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use of animal models

mini BrainCamp 2020-04-30

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why use animal models?

instead of humans, cell cultures, or artificial networks

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why use animal models?

⏵invasive approaches are needed to reveal neural activity

use of human subjects is not always morally permissible

animal-free alternatives are not always suitable

⏵preclinical trials are needed to establish drug safety

⏵organisms are more complex than the sum of their parts

animal models have other useful properties

⏵some features cannot be recapitulated in vitro

⏵shorter life span

⏵large brood size

⏵genetic amenability

⏵simple maintenance

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what animals are used?

average change in DNA

0.5%

32%

1%

2%

4%

8%

16%

68

million years ago

125

250

500

1000

2000

4000

monkeys

mice, rats

finches, owls, chickens

zebrafish

fruit fly

nematode

bacteria

16S/18S rRNA

50%

32%

20%

10%

5%

71%

protein

75%

56%

40%

non-coding

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some caveats

brains are similar, but not identical

laboratory animals are not the same as animals in the wild

a model animal must be representative of a wider group of organisms

mouse

monkey

human

mouse

human

behaviours are similar, but not identical

genes are similar, but not identical

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Caenorhabditis elegans — nematode

⏵short life cycle (3 d.)

from the PhD thesis of R.Durbin (1987)

⏵transparent

⏵small (1.5 mm long)

⏵XX hermaphrodite & XO male

⏵302 neurons, 56 glial cells

⏵invariant lineage

the only adult animal with a fully established connectome

useful for studying conserved signalling pathways

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studying signalling pathways in C. elegans

serotonin reuptake transporter

serotonin receptors

depressed mood

elated mood

PROZAC

humans:

C.elegans:

slow locomotion

fast locomotion

mutant with reduced function of protein A

A

B

two proteins involved in the serotonin pathway:

which one acts earlier?

mutant with reduced function of protein B

mutant with reduced function of both proteins A B

fast locomotion

slow locomotion

A

B

locomotion

serotonin

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Drosophila melanogaster — fruit fly

simple system for studying olfaction, courtship, aggression, sleep...

⏵short life cycle (~10 d.)

⏵transgenic lines

⏵small (~2 mm long)

⏵large brood size

from Gero Miesenbock’s lab (2018)

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Danio rerio — zebrafish

⏵vertebrate

⏵relatively short life cycle (90 d.) + long life span (4-5 y.)

⏵early transparency

⏵large brood size

⏵ex-utero development

used to study social behaviour, hunting, pain, sleep,

anxiety, epilepsy, depression, neurodegeneration...

useful for high-throughput drug screens

from Isaac Bianco’s lab (2019)

from Allan Kalueff’s lab (2014)

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Mus musculus — mouse

⏵physiologically similar to humans

⏵relatively short life cycle & span

⏵genetically amenable, inbred strains

most human diseases have mouse models

behavioural assays for many phenomena

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Macaca mulatta — rhesus monkey

used to study complex cognitive functions: attention, perception, working memory

⏵relatively long lifespan (<40 y.)

⏵genetic heterogeneity

from Shadlen & Newsome (2001)

evidence integration in lateral intraparietal cortex?

important for clinical application of deep brain stimulation & brain-machine interfaces

⏵expensive

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birds in neuroscience

◀ Bengalese finches:

birdsong production

barn owls: ▶

sound localisation

crows: ▶

number

representation

◀ chickens:

embryonic

development

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animal models are used to study behaviour on a circuit level

brains, behaviours & genes are similar but not identical

laboratory animal != wild animal

most popular: nematodes, fruit flies, zebrafish, rodents & primates

useful properties to have in an animal model:

recap

short life cycle

large brood size

genetic amenability

easy maintenance

transparency

similarity to humans

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Interesting cases

Phineas Gage

Henry Molaison

Jodie Miller

Patient Joe

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25 year old male
Foreman of a crew preparing railroad bed

CASE #1:�Phineas Gage (1848)

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Iron rod hurtled upward after explosion

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Consequences?

Optic nerve severed, lost left eye
Uninhibited personality

It is said that Phineas did not even lose consciousness but was sitting on the front porch talking to people walking by, while waiting for the doctor. He developed an infection after a few days but recovered. He lost use of his left eye after his optic nerve was severed, but most importantly, people who knew him all undoubtedly agreed that his personality had changed two months after he had been discharged from the hospital. He also suffered from multiple seizures for the next few years until his death in 1860. This is why he became very important to neurology, neuroscience, psychology general medicine etc, and still is to this day. �His prefrontral cortex was lesioned. He was able to walk, work travel anything the average person could do. However he became a ‘douchebag’. He went from being a polite businessman- like person to a perpetual drunk who showed no social inhibitions and sometimes partook in freakshows and sometimes had psychopathic tendencies

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Modern-day insights

White matter not as damaged
Death due to complications from epileptic convulsions

His official cause of death was complications from epileptic convulsions (uncontrollable muscle contractions). His skull is preserved at Harvard medical school. No autopsy was performed but his body was exhumed 7 years after his burial. Thanks to modern technology they were able to recreate Phineas’ lesion in 3D and get more insight as to what exactly happened. What they found was that the white matter in Gage’s brain sustained less damage than you might expect. It was the equivalent of a regular traumatic brain injury making him extremely lucky and the reason he survived. This case became substantial because of the fact that it was proof how physical changes to the brain can affect behaviour.

Their findings indicate that he suffered injuries to both the left and right prefrontal cortices, which would result in problems with emotional processing and rational decision-making

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Dr. Edward H. Williams, the first physician to respond later described what he found:

“I first noticed the wound upon the head before I alighted from my carriage, the pulsations of the brain being very distinct. Mr Gage, during the time I was examining this wound, was relating the manner in which he was injured to the bystander. I did not believe Mr Gage’s statement at that time but thought he was deceived. Mr Gage persisted in saying that the bar went through his head… Mr Gage got up and vomited; the effort of vomiting pressed out about half a teacupful of the brain, which fell upon the floor.”

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CASE #2:

Henry Gustav Molaison or HM (1953)

27 year old male
Radical treatment for extreme epilepsy
Removal of most of his hippocampus

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Consequences?

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“He was a very gracious man, very patient, always willing to try these tasks I would give him,” Dr. Milner, a professor of cognitive neuroscience at the Montreal Neurological Institute and McGill University, said in a recent interview. “And yet every time I walked in the room, it was like we’d never met. He could hold thoughts in his head for about 20 seconds. It was holding onto them without the hippocampus that was impossible. ”

Dr. Milner,psychologist, began giving him a variety of memory tests. It was a collaboration that would forever alter scientists’ understanding of learning and memory.

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CASE #3:

Jodie Miller (current)

3 year old female
Continuous seizures and falling to the left
Diagnosed with Rasmussen’s encephalitis
Treatment was to remove half of the brain

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Consequences?

Successful operation, no more seizures
But limited movement in her left arm and a limp

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Now an adult, Jodie has been married for four years and says she’s thankful that her parents went forward with the risky decision.

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CASE #4:

patient Joe