Description

The IDED chamber for the attentional set shifting task for mice and rats includes a chamber for convenient testing of individual rodents. The kit comes complete with the entire medium and odor set for testing up to 500 Trials. Convenient and easy to clean ceramic cups (8) allow for multiple tests and rotating chambers before cleaning in the testing in the chamber.

Digging Odor kit comes with the following odors (essential oil form): Clove Bud, Red Thyme, Lemon, Cinnamon Leaf, Rosemary, Citronella Java, Vanilla in jojoba oil, Anise Seed, Ginger, Nutmeg

Digging Medium Kit comes with the following mediums: Raffia, Green Felt, Brown foam, Crepe paper (yellow), Ribbon (turquoise), Metallic, Googly Eyes, Black Sequins, Pink Pom Poms, Pipe Cleaners

Odor Kit (Included)

Medium Kit (Included)

Documentation

Introduction

The Attentional Set Shifting Task (ASST) is a great tool to probe attention and cognitive flexibility in rodents mediated by the prefrontal cortex. The ASST was developed with respect to one of the most used neuropsychological tasks: The Cambridge Neuropsychological Test Automated Battery (CANTAB) that measures the intradimensional/extradimensional set shifting behavior to evaluate cognitive impairments in humans and non-human primates (Rock et al. 2013).

In rodents, the dimensions used to design the IDED task are odor and medium. Essentially, the animal is trained to associate and pay attention to a particular condition while disregarding the other, considering it as insignificant. When researchers reverse or change the conditions, this, in turn, requires the animal to use their executive functions to find the reward.

The dimension (odor or medium) which is to be associated with reward is determined a priori by the researchers. This dimension is used for both training and testing conditions. In order to determine whether the animal is cognitively flexible or not, the researchers switch the test conditions such that the reward will be associated with the alternate dimension, thus challenging the animal to update their behavior and knowledge.

An attentional set is formed when a subject learns to associate a set of rules to differentiate relevant from irrelevant cues. For instance, the animal learns to associate digging medium (supposed as a relevant cue) with the food reward disregarding the odor (supposed irrelevant cue). In subsequent trials, this association is reinforced; the type of digging medium and odor fluctuates, but the paired associated between medium and reward is kept intact. This reinforced rule turns into a cognitive set (Heisler et al. 2015).

Cognitive flexibility can be assessed by:

1. Reversal Learning – Challenges the subject to maintain the attention set. For instance, the previously negative stimuli (digging medium) is now positive, and the subject must learn to associate the previously negative medium with reward. The relevant cue rule is kept intact while reversing the rule learned to associate sub-stimuli with the reward.
2. Extradimensional shift- The formation of the attention set is challenged. If the reward was previously associated with the medium, it would now be associated with odor. If on the other hand, the reward was previously associated with odor, it will now be associated with the medium.

Usually, it is harder to learn the new conditions for a reward under the ED trial. It is even more challenging for animals with cognitive or pre-frontal impairments. Thus, by using animals, the IDED task chamber can create a scenario for testing the animals’ cognition based on their ability to override learned behaviors. The model works by teaching the mice the attentional set-shifting task and then presenting them with a variety of situations requiring the mice to modify or update the learned behavior.

A large number of neuropsychiatric and neurodevelopmental disorders are associated with subsequent cognitive impairments which interfere with adaptation and information processing due to inflexibility. For example, despite being distinct clinical conditions, depression, autism spectrum disorder, and schizophrenia are all interlaced with cognitive deficits. Cognition is also impaired in Parkinson’s disorder, autism spectrum disorders, and obsessive-compulsive disorder. The list goes on.

Researchers and scientists that wish to address the cognitive dysfunctions across disease models can do so by incorporating the IDED task chamber into their experiments. By using animal models with the IDED task chamber in pre-clinical studies to play out situations which require cognitive flexibility and response modification, it is possible to study the effects of certain interventions within a controlled, low-risk setting.

History

2.1. Origin

The Attentional set-shifting task was first introduced by Jennifer Birrell and Verity Brown, 2000 to study the effects of prefrontal lesions on rats’ behavior. Since the very inception, it has been accepted as a solid method for studying cognitive flexibility in animal models (Garner et al. 2006).

Birrell and Brown, 2000 conducted a simple discrimination (SD), a compound discrimination (CD), a reversal of the CD (CDR), an intra-dimensional shifting (IDS) and an extra-dimensional shifting (EDS). In their experiment, during the EDS task, it took the rats with lesions significantly more trials to reach the criterion than the control rats. These results indicate that rats with bilateral lesions of the medial frontal cortex have selective impairment in shifting of attentional set.

The rats with lesions and the control rats were able to learn the basic discrimination tasks and the intra-dimensional shifts without significant differences. But, when performing on the ED task, the lesioned rats took twice as many trials to reach criterion, thus demonstrating the effect of a lesioned pre-frontal cortex when it comes to attentional set-shifting.

A key finding is a sharp distinction between the data obtained from the ID and data from the ED dimensions, demonstrating internal validity (Garner et al., 2006). The same phenomenon can be observed in humans with impaired cognition. The fact that the ED condition requires more learning and effort demonstrates that the animal has difficulty set-shifting into a new, distinct dimension. If this was not the case, the data for the ED condition would not have been significantly different from the data gathered from the ID condition.

2.2. Developments

Since then, an array of experiments has been conducted with the help of the IDED chamber apparatus, demonstrating its versatility and usefulness.

Apparatus and Equipment

The ID/ED Task Chamber consists of two chambers, a testing area, and a waiting area. A guillotine-like start gate regulates the entry to the testing area. The testing chamber is further divided into two compartments with the aid of an acrylic partition. Each chamber in the testing area contains a ceramic bowl that can be filled with the digging medium and the odorant which can be selected from the odor and medium kits.

The separation between the waiting area and the testing area allows for easy preparation of the testing area. Each trial requires a “restart” in which the animal is returned to the waiting area. As soon as the start gate is lifted, the animal gains access to the testing area.

ASST Experimental Design

In general, the Attentional Set Shifting task comprises five discrimination phases/conditions: a simple discrimination (SD), a compound discrimination (CD), a reversal of the CD (CDR), an intra-dimensional shifting (IDS) and an extra-dimensional shifting (EDS).

• In the Simple Discrimination (SD) phase, the animal must select one medium over another within a dimension. For instance, when testing the odor dimension, attention to the nutmeg odor may be rewarded over rosemary odor. The animal learns a simple rule; paying attention to the nutmeg odor will be rewarded.

• During the Compound Discrimination (CD) phase, a second dimension is introduced, but the relevant dimension and correct mediums stay the same. Therefore, the animal must pay attention and respond to the former relevant dimension and medium, while ignoring an irrelevant dimension. For example, when testing the odor dimension, the subject might be rewarded for paying attention to the nutmeg medium while ignoring the irrelevant medium rosemary, along with the irrelevant digging medium (e.g., felt or paper which was introduced). The subject learns to maintain the rules learned in the SD task while ignoring the second dimension.

• In Reversal of the CD (CDR), all dimensions and mediums stay the same as in the CD phase, but the previously correct medium within a dimension is now incorrect. For example, in the odor dimension paying attention to the nutmeg odor is no longer rewarded. The subject now has to pay attention to the rosemary odor (digging medium still acts as an irrelevant dimension here). Hence the subject must reverse the rules it learned about the mediums within the dimensions earlier.

• In the Intra-Dimensional Shifting (IDS) phase, the digging mediums and odors change, but the relevant dimension stays the same as before. For example, now the digging mediums might be pompoms and sequence, and the odors might be cinnamon and cloves, but the subject will still be rewarded for paying attention to the same dimension as before; the odor dimension. Within the odor dimension, one odor medium will be rewarded over the other, here cinnamon.

• In the Extra-Dimensional Shifting (EDS) phase, the digging mediums and odors change. For example, now the digging mediums might be raffia and foam, and the odors might be citronella and anise. In this phase, the animal must shift its attention to the previously irrelevant dimension. For example, now the medium’s dimension is relevant over the odor dimension. For example, now the subject will be rewarded for digging in raffia.

Training Protocol

5.1. Preparatory Handling (Days 1-8)

1. For the first eight days of the experiment, you are simply handling the subjects. This procedure habituates them to the act of handling and thereby reduces any associated stress that may have otherwise occurred during testing.Note: Food restriction begins at the end of this 8-day stage.
2. On each day, measure and record the subject’s weight.You must also habituate the subject to dig within a ceramic pot, in order to retrieve a food reward. To ensure that the subject has associated a particular digging medium with the food, the subject needs to find the food eight times on the trot without performing a single error.

5.2. Food Restriction Period (Days 9-12)

1. Four days before the experiment begins, introduce the two ceramic pots into the subject’s box and place the small food pellets inside the ceramic pots to begin habituating the subject for feeding on the pots incrementally.Note: Feed the subject 1 gram of food on a daily basis. The subject’s weight is supposed to be maintained at 80-85% of what it was in the first eight days of handling. If its weight falls below 80%, then it is okay to increase the allotted food proportion to 2 grams.

2. The cage’s bedding is only to be changed one day prior to the acclimation stage; the bedding is not to be changed again until the completion of the testing procedure.

5.3. Acclimation Period (Days 13-14)

1. To reduce the stress of being in a new cage (the ID/ED chamber), take some of the bedding from the subject’s cage and sprinkle in the experimental chamber. The familiar smell serves to console the subject of the new environment and keeps stress levels low.
2. In the ID/ED chamber, place a ceramic pot filled with water in the center of the waiting area and the two previously used ceramic pots for feeding in the corners of the testing area. In the two ceramic pots, place food weighing approximately 20 mg in each pot (total of 40 mg).
3. Transfer the subject from its home cage to the waiting area of the ID/ED chamber.

4. After some time in the waiting area, the start gate is left open for the exploration of the new setting for one hour. Frequently put small food rewards into the ceramic pots to encourage exploration and interaction with the ceramic pots.
5. The experimenter must stay near the chamber and remain visible to the subject throughout the acclimation period. The subject will get used to the experimenter’s looming presence, thus reducing the likelihood that the experimenter’s presence will cause added stress during testing.

5.4. Training (Day 15)

The testing period starts simply and gradually builds up with stimuli and cues.

1. Place the food in each of the ceramic pots, place the subject in the waiting area, then finally lift the start gate so that the subject can get the reward. Give the subject only 3 minutes to find and get the reward.
2. After 3 minutes, shut the start gate and place the subject in the waiting area again.
3. Repeat this simple process several times.
4. Gradually, to instill the habit of digging, add clean bedding into the ceramic pots on top of the food. Placing more and more for each run. The allotted timeframe remains 3 minutes long. Do so until the subject can consistently dig and find the food.

5.5. Testing Period (Day 16-17)

1. Begin with the simple discrimination stage (SD): presenting the subject with only one cue. Let’s say, digging medium. Fill the ceramic pots with two distinct digging media, ensuring that the food reward is covered. Sprinkle cereal dust over each of the digging substrates to avoid a scent cue from the food reward.
2. Place the subject in the waiting area. Once you remove the start gate, start the timer. Again, 3 minutes is allowed per trial.
3. Remember, you have to record the subject’s behavior. Record whether the subject made a correct or incorrect attempt at digging. The subject’s behavior can also be recorded with an overhead Noldus Ethovision XT.
4. If after 3 minutes the subject still hasn’t made a choice, then the trial is recorded as an incorrect choice.
5. If the subject makes a choice and goes to explore a particular ceramic pot, you must immediately remove the pot that was not chosen. If the subject chooses a pot without a food reward (-), remove the other pot and let the subject explore the cage until time passes, so that it understands that there is no reward associated with that particular digging medium.
6. This same procedure is repeated continuously for all of the remaining trials and conditions (CD, Rev, IDS, and EDS). It is helpful to create a chart in advance that outlines precisely which odors and digging medium will be used for each condition.

Note: When adding the odor, give some time for the strong smell to air out a bit because strong odors are repulsive to rodents. The scent needs to dissipate slightly before being added to the testing chamber.

Literature Review

The Attentional Set Shifting Task (ASST) Chamber can be used to measure cognitive flexibility and attentional set shifting. The neural circuits involved in the attentional set-shifting can be assessed by lesioning the prefrontal cortex, dorsolateral prefrontal cortex, or orbitofrontal cortex. The IDED task presents a series of discrimination problems which require the animal to learn rules, then change their behavior when the rules change.

Cognitive flexibility is measured by reversal (CDR) and extra-dimensional shift. Reversal learning challenges the animal’s flexibility in that it must maintain the attentional set while altering the rule learned from a previous stage (CD). For example, if in the CD stage within the odor dimension, paying attention to the nutmeg odor was rewarded, and the rosemary odor had no reward; the reversal (CDR) would also be with the odor dimension, but attention to the rosemary odor would now be rewarded, rather than to the nutmeg odor. In extra-dimensional shift, the formation of an attentional set is challenged when the irrelevant dimension becomes the relevant dimension.

Typically, animals with lesions in the prior mentioned prefrontal areas take longer to learn the new rules and make more errors as their cognitive flexibility is impaired.

Furthermore, assessing the distinction between the ID and ED response yields information pertaining to the brain regions involved. One of the biggest advantages of this method is that you can closely study how certain neurotransmitter systems and modulators impact observable behavior and cognition.

Researchers by and large agree that the reversal phase of the task is highly mediated by the orbitofrontal cortex, while the ED tasks are governed by the medial and lateral prefrontal cortex (Scheggia et al., 2014). You can hone in on these regions and study how your treatment or intervention impacts the relevant neuroanatomy in parallel with observable behavior.

6.1 Pharmacological Studies

Human neurodegenerative diseases and other neurological disorders have been known to have a significant effect on the cognitive processes of forming, maintaining and shifting attentional set, which are mediated by the frontal cortex in mammals and can be modulated by pharmacological manipulation (Kesner and Churchwell 2011; Chudasama 2011; Dalley et al. 2004; Robbins 2000; Miller and Cohen 2001).

Understanding, not only the cause but also the effects of the dysfunction arising from human neuropsychiatric disorders (such as schizophrenia, attention-deficit/hyperactivity disorder, and addiction) and neurodegenerative diseases (such as Alzheimer’s and Parkinson’s diseases) is vital in developing effective treatments to restore cognitive performance. Although the dysfunctions may appear superficially similar, the pathology associated with each disorder and diseases differ. Thus a successful assessment and treatment should be tailored with an overall understanding of the pathology, specific dysfunctional aspects of cognitive flexibility and discerning judgment of the affected cognitive processes (Brown et al. 2016).

Below are some examples of how the IDED chamber has been used to study behavior upon drug administration.

5-HT₆ receptor antagonist: SB-399665

In a 2005 study by Hatcher et al., it was demonstrated administering the 5-HT₆ receptor antagonist, SB-399665, in rats greatly decreased their amount of errors when compared to a controlled group. Furthermore, the 5-HT₆ receptor antagonist virtually eradicated any delays or errors when completing the ED portion of the experiment, signifying the drug’s potency in affecting this attentional system.

Desipramine

Rats’ performance on the attentional set-shifting test significantly improved when they were chronically administered desipramine (DMI). The treated rats’ showed a decrease in total errors and their performance on the extradimensional component of the task was significantly better.

DMI is an antidepressant drug that works as a selective norepinephrine reuptake inhibitor. In addition to performing the standard experiment, microdialysis was conducted on these rats to measure the extracellular levels of the neurotransmitter norepinephrine in the medial prefrontal cortex.

Thanks to the DMI, the extracellular norepinephrine levels increased in parallel to cognitive flexibility as measured by the rats’ performance (Lapiz, Bondi, & Morilak, 2007).

Ketamine & Ro 25-6981

Ketamine interferes with learning due to its antagonistic effect on NMDA receptors which are crucial for learning. Ketamine consistently impairs the animals’ performance by increasing both their errors and time per task.

The deficits attributable to ketamine can be reversed by administering Ro 25-6981, making the animals’ performance comparable to those of the control group (Kos et al., 2011).

Tolcapone

The prefrontal cortex, as stated earlier, is a major contributor to successful attention. A particular gene, the catechol-O-methyltransferase (COMT) gene, influences the prefrontal cortex by mediating relevant enzymes. However, even though it is clear that there’s catecholaminergic involvement, the neurotransmission mechanism between the COMT gene and subsequent behavioral performance has remained unclear.

To investigate the relationship between the COMT gene, drugs, and performance, a study was conducted on rats that needed to complete the IDED task.

Administering tolcapone, a drug typically given to Parkinson’s patients increases rats’ performance for ED set shifting which otherwise would have remained impaired due to a poorly functioning COMT gene. Upon performing microdialysis on rats that were given tolcapone, the extracellular levels of dopamine were significantly higher in the medial prefrontal cortex (Tunbridge et al., 2004).

Sertindole & Modafinil

In 2008, Goetghebeur and Dias conducted an experiment comparing the effect of various drugs on phencyclidine (PCP) treated rats which serve as a model for schizophrenia. The study had four different groups, each group being assigned to a different drug. Out of the multiple conditions, only the PCP-induced rats that were given sertindole or modafinil displayed improvement in reversing the ED deficit.

Nicotinic Acetylcholine receptor agonists

Nicotine-induced improvements in different aspects of cognitive function (including memory and attention) have been successfully demonstrated in studies involving both humans and experimental animals. Since prefrontal cortex is said to have pronounced involvement in the modulation of cognitive processes and executive functions, efforts have constantly been made to understand how attentional processes are enhanced by nicotine acting at nicotinic acetylcholine receptors.

In experiments conducted by Allison et al. 2013, it was observed that when the subject was injected with nicotine, both acutely and following repeated pre-exposure, there was a significant improvement in Intra-dimensional (ID) and Extra-dimensional (ED) set-shifting performance in the task. Administration of varying dosage of nicotine (0.05 mg/kg, 0.1 mg/kg and 0.2 mg/kg) also revealed that attentional flexibility is dose-dependent.

In an another study aimed to understand effectiveness of activation of nAChRs with selective nicotinic receptor agonists in treatment of cognitive deficits observed in schizophrenia (Wood et al., 2016) as an extension of the aforementioned study, the results showed the advantage of targeting nAChRs to enhance cognitive flexibility, especially the α7 and β2* receptor subtypes.  Compound A (α7 nAChR agonist) showed to enhance the subject’s ability in switching between ED set shifting selectively while the α7 nAChR agonist SSR180711 showed improvement in EDS when tested in a smaller dose (3 mg/kg). On the other hand, the selective β2* nAChR agonist 5IA-85380 and nicotine showed improved cognitive between both ED and ID set shifting.

Positive allosteric modulator and α7 nicotinic acetylcholine receptor partial agonists

The Positive allosteric modulator, 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide (PAM‐2) was shown to be a potential candidate for the treatment of cognitive disorders when tested for pro-cognitive activity in conjunction with α7 nAChR receptors DMXBA and A-582941 (Potasiewicz et al. 2015). Post hoc analysis, after attentional set-shifting task, revealed that the subject’s cognitive flexibility was specifically enhanced by acute administration of DMXBA (1.0 mg•kg−1), A-582941 (0.3 and 1.0 mg•kg−1), and PAM-2 (1.0 mg•kg−1).  It was also observed that co-administration of PAM-2 with either DMXBA or A-582941 facilitated cognitive performance. PAM-2 was also shown to reverse object recognition impairment induced by scopolamine.

Sample Data

Common measurements for the attentional set-shifting task include:

• Trials to reach criterion: Many studies plot out the “trials to reach criterion” in a bar-graph format with each column indicating a different condition.

• Total errors per condition: Graphing the “total errors per condition” is also frequently done, demonstrating the inverse relationship between errors decreasing and the animal learning to associate a stimulus with reward.

Trial duration: The time it takes to complete the task on average or “trial duration” is frequently measured and assessed within this experimental set-up.

Latency to respond: can be recorded with a modified version of the maze which contains nose-poke holes. The time (in seconds) it takes from opening the start gate to the rodent poking its nose through the holes is recorded.

8. Translational Research

Attentional set-shifting is defined as the ability to transition between cognitive-attentional sets and has been used as a measure of cognitive flexibility and executive functions over six decades in the investigation of human cognition. Wisconsin Card Sorting Test (WCST) and a more recent refined version of intra- and extra-dimensional attentional set-shifting (ID/ED) of the CANTAB have been extensively used in neuropsychological tasks for measuring attentional set-shifting and cognitive flexibility, and in identifying specific cognitive abnormalities in a wide range of mental disorders in humans.

The IDED task modified for animals has high predictive value and construct validity, making performance comparable to those attentional set-shifting tasks which are performed by humans (Birrell & Brown, 2000).

In a schizophrenic mouse model, for example, to determine whether mice would perform comparably to schizophrenic patients on the ASST, the mice were administered phencyclidine (PCP), a drug used for inducing a schizophrenic model, and then measured based on the IDED tasks. The mice in the 1.3 mg/kg of PCP condition displayed poor performance when it came to the extra-dimensional shift task results which parallel those in human schizophrenic patients (Laurent & Podhorna, 2004).

9 . Strengths & Limitations

9.1. Strengths

• The IDED task chamber is used to study cognition flexibility and can be used for many types of disease models. Since many neurological conditions inevitably impact cognition in some form or another, the IDED task chamber can be used for a variety of experiments.
• Due to its relatively compact size, you can set up the chamber almost anywhere. Many labs that make use of the IDED chamber have parallel workstations where researchers are working simultaneously, verging on the epitome of efficiency.
• By working in a setting with such high experimental control, you can closely monitor and determine the impact of environmental, genetic, and epigenetic factors on cognition.
• The start gate reduces experimenter interaction with animals and therefore makes studies with rodents more translational to humans.
• The experiment can more closely mimic the Cambridge Neuropsychological ID/ED Test which is conducted with humans.

9.2. Limitations

It can be confusing to keep track of the experimental conditions, which stimuli indicate what, when to reverse, etc. The key is to stay organized and to keep your charts, notes, and experimental outline with you.

10. Summary and Key Points

• By associating cognitive abilities with the pre-frontal cortex, for example, researchers have been able to isolate treatments and interventions in animal models before translating them over to humans. Thus, nearing one step closer towards finding feasible solutions for rejuvenating cognition and executive functions.
• The IDED chamber is a great tool to have in any laboratory working with animals and searching to better understand cognition across a variety of circumstances, from neurodegenerative and psychiatric conditions to genetics and pharmaceutical developments. Plus, it is convenient to set-up, enabling multiple work-stations and experiments to be conducted simultaneously.
• The IDED chamber creates a scenario in which the animal is trained to search for a reward by associating a particular stimulus with food, only to re-learn new rules for finding the reward under different experimental conditions, thus demonstrating cognitive flexibility.
• Typically, the animal learns to discriminate the reward with a particular cue (such as the scent of vanilla). Then, it’s challenged to learn to associate a reward with an entirely different odor (lemon, for example) and must forget the previous condition, in order to learn the newer one. This is known as the intra-dimensional shift.
• When the animal completely crosses dimensions during task learning, now having to associate digging medium (for example), rather than odor, this is referred to as the extra-dimensional shift.
• Animals with damage to prefrontal cortex areas including the medial frontal cortex, orbitofrontal, and medial prefrontal cortical areas show impairments in cognitive flexibility and attentional task shifting.
• Thus, the IDED chamber enables researchers to test the animals’ cognitive flexibility, quickness to learn, trial duration, and errors, in order to gauge how well the animal performs under specific experimental conditions.

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