PMC:2938983 / 13554-19063 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/2938983","sourcedb":"PMC","sourceid":"2938983","source_url":"https://www.ncbi.nlm.nih.gov/pmc/2938983","text":"Touchscreen-Based Measure of Reversal Learning in Mice\nVarious tasks have been developed to measure reversal in rats and mice in maze (Mackintosh et al., 1968; Ragozzino et al., 1999; Stefani et al., 2003; Floresco et al., 2008) as well as operant settings (e.g., Ferry et al., 2000; Schoenbaum et al., 2000; Bohn et al., 2003a,b; Schoenbaum et al., 2004) (Figures 2B–D). In an effort to provide a procedure that was more analogous and comparable to reversal tasks being employed in patients (Robbins et al., 1994) and higher species (non-human primates), Bussey and colleagues established a touchscreen-based operant system in which rats and mice learn to discriminate and reverse between two visual stimuli projected onto a touch-sensitive computer screen (Bussey et al., 1994, 2001) (Figure 2E). Demonstrating the translatable potential for mapping mouse studies onto systems in the human, reversal performance in this system is PFC-dependent, as confirmed by lesion studies in the rat (Bussey et al., 1997; Chudasama and Robbins, 2003) and to some extent in the mouse (Brigman and Rothblat, 2008).\nIn addition to its comparability to human measures of reversal, this paradigm has several unique benefits (for discussion, see Bussey et al., 2008). Of note, the automation of the task makes it relatively free of experimenter influences that can vary across individuals and laboratories, and influence results (Crabbe et al., 1999). The system is also very flexible and can be easily adapted to test for other forms of cognition and executive function other than discrimination and reversal, such as extinction (Hefner et al., 2008), spatial paired-associate learning (associating an object with a spatial location) (Talpos et al., 2009) and pattern separation (discrimination of perceptually similar stimuli) (Clelland et al., 2009).\nIn our formulation of the task (Izquierdo et al., 2006; Brigman et al., 2008) (Figure 3), mice are first trained to initiate the appearance of the stimuli on-screen by a head entry into a magazine where food pellets are delivered (Figure 3A). There is then some training to shape the mouse to touch the screen to obtain reward before discrimination learning begins (Figure 3B). Discrimination is typically between two (i.e., pairwise) distinct visual stimuli, with responses on one stimulus rewarded with food and responses on the other producing a timeout period during which additional responses cannot be made (Figure 3C). After reaching a pre-determined criterion of discrimination (e.g., \u003e85% correct choices), the stimulus-reward contingencies are reversed and the subject must inhibit perseverative responses to the previously rewarded stimulus and learn to respond to the alternate, previously unrewarded, stimulus (Figure 3D).\nFigure 3 Touchscreen-based operant system for assaying discrimination and reversal learning in mice. Training and testing entails four stages. (A) To first teach the mouse to associate rewards with visual stimuli on the touchscreen, food pellets and stimuli are presented concomitantly. (B) Next, the mouse must respond to stimuli on the screen to obtain a reward (and also initiate new trials via a head-entry into the magazine). (C) During discrimination learning, two novel stimuli are presented on the screen, and the mouse must respond to one stimulus (to obtain reward) and not the other (to avoid non-reward and a timeout phase during which no new trials can be initiated). (D) In the final stage, the stimulus-reward contingency is reversed, and the mouse must now respond to the previously unrewarded stimulus to obtain reward. Note: the left/right position of rewarded stimuli varies pseudorandomly across trials, and the type of rewarded stimulus is counterbalanced across mice. The capacity for this system to concurrently assess discrimination as well as reversal learning provides an excellent internal control, not only for learning and behavioral performance generally, but also because discrimination is impaired in some cases of schizophrenia. For example, discrimination and reversal learning were significantly impaired in chronic hospitalized schizophrenic patients with frontal lobe damage (Pantelis et al., 1999). Interestingly, more stabilized patients were found to be more specifically impaired on reversal and EDS shifts (Elliott et al., 1995; Waltz and Gold, 2007) and some first-episode schizophrenics exhibited even more restricted, EDS-only, impairment (Hutton et al., 1998; Joyce et al., 2002; Braw et al., 2008). These findings raise the interesting possibility that the profile of discrimination/reversal/set-shifting impairment may be graded in a manner corresponding to the chronicity of schizophrenia (Joyce et al., 2002). On the other hand, there are clinical data showing clear deficits in both reversal and set-shifting in first-episode schizophrenics, and especially in those patients with prominent thought disorganization symptoms (Barnett et al., 2005; Murray et al., 2008; Leeson et al., 2009). One interpretation of these findings is that the breadth and pattern of deficits in discrimination/reversal/set-shifting may be more of a marker for specific subtypes of the disease rather than of disease severity (Leeson et al., 2009). The touchscreen procedure could prove to be valuable for delineating discrimination and reversal impairments in mouse models, and thereby shed light on the pathophysiology underlying their dissociation in different subpopulations of schizophrenic patients.","divisions":[{"label":"Title","span":{"begin":0,"end":54}},{"label":"Figure 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