New translational assays for preclinical modelling of cognition in schizophrenia: The touchscreen testing method for mice and rats

doi:10.1016/j.neuropharm.2011.04.011

Neuropharmacology

Volume 62, Issue 3, March 2012, Pages 1191-1203

https://doi.org/10.1016/j.neuropharm.2011.04.011 Get rights and content

Abstract

We describe a touchscreen method that satisfies a proposed ‘wish-list’ of desirables for a cognitive testing method for assessing rodent models of schizophrenia. A number of tests relevant to schizophrenia research are described which are currently being developed and validated using this method. These tests can be used to study reward learning, memory, perceptual discrimination, object-place associative learning, attention, impulsivity, compulsivity, extinction, simple Pavlovian conditioning, and other constructs. The tests can be deployed using a ‘flexible battery’ approach to establish a cognitive profile for a particular mouse or rat model. We have found these tests to be capable of detecting not just impairments in function, but enhancements as well, which is essential for testing putative cognitive therapies. New tests are being continuously developed, many of which may prove particularly valuable for schizophrenia research.

This article is part of a Special Issue entitled ‘Schizophrenia’.

Highlights

► We describe a touchscreen method for assaying cognition in rodent models. ► A number of tests relevant to schizophrenia research are described. ► The tests can be used to study multiple aspects of cognition. ► The tests can be combined in a flexible battery to establish a cognitive profile. ► The tests are capable of detecting both impairments and enhancements in function.

Section snippets

Introduction: cognitive testing in preclinical schizophrenia research

“Antipsychotic drugs have emptied out our mental institutions, but have delivered their residents to impoverished lives outside. Research has linked elements of this poor psychosocial function to persistent cognitive impairments.” (Geyer and Tamminga, 2004)

It is now widely understood that the profound cognitive changes in schizophrenia, as much as the so-called ‘positive’ and ‘negative’ symptoms (see other articles in this issue), require understanding and treatment. To this end, major

The touchscreen testing method

With the wish-list in mind, we have developed an automated apparatus and method that uses a computer monitor to present stimuli, and an infra-red ‘touch-screen’ assembly with which an animal can register its response (Fig. 1). Rewards can be food pellets or liquid reinforcers such as strawberry milkshake (which we have found to be particularly motivating, ameliorating some of the problems that can be associated with decreased motivation described above). We have developed a number of tests that

A ‘flexible’ battery approach

“All putative animal models [of neuropsychiatric disorders] should be evaluated with the broadest range possible of behavioral assays” Nestler and Hyman (2010)

Although each of the above tasks can be used alone, we would advocate the use of a ‘battery’ approach to establish a cognitive profile of an animal. In this way a given task in the battery not only yields useful results in its own right, it can serve as a control for other tasks in the battery. Thus, if an animal fails object-place paired

Summary

The touchscreen testing method satisfies what we think is a fairly non-controversial ‘wish-list’ of desirables for a cognitive testing method for assessing rodent models of schizophrenia. A number of tests relevant to schizophrenia research are currently being validated. These tasks can be deployed using a ‘flexible battery’ approach to establish a cognitive profile for a particular mouse model. We have found these tasks to be capable of detecting not just impairments in function, but

Acknowledgements

All authors contributed equally to the preparation of this manuscript; names are listed alphabetically. The authors would like to thank Trevor Robbins for comments on an early version of the manuscript and John Talpos for kindly providing some components of Fig. 1. This work was supported by funding from the Commonwealth Trust, Janssen Pharmaceutica, the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program, and the Innovative Medicines Initiative Joint Undertaking (IMI)

References (207)

J.P. Aggleton et al.
Removal of the hippocampus and transection of the fornix produce comparable deficits on delayed non-matching to position by rats
Behav. Brain Res.
(1992)
J.B. Aimone et al.
Adult neurogenesis: integrating theories and separating functions
Trends Cogn. Sci.
(2010)
N. Amitai et al.
Increased impulsivity and disrupted attention induced by repeated phencyclidine are not attenuated by chronic quetiapine treatment
Pharmacol. Biochem. Behav.
(2009)
N. Amitai et al.
Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-d-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia
Biol. Psychiatry
(2010)
A.F.T. Arnsten et al.
The effects of 5-HT3 receptor antagonists on cognitive performance in aged monkeys
Neurobiol. Aging
(1997)
G. Aubin et al.
Daily activities, cognition and community functioning in persons with schizophrenia
Schizophr. Res.
(2009)
E. Bartok et al.
Cognitive functions in prepsychotic patients
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2005)
C. Beasley et al.
Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia
Neurosci. Lett.
(2001)
B. Bogerts et al.
Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia
Psychiatry Res.
(1990)
T.S. Braver et al.
Cognition and control in schizophrenia: a computational model of dopamine and prefrontal function
Biol. Psychiatry
(1999)

T.J. Bussey et al.

Distinct patterns of behavioural impairments resulting from fornix transection or neurotoxic lesions of the perirhinal and postrhinal cortices in the rat

Behav. Brain Res.

(2000)

Y. Chudasama et al.

Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity

Behav. Brain Res.

(2003)

Y. Chudasama et al.

Functions of frontostriatal systems in cognition: comparative neuropsychopharmacological studies in rats, monkeys and humans

Biol. Psychol.

(2006)

S. Dakin et al.

Weak suppression of visual context in chronic schizophrenia

Curr. Biol.

(2005)

J.W. Dalley et al.

Deficits in impulse control associated with tonically-elevated serotonergic function in rat prefrontal cortex

Neuropsychopharmacology

(2002)

N.A. DeCarolis et al.

Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation

Neuropharmacology

(2010)

C. Diaz-Asper et al.

Context binding in schizophrenia: effects of clinical symptomatology and item content

Psychiatry Res.

(2008)

G. Donohoe et al.

Are relational style and neuropsychological performance predictors of social attributions in chronic schizophrenia?

Psychiatry Res.

(2008)

X. Duan et al.

Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain

Cell

(2007)

L. Duffy et al.

Cognition in transmembrane domain neuregulin 1 mutant mice

Neuroscience

(2010)

H. Eichenbaum

The hippocampus and mechanisms of declarative memory

Behav. Brain Res.

(1999)

P.F. Fitzgerald et al.

Does gene deletion of AMPA GluA1 p.enocopy features of schizoaffective disorder?

Neurobiol. Dis

(2010)

T.E. Goldberg et al.

Relations between neuropsychological performance and brain morphological and physiological measures in monozygotic twins discordant for schizophrenia

Psychiatry Res.

(1994)

B. Grayson et al.

Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat

Behav. Brain Res.

(2007)

A. Holmes et al.

Pharmacological facilitation of fear extinction and the search for adjunct treatments for anxiety disorders–the case of yohimbine

Trends Pharmacol. Sci.

(2010)

A. Holmes et al.

Stress-induced prefrontal reorganization and executive dysfunction in rodents

Neurosci. Biobehav. Rev.

(2009)

A. Izquierdo et al.

Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice

Behav. Brain Res.

(2006)

J.D. Jentsch et al.

Impairments of reversal learning and response perseveration after repeated, intermittent cocaine administrations to monkeys

Neuro-psychopharmacology

(2002)

R.M. Karlsson 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

Biol. Psychiatry

(2008)

G. Keilhoff et al.

Increased neurogenesis in a rat ketamine model of schizophrenia

Biol. Psychiatry

(2004)

D. Kim et al.

Magnocellular contributions to impaired motion processing in schizophrenia

Schizophr. Res.

(2006)

N. Amitai et al.

Cognitive-disruptive effects of the psychotomimetic phencyclidine and attenuation by atypical antipsychotic medications in rats

Psychopharmacology

(2007)

A. Bakker et al.

Pattern separation in the human hippocampal CA3 and dentate gyrus

Science

(2008)

D.M. Barch et al.

CNTRICS final task selection: working memory

Schizophr. Bull.

(2009)

(2010)

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New translational assays for preclinical modelling of cognition in schizophrenia: The touchscreen testing method for mice and rats

Abstract

Highlights

Section snippets

Introduction: cognitive testing in preclinical schizophrenia research

The touchscreen testing method

A ‘flexible’ battery approach

Summary

Acknowledgements

Behav. Brain Res.

Trends Cogn. Sci.

Pharmacol. Biochem. Behav.

Biol. Psychiatry

Neurobiol. Aging

Schizophr. Res.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Neurosci. Lett.

Psychiatry Res.

Biol. Psychiatry

Behav. Brain Res.

Behav. Brain Res.

Biol. Psychol.

Curr. Biol.

Neuropsychopharmacology

Neuropharmacology

Psychiatry Res.

Psychiatry Res.

Cell

Neuroscience

Behav. Brain Res.

Neurobiol. Dis

Psychiatry Res.

Behav. Brain Res.

Trends Pharmacol. Sci.

Neurosci. Biobehav. Rev.

Behav. Brain Res.

Neuro-psychopharmacology

Biol. Psychiatry

Biol. Psychiatry

Schizophr. Res.

Cognitive-disruptive effects of the psychotomimetic phencyclidine and attenuation by atypical antipsychotic medications in rats

Psychopharmacology

Pattern separation in the human hippocampal CA3 and dentate gyrus

Science

CNTRICS final task selection: working memory

Schizophr. Bull.

Visuospatial learning and executive function are independently impaired in first-episode psychosis

Psychol. Med.

A computer-automated touchscreen paired-associates learning (PAL) task for mice: impairments following administration of scopolamine or dicyclomine, and improvements following donepezil

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Haloperidol and clozapine have dissociable effects in a model of attentional performance deficits induced by blockade of NMDA receptors in the mPFC

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Double dissociation of the effects of medial and orbital prefrontal cortical lesions on attentional and affective shifts in mice

J. Neurosci.

Discrimination accuracy and decision biases in different types of reality monitoring in schizophrenia

J. Nerv. Ment. Dis.

Discrimination of multidimensional visual stimuli by mice: Intra- and extradimensional shifts

Behav. Neurosci.

Effects of subchronic phencyclidine (PCP) treatment on social behaviors, and operant discrimination and reversal learning in C57BL/6J mice

Front Behav. Neurosci.

Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit

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