Towards effective translation:
dissecting cognition in mice and humans
using touchscreens
Jess Nithianantharajah
Florey Institute of Neuroscience and Mental Health
University of Melbourne
We can perform a range of complex
mental processes
– Memory
 working memory
 visual memory (objects)
 spatial memory (locations)
 visuo-spatial memory (objects and locations)
– Executive function
 planning
 cognitive flexibility
 rule acquisition
 problem solving
 initiating appropriate actions
 inhibiting inappropriate actions
– Attention
Complex deficits in cognitive diseases
•
ie., cognitive deficits in psychiatric disorders
– Memory
 working memory
 visual memory (objects)
 spatial memory (locations)
 visuo-spatial memory (objects and locations)
– Executive function
 planning
 cognitive flexibility
 rule acquisition
 problem solving
 initiating appropriate actions
 inhibiting inappropriate actions
– Attention
Complex deficits in cognitive diseases
•
ie., cognitive deficits in psychiatric disorders
– Memory
 working memory
 visual memory (objects)
 spatial memory (locations)
 visuo-spatial memory (objects and locations)
–
How do we model these
complex mental processes in
Executive function
animals?
 planning





cognitive flexibility
rule acquisition
problem solving
initiating appropriate actions
inhibiting inappropriate actions
– Attention
Human cognitive
testing
eg., CANTAB, CogState, Cognitive
Performance Testing Services
Human cognitive
testing
eg., CANTAB, CogState, Cognitive
Performance Testing Services
Human cognitive
testing
eg., CANTAB, CogState, Cognitive
Performance Testing Services
Rodent cognitive
testing
Touchscreen cognitive testing
method for rodents
Tim Bussey & Lisa Saksida, Cambridge University
Touchscreen cognitive testing
method for rodents
Tim Bussey & Lisa Saksida, Cambridge University
Campden Instruments UK
Touchscreen cognitive testing
method for rodents
Tim Bussey & Lisa Saksida, Cambridge University
• method of testing comparable to that used in humans
- same types of stimulus materials (objects and locations on a
computer screen)
- same types of responses (responses directly made to the stimuli
on the screen)
- allows assessment of a ‘battery’ of tests to establish a cognitive
profile under same conditions
Probing simple and complex
cognitive functions
SIMPLE
COMPLEX
Synapses are fundamental units for
information processing
PSD
700 -1500 proteins
NRC
77 - 185 proteins
Mutations in postsynaptic density (PSD) genes have been implicated in over 130
brain diseases (Bayes et al., 2011)
MAGI
Adapted from Huguet, Ey & Bougeron, 2013 Ann Rev Genom Human Genet.
Scaffold proteins binding the NMDAR
MAGI
Adapted from Huguet, Ey & Bougeron, 2013 Ann Rev Genom Human Genet.
Dlg family of scaffold proteins
Membrane Associated Guanylate Kinase (MAGUK)
-Intracellular scaffolds that are key for assembling neurotransmitter receptors and
enzymes into signalling complexes
Dlg:
• Dlg1/SAP-97
• Dlg2/PSD-93
• Dlg3/SAP102
• Dlg4/PSD-95
Dlg family of scaffold proteins
Membrane Associated Guanylate Kinase (MAGUK)
-Intracellular scaffolds that are key for assembling neurotransmitter receptors and
enzymes into signalling complexes
Dlg:
• Dlg1/SAP-97
• Dlg2/PSD-93
• Dlg3/SAP102
• Dlg4/PSD-95
Visual learning:
Two choice visual discrimination
Dlg2 show normal and Dlg3-/Y show faster
visual discrimination
Dlg2 show normal and Dlg3-/Y show faster
visual discrimination
Perceptual processing ability normal
Loss of Dlg3 enhances visual discrimination
Nithianantharajah et al., 2013 Nature Neuroscience
Object-location associate learning
Dlg2 is required for visuo-spatial learning
Dlg2 is required for visuo-spatial learning
while Dlg3 is not
Dlg2 is required for visuo-spatial learning
while Dlg3 is not
Double genetic dissociation
in two forms of complex learning
(Dlg3 in visual and Dlg2 in visuo-spatial)
Nithianantharajah et al., 2013 Nature Neuroscience
Are the genes that are involved in the acquisition of
information also required for the flexibility of that
information/memories?
A test for cognitive flexibility: reversal learning
\
Dlg3 is not required, but Dlg2 is essential for
cognitive flexibility
\
Dlg3 is not required, but Dlg2 is essential for
cognitive flexibility
\
Vary task difficulty with manipulation
of stimuli
Simple
Complex
Dlg2-/- mice show normal visual discrimination learning,
but impaired reversal learning
Reversal learning
Visual Discrimination
Attention is fundamental for learning
Five-choice serial reaction time task (5-CSRTT)
•
Measures attention and behavioural inhibition
• Accuracy (% of correct choices)
• Omissions (failure to respond – ‘degraded
vigilance’)
• Premature Responses (‘impulsivity’)
• Perseverative Responses (‘compulsivity)’
• Response latency (‘speed of processing’)
• Consumption latencies (‘motivation’)
Dlg2 and Dlg3 show opposing regulatory roles
in attentional processing
Dlg2 and Dlg3 show opposing regulatory roles
in attentional processing
Dlg2 and Dlg3 show opposing regulatory roles
in attentional processing
Double dissociation in
behavioural inhibition and attentional function
Dlg paralogs play central and distinct roles in
different aspects of cognition
Nithianantharajah et al., 2013 Nature Neuroscience
Dlg paralogs in cognitive disorders
Mutations in DLG2 associated with Schizophrenia
(Walsh et al.,2008; International Schizophrenia Consortium, 2008; Kirov et al., 2011)
Dlg paralogs in cognitive disorders
Mutations in DLG3 implicated in X-linked mental retardation
(Tarpey et al., 2004)
Can we improve how we report behavioural data?
Towards a more standardised method of
behavioural reporting
Effect size (Cohen’s d, Z-score) - the degree to which a measure is different
compared to control preference
Performance on variables
above control levels indicated in red
Performance on variables
below control levels represented in blue
6 cognitive tests: 17 measures
6 cognitive tests: 17 measures
Comparative cognitive testing in humans and mice
Humans carrying copy number variations (CNVs) in Dlg2 have been reported
(Walsh et al.,2008; International Schizophrenia Consortium, 2008; Kirov et al., 2011)
Nithianantharajah & Grant, 2013 Neurobiol. Learn Mem
Nithianantharajah et al., 2013 Nature Neuroscience
Homologous cognitive testing in mice and humans
Conservation of Dlg2 cognitive functions
The Dlg2 phenotype in mice is
very specific as it is unique
in a total of 15 other gene
knockouts tested
to date
Nithianantharajah et al., 2013 Nature Neuroscience
Extending the translational tool
between humans and mice
Mouse PAL for humans - test humans on the same object-location task used in mice?
Nithianantharajah et al., in preparation
Conclusions & future directions
• Touchscreen assays are valuable tool in modeling cognitive
impairments relevant to human cognitive disorder
- mice are good models of human cognition
• Need for standardisation and systematic analysis of
cognition in mice (and humans)
• Homologous genetic/cognitive testing in mice and humans
• Approach will pave way forward for understanding the
genetic basis of different aspects of cognition and cognitive
diseases
Acknowledgements
University of Edinburgh
University of Cambridge
Seth Grant
Tim Bussey
Lisa Saksida
Noboru Komiyama
Kathryn Elsegood
David Fricker
Ellie Tuck
Carola Romberg
Translational Cognitive Neuroscience Lab
The Wellcome Trust Sanger Institute
RSF
Department of
Psychiatry,
University of Edinburgh
Andrew McKechanie
Mandy Johnstone
Douglas Blackwood
University of Nottingham
Richard Emes
Coordinated human clinical testing on an
international scale
• International collaborations to have access to
rare mutations
• Multiple diseases and mutations
• Databases and standards
Future directions