8]  J. Callicott,et al.  Prefrontal cognitive systems in schizophrenia : Towards human genetic brain mechanisms , 2009, Cognitive neuropsychiatry.

[9]  A. Holmes,et al.  Stress-induced prefrontal reorganization and executive dysfunction in rodents , 2009, Neuroscience & Biobehavioral Reviews.

[10]  L. Saksida,et al.  Assessment of Glutamate Transporter GLAST (EAAT1)-Deficient Mice for Phenotypes Relevant to the Negative and Executive/Cognitive Symptoms of Schizophrenia , 2009, Neuropsychopharmacology.

[11]  L. Saksida,et al.  A novel touchscreen-automated paired-associate learning (PAL) task sensitive to pharmacological manipulation of the hippocampus: a translational rodent model of cognitive impairments in neurodegenerative disease , 2009, Psychopharmacology.

[12]  J. Roder,et al.  Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice. , 2008, Learning & memory (Cold Spring Harbor, N.Y.).

[13]  L. Saksida,et al.  Effects of Subchronic Phencyclidine (PCP) Treatment on Social Behaviors, and Operant Discrimination and Reversal Learning in C57BL/6J Mice , 2008, Front. Behav. Neurosci..

[14]  A. Holmes,et al.  Loss of Glial Glutamate and Aspartate Transporter (Excitatory Amino Acid Transporter 1) Causes Locomotor Hyperactivity and Exaggerated Responses to Psychotomimetics: Rescue by Haloperidol and Metabotropic Glutamate 2/3 Agonist , 2008, Biological Psychiatry.

[15]  Geoffrey Schoenbaum,et al.  Double Dissociation of the Effects of Medial and Orbital Prefrontal Cortical Lesions on Attentional and Affective Shifts in Mice , 2008, The Journal of Neuroscience.

[16]  J. Arnt,et al.  Reversal of Subchronic PCP-Induced Deficits in Attentional Set Shifting in Rats by Sertindole and a 5-HT6 Receptor Antagonist: Comparison Among Antipsychotics , 2008, Neuropsychopharmacology.

[17]  J. Feldon,et al.  Affective and cognitive effects of global deletion of &agr;3-containing gamma-aminobutyric acid-A receptors , 2008, Behavioural pharmacology.

[18]  D. Weinberger,et al.  Genetic Dissection of the Role of Catechol-O-Methyltransferase in Cognition and Stress Reactivity in Mice , 2008, The Journal of Neuroscience.

[19]  L. Saksida,et al.  Impaired Fear Extinction Learning and Cortico-Amygdala Circuit Abnormalities in a Common Genetic Mouse Strain , 2008, The Journal of Neuroscience.

[20]  E. T. Bullmore,et al.  Reinforcement and Reversal Learning in First-Episode Psychosis , 2008, Schizophrenia bulletin.

[21]  Charan Ranganath,et al.  The Cognitive Neuroscience of Memory Function and Dysfunction in Schizophrenia , 2008, Biological Psychiatry.

[22]  L. Saksida,et al.  The touchscreen cognitive testing method for rodents: how to get the best out of your rat. , 2008, Learning & memory.

[23]  Michael F. Green,et al.  Identifying Cognitive Mechanisms Targeted for Treatment Development in Schizophrenia: An Overview of the First Meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative , 2008, Biological Psychiatry.

[24]  B. Glenthøj,et al.  Evaluation of a neurodevelopmental model of schizophrenia—Early postnatal PCP treatment in attentional set-shifting , 2008, Behavioural Brain Research.

[25]  S. Floresco,et al.  Inactivation of the medial prefrontal cortex of the rat impairs strategy set-shifting, but not reversal learning, using a novel, automated procedure , 2008, Behavioural Brain Research.

[26]  Lisa M. Wiedholz,et al.  Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and ‘schizophrenia-related’ behaviors , 2008, Molecular Psychiatry.

[27]  J. Crawley,et al.  Deficits in social behavior and reversal learning are more prevalent in male offspring of VIP deficient female mice , 2008, Experimental Neurology.

[28]  B. Morris,et al.  Subchronic and chronic PCP treatment produces temporally distinct deficits in attentional set shifting and prepulse inhibition in rats , 2008, Psychopharmacology.

[29]  J. Brigman,et al.  Stimulus specific deficit on visual reversal learning after lesions of medial prefrontal cortex in the mouse , 2008, Behavioural Brain Research.

[30]  Geoffrey Schoenbaum,et al.  The Role of Orbitofrontal Cortex in Drug Addiction: A Review of Preclinical Studies , 2008, Biological Psychiatry.

[31]  L. Saksida,et al.  Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit. , 2008, Learning & memory.

[32]  N. Berardi,et al.  Hyperactivity and novelty-induced hyperreactivity in mice lacking Rac3 , 2008, Behavioural Brain Research.

[33]  S. Gabay,et al.  Habituation, discrimination and anxiety in transgenic mice overexpressing acetylcholinesterase splice variants , 2007, Brain Research.

[34]  Y. Levkovitz,et al.  Cognition in young schizophrenia outpatients: comparison of first-episode with multiepisode patients. , 2007, Schizophrenia bulletin.

[35]  Jia-min Zhuo,et al.  Early discrimination reversal learning impairment and preserved spatial learning in a longitudinal study of Tg2576 APPsw mice , 2007, Neurobiology of Aging.

[36]  James A. Waltz,et al.  Probabilistic reversal learning impairments in schizophrenia: Further evidence of orbitofrontal dysfunction , 2007, Schizophrenia Research.

[37]  J. Gogos,et al.  Modeling Madness in Mice: One Piece at a Time , 2006, Neuron.

[38]  H. Würbel,et al.  Animal neuropsychology: Validation of the Intra-Dimensional Extra-Dimensional set shifting task for mice , 2006, Behavioural Brain Research.

[39]  P. Greengard,et al.  Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32‐dependent pathways: evidence from PDE1B‐DARPP32 double‐knockout mice , 2006, Genes, brain, and behavior.

[40]  A. Nairn,et al.  Assessment of cognitive function in the heterozygous reeler mouse , 2006, Psychopharmacology.

[41]  G. González-Burgos,et al.  Pathophysiologically based treatment interventions in schizophrenia , 2006, Nature Medicine.

[42]  Lisa M. Saksida,et al.  Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice , 2006, Behavioural Brain Research.

[43]  G. Reynolds,et al.  Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat , 2006, Journal of psychopharmacology.

[44]  J. Brigman,et al.  Executive functions in the heterozygous reeler mouse model of schizophrenia. , 2006, Behavioral neuroscience.

[45]  T. Miyakawa,et al.  Schizophrenia-Relevant Behavioral Testing in Rodent Models: A Uniquely Human Disorder? , 2006, Biological Psychiatry.

[46]  J. Coyle,et al.  Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis , 2006, Cellular and Molecular Neurobiology.

[47]  G. Reynolds,et al.  The effect of atypical and classical antipsychotics on sub-chronic PCP-induced cognitive deficits in a reversal-learning paradigm , 2006, Behavioural Brain Research.

[48]  S. Dunnett,et al.  Selective extra-dimensional set shifting deficit in a knock-in mouse model of Huntington's disease , 2006, Brain Research Bulletin.

[49]  A. Hariri,et al.  Genetics of emotional regulation: the role of the serotonin transporter in neural function , 2006, Trends in Cognitive Sciences.

[50]  D. Grandy,et al.  Dopamine D2 receptors mediate reversal learning in male C57BL/6J mice , 2006, Cognitive, affective & behavioral neuroscience.

[51]  S. Kõks,et al.  Heterozygous mice with Ric-8 mutation exhibit impaired spatial memory and decreased anxiety , 2006, Behavioural Brain Research.

[52]  A. Roberts,et al.  Primate orbitofrontal cortex and adaptive behaviour , 2006, Trends in Cognitive Sciences.

[53]  B. Grant,et al.  The association between stress and drinking: modifying effects of gender and vulnerability. , 2005, Alcohol and alcoholism.

[54]  R. Morris,et al.  Conditional Inactivation of Presenilin 1 Prevents Amyloid Accumulation and Temporarily Rescues Contextual and Spatial Working Memory Impairments in Amyloid Precursor Protein Transgenic Mice , 2005, The Journal of Neuroscience.

[55]  Patrick R Hof,et al.  Mice lacking dopamine D2 and D3 receptors exhibit differential activation of prefrontal cortical neurons during tasks requiring attention. , 2005, Cerebral cortex.

[56]  Mario R. Capecchi,et al.  Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century , 2005, Nature Reviews Genetics.

[57]  L. Saksida,et al.  Discrimination of multidimensional visual stimuli by mice: intra- and extradimensional shifts. , 2005, Behavioral neuroscience.

[58]  Peter B. Jones,et al.  Visuospatial learning and executive function are independently impaired in first-episode psychosis , 2005, Psychological Medicine.

[59]  Claude Messier,et al.  Longitudinal evaluation of memory performance and peripheral neuropathy in the Ins2C96Y Akita mice , 2005, Behavioural Brain Research.

[60]  E. Murphy,et al.  PDE10A inhibition reverses subchronic PCP‐induced deficits in attentional set‐shifting in rats , 2005, The European journal of neuroscience.

[61]  Brian J. Morris,et al.  Impairment in perceptual attentional set-shifting following PCP administration: a rodent model of set-shifting deficits in schizophrenia , 2005, Psychopharmacology.

[62]  C. Large,et al.  Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and d-amphetamine in the rat , 2005, Psychopharmacology.

[63]  J. Crawley.  Designing mouse behavioral tasks relevant to autistic-like behaviors. , 2004, Mental retardation and developmental disabilities research reviews.

[64]  D. Bartsch,et al.  Stress-Induced Anhedonia in Mice is Associated with Deficits in Forced Swimming and Exploration , 2004, Neuropsychopharmacology.

[65]  E. Lander,et al.  Finishing the euchromatic sequence of the human genome , 2004 .

[66]  J. Bonfield,et al.  Finishing the euchromatic sequence of the human genome , 2004, Nature.

[67]  H. Rauvala,et al.  Impaired behavioural flexibility and memory in mice lacking GDNF family receptor α2 , 2004, The European journal of neuroscience.

[68]  Seth J. Ramus,et al.  Cocaine‐experienced rats exhibit learning deficits in a task sensitive to orbitofrontal cortex lesions , 2004, The European journal of neuroscience.

[69]  H. Lipp,et al.  Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1 , 2004, The European journal of neuroscience.

[70]  J. Podhorná,et al.  Subchronic phencyclidine treatment impairs performance of C57BL/6 mice in the attentional set-shifting task , 2004, Behavioural pharmacology.

[71]  J. Rawlins,et al.  Spatial reference memory in GluR‐A‐deficient mice using a novel hippocampal‐dependent paddling pool escape task , 2004, Hippocampus.

[72]  B. Yee,et al.  Behavioral and neurochemical characterization of transgenic mice carrying the human presenilin-1 gene with or without the leucine-to-proline mutation at codon 235 , 2003, Experimental Neurology.

[73]  T. Robbins,et al.  Dissociable Contributions of the Orbitofrontal and Infralimbic Cortex to Pavlovian Autoshaping and Discrimination Reversal Learning: Further Evidence for the Functional Heterogeneity of the Rodent Frontal Cortex , 2003, The Journal of Neuroscience.

[74]  T. Doetschman,et al.  Protein tyrosine phosphatase alpha (PTPα) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety , 2003, Brain Research.

[75]  W. Hauber,et al.  NMDA receptors in the rat orbital prefrontal cortex are involved in guidance of instrumental behaviour under reversal conditions. , 2003, Cerebral cortex.

[76]  Bita Moghaddam,et al.  Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability. , 2003, Behavioral neuroscience.

[77]  J. Rawlins,et al.  GluR-A-Deficient mice display normal acquisition of a hippocampus-dependent spatial reference memory task but are impaired during spatial reversal. , 2003, Behavioral neuroscience.

[78]  Wolfgang Hauber,et al.  Orbital prefrontal cortex and guidance of instrumental behaviour in rats under reversal conditions , 2003, Behavioural Brain Research.

[79]  F. Plattner,et al.  Improved reversal learning and altered fear conditioning in transgenic mice with regionally restricted p25 expression , 2003, The European journal of neuroscience.

[80]  S. File,et al.  A review of 25 years of the social interaction test. , 2003, European journal of pharmacology.

[81]  G. Reynolds,et al.  The atypical antipsychotic ziprasidone, but not haloperidol, improves phencyclidine-induced cognitive deficits in a reversal learning task in the rat , 2003, Journal of psychopharmacology.

[82]  T. Robbins,et al.  Executive dysfunction in first-episode schizophrenia and relationship to duration of untreated psychosis: The West London Study , 2002, British Journal of Psychiatry.

[83]  A. Lichtman,et al.  Evaluation of CB1 receptor knockout mice in the Morris water maze. , 2002, The Journal of pharmacology and experimental therapeutics.

[84]  H. Lipp,et al.  Attentional set-shifting in mice: modification of a rat paradigm, and evidence for strain-dependent variation , 2002, Behavioural Brain Research.

[85]  J. Bureš,et al.  Specific spatial learning deficits become severe with age in β-amyloid precursor protein transgenic mice that harbor diffuse β-amyloid deposits but do not form plaques , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[86]  L. Saksida,et al.  Discrimination of computer-graphic stimuli by mice: a method for the behavioral characterization of transgenic and gene-knockout models. , 2001, Behavioral Neuroscience.

[87]  S. Turner,et al.  Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695* , 2001, The Journal of Biological Chemistry.

[88]  V. Denenberg,et al.  Facilitated stimulus-response associative learning and long-term memory in mice lacking the NTAN1 amidase of the N-end rule pathway , 2001, Brain Research.

[89]  R. Roth,et al.  Object retrieval/detour deficits in monkeys produced by prior subchronic phencyclidine administration: evidence for cognitive impulsivity , 2000, Biological Psychiatry.

[90]  G. Schoenbaum,et al.  Changes in Functional Connectivity in Orbitofrontal Cortex and Basolateral Amygdala during Learning and Reversal Training , 2000, The Journal of Neuroscience.

[91]  P. Greengard,et al.  DARPP-32 knockout mice exhibit impaired reversal learning in a discriminated operant task , 2000, Brain Research.

[92]  V. Brown,et al.  Medial Frontal Cortex Mediates Perceptual Attentional Set Shifting in the Rat , 2000, The Journal of Neuroscience.

[93]  J. Price,et al.  Effects of excitotoxic lesions in the ventral striatopallidal–thalamocortical pathway on odor reversal learning: inability to extinguish an incorrect response , 2000, Experimental Brain Research.

[94]  A. Granholm,et al.  Loss of Cholinergic Phenotype in Basal Forebrain Coincides with Cognitive Decline in a Mouse Model of Down's Syndrome , 2000, Experimental Neurology.

[95]  A. Diamond,et al.  Cognitive Deficits in a Genetic Mouse Model of the Most Common Biochemical Cause of Human Mental Retardation , 1999, The Journal of Neuroscience.

[96]  T. Robbins,et al.  Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage , 1999, Schizophrenia Research.

[97]  J. Crabbe,et al.  Genetics of mouse behavior: interactions with laboratory environment. , 1999, Science.

[98]  R. Roth,et al.  The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia , 1999, Neuropsychopharmacology.

[99]  R P Kesner,et al.  Involvement of rodent prefrontal cortex subregions in strategy switching. , 1999, Behavioral neuroscience.

[100]  U. Frey,et al.  Deficits in memory tasks of mice with CREB mutations depend on gene dosage. , 1998, Learning & memory.

[101]  D. Hampson,et al.  Altered spatial learning and memory in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. , 1998, Behavioral neuroscience.

[102]  T. Robbins,et al.  Executive function in first-episode schizophrenia , 1998, Psychological Medicine.

[103]  T. Bussey,et al.  Triple dissociation of anterior cingulate, posterior cingulate, and medial frontal cortices on visual discrimination tasks using a touchscreen testing procedure for the rat. , 1997, Behavioral neuroscience.

[104]  R. Roth,et al.  Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. , 1997, Science.

[105]  R. Roth,et al.  Subchronic Phencyclidine Administration Reduces Mesoprefrontal Dopamine Utilization and Impairs Prefrontal Cortical-Dependent Cognition in the Rat , 1997, Neuropsychopharmacology.

[106]  A. Bartke,et al.  Inhibitory Avoidance and Appetitive Learning in Aged Normal Mice: Comparison with Transgenic Mice Having Elevated Plasma Growth Hormone Levels , 1997, Neurobiology of Learning and Memory.

[107]  P. Goldman-Rakic.  The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive. , 1996, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[108]  T. Robbins,et al.  Neuropsychological evidence for frontostriatal dysfunction in schizophrenia , 1995, Psychological Medicine.

[109]  P. Rabbitt,et al.  Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. , 1994, Dementia.

[110]  J. Krystal,et al.  Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. , 1994, Archives of general psychiatry.

[111]  T. Bussey,et al.  A novel automated touchscreen procedure for assessing learning in the rat using computer graphic stimuli , 1994 .

[112]  I. Weiner,et al.  From an animal model of an attentional deficit towards new insights into the pathophysiology of schizophrenia. , 1992, Journal of psychiatric research.

[113]  D. Javitt,et al.  Recent advances in the phencyclidine model of schizophrenia. , 1991, The American journal of psychiatry.

[114]  M. F. Elias,et al.  Reversal learning and RNA labeling in neurological mutant mice and normal littermates. , 1972, Physiology & behavior.

[115]  N. Mackintosh,et al.  Factors underlying improvement in serial reversal learning. , 1968, Canadian journal of psychology.

[116]  D. A. Grant,et al.  A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a Weigl-type card-sorting problem. , 1948, Journal of experimental psychology.

[117]  D. Grandy,et al.  Dopamine D 2 receptors mediate reversal learning in male C57BL/6J mice , 2010 .

[118]  T. Robbins.  Synthesizing schizophrenia: a bottom-up, symptomatic approach. , 2005, Schizophrenia bulletin.

[119]  Paul J. Harrison,et al.  Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence , 2005, Molecular Psychiatry.

[120]  A. Lichtman,et al.  Evaluation of CB 1 Receptor Knockout Mice in the Morris Water Maze , 2002 .

[121]  JaneR . Taylor,et al.  Impaired Inhibition of Conditioned Responses Produced by Subchronic Administration of Phencyclidine to Rats , 2001, Neuropsychopharmacology.

[122]  E. Miller,et al.  An integrative theory of prefrontal cortex function. , 2001, Annual review of neuroscience.

[123]  A. Ouwehand,et al.  the effect , 2002 .