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Using Touchscreen Operant Systems to Study Cognitive Behaviors in Rodents
Experts present methodology and best practices of Bussey-Saksida Touchscreen Systems used for the cognitive evaluation of rodents.
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Our Talk Today
1. Background
2. Hardware Requirements
3. ABET II Touch Software
4. Validated Tasks
5. Integrating with other systems
• The Cambridge Neuropsychological Test Automated Battery (CANTAB) was first developed 30 Years Ago
• Designed from a knowledge animal behavioral tests
• Proven tests sensitive to specific brain areas
• Presented on touchscreens
• Abstract shapes used to eliminate differences in language and culture.
Touchscreen Testing Background – Human CANTAB Tests
• Some of the Human tasks made suitable for Non-Human Primates
• Complex tasks broken down into their constituent elements
• Tests proven to be sensitive to the same specific brain areas as the human tests
Touchscreen Testing Background – Monkey CANTAB
• Work gone full circle to develop equivalent tasks for rodent
• Complex tasks broken down into their constituent elements
• Tests proven to be sensitive to the same specific brain areas as the human tests
• Initial work in standard operant chambers with touchscreen bolted
Rodent Touchscreen Development
• Chamber design – Keep the animal focused on the task
• Effective training
• Flexible data analysis
• Validated Tasks – Functional equivalence to Human Tasks
• On going development of tasks
Important Considerations in designing translational Rodent Tasks
• use in place of levers – e.g. PR task
• use in place of nose pokes – e.g. 5-choice serial reaction time task
• Response to different images adds further function over more traditional operant chambers
• A wide range of stimuli positions available
• Further flexibility by adding elements from more standard chambers – levers, lights, sound etc.
• Addition of video adding a further element to testing.
Touchscreens Flexibility
Additional information can be gained by seamlessly integrating with other cognitive measures:
Electrophysiology Recording
Video Tracking
Optogenetics
Touchscreen Integration…
System Layout
1. Single Computer
2. Digital I/O Interface
3. Four TouchscreenChambers
Computer
Box 1 Box 2 Box 3 Box 4
Digital I/O Interface
Video & Touch Data
Inputs/Outputs
Mouse Chamber
1. Touchscreen
2. Mask (paradigm specific)
3. Reward Pump
4. Reward Bottles
5. Perforated Floor
6. Waste Pan
7. Ambulatory IR Beams
1
2
3
45
6
7
Mouse Chamber
1. Touchscreen
2. Trapezoidal Walls & Lid
3. Reward Trough
4. Reward Bottles
5. Ambulatory IR Beams
6. Pull-out roller shelf
7. House Light/Fan/Speaker
1
2
3
4
5
6
7
Touchscreens – IR Technology
Lots of ‘touch’ technologies available…IR Technology provides:
No force requirements
Behaviorally similar to nosepoke
No interference with telemetry
Easy identification of ‘discrete’ and ‘intended’ touches
** Other touch technologies can be used, but not as effectively.
• Modular Walls – add standard operant accessories (levers, lights, nosepokes, ect.)
• Tether compatible walls, lid, and reward trough – for canulas, neural recording, or optogentics fibers
• Easy-Install Kit – four chambers neatly mounted on their own car for mobility and ease of use
• Grid Shock – Aversive foot shock
• TTL Breakout box – Trigger 3rd party equipment
Additional Options
Touchscreens vs. Operant
• Versatile – can run multiple paradigms on a single chamber
• Flexible – change spatial location on a trail by trial basis automatically
• Powerful – use custom images, control stimuli locations, adjust the paradigm
ABET II Touch
Tab Name Description
Environment Designer Identify what hardware (lights, lever, reward pump) is connected
Schedule Designer Create, open, and edit schedule files which control the chambers
Execution Manager Run schedule files in the chambers with independent control
Analysis Set DesignerCreate, open, and edit analysis files which pull out important metrics from the RAW data
Data ViewerReview RAW data or run analysis files to create daily performance reports
ABET II Touch – Environment Designer
1. Chambers
2. Touch monitor settings
3. Inputs – IR Beams, Levers, NosePokes
4. Outputs –HouseLight, Reward, Tone, TrayLight
1
3 4
2
Identify what hardware (lights, lever, reward pump) is connected
1
3
4
2
ABET II Touch – Schedule Designer
Create, open, and edit schedule files which control the chambers
1. Schedule information
2. Variables, Lists, Arrays
3. Schedule structure and progression
4. Code view of selected group
13
4
2
ABET II Touch – Execution Manager
Run schedule files in the chambers with independent control
1. Chambers
2. Session end criterion – Max trials or time
3. Database selection for data saving
4. Session Information – Animal ID, user, weight, dose, …
ABET II Touch – Analysis Set Designer
Create, open, and edit analysis files which pull out important metrics from the RAW data
1
3
4
1. Analysis file information
2. Analysis Item – Path, counter, evaluation
3. Analysis Point –Start/stop, variable, time point
4. Code view of selection
2
13
4
2
ABET II Touch – Data Viewer
Review RAW data or run analysis files to create daily performance reports
1. Database search for specific sessions
2. Analysis tab to run analysis files
3. Various views of group statistics
4. Report Editor –create your own spreadsheet design and easily export
ABET II Touch - Features
Setup and control various hardware configurations
Easily create and modify your schedules
Load your own images into the schedules
Independent control and millisecond timing
Quickly view “meaningful data” after running
Guided interface reduces learning curve
Additional Online Resources
Download the Bussey-Saksida Rodent Touch System Brochure
Join our Rodent Touchscreen Users Forum
CHAMBERS AND COMPONENTS FOR RATS
CHAMBERS FOR ELECTROPHYSIOLOGY
CHAMBERS AND COMPONENTS FOR MICE
Validated Tasks – A Turnkey Solution
1. The Tasks
2. Application to different Neural Area
3. Training Times
4. Rodent strains
5. The PAL task
• Pairwise / Visual Discrimination (PD)
• Pairwise Associate Learning (PAL)
• Visuomotor Conditional Learning (VMCL)
• Location Discrimination (LD)
• Trial Unique Nonmatching to Location (TUNL)
• 5-Choice Serial Reaction Time Task (5-CSRTT)
• Autoshaping (AUTO)
• Extinction (EXT)
• Progressive Ratio (PR); Effort Related Choice (ERC)
• Rodent Continuous Performance Test (rCPT)
The Tasks
TaskExample Neural Systems Involved
Clinical Area Showing Impairment
Pairwise / Visual Discrimination (PD)
Prefrontal Cortex, Perirhinal Cortex, Striatum, Dopamine System, Cholinergic System, NMDA receptors
Huntingdon’s, Schizophrenia, Parkinson’s
Pairwise Associate Learning (PAL)
Hippocampus, Cholinergic System, NMDA Receptors, AMPA Receptors
Alzheimer’s, Schizophrenia
Visuomotor Conditional Learning (VMCL)
Dorsal Striatum, Posterior Cingulate Cortex Huntingdon’s, Parkinson’s
Location Discrimination (LD) Hippocampus, NeurogenesisAlzheimer’s, Schizophrenia, Depression
Trial Unique Nonmatching to Location (TUNL)
Hippocampus, Cholinergic System, NMDA Receptors Alzheimer’s
TaskExample Neural Systems Involved
Clinical Area Showing Impairment
5-Choice Serial Reaction Time Task (5-CSRTT)
Prefrontal Cortex, Basal Forebrain, Serotonin (Impulsivity), Cholinergic System (Accuracy), Noradrenaline (Distraction), Dopamine (Motivation)
Huntingdon’s, Schizophrenia, Alzheimer’s, Depression, ADHD, OCD
Autoshaping (AUTO)Ventral Striatum, Amygdala Anterior Cingulate Cortex
Huntingdon’s
Extinction (EXT) Infralimbic, Ventral Striatum, Amygdala ADHD, OCD
Progressive Ratio (PR); Effort Related Choice (ERC)
Dopamine systemHuntingdon’s, Schizophrenia, Alzheimer’s
Rodent Continuous Performance Test (rCPT)
Hippocampus, Cholinergic System, NMDA Receptors
Schizophrenia, Alzheimer’s, ADHD, OCD
Task Training Time - Rats Training Time - Mice
Pre-training to touch image and initiate (PD, PAL, LD, VMCL, TUNL)
1-2 weeks1-2 weeks (e.g. 7-8 week old C57BL6J mice: 5 days)
Pairwise/Visual Discrimination (PD) 5-7days 5-7 days for young mice
Pairwise Associate Learning (PAL) 35-45 sessions to 80% 35-45 sessions to 70%
Visuomotor Conditional Learning Approximately 20 sessions Approximately 20 sessions
Location Discrimination (LD) 2-4 weeks 2-4 weeks
Trial Unique Nonmatching to Location (TUNL)
Approximately 4 weeks 14-16 sessions
5-Choice Serial Reaction Time Task(5-CSRTT)
~30 sessionsPre-training (av. 10 days) and 3 weeks to 80% @ 2sec
Task Training Time - Rats Training Time - Mice
Autoshaping (AUTO) Several sessions Several sessions
Extinction (EXT)~4 days training and a few days extinction
~4 days training and a few days extinction
Progressive Ratio (PR); Effort Related Choice (ERC)
16 days to train mice from the first habituation session to reach stable PR performance.
Rodent Continuous Performance Test (rCPT)
~ 24 sessions
Rats
• Lister hooded, Pigmented DA strain, Sprag-Dawley, Long-Evans
• Genetic Absence Epilepsy Rats from Strasbourg (GAERS) -showed a significant deficit on PD, compared to the non-epileptic control (NEC) strain. (John Howland – work to be published)
Rodent strains used with Touchscreen chambers
Mice
• C57BL/6, C57BL/6J, DBA/2J, C57BL/6JRj, Heterozygous NR2A (HET), 5HTT null KO and HET, M1R-/- (show increased perseveration), TgCRND8, DLg1, Dlg2, Dlg3 & Dlg4 mutations
• Showing deficits in the PD task - R6/2, NR2A KO
• Showing impairment in the 5-CSRTT –3xTgAD, M1R-/- (show increased perseveration)
Rodent strains used with Touchscreen chambers
Translational Tasks
Paired associate learning
5-Choice serial reaction time
Spatial Working Memory
Frontal Temporal
Frontal
Frontal Parietal
Set shifting
Visual Discrimination and reversal
Continuous Performance Task Frontal Temporal
Frontal
Frontal
Example Patient Profile
-2.5
-2
-1.5
-1
-0.5
0
Pattern Spatial PAL IDED
Alzheimer’s
Parkinson’s
Standard deviations
fromcontrolmean
Paired Associative Learning (PAL)
Highly sensitive to cognitive decline in Alzheimer’s disease
Activates neural correlates for new learning & memory
Paired Associative Learning (PAL) – Human Task
1. Boxes open in a random order to reveal an abstract shape
2. Then the shapes are shown in a random order in the centre of the screen. The subject touches the boxes where they first saw the shape
3. The process is repeated until no mistakes are made
0
20
40
60
80
100
120
140
PA
L e
rro
rs
-4 0 4 8 12 16 20 24 28
Time point (months)
pDAT
QD1
QD2
Normal controls
Fowler, K. S., Saling, M. M., Conway, E. L., Semple, J. M. and Louis, W. J. (1997) Computerized neuropsychological tests in the early detection of dementia: prospective findings. Journal of the International Neuropsychological Society, 3, 139-146.
Sensitivity of PAL to decline in Alzheimer’s Disease
Sensitivity of PAL to decline in Alzheimer’s Disease
• The 34 error cut-off (shown by red line) would have discriminated at the 6-month point who in the QD group would go on to receive AD diagnoses and who would not.
Sensitivity of PAL to decline in Alzheimer’s Disease
Swainson, R., Hodges, J. R., Galton, C. J., Semple, J., Michael, A., Dunn, B. D., Iddon, J. L., Robbins, T. W. and Sahakian, B. J. (2001) Early detection and differential diagnosis of Alzheimer's disease and depression with neuropsychological tasks. Dementia and Geriatric Cognitive Disorders, 12 (4), 265-280.
Monkey PAL
• Rhesus Monkeys readily acquire the CANTAB-PAL task and performance is graded by task difficulty
• Repeated attempts to learn a given set of stimulus-location associations improves completion accuracy
• Ketamine and scopolamine both impair the initial attempt in a dose-dependent fashion.
• Monkeys treated with ketamine require additional attempts to learn a set of stimulus-location associations
• Monkeys treated with scopolamine make fewer attempts and do not improve with repeated opportunities
• The CANTAB-PAL task may serve to distinguish a lack of sustained attention from impaired memory
Taffe et al, Psychopharmacology (2002), 160, 253-262
PAL Training
1. Animal handling
2. Food Deprivation
3. Habituation to touchscreen chamber
4. Pavlovian training to associate reward with images on the screen
5. Training to touch the screen
6. Training to initiate the tasks
7. Training to ignore blank windows
8. The PAL task
PAL Task Manipulations and Validation
S+ S-
sPA
L
Antagonism of NMDA (shown above) or AMPA receptors in the hippocampus impairs performance in rats on dPAL, but not on sPAL
Talpos JC, Winters BD, Dias R, Saksida LM, Bussey TJ, Psychopharmacology 2009 157
S+ S-
dPA
L
PAL Task –a translational task
Humans with DLG2 mutations and Dlg2-knockout mice both show impairment on the dPALtask.
Nithianantharajah et al, Nature Neuroscience, 201316
Tasks overview
• Wide range of validated tasks
• Covering a range of cognitive functions
• Training from a few days to 1-2 months
• Used with a range of rat and mouse strains, including KO strains.
• Offers an alternatives to standard lever and nose-poke responses
Electrophysiology Integration
Chambers compatible for neural recordings:
Sound Attenuation Chamber lined with EMI resistant paint/stainless steel
Touchscreens have additional EMI reducing film
Electrical components/cables are shielded
TTL event lines to mark events on neural data files
Optogenetics & Video Tracking
Increased height Sound Attenuation Chambers
Additional TTL output lines for triggering/marking events
Walls and reward receptacle have been designed for animals with head caps
Upper rolling shelf for easy mounting
• All the features of previous electrophysiology chambers
• Integrated auto-retract tether with shielded cable
• Digital headstage and range of electrodes
• Synchronous video acquisition and event markers in the neural data
• Each component is designed specifically for use in the touchscreenchambers
Fully Integrated Solution
Tethered and Wireless options
Thank You!If you have questions for the presenters please contact them by email.
For additional information on the solutions presented in this webinar please visit:
www.lafayetteinstrument.comJulie Gill, PhD
Matt [email protected]