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Scientific Foundations > Animal Models of Neuropsychiatric Disorders > Flashcards

Animal Models of Neuropsychiatric Disorders Flashcards

1
Q

How do MRIs used for mice differ from humans, in both research and clinical practice?

A

▪️ Stronger for mice (9.4T +)
▪️ Can use up to 7T for research but may induce nausea or headache
▪️ ~3T for clinical practice

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2
Q

What is phase I of a clinical trial?

A

▪️ First time in humans (healthy)
▪️ What is the maximum dose that can be given safely?
▪️ Check for side effects

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3
Q

What is phase II of a clinical trial?

A

▪️ First time in patients
▪️ Still monitor safely but more importantly check for efficacy

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4
Q

What is phase III of a clinical trial?

A

Larger scale study in many patients

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5
Q

What is phase IV of a clinical trial?

A

Development an marketing

Important to get feedback from clinicians

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6
Q

How long does it typically take to develop a drug?

A

15-20 years

(costs ~2 billion)

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6
Q

How long does it typically take to develop a drug?

A

15-20 years

(costs ~2 billion)

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7
Q

How can understanding of genetics and neural circuits aid in the discovery of novel treatments in neuropsychiatry?

A
  1. Genetics influencing target/pathway selection
  2. Determining synaptic changes
  3. Integrating circuit knowledge of the disease pathology
  4. Translational behavioural testing
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8
Q

What is forward translation?

A

Testing from rodents, to non-human primates, to human volunteers, to patients

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9
Q

What is optogenetics?

A

The use of light to control neurons that have been genetically modified to express light-sensitive proteins (either activate or inhibit)

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10
Q

How does optogenetic fMRI work?

A

▪️ 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

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11
Q

Why are mice models particularly useful for studying development/longitudinal progression?

A

They have a much shorter development/life expectancy

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12
Q

What are the main limitations of clinical studies into neurological correlates of ASD?

A

▪️ 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

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13
Q

What is the main assumption that underlies the use of animals to model human disorders?

A

Basic physiological, metabolic, and developmental pathways are conserved over the course of evolution

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14
Q

What are the main benefits of animal models?

A

▪️ Mouse genome easily manipulated
▪️ Reduced interindividual variability
▪️ Pre and postnatal characterisation
▪️ Controlled environment
▪️ Large groups and longitudinal
▪️ Multiple imaging modalities and postmortem

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15
Q

What is face validity?

A

The extent to which animal phenotype resembles human symptoms

16
Q

What is construct validity?

A

The extent to which the aetiology and underlying mechanism is the same as in human disorder

17
Q

What is predictive validity?

A

The extent to which it reliably predicts treatment response in human patients

18
Q

What specific considerations should be acknowledged when studying animal models of autism?

A

▪️ 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)

19
Q

What are the main steps to translational research using animal models?

A
  1. Define abnormality of interest
  2. Build model system to recreate abnormality
  3. Find and characterise abnormality in model
  4. Define genes/define mechanism
  5. Pursue treatments reducing expression of genes or that block the mechanism
20
Q

Why are repetitive disorders and aggression in ASD good targets for interventions?

A

▪️ Most difficult aspect to cope with (both patient and carer)
▪️ Negatively impact learning and socialisation
▪️ Corticostriatal circuitry as pathophysiology?

21
Q

Why are BTBR mice a good model of ASD?

A

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)

22
Q

What are the two ways we can use animal models to identify treatments?

A
  1. Apply drug then find disease mechanism
  2. Understand disease mechanism then find drug
23
Q

What is NAC and what does it show in BTBR mice?

A

▪️ Reduces synaptic glutamate
▪️ Used for severe repetitive behaviour in children with ASD
▪️ Reduces digging behaviours in mice and striatum activity

24
Q

How can oxytocin be used for ASD?

A

▪️ Used for repetitive behaviours
▪️ Reduces grooming in BTBR mice - increased activity in hypothalamus

25
Q

What is Williams syndrome?

A

▪️ Spontaneous deletion on Chr 7
▪️ Cocktail party personality (social, no anxiety, empathic)
▪️ Facial characteristics
▪️ LD, neurological problems
▪️ Good hearing, musical abilities, and face processing
▪️ Poor number and visueospatial skills

26
Q

What fMRI brain changes are involved in Williams syndrome?

A

▪️ Increased primary auditory cortex
▪️ Abnormal dorsal visual stream processing (visuospatial) but intact ventral (recognition)
▪️ Little activation of amygdala in response to threatening faces

27
Q

How can you diagnose William’s syndrome?

A

▪️ FISH - shows one copy of elastin gene
▪️ Deletion of elastin and vascular abnormality - can use to identify missing genes in WS

28
Q

What can Ts65Dn mice be used for?

A

Modelling phenotypic and genotypic aspects of DS

(partial trisomy Chr 16)

29
Q

What have Ts65Dn mice taught us about DS?

A

Overinhibition!
▪️ Reduced density of excitatory synapses with concurrent sparing of inhibitory (increased inhibitory tone)
▪️ Induction and maintenance of LTP is impaired by excessive inhibition

30
Q

What pharmacological interventions shows promise for over-inhibition in DS?

A

▪️ GABA-A antagonist (PTZ)
▪️ GABA-A inverse agonism

31
Q

What have GABA-A inverse agonists shown in mouse models?

A

▪️ Enhance cognitive functions BUT some have proconvulsive and anxiogenic effects
▪️ Best result with alpha-5 receptors in hippocampus and cortex - enhance memory and LTP

32
Q

What have Ts1Cje mouse models be useful for?

A

Development of prenatal treatment for Down syndrome

ALGERNON (altered generations of neurons):
▪️ promoted normal growth of cortex
▪️ normal thickness of cortical layer
▪️ improved learning ability
▪️ prevents development of impaired cognitive behaviours

33
Q

What are the main symptoms of fragile X?

A

▪️ Worse in males
▪️ Mild to mod ID
▪️ Long narrow face, large ears
▪️ Social anxiety, aggression, hyperactivity
▪️ Poor math (reduced brain activation)
▪️ ASD?

34
Q

What is the aetiology of fragile X?

A

▪️ Mutation in untranslated region of FMR1 gene
▪️ Polymorphic CCG repeat
▪️ Hypermethylation - gene inactivation
▪️ Normal, premutation, or full mutation allele depending on length

35
Q

What mouse model can be used for fragile X?

A

FXS - FMR1 gene inactivated to tell use what FMRP does

36
Q

What is shown in FXS mice?

A

▪️ Subtle cognitive problems (similar profile to humans)
▪️ Audiogenic seizures
▪️ Impairment of glutamate pathway regulation
▪️ Overactive regulation of strength of neural connections for learning
▪️ Abnormal dendritic spines

37
Q

What is CTEP treatment and what does it show in FXS mice?

A

▪️ Blocks specific glutamate pathways
▪️ Corrects LTD
▪️ Corrects elevated dendritic spine density and hyperactivity
▪️ Normalised neural activity in amygdala and lateral hypothalamus
▪️ Decreased activity in hippocampus
▪️ Increase activity in primary sensorimotor areas

38
Q

What are the three Rs for good science?

A

Principle to improve animal welfare and scientific accuracy

  1. Refinement (make animals lives better)
  2. Reduction (few animals as possible)
  3. Replacement (non-animal alternative where possible)

Scientific Foundations (27 decks)

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