Brigman et al. Executive functions A collection of higher-order mental processes that exert control over information processing, allowing for the ability to control, adapt and direct behavior in a manner appropriate to current environmental demands. These include, but are not limited to, attention, working memory, behavioral ﬂexibility and inhibition, and decision making. These processes are mediated by a well-conserved neural circuitry, including the prefrontal cortex (PFC) and interconnected subcortical regions, such as the striatum. Reversal learning A measure of cognitive ﬂexibility applicable across species in which subjects ﬁrst learn a stimulus-reward association, then the reward association is switched. This ostensibly simple process taxes multiple executive functions, including attention, working memory and response inhibition. Cognitive ﬂexibility Cognitive ﬂexibility is a critical executive function that can be broadly deﬁned as the ability to adapt behaviors in response to changes in the environment. The Wisconsin Card Sorting Task (WCST) is commonly used to test cognitive ﬂexibility in schizophrenic patients, and analogs have been developed for rodents (e.g., Birrell and Brown “digging task,” Birrell and Brown, 2000). In a collaborative venture with Bussey, Saksida and colleagues, 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 (Izquierdo et al., 2006), and by validating existing models of schizophrenia, such as subchronic phencycli- dine (PCP) treatment, in the touchscreen system and other mouse assays. We have sought to uti- lize these assays to elucidate mechanisms sub- serving complex behaviors and disease-related behavioral dysfunctions. As part of these efforts, we have examined pharmacological models of schizophrenia in our tasks, and recently reported on the effects of subchronic PCP treatment on social behavior and cognition (touchscreen-based visual discrimination and reversal learning) in non-mutant mice (Brigman et al., 2009). Here, we summarize these results and put them in the larger context of ongoing efforts in the ﬁeld to develop valid models of schizophrenia, or at least assays for some of the main symptoms of the disease, in mice. We begin with a brief overview of how the major symptoms of schizophrenia are clini- cally categorized and assayed by mouse behavioral tests. We go on to discuss in greater detail various mouse assays for “cognitive ﬂexibility”, including reversal learning – a type of executive function impaired in schizophrenia that we and others have highlighted as a particularly tractable, translatable process to measure in rodent models of schizo- phrenia. We end with some concluding remarks on some key questions to be addressed in future work. MODELING MAJOR SYMPTOM CATEGORIES OF SCHIZOPHRENIA IN MICE Schizophrenia is a highly heterogeneous disorder of myriad symptoms. The presentation of differ- ent symptoms and their severity varies consider- ably across patients. While this complexity cannot be fully recapitulated in the mouse, speciﬁc symp- tom categories can be behaviorally modeled in mice. A constructive starting point has been to demarcate schizophrenia-related phenotypes into the clinical categories of positive, negative and cognitive/executive symptoms (Arguello and Gogos, 2006; Powell and Miyakawa, 2006). Positive symptoms are so-called because they add to the normal behavioral repertoire.While a mouse test for hallucinations has not yet been proffered, Figure 1 | Mouse behavioral assays for the major symptom categories of schizophrenia. Positive symptoms. The psychomotor agitation and hyper-responsivity to psychotomimetic drugs found in schizophrenia can be modeled in mice by testing locomotor responses in novel and stressful environments (A) and locomotor hyperactivity-inducing effects of psychotomimetics, such as NMDAR antagonists (B), respectively. Negative symptoms. Schizophrenia is often associated with blunted affect, social withdrawal, and loss of pleasure in normally rewarding activities (anhedonia). Social interactions with other mice (C) and decreased preference or motivation to obtain rewarding substances, such as sucrose (D), can be assessed as a means to model these negative symptoms. Cognitive/executive symptoms. Abnormalities in cognition and executive functions are a prominent feature of schizophrenia and range from deﬁcits i n episodic memory, poor attention and sensorimotor gating, to impaired reversal learning and set-shifting. Learning and memory can be tested in mice using, e.g., the reference memory version of the Morris water maze (E), while prepulse inhibition of the startle response provides a ready measure of sensorimotor gating (F). 20 | May 2010 | Volume 4 | Issue 1 www.frontiersin.org