Animal Models of Neuropsychiatric Disorders Flashcards
How do MRIs used for mice differ from humans, in both research and clinical practice?
▪️ Stronger for mice (9.4T +)
▪️ Can use up to 7T for research but may induce nausea or headache
▪️ ~3T for clinical practice
What is phase I of a clinical trial?
▪️ First time in humans (healthy)
▪️ What is the maximum dose that can be given safely?
▪️ Check for side effects
What is phase II of a clinical trial?
▪️ First time in patients
▪️ Still monitor safely but more importantly check for efficacy
What is phase III of a clinical trial?
Larger scale study in many patients
What is phase IV of a clinical trial?
Development an marketing
Important to get feedback from clinicians
How long does it typically take to develop a drug?
15-20 years
(costs ~2 billion)
How long does it typically take to develop a drug?
15-20 years
(costs ~2 billion)
How can understanding of genetics and neural circuits aid in the discovery of novel treatments in neuropsychiatry?
- Genetics influencing target/pathway selection
- Determining synaptic changes
- Integrating circuit knowledge of the disease pathology
- Translational behavioural testing
What is forward translation?
Testing from rodents, to non-human primates, to human volunteers, to patients
What is optogenetics?
The use of light to control neurons that have been genetically modified to express light-sensitive proteins (either activate or inhibit)
How does optogenetic fMRI work?
▪️ Light sensitive opsins targeted to neurons of choice (via virus) and activated by light
▪️ Optogenetic modulation triggers behavioural effects (opens ion channels)
▪️ fMRI used to identify brain-wide effects
Why are mice models particularly useful for studying development/longitudinal progression?
They have a much shorter development/life expectancy
What are the main limitations of clinical studies into neurological correlates of ASD?
▪️ Small and heterogeneous patient group
▪️ Cross-sectional - difficult to do longitudinal
▪️ No multimodal imaging - time consuming and expensive
▪️ Lack of correlation with post-mortem analysis
What is the main assumption that underlies the use of animals to model human disorders?
Basic physiological, metabolic, and developmental pathways are conserved over the course of evolution
What are the main benefits of animal models?
▪️ Mouse genome easily manipulated
▪️ Reduced interindividual variability
▪️ Pre and postnatal characterisation
▪️ Controlled environment
▪️ Large groups and longitudinal
▪️ Multiple imaging modalities and postmortem
What is face validity?
The extent to which animal phenotype resembles human symptoms
What is construct validity?
The extent to which the aetiology and underlying mechanism is the same as in human disorder
What is predictive validity?
The extent to which it reliably predicts treatment response in human patients
What specific considerations should be acknowledged when studying animal models of autism?
▪️ Deficits in behaviours that are similar to core symptoms (e.g., impaired social interaction, increased stereotypies)
▪️ Phenotype due to insult during early development (e.g., genetics, prenatal exposure)
▪️ Additional phenotypes present in subset of patients (e.g., co-morbidities, structural abnormalities, macrocephaly)
What are the main steps to translational research using animal models?
- Define abnormality of interest
- Build model system to recreate abnormality
- Find and characterise abnormality in model
- Define genes/define mechanism
- Pursue treatments reducing expression of genes or that block the mechanism
Why are repetitive disorders and aggression in ASD good targets for interventions?
▪️ Most difficult aspect to cope with (both patient and carer)
▪️ Negatively impact learning and socialisation
▪️ Corticostriatal circuitry as pathophysiology?
Why are BTBR mice a good model of ASD?
They exhibit repetitive behaviours such as digging and grooming, as well as social difficulties (face validity)
Missing corpus callosum BUT unsure why this results in behaviour (construct validity)
What are the two ways we can use animal models to identify treatments?
- Apply drug then find disease mechanism
- Understand disease mechanism then find drug
What is NAC and what does it show in BTBR mice?
▪️ Reduces synaptic glutamate
▪️ Used for severe repetitive behaviour in children with ASD
▪️ Reduces digging behaviours in mice and striatum activity
