Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia

Abstract

Cognitive deficits in schizophrenia are among the core symptoms of the disease, correlate with functional outcome, and are not well treated with current antipsychotic therapies. In order to bring together academic, industrial, and governmental bodies to address this great ‘unmet therapeutic need’, the NIMH sponsored the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. Through careful factor analysis and consensus of expert opinion, MATRICS identified seven domains of cognition that are deficient in schizophrenia (attention/vigilance, working memory, reasoning and problem solving, processing speed, visual learning and memory, verbal learning and memory, and social cognition) and recommended a specific neuropsychological test battery to probe these domains. In order to move the field forward and outline an approach for translational research, there is a need for a “preclinical MATRICS” to develop a rodent test battery that is appropriate for drug development. In this review, we outline such an approach and review current rodent tasks that target these seven domains of cognition. The rodent tasks are discussed in terms of their validity for probing each cognitive domain as well as a brief overview of the pharmacology and manipulations relevant to schizophrenia for each task.

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

“…Visual memory deficits may be measured by recognition tasks such as the novel object recognition (NOR) paradigm as described in TURNS [reviewed in Dere et al, (2007), Winters et al (2008), Young et al (2009)]. A recognition memory task allows the comparison between presented stimuli and previously stored information.…”

“…The 5-choice Serial Reaction Time Task (5-CSR) is detailed in other reviews (Robbins, 2002;Chudasama & Robbins, 2004;Young et al, 2009) Extensive work using excitotoxic agents to lesion specific areas of the brain has elucidated certain brain regions with direct involvement in performance of the task. The first is the prefrontal cortex (PFC), in which specific behavioural aspects of the task can be dissociated to specific sub-regions such as the mPFC, orbitofrontal, infralimbic and prelimbic cortices.…”

“…There have been some excellent recent and extensive reviews in this subject area. These include -the use of the MATRICS test battery as a guide to using preclinical tests for studying novel targets for cognitive improvement in schizophrenia (Young et al 2009); exploration of the mechanisms by which NMDA receptor antagonism provides a relevant model of schizophrenia in animals (Jentsch and Roth, 1999;Coyle, 2006;Large, 2007-focusing on novel therapies; Morris et al 2005;Mouri et al 2007); the use of isolation rearing as a neurodevelopmental model (Fone and Porkess, 2008); and strategies for improving pharmacotherapy of schizophrenia ). In addition the debate continues concerning the value (or otherwise) of current antipsychotic medication for improvement of cognitive deficit symptoms in the clinic.…”

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

“…To examine the effect of VGLUT1-targeting shRNA 5 on learning and memory, mice underwent a range of tasks with translational relevance to three distinct cognitive domains affected in schizophrenia (Young et al, 2009;Orosz et al, 2008). First, nonspatial visual recognition memory was examined using a hippocampal-dependent NOD task (Hammond et al, 2004;Broadbent et al, 2004) based on rodents innate preference for novelty, rather than food reward or negative reinforcement, which therefore involves similar motivational conditions to those under which human memory is normally assessed.…”

“…PPI is a well-recognized measure of sensorimotor gating and preattentional processing, which is deficient in patients with schizophrenia (Young et al, 2009) and known to be regulated by the hippocampus, prefrontal cortex, amygdala, striatum, nucleus accumbens, and thalamus (Koch, 1999;Swerdlow et al, 2001). In the current study, when PPI was examined 19-20 days after lentiviral vector administration, control and VGLUT1-targeting shRNA-treated mice both exhibited the normal attenuation of startle by increased prepulse amplitude (F (3, 52) ¼ 6.585, Po0.001) with no main Cognitive testing concluded with assessment of associative learning and memory in a contextual fear conditioning task.…”