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1.  Results are comparable to the effects observed in the conventional 5-CSRTT.

2. Finishes the operant training of mice in a tenth of the time it would for the conventional method.

3. Time of training is sufficiently fast enough to enable the study of adolescent stages.

4. Minimizes long-term stress in test animals that would be induced by excessive human handling.

5. Allow mice to follow it's own circadian rhythm.

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Photo Credit: https://www.yourgenome.org/stories/of-mice-and-men

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Ability to detect strain differences shows maintenance of sensitivity in testing

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Ability to detect strain differences shows maintenance of sensitivity in testing

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Figure 7: The grey graphs
show the performance of
different strains of mice
in 5-CSRTT. We see, as
expected, that the BXD16
and BXD62 mice fall on
opposite extremes in
relation to attention and
impulsivity, with DBA/2J
and C57BL/6J mice
falling in between. In the performance results for SP-5C, we see a mimicking of the conventional results. The accuracy was lowest in BXD16 mice and highest in BXD62 mice, and the opposite was seen for premature responses. However, due to the small number of animals within these two strains (at 6) and a large variation observed in BXD16 mice, these differences did not reach significance. BXD16 mice did show significantly more premature responses than the 21 C57BL/6J mice.

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Figure 6: Researchers were also able to successfully prove compatibility with acute drug testing. Scopolamine, known to reduce attention in C57BL/6J mice, significantly reduced accuracy in a dose dependent manner in SP-5C during the first 2 hours after administration. We also saw an increasing trend in premature responses based on the administration of scopolamine. The day of administration had no effect on accuracy or premature responses, showing we didn’t increase stressors, and accuracy returned to pre-administration levels in the 2 days between drug administration days.

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Reduced Experiment Time Allows Measurement of Adolescent Mice

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Reduced Experiment Time Allows Measurement of Adolescent Mice

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Figure 2: The SP-5C protocol took an average of 4.3 days to finish until the criterion achievement was reached 5 times for SD1. The conventional 5-CSRTT mice needed an average of 51.5 days to finish 10 sessions in SD1 (the SP-5C equivalent). Thus, novel task protocol in SP-5C was completed almost 10 times faster.

Figure 3: The mice began self-pacing themselves according to their own intrinsic circadian rhythms, and showed greater activity during the dark phase (from 19h to 7h) especially towards the beginning of the dark phase (with the darker colored bars representing the dark phase). 83% of all stimulus duration trials occurred during the dark phase. Patterns related to circadian rhythm appeared to be isolated only to mice starting trials, as the task measures related to attention and impulsivity remained unaffected. This suggests that self-pacing of trials has little effect on performance, as it stays relatively constant all day.

Figure 4:  Different performance measures taken from 5 week and 10 week old mice undergoing SP-5C are compared to mice undertaking the conventional 5-CSRTT protocol. While accuracy came close to being lower in the SP-5C protocol compared to conventional, the 5 and 10 week old C57BL/6J mice were not significantly different on any of the performance measures.

Figure 5: Performance
during variable intertrial
intervals and variable
stimulus duration, in
which the duration of ITI
significantly affected
premature responses,
and the duration of SD also significantly affected accuracy. The protocol itself  did not have a significant effect on premature responses or accuracy. SP-5C did not compromise the expected effects of manipulating ITI or SD on
attention and impulsivity, and thus adult and adolescent mice can be more efficiently tested here than in the conventional protocol.

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EF develops during adolescence, and many psychiatric disorders can significantly impair these functions. In order to study executive functions in adolescence animal models, short duration tasks are critical. However, current measuring methods in this field require prolonged training periods (which exceed the weeks long adolescence period within mice), hence unable to give a proper assessment. A new protocol should be established to address these issues while maintaining the current protocol's efficacy.

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1. The efficiency of SP-5C compared to the 5-CSRTT.

Duration of each protocol until reaching completion criterion.

2. SP-5C's compatibility with acute drug treatment.

Scopolamine treatment - muscarinic acetylcholine receptor -  reduces attention

Performance data was collected.

3. SP protocol’s efficacy on detecting strain differences - BXD16, BXD62 C57BL/6J and DBA/2J.

performance data was collected during dark phase.

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Figure 1: The Schematic of SP-5C. The authors denote the configuration as the CombiCage.

CombiCage - homecage with shelter and water spout connected with the operation chamber.

Connected just before the protocol and left uninterrupted for 24 hours.

No restriction on the number of trials during

Separate light phase and dark phase

Also last until mice reach completion criterion

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Video 1: A brief video demonstration of the conventional 5-CSRTT.

The front end of the operant chamber: 5 holes that are paired with a light stimulus.

The back end of the operant chamber: food pellet dispenser

Light stimulus flashes, mice are expected to perform a nose poke within 5 seconds in the corresponding hole.

Accurately performing the task = reward by food

error performing the task = punished by 5 seconds of darkness.

Errors of commission - nose poke at the wrong hole.

Errors of omission - did not respond within the time limit.

Premature responses - respond before the stimulus was presented.

Task runs for 25 minutes/day

Last until mice reach completion criterion

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Conventional 5-Choice Serial Reaction Time Task Protocol

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Conventional 5-Choice Serial Reaction Time Task Protocol

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Methods and Materials - What Changed? How are They Different?

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Methods and Materials - What Changed? How are They Different?

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1. The sample size is relatively small.  Around 7 or 8 mice for each strain that was tested in the new SP-5C model.

2. The experimental test of mice correctly responding to the stimulus of "a flashing light" is too broad and multifactorial. Does not only depend on attention.

3. Results showed scopolamine was able to reduced accuracy in SP-5C. However, this reduction in accuracy might be attributed to memory impairment rather than the proposed attentional deficit, since scopolamine has a more significant effect on memory than attention (Chudasama, Dalley, Nathwani, Bouger, & Robbins, 2004).

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Current Protocols that Measures Attentional deficits and Impulsivity (visuospatial sustained and divided attention)

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Current Protocols that Measures Attentional deficits and Impulsivity (visuospatial sustained and divided attention)

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Conventional 5-choice serial reaction time task (5-CSRTT):
An automated operant conditioning task that measures rodent attention, originally developed by Robbins and colleagues (Bhandari, Daya, and Mishra. 2016). the protocol Measures various parameters including response accuracy, speed of processing, motivation, and impulsivity (Bhandari et al. 2016)

Disadvantages of 5-CSRTT

Prolonged training (months to complete)

Food restrictions - to motivate mice during task

Excessive animal handling

Labour intensive

Limit to adult subjects due to long training time

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such as Schizophrenia, Attention-deficit hyperactivity disorder (ADHD), and Substance abuse disorders impair psychological and executive functions. It is caused by a major development issue in the prefrontal cortex which controls executive functions (EF).

Executive functions (EF) include:

Attention

Cognitive flexibility

Working memory

Problem-solving

(Shepard, Beckett, and Coutellier. 2017)

EF develops throughout adolescence to reach full maturity in adulthood (Best & Miller. 2010; Satterthwaite et al. 2013), thus many psychiatric disorder symptoms emerge during adolescence. Attention and inhibitory control of executive functions in animal models are mainly investigated.

Increased impulsivity is a risk factor for drug abuse. Repeated administration of

μ opioid receptor agonists may lead to increased impulsivity (e.g. delay discounting) thus increasing the risk of drug abuse (Maguire, Henson and France. 2016).

Effects of morphine on motor impulsivity increase when there's repeated administration of morphine (Maguire et al. 2016).

Photo Credit: http://serenelifehospital.org/psychiatric-disorders

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The SP-5C is a newly developed operant training protocol and this study is the first to assess its reliability. The study had demonstrated that the SP-5C could accurately differentiate genetic differences between distinct strains as well as identify acute behavioural changes following drug treatment. Notably, experimental training time was shown to be reduced from 50 days in the conventional method to 5 days in the new model being tested. The dramatic reduction in training time allows adolescent animals to be studied under the SP-5C protocol. This contrasts with the traditional model where adolescence testing was not possible due to the prolonged training time. Furthermore, many literatures suggest that most psychiatric disorders manifest during adolescence, allowing the SP-5C model to culminate its potential (Giedd, Keshavan, & Paus, 2008). Additionally, the study suggested that self-pacing allowed the mice to abide by their circadian rhythms and by doing so, motivation levels remain consistent. Conclusively, the authors of the original paper suggested that the novel SP-5C model is suitable for assessing attention and impulsivity in mice models of neurodevelopmental disorders all while accelerating the process tenfold. A study done by Ciampoli et al. utilized the idea of the rapid self-paced model to demonstrate and confirm that it effectively assesses impulsivity, attentiveness and processing speed in adolescent mice (Ciampoli, Contarini, Mereu, & Papaleo, 2017). Subsequently, Ciampoli et al. suggested that this protocol has potential translational validity in human genetic and pharmacological studies (Ciampoli et al., 2017).

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1. SP-5C Protocol reduced training time to 5 days compared with the conventional protocol which took 50 days.

2. SP-5C Protocol was able to detect drug effects effectively.

3.  SP-5C protocol was able to identify strain differences.

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As previously discussed, the new SP-5C model upholds many benefits as it dramatically reduces experimental time, therefore enabling the accurate and effective study of adolescence. Arguably, this would be most beneficial in the field of research pertaining to psychiatric disorders and adolescent neurobiology
(Patel, Stolerman, Asherson, & Sluyter, 2006). However, there are major uncertainties that should be addressed before relying on the model's applicability. Recall, the model utilizes very brief flashes of light to indicate which one of the five holes would give a reward. The authors used this as a task to measure attention and impulsivity differences in several mice strains. However, measuring attention by itself is quite specific for a generalized task that requires much more than just one factor. For example, after the brief flash of light, the mice would have to utilize its short-term memory to recall from which hole the light came from. Based on previous literature, at least two of the mice used in this study, C57BL and DBA/2 are suggested to exhibit differences in memory performance (Nguyen et al., 2000; Pattij et al., 2007). Thus, it can be speculated that the results in Asai et al.'s study could be confounded by memory differences between strains. Since scopolamine is suggested to inhibit memory more so than attention, the authors should retest all four mice with scopolamine in the SP-5C model (Chudasama, Dalley, Nathwani, Bouger, & Robbins, 2004). Unlike their original experiment of detecting scopolamine drug effects in a single strain only, the suggested procedure will instead use scopolamine to reduce the influence of memory and all four mice strains will be compared. If the new results are different than current results by Asai et al., it would mean that memory had a profound influence. Then it can be suggested that the SP-5C model cannot measure certain specific variables, rendering it only useful for drug effect elucidation.

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Original article
Remmelink, E., Chau, U., Smit, A. B., Verhage, M., & Loos, M. (2017). A one-week 5-choice serial reaction time task to measure impulsivity and attention in adult and adolescent mice. Scientific Reports,7, 42519. https://doi.org/10.1038/srep42519
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Video

Leonardo Silenieks. (2015). 5CSRTT (5-choice serial reaction time task) with Long Evans rat. Retrieved from https://www.youtube.com/watch?v=yXDpjUW0vwQ

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Shepard, R., Beckett, E., & Coutellier, L. (2017). Assessment of the acquisition of executive function during the transition from adolescence to adulthood in male and female mice. Developmental Cognitive Neuroscience, 28, 29-40. doi:10.1016/j.dcn.2017.10.009