lecture 18 - Using animal models to investigate genetic effects on behaviour Flashcards
What is an animal model?
‘A living, non-human being used to understand the biological basis of healthy and pathological human phenotypes, and how to alleviate the latter, without the risk of harming
an actual human being during the process’
Criteria for a good animal model
* ‘Face validity’ (i.e. does the model resemble the human phenotype?)
* ‘Construct validity’ (i.e. do the model and the human phenotype share common
biological underpinnings?)
* ‘Predictive validity’ i.e. do therapeutic drugs have same effect in humans and model? Can model be used to screen for new treatments?
Types of animal model - surgical
- Occlusion of middle cerebral artery (stroke)
- Brain lesions
- Gonadectomy
Types of animal model - Administration of chemical or biological agents or radiation
- Metrazol (pentylenetetrazol) administration (epilepsy)
- Immunisation with auto-antigen (autoimmune disorders)
- Administration of pathogenic and non-pathogenic micro-organisms (infectious diseases) (effects of gut
microbiota on brain function) - Neurotransmitter agonists/antagonists or enzyme inhibitors (healthy/pathological behaviours)
Types of animal model - Genetic
- Manipulation of genomic DNA
- Administration of genetic material (to affect transcription/translation, as an experimental tool)
Advantages of using animal models to understand gene (dys)function
- Examine in vivo effects of manipulation on brain function/behaviour (emergent property
of integrated physiological systems) cf. cellular models; similarity of physiology to humans - Accessibility of neural tissue and amenability to procedures that would not be ethical in
humans e.g. interactions between drug administration and genetic lesion - Can be maintained in large colonies
- Good breeders with short generation times
- Experimental control (regulated genetic background, environment)
- Genomes amenable to genetic manipulation; similarity with human genome
- Wide repertoire of sophisticated behaviours
Disadvantages of (genetic) animal models
- Genetic and physiological divergence from humans
- Different evolutionary histories (e.g. sensory modalities, social groupings)
- Limited range of genetic modifications possible - now there are more technologies
- Relevance to complex human behaviours influenced by combined effects of many genes –
endophenotypes! Hard to look at age-related diseases e.g. AD or HD - Ethical issues regarding possible adverse effects (e.g. ‘psychiatric’ phenotypes)
- Inability to accurately model human-specific phenotypes e.g. language, psychosis
- Models rarely have true face, construct and predictive validity
Commonly used genetic animal models
- GM non-human primates are very rarely used for research,
but do exist (rhesus monkey ANDi, GFP transgene)
Chan et al. (2001) Science 291:309-12 - Caenorhabditis elegans (nematode worm)
- Drosophila melanogaster (fruit fly)
- Danio rerio (zebrafish)
- Prairie (monogamous) and meadow (promiscuous) voles
- Mus musculus (and other mouse sub-species)
- Rattus norvegicus (rat)
C. elegans
- Molecular and developmental characterisation by Brenner (early 1970s); first multicellular organism to have its genome sequenced
- Well-defined developmental fate for every cell (1031 in adult male); transparent
- Simplest organism with a nervous system (302 neurons); ‘connectome’ characterised
- Many strains with defined genetic mutations; can be frozen and thawed for storage and transport
- Can be exposed to double-stranded RNAi (infusion, injection or through bacterial ingestion) to disable individual genes
- Can be administered drugs readily
- Exhibits chemotaxis, thermotaxis, learning and memory, mating behaviours
- Can be used to study complex processes e.g. nicotine dependence (acute response, tolerance, withdrawal and sensitisation)
D. melanogaster
- Used as a genetic model from early 1900s onwards; genome sequenced and published in 2000
- Have lots of mitochondria for flight - neurodegenerative diseases such as alchzeimers are caused by changes in mitochondria function - can use flies to see how to treat
- Only four pairs of chromosomes (3 autosome pairs, and one sex chromosome pair); used to
study fundamental mechanisms of transcription and translation - Genome can be readily manipulated (since 1987)
- Morphology (including ‘nervous system’) easily identifiable
- Used as a genetic model for neurodegenerative
disorders (PD, AD, HD) and effects of oxidative
stress/ageing - Also used to examine genetics of circadian rhythm,
sensory function, locomotor activity, courtship, pain,
and learning and memory
Zebrafish
- Used as a lab model from 1960s onwards; reference genome sequence published in 2013
- Genome can be readily manipulated
- Expression of specific genes can be acutely altered through use of ‘morpholino antisense oligonucleotides’
(bind to mRNA sequences and prevent translation to protein) - Embryos large, robust, transparent and able to develop outside of the mother
- Well-characterised, easily observable and testable range of (developmental) behaviours
- Diurnal sleep cycle
- Anxiety-related and exploratory behaviours
- Chemosensory behaviours
- Response choice and inhibition
- Social behaviours
- Cognitive and executive functions
- Similar response to mammals in toxicity testing – utility for high-throughput screening of novel therapeutics?
three- choice serial reaction time task for zebrafish - Parker et al
Rodents (mice and rats)
- Mice used as lab models since 16th Century by, inter alia, Harvey, Hooke, Priestley and Mendel; rats used as
models from early 1800s – first animal domesticated for purely scientific reasons - Mouse (C57BL/6 strain) genome sequenced and published in 2002 (second mammalian genome after
human); rat genome sequenced and published in 2004 - Mouse genome readily manipulated; rat genome less so, until recently (see later)
- Mammals, therefore high degree of genetic and physiological homology with humans
- Range of sophisticated behavioural phenotypes; can examine genetic effects on:
- Courtship and mating behaviours
- Dam-pup interactions
- Social behaviours
- Circadian rhythms
- Motor function
- Anxiety-related and exploratory behaviours
- Cognition and executive function
Genetic rodent models
The rodent genome may be modified in a number of ways to assess effects on brain and behaviour:
* Selective breeding (inbreeding/outbreeding)
* Gene ‘knockout’
* Transgenesis and ‘knock-in’
* Mutagenesis using chemicals or radioactivity
* Chromosomal mutations
selective breeding
Inbreeding (mainly mice): Selected members of a founder strain are repeatedly inbred over many generations to
(theoretically) ensure genetic homogeneity (→ less phenotypic variability, can dissociate genetic vs. environment
influences)
Commonly used inbred strains include C57BL/6, BALB/c, 129 and BTBR (autism), and Spontaneously Hypertensive
Rat (ADHD); inbred strains can differ significantly in appearance and behaviour (polymorphisms)
Outbreeding: Members of a founder strain are bred to unrelated individuals to ensure genetic heterogeneity
(→ more phenotypic variability (more like humans?), ‘hybrid vigour’)
Commonly used outbred strains include CD-1, MF1, Swiss-Webster (mice) and Lister Hooded, Long-Evans,
Sprague Dawley and Wistar (rats)
