Establishing a novel cognitive task in rats of relevance to schizophrenia

published: 12 March 2015 in Frontiers in Human Neuroscience, 9. Abstract Hyperlink: http://www.frontiersin. org/10.3389/conf.fnhum. 2015.217. 00316/event_abstractHyperlink: http://www.frontiersin. org/10.3389/conf.fnhum. 2015.217. 00316/event_abstract Chapter 3. Comparison of 5CSRTT and SDT 35 3.2. 2 Introduction Cognitive symptoms are the strongest predictor of functional outcomes in patients with schizophrenia, yet current antipsychotic medications are no more effective in treating cognitive symptoms than those developed in the 1950’s (Green et al., 2000; Keefe et al., 2007). To guide future clinical research in the development of more effective medications, the MATRICS panel was formed (Green and Nuechterlein, 2004). For each domain of cognition, tasks administered in human subjects were selected as part of a cognitive battery for assessing the efficacy of novel medications (Nuechterlein et al., 2008). Within the domain of attention/vigilance they selected versions of the CPT (Nuechterlein et al., 2008). Following these recommendations the CNTRICS panel devised a similar list of tasks for evaluating these cognitive domains in animals (Carter and Barch, 2007). These tasks were selected based on evidence of face, predictive and construct validity relative to the human CPT and each has been reverse-translated back into human tasks (Demeter et al., 2008; Young et al., 2009a; Young et al., 2013b; Worbe et al., 2014). A key issue that was raised throughout this process was the need for greater translational validity between rodent and human tasks (Hagan and Jones, 2005; Young et al., 2009a). The purpose of this study was to further develop a CPT-like task for the assessment of attention in rodents. Firstly, elements of the human CPT and dissimilarities with current rodent protocols were carefully considered. The human CPT exists in many versions with deficits in schizophrenia patients widely reported (Earle-Boyer et al., 1991; Cornblatt and Keilp, 1994). These deficits have even been suggested to represent an endophenotype of schizophrenia as there is evidence of mild deficits in first-degree relatives, stability in patients from first-episode through to remission, and a lack of correlation between severity of psychotic symptoms and CPT deficits (Chen and Faraone, 2000; Snitz et al., 2006; Gur et al., 2007; Delawalla et al., 2008; Richard et al., 2013). A common feature of continuous performance tasks is the rapid presentation of stimuli where the subject is required to monitor, identify and respond to target stimuli. Key outcome measures are the accuracy of responding and the reaction times of participants, with both measures altered in schizophrenia patients. By translating important features of the human CPT into a rodent task, researchers can more invasively investigate how attentional deficits are related to neurobiological changes and test novel drug targets for treating cognitive symptoms in schizophrenia. Chapter 3. Comparison of 5CSRTT and SDT 36 The corresponding rodent tasks selected for the domain of attention were the 5CSRTT, 5C-CPT and SAT (Lustig et al., 2013). The 5CSRTT has been widely used in rats and mice with extensive investigation of the underlying neurobiology and use of pharmacological agents to probe performance (Robbins, 2002). It has been shown to be highly sensitive to pharmacological agents and to manipulations used in animal models of schizophrenia (Chudasama and Robbins, 2004; Featherstone et al., 2007b; Fletcher et al., 2007; Paine and Carlezon, 2009). The 5CSRTT requires rodents to attend to an array of five apertures and make a nose poke response into an illuminated aperture. As an extension of this paradigm, the 5C-CPT incorporates a subset of trials requiring inhibition of responding when all five apertures illuminate to receive a reward. Therefore the 5C-CPT allows the assessment of response inhibition, which is an important component of executive functioning. A clear difference between human CPT and the rodent 5CSRTT is the use of a spatial array of stimuli and response locations. In contrast, a single, constant position is typically used for presenting stimuli and responding on the CPT for human subjects. While the rodent may correctly identify the response location via a spatial stimulus-response association in the 5CSRTT, the human CPT requires the maintenance of a rule to determine the correct response based on stimulus properties. Hence, the use of a rule is a valuable feature of the rodent SAT protocol when considering translational task components. The SAT requires the detection of a single, central stimulus followed by a response on the correct lever to receive a reward (McGaughy and Sarter, 1995a). On a subset of trials, a flashing light can also be presented to assess performance changes during dSAT. The SAT has incorporated the use of a rule about the properties of a single stimulus, however it has not been as widely used or validated as the 5CSRTT. In both these tasks a major issue that has not been addressed is the lack of control over the rodent’s body position during stimulus presentation. In human studies the subject is often placed in a fixed position relative to the stimuli and maintains eye gaze in the direction of the stimulus stream. However, in rodent tasks, the animal can move anywhere within the operant chamber and may not have the stimuli within their visual field when it is presented. This leads to a number of differences in the interpretation of performance measures between human and rodent testing. Firstly, accuracy will depend on the body position of the rodent during stimuli presentation. However, body position cannot be determined without additional video recording and tracking analysis. Secondly, the lack of control over body position interferes with the interpretation of omission errors. In human studies an omission most likely occurs when Chapter 3. Comparison of 5CSRTT and SDT 37 the subject misses a stimuli due to a lapse in vigilance, whereas in rodents studies an omission may occur for any number of reasons including grooming, sleeping or investigating the chamber. To demonstrate the importance of body position, we analysed video recordings from our previous 5CSRTT study in rats (Turner et al., 2013) and show that more omissions occurred when the rat was more distant and had their head turned during stimulus onset (see Figure 3.1). Figure 3.1 5CSRTT Body Position On 5CSRTT the angle of the rat’s head and distance from the stimulus are important for correct identification of the illuminated aperture. Correct responses typically occurred when the rat was very close to or looking straight at the 5-hole wall. However, rats were frequently on the other side of the chamber and looking away from the 5 holes prior to an omission (dotted line indicates half the width of the chamber). The plot shows individual responses from seven rats with correct, incorrect and omission responses. Another point raised by CNTRICS for the optimisation of rodent testing included reducing the training time to encourage more widespread use (Lustig et al., 2013). Reducing the time required to train rodents on cognitive tasks would also promote preclinical screening of novel compounds, which has been limited due to the extensive investment required. Another issue that has been raised is the acknowledgment that no task provides a pure assessment of a single cognitive modality and therefore a number of behaviour measures should be considered when interpreting changes in performance. Therefore, it was suggested that tasks should endeavour to include dimensions where performance can be concurrently observed over a range of difficulties, such that deficits due to more general impairments can be isolated from cognitive deficits (Lustig et al., 2013). This would serve 0 50 100 150 200 0 5 10 15 20 25 Head Angle (°) D is ta nc e (c m ) 5CSRTT Body Position