Modelling Madness Susan Totterdell

Madness in Art

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

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

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

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

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

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

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

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

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)

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

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.

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

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

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

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

Prepulse inhibition of acoustic startle

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

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

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

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