1. Modelling Madness
Susan Totterdell

2. Madness in Art

3. Can we study mental disorders in animals?
Are such disorders uniquely human
Can we know if an animal is depressed or psychotic?

4. Talk plan What makes an animal model
Outline of two major brain disorders
schizophrenia, depression
Suggested models
Model Validation
Example of validation process
Conclusions

5. What is a model?
Any experimental preparation developed for the purpose of studying a condition in the same or different species….
Typically models are preparations in animals that attempt to mimic a human condition

6. Purposes of an animal model
Mimic the syndrome in its entirety
Difficult if your knowledge of the syndrome is incomplete and changing
Study potential therapeutic treatments
Tends to concentrate on effects of known drugs which may limit their ability to identify new drugs with novel mechanisms of action

7. Other types of animal model
Mimic only specific signs and symptoms
Symptoms being modelled may not be diagnostic for the disorder but should be reliably measured and defined
Mimic the psychological constructs thought to be affected in the disorder
Useful for studies that involve both patients and putative models

8. Schizophrenia Affects 1% of the population World wide distribution
Positive and negative symptoms
Genetic element
Developmental
Brain tissue lost
Treated by dopamine antagonists

9. What types of models? In schizophrenia
Developmental - isolation rearing
Pharmacological - Psychostimulants
Genetic - NR1 subunit knock down
Lesion - neonatal ventral hippocampal lesion 10 20 30 40 50 60 70
Drug-induced
Developmental
Lesion-induced
Genetic

10. Depression Affects 10-15% of the population World wide distribution
Genetic predisposition
Psychological & physiological symptoms
Involves loss of brain tissue
Treated by increasing 5-HT levels

11. What types of models? Models of depression
Uncontrollable Stress (learned helplessness)
replicates the whole illness
do patients display learned helplessness?
Behavioural Despair (+/- US)
forced swim
drugs reverse effects acutely
Reward models (US or CMS)
anhedonia - working for reward
reversed by chronic not acute drug treatment
Genetic models
aim to reproduce aetiology
complex, polygenic (5-HT, stress signalling, neurotrophins)

12. Model validation
Models are only as sound as the information currently available in the clinical literature
Models assume a common basis for the behaviour and physiology of various species
Models should be reliable in terms of induction and outcome.
Variability cannot always be considered an error

13. Model validation - predicitve
PREDICTIVE VALIDITY
The ability of the model to predict the human phenomenon. Usually this refers to treatment (pharmacological isomorphism)
The most important criterion since the scientific process requires the testing of predictions
Predictive validity and reliability may be sufficient to define a good model.

14. Model validation- construct
CONSTRUCT VALIDITY
The accuracy with which a model measures what it is intended to measure
Often considered the most important criterion but rarely established
Ongoing modification of the model as ideas about the disorder evolve

15. Model validation - face
FACE VALIDITY
The model resembles the disease being studied
Different species may not reflect similar symptoms even if the aetiology of the condition is known
Similarities between symptoms do not necessarily implicate similar aetiologies

16. Isolation rearing model
Increased aggression
Disrupts DA, 5-HT systems
Alters response to amphetamine
Disrupts PPI

17. Isolation rearing model
Pulse
Pre-pulse
Pre-pulse + pulse

18. Prepulse inhibition of acoustic startle

19. Changes in the PFC Volume: significant reduction Neuron number:
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00 1
Mean ± SEM volume/mm3
Batch 3
Batch 2
Batch 1 * ( )
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9 6
6.1 1
Mean ± SEM volume/mm3
Batches 1, 2 & 3
Neuron number:
no significant change
total neuron number
50000
100000
150000
200000
250000
300000
350000
400000
450000 1
Mean ± SEM neuron number
Batch 3
Batch 2
Batch 1 *
Day-Wilson et al., Neuroscience 2006

20. GAT-1 immunoreactivity
Chandelier cells
GAT-1 immunoreactivity
in rat PFC
Lewis et al.
Hardwick et al., Brain Research 2006

21. Conclusions from these studies
Animal models have a role to play in studies of human brain disorders
Isolation-rearing has predictive validity and aspects of face, construct validity
Behavioural/neuropathological
Developmental
Novel treatments
It is possible to compare data gained using a range of experimental techniques
This model may provide a useful way to identify novel therapeutic targets

22. General conclusions
It is probably not possible to model complex brain disorders in animals
Animal models are useful to relate symptoms to particular pathological changes
Animal models are crucial to pre-clinical screening of drugs
Genetic models will have to reflect the polygenic nature of these disorders