Name: the attentional set shifting task: a measure of cognitive flexibility in mice
Uploaded: 2015-02-04T13:00:00
Description: Watch this Scientific Journal Video about The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice at JoVE.com

This research was supported by grants R01-MH090127, P30-MH089868 from the National Institute of Mental Health and award number UL1TR001120 from the National Center for Advancing Translational Sciences.&#160; The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH or NCATS. Additionally, we would like to gratefully acknowledge Dr. David Morilak for his valuable expertise in guiding the early method development.

NOTE: Animals used in this study are male C57Bl/6J mice between 4 and 6 months of age for optimal results. Mice are maintained on a reverse light cycle in order to conveniently test them during the active (dark) phase. If behavior is performed in a room separate from housing, mice are allowed at least 1 hr to acclimate following transportation to the testing room. Behavioral testing is performed under red light conditions minimize disruption to the normal activity of the mice as little as possible while still allowing th...

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Deficits in cognitive flexibility mediated by the PFC represent a significant disability associated with a variety of neurological and neuropsychiatric disorders, and can have a major impact on outcomes and quality of life of individuals suffering from these disorders. Optimization of the AST for use in mice is vital to investigating the genetic underpinnings in diseases coupled to prefrontal cortical mediated cognitive dysfunction. We have found that the method described above is a reliable measure of a specific cogniti...

The attentional set shifting task (AST) was developed as a measure of attention and cognitive flexibility in rats over a decade ago1,2. AST is modeled after the intradimensional /extradimensional component of the Cambridge Neuropsychological Test Automated Battery (CANTAB) which is used to identify cognitive dysfunction in humans and non-human primates3,4. While the ability to learn simple rules remains intact, deficits in learning to modify a response when the rules have changed are found in patients suffering from a variety of neuropsychiatric disorders (i.e., schizophrenia, obsessive compulsive disorder, depression), neurodegenerative disorders (i.e., Parkinson&#8217;s disease) and in patients with lesions to the pre-frontal cortex5. More generally, these patients are described as having deficits in cognitive flexibility. Analogous deficits have been shown in both non-human primates and rodents when lesions to the prefrontal cortex have been induced1,6-8. These deficits indicate a state of cognitive inflexibility or an impaired ability to shift attentional set.
An attentional set is formed when a subject learns that a set of rules can be applied to complex stimuli in order to differentiate relevant from irrelevant cues. For example, in the AST, animals will learn to pay attention and respond to the relevant cue (i.e., digging medium) and ignore an irrelevant cue (i.e., odor), by pairing a food reward with the medium. This association is then reinforced in subsequent tasks where the type of digging medium and odor changes, but the paired association between medium and reward remains. This reinforced rule forms a cognitive set. Two stages within the AST protocol measure aspects of cognitive flexibility: reversal and the extra-dimensional shift. At the reversal stage, the previously negative stimuli within one dimension (medium in this example) is now positive, which challenges the animal to ignore the positive stimuli from the previous stage. For example, if felt digging medium was the positive stimuli in the previous stage and paper was the negative stimuli, now the reverse is true. This challenges the animal&#8217;s flexibility in that it must maintain the attentional set (i.e., medium is the relevant dimension) while altering the rule learned for stimulus and reward pair within a dimension. The formation of an attentional set is challenged at the extra-dimensional shift stage, when the irrelevant dimension (odor in this example) becomes the relevant dimension. A perseverative response, as indicated by a continued choice using the previously learned rule, at either stage reflects a deficit in cognitive flexibility.
Lesion studies in both non-human primates and rodents have shown specific regions of the prefrontal cortex can be attributed to the ability to perform particular stages of the AST1,9. Lesions to the orbitofrontal cortex (OFC), a subregion of the prefrontal cortex (PFC), have been shown to induce deficits in reversal learning on the AST8. Additionally, lesions to the medial prefrontal cortex (MPFC) lead to specific difficulties in performing the extra-dimensional shift.
While numerous studies using the AST have been performed in rats and non-human primates, relatively few have utilized AST as a measure of cognitive function in mice. Given the ease of genetic manipulation in mice, and the critical need to measure prefrontal cortex function in studying a variety of disorders, adapting and validating this behavioral measure in mice is an important addition to research on diseases associated with PFC dysfunction. The protocol detailed here is a modification of the procedure by Birrell and Brown1 that is optimized for application in mice and reflects many of the mouse-specific adaptations that have been previously reported2,6,10-13.

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the attentional set shifting task: a measure of cognitive flexibility in mice

Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain&#160;to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders. However, preclinical behavioral assays used to assess these deficits in mouse models which can be readily manipulated genetically and could provide the basis for studies of new treatment avenues have been underutilized. Here we describe the adaptation of a behavioral assay, the attentional set shifting task (AST), to be performed in mice to assess prefrontal cortex mediated cognitive deficits. The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents, providing excellent face, construct and predictive validity.

The typical dependent measure in this test is the number of trials per stage to meet criterion (or 8 correct consecutive choices). Figure 4A shows the average number of trials to meet criterion at each stage in untreated C57BL/6J using the AST. As mice form an attentional set on the relevant cue dimension (odor or media), performance will improve, as indicated by a reduction in trials to meet criterion in successive intradimensional shifts, and the reversal stages and the extradimensional shift will requ...

Watch this Scientific Journal Video about The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice at JoVE.com

The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice

The goal of this protocol is to perform a behavioral assay such as the attentional set shifting task (AST) to assess prefrontal cortex-mediated cognitive flexibility in mice.

Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many ...

the-attentional-set-shifting-task-measure-cognitive-flexibility

Research

JoVE Journal

Behavior

The Crossmodal Congruency Task as a Means to Obtain an Objective Behavioral Measure in the Rubber Hand Illusion Paradigm

The rubber hand illusion (RHI) is a popular experimental paradigm. Participants view touch on an artificial rubber hand while the participants' own hidden hand is touched. If the viewed and felt touches are given at the same time then this is sufficient to induce the compelling experience that the rubber hand is one's own hand. The RHI can be used to investigate exactly how the brain constructs distinct body representations for one's own body. Such representations are crucial for successful interactions with the external world. To obtain a subjective measure of the RHI, researchers typically ask participants to rate statements such as "I felt as if the rubber hand were my hand". Here we demonstrate how the crossmodal congruency task can be used to obtain an objective behavioral measure within this paradigm.
The variant of the crossmodal congruency task we employ involves the presentation of tactile targets and visual distractors. Targets and distractors are spatially congruent (i.e. same finger) on some trials and incongruent (i.e. different finger) on others. The difference in performance between incongruent and congruent trials - the crossmodal congruency effect (CCE) - indexes multisensory interactions. Importantly, the CCE is modulated both by viewing a hand as well as the synchrony of viewed and felt touch which are both crucial factors for the RHI.
The use of the crossmodal congruency task within the RHI paradigm has several advantages. It is a simple behavioral measure which can be repeated many times and which can be obtained during the illusion while participants view the artificial hand. Furthermore, this measure is not susceptible to observer and experimenter biases. The combination of the RHI paradigm with the crossmodal congruency task allows in particular for the investigation of multisensory processes which are critical for modulations of body representations as in the RHI.

We demonstrate how an objective measure can be employed in the widely employed rubber hand illusion paradigm. This measure is obtained by modifying the well-established crossmodal congruency task. This task allows the investigation of multisensory processes which are critical for modulations of body representations as in the rubber hand illusion.

The rubber hand illusion (RHI) is a popular experimental paradigm. Participants view touch on an artificial rubber hand while the participants' own hidden ...

A Dual Task Procedure Combined with Rapid Serial Visual Presentation to Test Attentional Blink for Nontargets

When viewers search for targets in a rapid serial visual presentation (RSVP) stream, if two targets are presented within about 500 msec of each other, the first target may be easy to spot but the second is likely to be missed. This phenomenon of attentional blink (AB) has been widely studied to probe the temporal capacity of attention for detecting visual targets. However, with the typical procedure of AB experiments, it is not possible to examine how the processing of non-target items in RSVP may be affected by attention. This paper describes a novel dual task procedure combined with RSVP to test effects of AB for nontargets at varied stimulus onset asynchronies (SOAs). In an exemplar experiment, a target category was first displayed, followed by a sequence of 8 nouns. If one of the nouns belonged to the target category, participants would respond &#8216;yes&#8217; at the end of the sequence, otherwise participants would respond &#8216;no&#8217;. Two 2-alternative forced choice memory tasks followed the response to determine if participants remembered the words immediately before or after the target, as well as a random word from another part of the sequence. In a second exemplar experiment, the same design was used, except that 1) the memory task was counterbalanced into two groups with SOAs of either 120 or 240 msec and 2) three memory tasks followed the sequence and tested remembrance for nontarget nouns in the sequence that could be anywhere from 3 items prior the target noun position to 3 items following the target noun position. Representative results from a previously published study demonstrate that our procedure can be used to examine divergent effects of attention that not only enhance targets but also suppress nontargets. Here we show results from a representative participant that replicated the previous finding.&#160;

This paper describes a novel dual task procedure combined with Rapid Serial Visual Presentation to look at attentional blink at varied stimulus onset asynchronies. This experimental procedure differed from others in that it tested attentional blink for nontargets.

When viewers search for targets in a rapid serial visual presentation (RSVP) stream, if two targets are presented within about 500 msec of each other, the ...

An Operant Intra-/Extra-dimensional Set-shift Task for Mice

Alterations in executive control and cognitive flexibility, such as attentional set-shifting abilities, are core features of several neuropsychiatric diseases. The most widely used neuropsychological tests for the evaluation of attentional set-shifting in human subjects are the Wisconsin Card Sorting Test (WCST) and the CANTAB Intra-/Extra-dimensional set shift task (ID/ED). These tasks have proven clinical relevance and have been modified and successfully adapted for research in animal models. However, currently available tasks for rodents present several limitations, mainly due to their manual-based testing procedures, which are hampering translational advances in psychiatric medicine. To overcome these limitations and to better mimic the original version in primates, we present the development of a novel operant-based two-chamber ID/ED "Operon" task for rodents. We demonstrated the effectiveness of this novel task to measure different facets of cognitive flexibility in mice including attentional set formation and shifting, and reversal learning. Moreover, we show the high flexibility of this task in which three different perceptual dimensions can be manipulated with a high number of stimuli cues for each dimension. This novel ID/ED Operon task can be an effective preclinical tool for drug testing and/or large genetic screening relevant to the study of executive dysfunction and cognitive symptoms found in psychiatric disorders.

Attentional set-shifting cognitive abnormalities are a core feature of many psychiatric diseases. Here, we present the development of a novel automatic system for the effective study of attentional set-shifting abilities, executive functions and other cognitive abilities in mice with high translational validity to human studies.

Alterations in executive control and cognitive flexibility, such as attentional set-shifting abilities, are core features of several neuropsychiatric ...

The Emotional Stroop Task: Assessing Cognitive Performance under Exposure to Emotional Content

The emotional Stroop effect (ESE) is the result of longer naming latencies to ink colors of emotion words than to ink colors of neutral words. The difference shows that people are affected by the emotional content conveyed by the carrier words even though they are irrelevant to the color-naming task at hand. The ESE has been widely deployed with patient populations, as well as with non-selected populations, because the emotion words can be selected to match the tested pathology. The ESE is a powerful tool, yet it is vulnerable to various threats to its validity. This report refers to potential sources of confounding and includes a modal experiment that provides the means to control for them. The most prevalent threat to the validity of existing ESE studies is sustained effects and habituation wrought about by repeated exposure to emotion stimuli. Consequently, the order of exposure to emotion and neutral stimuli is of utmost importance. We show that in the standard design, only one specific order produces the ESE.

The emotional Stroop effect (ESE) is the result of longer naming latencies to ink colors of emotion words than those of neutral words. This report refers to potential sources of confounding and includes a modal experiment that provides the means to control for them.

The emotional Stroop effect (ESE) is the result of longer naming latencies to ink colors of emotion words than to ink colors of neutral words. The ...

The Deese-Roediger-McDermott (DRM) Task: A Simple Cognitive Paradigm to Investigate False Memories in the Laboratory

The Deese,&#160;Roediger and McDermott&#160;(DRM) task is a false memory paradigm in which subjects are presented with lists of semantically related words (e.g., nurse, hospital, etc.) at encoding. After a delay, subjects are asked to recall or recognize these words. In the recognition memory version of the task, subjects are asked whether they remember previously presented words, as well as related (but never presented) critical lure words (&#39;doctor&#39;). Typically, the critical word is recognized with high probability and confidence. This false memory effect has been robustly demonstrated across short (e.g., immediate, 20 min) and long (e.g., 1, 7, 60 d) delays between encoding and memory testing. A strength of using this task to study false memory is its simplicity and short duration. If encoding and retrieval components of the task occur in the same session, the entire task can take as little as 2 - 30 min. However, although the DRM task is widely considered a &#39;false memory&#39; paradigm, some researchers consider DRM illusions to be based on the activation of semantic memory networks in the brain, and argue that such semantic gist-based false memory errors may actually be useful in some scenarios (e.g., remembering the forest for the trees; remembering that a word list was about &#34;doctors&#34;, even though the actual word &#34;doctor&#34; was never presented for study). Remembering the gist of experience (instead of or along with individual details) is arguably an adaptive process and this task has provided a great deal of knowledge about the constructive, adaptive nature of memory. Therefore, researchers should use caution when discussing the overall reach and implications of their experiments when using this task to study &#39;false memory&#39;, as DRM memory errors may not adequately reflect false memories in the real world, such as false memory in eyewitness testimony, or false memories of sexual abuse.

The Deese-Roediger-McDermott DRM Task: A Simple Cognitive Paradigm to Investigate False Memories in the Laboratory

Here we present the Deese,&#160;Roediger and McDermott&#160;(DRM) task, a tool to study false memories in the laboratory. Subjects study lists of semantically related words (e.g.,&#160;nurse, sick, etc.), and later falsely remember an unstudied word (doctor) that represents the gist, or theme, of the word list.

The Deese,&#160;Roediger and McDermott&#160;(DRM) task is a false memory paradigm in which subjects are presented with lists of semantically related words ...

New Variations for Strategy Set-shifting in the Rat

Behavioral flexibility is crucial for survival in changing environments. Broadly defined, behavioral flexibility requires a shift of behavioral strategy based on a change in governing rules. We describe a strategy set-shifting task that requires an attentional shift from one stimulus dimension to another. The paradigm is often used for testing cognitive flexibility in primates. However, the rodent version has not been as extensively developed. We have recently extended an established set-shifting task in the rat1 by requiring attention to different stimuli according to context. All the experimental conditions required animals to choose either a left or right lever. Initially, all animals had to choose on the basis of the location of the lever. Subsequently, a change in the rule occurred, which required a shift in set from location-based rule to a rule in which the correct lever was indicated by a light cue. We compared performance on three different versions of the task, in which the light stimulus was either novel, previously relevant, or previously irrelevant. We found that specific neurochemical lesions selectively impaired the ability to make particular types of set shift as measured by the performance on the different versions of the task.

Set-shifting, a form of behavioral flexibility, requires an attentional shift from one stimulus dimension to another. We extended an established rodent set-shifting task1 by requiring attention to different stimuli according to context. The task was combined with specific lesions to identify neuron subtypes underlying a successful shift.

Behavioral flexibility is crucial for survival in changing environments. Broadly defined, behavioral flexibility requires a shift of behavioral strategy ...

Introducing Clicker Training as a Cognitive Enrichment for Laboratory Mice

Establishing new refinement strategies in laboratory animal science is a central goal in fulfilling the requirements of Directive 2010/63/EU. Previous research determined a profound impact of gentle handling protocols on the well-being of laboratory mice. By introducing clicker training to the keeping of mice, not only do we promote the amicable treatment of mice, but we also enable them to experience cognitive enrichment. Clicker training is a form of positive reinforcement training using a conditioned secondary reinforcer, the "click" sound of a clicker, which serves as a time bridge between the strengthened behavior and an upcoming reward. The effective implementation of the clicker training protocol with a cohort of 12 BALB/c inbred mice of each sex proved to be uncomplicated. The mice learned rather quickly when challenged with tasks of the clicker training protocol, and almost all trained mice overcame the challenges they were given (100% of female mice and 83% of male mice). This study has identified that clicker training for mice strongly correlates with reduced fear in the mice during human-mice interactions, as shown by reduced anxiety-related behaviors (e.g., defecation, vocalization, and urination) and fewer depression-like behaviors (e.g., floating). By developing a reliable protocol that can be easily integrated into the daily routine of the keeping of laboratory mice, the lifetime experience of welfare in the mice can be improved substantially.

The development of new refinement strategies for laboratory mice is a challenging task that contributes towards fulfilling the 3R principle. This protocol introduces clicker training as a cognitive enrichment program for laboratory mice.

Establishing new refinement strategies in laboratory animal science is a central goal in fulfilling the requirements of Directive 2010/63/EU. Previous ...

The "Motor" in Implicit Motor Sequence Learning: A Foot-stepping Serial Reaction Time Task

This protocol describes a modified serial reaction time (SRT) task used to study implicit motor sequence learning. Unlike the classic SRT task that involves finger-pressing movements while sitting, the modified SRT task requires participants to step with both feet while maintaining a standing posture. This stepping task necessitates whole body actions that impose postural challenges. The foot-stepping task complements the classic SRT task in several ways. The foot-stepping SRT task is a better proxy for the daily activities that require ongoing postural control, and thus may help us better understand sequence learning in real-life situations. In addition, response time serves as an indicator of sequence learning in the classic SRT task, but it is unclear whether response time, reaction time (RT) representing mental process, or movement time (MT) reflecting the movement itself, is a key player in motor sequence learning. The foot-stepping SRT task allows researchers to disentangle response time into RT and MT, which may clarify how motor planning and movement execution are involved in sequence learning. Lastly, postural control and cognition are interactively related, but little is known about how postural control interacts with learning motor sequences. With a motion capture system, the movement of the whole body (e.g., the center of mass (COM)) can be recorded. Such measures allow us to reveal the dynamic processes underlying discrete responses measured by RT and MT, and may aid in elucidating the relationship between postural control and the explicit and implicit processes involved in sequence learning. Details of the experimental set-up, procedure, and data processing are described. The representative data are adopted from one of our previous studies. Results are related to response time, RT, and MT, as well as the relationship between the anticipatory postural response and the explicit processes involved in implicit motor sequence learning.

The &quot;Motor&quot; in Implicit Motor Sequence Learning: A Foot-stepping Serial Reaction Time Task

We introduce the foot-stepping serial reaction time (SRT) task. This modified SRT task, complementing the classic SRT task that involves only finger-pressing movement, better approximates daily sequenced activities and allows researchers to study the dynamic processes underlying discrete response measures and disentangle the explicit process operating in implicit sequence learning.

This protocol describes a modified serial reaction time (SRT) task used to study implicit motor sequence learning. Unlike the classic SRT task that ...

Eye Tracking During Visually Situated Language Comprehension: Flexibility and Limitations in Uncovering Visual Context Effects

The present work is a description and an assessment of a methodology designed to quantify different aspects of the interaction between language processing and the perception of the visual world. The recording of eye-gaze patterns has provided good evidence for the contribution of both the visual context and linguistic/world knowledge to language comprehension. Initial research assessed object-context effects to test&#160;theories of modularity in language processing. In the introduction, we describe how subsequent investigations have taken the role of the wider visual context in language processing as a research topic in its own right, asking questions such as how our visual perception of events and of speakers contributes to&#160;comprehension informed by&#160;comprehenders&#39; experience. Among the examined aspects of the visual context are actions, events, a speaker&#39;s gaze, and emotional facial expressions, as well as spatial object configurations. Following an overview of the eye-tracking method and its different applications, we list the key steps of the methodology in the protocol, illustrating how to successfully use it to study visually-situated language comprehension. A final section presents three sets of representative results and illustrates the benefits and limitations of eye tracking for investigating the interplay between the perception of the visual world and language comprehension.

The present article reviews an eye-tracking methodology for studies on language comprehension. To obtain reliable data, key steps of the protocol must be followed. Among these are the correct set-up of the eye tracker (e.g., ensuring good quality of the eye and head images) and accurate calibration.

The present work is a description and an assessment of a methodology designed to quantify different aspects of the interaction between language processing ...

Using Rapid Serial Visual Presentation to Measure Set-Specific Capture, a Consequence of Distraction While Multitasking

This method uses a rapid serial visual presentation (RSVP) paradigm to measure the cost of distraction when participants maintain multiple search goals. The protocol identifies two types of distraction within a single task - contingent attentional capture and set-specific capture - that represent different types of limitations of cognitive processing. Participants search for letters in two or more &#34;target&#34; ink colors (e.g., green and orange) within a continuous RSVP stream of heterogeneously colored letters, while ignoring two peripheral RSVPs of letters. Upon detecting a target, participants are to identify the letter. On some trials, target-colored distractors appear in the periphery just prior to the presentation of a target, causing a drop in target identification performance. Contingent attentional capture is observed by examining performance on trials in which the peripheral distractor is the same color as the target on that trial (e.g., both orange). Set-specific capture is represented by performance on trials in which the peripheral distractor is target-colored (e.g., orange), but not the same color as the target on that trial (e.g., green.) By varying the amount of time (i.e., the number of stimuli appearing) between the presentation of the distractor and the target, researchers can observe how participants recover from these distraction costs over time. As compared to static displays that are often used to measure contingent attentional capture, the dynamic display produces much larger effects, allowing the researcher to identify subtle effects of smaller manipulations. An unusual aspect of our design is that it employs a continuous display; &#34;filler&#34; stimuli connect one trial to the next seamlessly, and participants respond during this interval whenever they detect a target. The continuous display reduces chance performance to near-zero levels (rather than 50%) and provides researchers with a more sensitive measure of performance differences across trial types.

This method uses a dynamic visual display to index costs of distraction during visual search, including both &#34;contingent attentional capture&#34; and &#34;set-specific capture,&#34; which is a cost of distraction that occurs when the participants maintain multiple search goals simultaneously. This method has revealed basic mechanisms and limitations of visual attention.

This method uses a rapid serial visual presentation (RSVP) paradigm to measure the cost of distraction when participants maintain multiple search goals. ...