Towards effective translation: dissecting cognition in mice and humans using touchscreens
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1 Towards effective translation: dissecting cognition in mice and humans using touchscreens Jess Nithianantharajah Florey Institute of Neuroscience and Mental Health University of Melbourne
2 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
3 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
4 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 How do we model these complex mental processes in animals?
5 Human cognitive testing eg., CANTAB, CogState, Cognitive Performance Testing Services
6 Human cognitive testing eg., CANTAB, CogState, Cognitive Performance Testing Services
7 Human cognitive testing Rodent cognitive testing eg., CANTAB, CogState, Cognitive Performance Testing Services
8 Touchscreen cognitive testing method for rodents Tim Bussey & Lisa Saksida, Cambridge University
9 Touchscreen cognitive testing method for rodents Tim Bussey & Lisa Saksida, Cambridge University Campden Instruments UK
10
11 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
12 Probing simple and complex cognitive functions SIMPLE COMPLEX
13 Synapses are fundamental units for information processing PSD proteins NRC proteins Mutations in postsynaptic density (PSD) genes have been implicated in over 130 brain diseases (Bayes et al., 2011)
14 MAGI Adapted from Huguet, Ey & Bougeron, 2013 Ann Rev Genom Human Genet.
15 Scaffold proteins binding the NMDAR MAGI Adapted from Huguet, Ey & Bougeron, 2013 Ann Rev Genom Human Genet.
16 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
17 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
18 Visual learning: Two choice visual discrimination
19 Dlg2 show normal and Dlg3-/Y show faster visual discrimination
20 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
21 Object-location associate learning
22 Dlg2 is required for visuo-spatial learning
23 Dlg2 is required for visuo-spatial learning while Dlg3 is not
24 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
25 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 \
26 Dlg3 is not required, but Dlg2 is essential for cognitive flexibility \
27 Dlg3 is not required, but Dlg2 is essential for cognitive flexibility \
28 Vary task difficulty with manipulation of stimuli Simple Complex
29 Dlg2 -/- mice show normal visual discrimination learning, but impaired reversal learning Reversal learning Visual Discrimination
30 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 )
31 Dlg2 and Dlg3 show opposing regulatory roles in attentional processing
32 Dlg2 and Dlg3 show opposing regulatory roles in attentional processing
33 Dlg2 and Dlg3 show opposing regulatory roles in attentional processing Double dissociation in behavioural inhibition and attentional function
34 Dlg paralogs play central and distinct roles in different aspects of cognition Nithianantharajah et al., 2013 Nature Neuroscience
35 Dlg paralogs in cognitive disorders Mutations in DLG2 associated with Schizophrenia (Walsh et al.,2008; International Schizophrenia Consortium, 2008; Kirov et al., 2011)
36 Dlg paralogs in cognitive disorders Mutations in DLG3 implicated in X-linked mental retardation (Tarpey et al., 2004)
37 Can we improve how we report behavioural data?
38 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
39
40 6 cognitive tests: 17 measures
41 6 cognitive tests: 17 measures
42 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
43 Nithianantharajah et al., 2013 Nature Neuroscience
44 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
45 Extending the translational tool between humans and mice Mouse PAL for humans - test humans on the same object-location task used in mice?
46
47 Nithianantharajah et al., in preparation
48 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
49 Acknowledgements University of Edinburgh Seth Grant Noboru Komiyama Kathryn Elsegood David Fricker Ellie Tuck University of Cambridge Tim Bussey Lisa Saksida Carola Romberg Translational Cognitive Neuroscience Lab The Wellcome Trust Sanger Institute RSF Department of Psychiatry, University of Edinburgh University of Nottingham Richard Emes Andrew McKechanie Mandy Johnstone Douglas Blackwood
50 Coordinated human clinical testing on an international scale International collaborations to have access to rare mutations Multiple diseases and mutations Databases and standards
51 Future directions
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