Relationship between psychiatric disorders and executive functions: Attention and inhibitory control by Adam Lin https://padlet.com/adamlin8568/la9m1qhq471b Edward Chan (1002109728), Sheila Rasouli (1003665820), Adam Lin (1002448568) & Anson Lau (1002448390) en-us 2018-12-03 01:24:29 UTC 2024-10-14 20:39:37 UTC hello@padlet.com Background & Introduction edwardchanmingfai https://padlet.com/adamlin8568/la9m1qhq471b/wish/311016226 2018-12-04 17:13:24 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/311016226 Discussion adamlin8568 https://padlet.com/adamlin8568/la9m1qhq471b/wish/311940809 2018-12-06 17:48:30 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/311940809 Critique adamlin8568 https://padlet.com/adamlin8568/la9m1qhq471b/wish/311940955 2018-12-06 17:48:44 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/311940955 Conclusion adamlin8568 https://padlet.com/adamlin8568/la9m1qhq471b/wish/311941080 2018-12-06 17:48:58 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/311941080 adamlin8568 https://padlet.com/adamlin8568/la9m1qhq471b/wish/311941184 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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Best, J. R., & Miller, P. H. (2010). A Developmental Perspective on Executive Function. Child Development, 81(6), 1641-1660. doi:10.1111/j.1467-8624.2010.01499.x

Bhandari, J., Daya, R., & Mishra, R. K. (2016). Improvements and important considerations for the 5-choice serial reaction time task—An effective measurement of visual attention in rats. Journal of Neuroscience Methods, 270, 17-29. doi:10.1016/j.jneumeth.2016.06.002

Chudasama, Y., Dalley, J. W., Nathwani, F., Bouger, P., & Robbins, T. W. (2004). Cholinergic modulation of visual attention and working memory: dissociable effects of basal forebrain 192-IgG-saporin lesions and intraprefrontal infusions of scopolamine. Learning & Memory (Cold Spring Harbor, N.Y.), 11(1), 78–86. https://doi.org/10.1101/lm.70904

Ciampoli, M., Contarini, G., Mereu, M., & Papaleo, F. (2017). Attentional Control in Adolescent Mice Assessed with a Modified Five Choice Serial Reaction Time Task. Scientific Reports, 7. https://doi.org/10.1038/s41598-017-10112-8

Giedd, J. N., Keshavan, M., & Paus, T. (2008). Why do many psychiatric disorders emerge during adolescence? Nature Reviews. Neuroscience, 9(12), 947–957. https://doi.org/10.1038/nrn2513

Maguire, D., Henson, C., & France, C. (2016). Daily morphine administration increases impulsivity in rats responding under a 5-choice serial reaction time task. British Journal of Pharmacology,173(8), 1350-1362. doi:10.1111/bph.13434

Nguyen, P. V., Abel, T., Kandel, E. R., & Bourtchouladze, R. (2000). Strain-dependent Differences in LTP and Hippocampus-dependent Memory in Inbred Mice. Learning & Memory, 7(3), 170–179. https://doi.org/10.1101/lm.7.3.170

Patel, S., Stolerman, I. P., Asherson, P., & Sluyter, F. (2006). Attentional performance of C57BL/6 and DBA/2 mice in the 5-choice serial reaction time task. Behavioural Brain Research, 170(2), 197–203. https://doi.org/10.1016/j.bbr.2006.02.019

Pattij, T., Janssen, M. C. W., Loos, M., Smit, A. B., Schoffelmeer, A. N. M., & Gaalen, M. M. V. (2007). Strain specificity and cholinergic modulation of visuospatial attention in three inbred mouse strains. Genes, Brain and Behavior, 6(6), 579–587. https://doi.org/10.1111/j.1601-183X.2006.00284.x

Satterthwaite, T. D., Wolf, D. H., Erus, G., Ruparel, K., Elliott, M. A., Gennatas, E. D., . . . Gur, R. E. (2013). Functional Maturation of the Executive System during Adolescence. Journal of Neuroscience, 33(41), 16249-16261. doi:10.1523/jneurosci.2345-13.2013

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
]]> 2018-12-06 17:49:11 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/311941184 adamlin8568 https://padlet.com/adamlin8568/la9m1qhq471b/wish/311941252 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. ]]> 2018-12-06 17:49:19 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/311941252 Major Findings ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/311945707
  • SP-5C Protocol reduced training time to 5 days compared with the conventional protocol which took 50 days.
  • SP-5C Protocol was able to detect drug effects effectively.
  •  SP-5C protocol was able to identify strain differences.
    • ]]>     2018-12-06 17:57:24 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/311945707     ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/311954768 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). ]]> 2018-12-06 18:13:10 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/311954768 Results sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/311983513 2018-12-06 19:00:19 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/311983513 Psychiatric disorders edwardchanmingfai https://padlet.com/adamlin8568/la9m1qhq471b/wish/311994339 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
    ]]>     2018-12-06 19:17:55 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/311994339     Original Paper edwardchanmingfai https://padlet.com/adamlin8568/la9m1qhq471b/wish/312121664 2018-12-07 06:10:37 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312121664 Current Protocols that Measures Attentional deficits and Impulsivity (visuospatial sustained and divided attention) edwardchanmingfai https://padlet.com/adamlin8568/la9m1qhq471b/wish/312151890 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
    ]]>     2018-12-07 09:24:36 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312151890     Limitations of the Study adamlin8568 https://padlet.com/adamlin8568/la9m1qhq471b/wish/312468067
  • The sample size is relatively small.  Around 7 or 8 mice for each strain that was tested in the new SP-5C model.
  • 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.  
  • 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).
    • ]]>     2018-12-08 06:50:24 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312468067     Methods and Materials - What Changed? How are They Different? ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/312521060 2018-12-08 16:19:01 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312521060 Conventional 5-Choice Serial Reaction Time Task Protocol ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/312522100 2018-12-08 16:25:55 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312522100 ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/312524408 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
    ]]>     2018-12-08 16:41:01 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312524408     Self-Paced 5-CSRTT Protocol (SP-5C) ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/312525995 2018-12-08 16:52:10 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312525995 ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/312526649 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
    ]]>     2018-12-08 16:56:57 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312526649     The Tests - 3 Aspects ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/312528508
  • The efficiency of SP-5C compared to the 5-CSRTT. 
    • Duration of each protocol until reaching completion criterion.
  • SP-5C's compatibility with acute drug treatment.
    • Scopolamine treatment - muscarinic acetylcholine receptor -  reduces attention
    • Performance data was collected.
  • SP protocol’s efficacy on detecting strain differences - BXD16, BXD62 C57BL/6J and DBA/2J.
    • performance data was collected during dark phase.
    • ]]>     2018-12-08 17:09:54 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312528508     Purpose of Study: edwardchanmingfai https://padlet.com/adamlin8568/la9m1qhq471b/wish/312565429 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.]]> 2018-12-08 22:28:32 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312565429 edwardchanmingfai https://padlet.com/adamlin8568/la9m1qhq471b/wish/312582301 2018-12-09 03:59:01 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312582301 Reduced Experiment Time Allows Measurement of Adolescent Mice sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/312738004








    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. ]]>     2018-12-10 00:15:03 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312738004     Compatible with Acute Drug Testing sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/312738101






    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.]]>     2018-12-10 00:16:10 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312738101     Ability to detect strain differences shows maintenance of sensitivity in testing sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/312741607
    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.]]>     2018-12-10 00:45:06 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312741607     sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/312784662 2018-12-10 06:25:13 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312784662 Future Directions ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/312785243 2018-12-10 06:29:34 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312785243 sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/312787023 2018-12-10 06:43:14 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312787023 sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/312789211 2018-12-10 06:59:36 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312789211 sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/312790746 2018-12-10 07:09:56 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312790746 sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/312790912 2018-12-10 07:10:50 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312790912 ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/312790953 Photo Credit: https://www.yourgenome.org/stories/of-mice-and-men]]> 2018-12-10 07:11:09 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312790953 Advantages of SP-5C ansonlau99 https://padlet.com/adamlin8568/la9m1qhq471b/wish/312791361
  •  Results are comparable to the effects observed in the conventional 5-CSRTT.
  • Finishes the operant training of mice in a tenth of the time it would for the conventional method.
  • Time of training is sufficiently fast enough to enable the study of adolescent stages.
  • Minimizes long-term stress in test animals that would be induced by excessive human handling. 
  • Allow mice to follow it's own circadian rhythm.
    • ]]>     2018-12-10 07:13:44 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312791361     sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/312812188 2018-12-10 08:41:43 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312812188 sheila_rasouli https://padlet.com/adamlin8568/la9m1qhq471b/wish/312815667 2018-12-10 08:55:40 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312815667 References edwardchanmingfai https://padlet.com/adamlin8568/la9m1qhq471b/wish/312828041 2018-12-10 09:46:34 UTC https://padlet.com/adamlin8568/la9m1qhq471b/wish/312828041