A schizophrenia relevant 5-Choice Serial Reaction Time Task for mice assessing broad monitoring, distractibility and impulsivity

Abstract

The 5-Choice Serial Reaction Time Task (5-CSRTT) is an automated test for rodents allowing the assessment of multiple cognitive measures. Originally designed to assess cognitive deficits relevant to attention deficit hyperactivity disorder, it has been widely used in the investigation of neural systems of attention. In the current study, we have set up a modified version, which reduced the training phase to only 8-9 days with minimal food deprivation and without single-housing. Furthermore, based on evidence that patients with schizophrenia are more impaired in broad monitoring abilities than in sustained attention, we successfully developed a protocol replicating the Spatial Attentional Resource Allocation Task (SARAT), used in humans to assess broad monitoring. During this task, when the target appeared at a single pre-cued location, mice selectively responded faster. Instead, increasing the number of validly cued locations proportionately decreased accuracy. We then validated a protocol which is relevant for neuropsychiatric disorders in which additional irrelevant pre-cue lights selectively disrupted attention (distractibility). Finally, we improved previously used protocols changing inter-trial intervals from 5 to 7 s by randomly presenting this shift only in 20% of the trials. This resulted in a selective effect on premature responses (impulsivity), with important implications for schizophrenia as well as for other mental disorders. Therefore, this revised 5-CSRTT reduced training and stress on the animals while selectively measuring different cognitive functions with translational validity to schizophrenia and other psychiatric disorders.

Attentional Control in Adolescent Mice Assessed with a Modified Five Choice Serial Reaction Time Task

“…green flashing lights) randomly presented within the same session to more directly compare attentional performance with that of non-distractor trials, in order to avoid potential habituation processes found with noises 37 and confusion with the use of house lights 59 as reported in adults. Finally, as also previously discussed 47 , we were able to demonstrate clear differences between the SARAT and distractor paradigms. Briefly, the combination of tasks used in the current work show that the cue lights were not simply treated as target stimulus lights, as only non-predictive cues decreased the accuracy and that this was directly proportional to the degree of unpredictability (e.g.…”

“…To test whether the SARAT and the Distractor paradigms could grasp distinct aspects of attentional control in adolescent mice, we further implemented these two paradigms (Fig. 2 : SARAT v2 and Distractor v2 paradigms), as done in adult mice 47 . In particular, with the SARAT version 2, we directly linked mice performance to the number of presented pre-cues (i.e.…”

“…To accentuate the effectiveness of this novel task for adolescent genetically modified mice, we tested two mice lines which we previously assessed in the 5CSRTT at adult age 47 . Specifically, we tested dopamine transporter (DAT) and catechol-O-methyltransferase (COMT) heterozygous (+/−) knockout mutant male mice, because they are clinically relevant mouse models with effects on cognitive functions that recapitulate the effects of similar genetic variations in humans 35 , 48 , 49 .…”

Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders

“…For rodents, discrete elements of attentional processes such as sustained and focused attention, impulse control, perseverative and reactivity-related functions can be effectively studied. In particular, one of the most effective and extensively used task in rodents is the 5-Choice Serial Reaction Time Task (5-CSRTT) which allows for measures of general attention, impulse control and processing speed (Carli et al, 1983;Ciampoli et al, 2017;Huang et al, 2017;Mereu et al, 2017;Robbins et al, 1993;Robbins, 2002;Voon et al, 2014). Conversely, the Distractor Condition Sustained Attention Task (dSAT) and the 5-Choice Continuous Performance Test (5C-CPT) are operant -based tasks developed as signal-detection tasks first in rodents (Barnes et al, 2012;Bushnell, 1999;Ciampoli et al, 2017;Huang et al, 2017;McGaughy and Sarter, 1995;Mereu et al, 2017;Mohler et al, 2001;Nuechterlein et al, 2009;Young et al, 2009) and then redesigned for humans, providing clinical translatability (Demeter et al, 2008;Young et al, 2013).…”

“…In particular, one of the most effective and extensively used task in rodents is the 5-Choice Serial Reaction Time Task (5-CSRTT) which allows for measures of general attention, impulse control and processing speed (Carli et al, 1983;Ciampoli et al, 2017;Huang et al, 2017;Mereu et al, 2017;Robbins et al, 1993;Robbins, 2002;Voon et al, 2014). Conversely, the Distractor Condition Sustained Attention Task (dSAT) and the 5-Choice Continuous Performance Test (5C-CPT) are operant -based tasks developed as signal-detection tasks first in rodents (Barnes et al, 2012;Bushnell, 1999;Ciampoli et al, 2017;Huang et al, 2017;McGaughy and Sarter, 1995;Mereu et al, 2017;Mohler et al, 2001;Nuechterlein et al, 2009;Young et al, 2009) and then redesigned for humans, providing clinical translatability (Demeter et al, 2008;Young et al, 2013). Similarly, based on the proven utility of the SARAT paradigm in distinguishing deficits in selective attention from broad monitoring alterations relevant to schizophrenia (Hahn et al, 2012;Hahn et al, 2006b), equivalent tasks have been developed in both adult and adolescent mice (Ciampoli et al, 2017;Huang et al, 2017;Mereu et al, 2017).…”