other positive symptoms, such as psychomotor agi- tation and hyper-responsivity to psychotomimetic drugs, can be modeled in mice by testing locomo- tor responses (particularly under provocative situa- tions, such as stressful environments) (Figure 1A), and locomotor hyperactivity-inducing effects of psychostimulants (e.g., amphetamine) and other psychotomimetics [e.g., N-methyl-Δ-aspartate receptor (NMDAR) antagonists dizocilpine/ MK-801 or PCP; Figure 1B]. Rodent models of schizophrenia have tradition- ally focused on positive symptoms, and this has provided many important mechanistic insights and drug leads. However, there has been a growing emphasis on studying, modeling and treating the negative and cognitive/executive symptoms of the disease (Carter et al., 2008). Negative symptoms (so-called because they subtract from the nor- mal behavioral repertoire) include blunted affect, social withdrawal and loss of pleasure in normally rewarding activities (anhedonia). Various rodent assays for social behavior and anhedonia (e.g., decreased preference or motivation to obtain rewarding substances such as sucrose) have been typically used to model other disorders, such as anxiety (File and Seth, 2003), autism (Crawley, 2004) and depression (Strekalova et al., 2004), but also lend themselves well to the study of abnor- malities in these behaviors in models of schizo- phrenia (Figures 1C,D). The category of cognitive/executive symptoms covers a range of abnormalities: from deﬁcits in episodic memory to impaired attention and sen- sorimotor gating. Assays for prepulse inhibition and latent inhibition provide ready measures of sensorimotor gating and selective attention, respectively, that can be applied across species (Figure 1F). Both have been widely employed as a screen for antipsychotics and a measure of schizophrenia-related phenotypes in mutant mice (Feldon and Weiner, 1992; Geyer et al., 2001). There are also numerous very well-studied methods for testing various forms of cognition, such as the spatial reference memory version of the Morris water maze (Figure 1E). However, although impaired episodic memory is one of the strongest features of the cognitive proﬁle of schizophrenia (Ranganath et al., 2008), rodent models of this disease have not relied upon such measures – perhaps because they do not distin- guish a model of schizophrenia from other con- ditions that are also characterized by memory deﬁcits, e.g., Alzheimer’s disease. MOUSE ASSAYS FOR COGNITIVE FLEXIBILITY Executive functions subserve the selection and processing of information necessary to plan, Cognitive ﬂexibility in mice control and direct behavior in a manner appro- priate to current environmental demands. Across species, these processes are mediated by neural circuitry including the prefrontal cortex (PFC) and interconnected subcortical regions, such as the striatum (Goldman-Rakic, 1996; Miller and Cohen, 2001; Floresco et al., 2009). Pathology in these circuits is a hallmark of schizophrenia (Robbins, 2005; Lewis and Gonzalez-Burgos, 2006; Tan et al., 2009), and is speciﬁcally tied to the profound executive deﬁcits exhibited by schizophrenic patients on measures of cognitive ﬂexibility described below. Cognitive ﬂexibility is a critical executive func- tion that can be broadly deﬁned as the ability to adapt behaviors in response to changes in the environment. The Wisconsin Card Sorting Task (WCST; Grant and Berg, 1948) has been one of the more commonly employed assays for impaired cognitive ﬂexibility in schizophrenic patients, and analogous versions have been developed for use in lower species, including mice (Table 2). In essence, these tasks involve the subject selecting between stimuli, which vary from one another in more than one perceptual dimension (or “set”), and being reinforced for choosing a stimulus based upon one speciﬁc dimension alone, e.g., odor. During an “intra-dimensional shift” (IDS), the form of the dimension the subject must choose is changed by the experimenter, e.g., from cinna- mon to chocolate odor. In an “extra-dimensional shift” (EDS), the correct dimension is changed altogether, such that choices must be guided by the new dimension (texture) while ignoring the previously rewarded dimension. In a rodent IDS/EDS analog of the WCST, rats (Birrell and Brown, 2000) or mice (Colacicco et al., 2002; Garner et al., 2006; Bissonette et al., 2008) dig in sand to make choices based on the dimension of texture or smell (Figure 2A). As in humans, this task is sensitive to PFC dam- age in rats (Birrell and Brown, 2000) and mice (Bissonette et al., 2008). One potentially salient difference with the human procedure is that the dimensions are in different sensory modalities [note: attempts to date to develop a IDS/EDS task using a single (visual) modality have not demon- strated the formation of an attentional set in the mouse (Brigman et al., 2005)]. Reversal learning provides another meas- ure of cognitive ﬂexibility. Subjects ﬁrst learn a stimulus-reward association, then the reward association is switched. Although reversal learn- ing has been described as hierarchically less complex than set-shifting, it requires ﬂexible switching between cues within the same percep- tual dimension or modality, and taxes multiple Frontiers in Neuroscience May 2010 | Volume 4 | Issue 1 | 21