Animal research

Human brain scanning methods are…

mostly observational… often tricky to understand the brain in action

Alternatiuves to animal research in Neuroscience - brain organiods

brain organiods - stem cells

Alternatiuves to animal research in Neuroscience - brain organiods - disadvantages

• no natural shaping through stimuli

• no blood vessels, immune system

• No interctaion with other organs

Alternatiuves to animal research in Neuroscience - brain organiods - advantages

• individual brain areas

• developmental research

Alternatives to animal research in Neuroscience - Computer models

• stimulate what happens in the brain using computer models, great for testing out what already occurred in the brain

Alternatives to animal research in Neuroscience - Computer models - advantages

• generate ideas

• predict testable outcomes

Alternatives to animal research in Neuroscience - Computer models - disadvantages

• built by humans

• cannot model the unknown

Alternatives to animal research in Neuroscience - human experiments disadvantages

• lacking detailed resolution

• mostly observable

• lack of perturbation methods

Alternatives to animal research in Neuroscience - human experiments advantages

• complex paradigms

• non invasive techniques

What do we mean by animal research - can be broken down into 2 areas

• licensed work - in the UK this is all activity covered by Animals act 1986, most of this is lab based but small amount outside lab

• Unlicensed work - generally observable (lab, farms, zoo, wild)

Why do animal work?

• advance human health

• for animal health

• researching disease

What are animals used for in research? - basic research

foundations for all scientific breakthroughs - forms the basis of much applied research

• how organisms behave develop and function

• E.g. understanding physiology, gene function, brain circuits, tissue, organs etc

What are animals used for in research? - applied research

• development of medicines and surgical operations, making vaccines and other ways to prevent disease

• treatment of disease for humans and animals

• it is law in the Uk that all new medicine must be tested in 2 species of mammal

it is law in the Uk that all new medicine must

be tested in 2 species of mammal

What are animals used for in research? - regulatory research

• procedures carried out to satisfy legal requirements in producing substrates, materials, chemical, including the testing of their safety e.g. chemicals in medicines, pestsitcides etc

What are animals used for in research? - breeding of genetically altered animals

• used to discover function of genes

• Embryonic development or aging of cells

• Used in the study of disease

• Removing (knock out) to adding (knock in) genes

• Transgenic - genes introduced from another spp e.g. human AD in mouse

Choosing the correct animal model

• 

animal research …. while controversial, its is an unavoidable

fact that AR has allowed the development of medicines, vaccines, surgical techniques and advanced scientific understanding in many areas

UK animal scientific procedures ACT (ASPA) - WHAT is a procedure? - learn this

any procedure applied to a protected animal for an experimental or other scientific purposes, or for an educational purpose, that may have the effect of causing an animal pain, suffering, distress or lasting harm equivalent to, or higher than, that caused by the introduction of a needle in accordance of good vertinary practice

UK animal scientific procedures ACT (ASPA) - experimental procedures involve using animals in scientific studies for purposes such as:

• basic research and the development of treatments

• safety testing of pharmaceuticals and other substances

• education

• specific surgical training and education

• species protection

UK animal scientific procedures ACT (ASPA) - procedures for creation and breeding…

involve the breeding of animals whose genes have mutated or been modified. These animals are used to produce genetically altered offspring for use in experiments but not themselves involves in experiments

Uk scientific procedures on animals - total procedures in 2021

3 million

procedures declined after

2013

experimental procedures by species in 2022

• Vast majority on mice, fish, birds (94%)

• Less tax 1%on protected species (cats, dogs horses and non-human primates)

Most common areas of focus in basis research in 2022

• most common nervous system

• then immune system

Animal procedures have severity ratings

• mild procedure = no harm, e.g. just cogntive maze

• Moderate = surgical procedure but not life threatening

• Severe - long term disease

in 2022, 2.7 million procedures were performed on live animals…. the majority were

rodents and fish, 45% were instances of breeding of GA animals for scientific use

• uk meat and fish eaters consume 2.2 billion animals every year

• 9 million cats and dogs have poor welfare

• 15 million wild bird and shot 20 million rats and mice killed as pests

Ethics - advocates for animal experiments

• human life = greater intrinsic value

• legislation protects animals from cruelty

• millions of animals killed every year for food

• few animals experience pain and killed before suffering

Ethics - opponents for animal experiments

• animals should have the same rights as humans

• strict controls don’t prevent all suffering

• research doesn’t translate well to humans

• deaths are unnecessary

• how do you know when they feel pain

• poor design/ invalid science

Clash of perspective on using animals

outcomes: benefits can outweigh harms vs instincts concerns; ANIMALS ARE NO MEANS TO ENDS

Origins of animal experiments - animals have been used in studies for at least 2,500 years

• Aristotle

• Galen

• Avenzoar

• Descartes

Origins of animal experiments - animals have been used in studies for at least 2,500 years - Rene

Descartes maintained the difference between animals and humans with us quote

• cogito ego sum - I think therefore I am

• he suggested that animals were unable to suffer because they did not have a ‘mind’ off soul. he proposed that animals were like machines and unable to feel pain

Origins of animal experiments - animals have been used in studies for at least 2,500 years - Darwin

• beloved that were only different in degrees, that actually animals could be seen as just the same evoluntary steps as humans

• - agreed that justifiable for real investigation, but not detestable curiosity

Origins of animal experiments - power to the people (1700-1800)

• power of public = stronger

• public becoming better eductated and informed on national and international matters

• Establishing unions to fight power systems; women’s right to vote, freedom of speech, intentional slave trade

• cruelty to animals act

Cruelty to animals act (1876)

• first legislation to protect animals and control research, unique for 50 years - lasted 110 years until ASPA

• 1907 - brown dog riots - public dissection of a stray dog

• 1985 - public interest began to rise, Peter signer - animal liberation, new brown dog statue erected

Russell and Burch - 3 R’s - LEARN - replacement

methods which avoid or replace the use of animals

Russell and Burch - 3 R’s - LEARN - reduction

methods that minimise the number of animals used per experiment

Russell and Burch - 3 R’s - LEARN - refinement

methods which minimise suffering and improve animal welfare

why would you protect animals in research?

• stressed animals dont give reliable results

• respect for animals

animal welfare - late 70s and 80s

• public outcry for animal research

• images of research from other countries changes public perception

• complaints against the unecceasry nature of some research gained traction in the public mind

• the consequence…. animals procedures act 1986

protected animals

all living vertebra, excluding cephalopods

Learn - Animals scientific procedures act 1986 - licences

Personal - authority to perform regulated procedures on protected animals

Project - authority for programme of work

Establishment - authority for premises where research is taking place

Learn - Animals scientific procedures act 1986 - licences

• legal obligation - 3r;s are embedded in national and international legislation which protects animals used for scientific purposes

• applicants asked for evidence that they have considered the 3r’s both from AWERB panel and home office

replacements examples

• absolute replacements - e.g. computer modelling, invertebrate species

• relative replacements such as in vitro work requiring animal cells or organs but no using live sentient animals

Reduce examples

• obtaining more data from one single animals

• improve experimental design, statistical powering and sharing data and resources

Refinement examples

• anaesthesia

• analgesia

• non-invasive techniques

• environmental enrichment minimising stress

How animals are used in research - animal models of memory - understanding memory and hippocampus - HM

• Head trauma, minor epileptic seizures

• at 27 his hippocampus was removed

• like waking from a dream… every day is alone in itself - coukdn’t form new memories

How animals are used in research - animal models of memory - understanding memory and hippocampus - HM - Brenda Milner

• Systematically tested HM

• Fine with sensory motor skills, but coukld’t use spatial memory - failed to reduce error on 215 memory trials

• Hm couldn’t link memories to specific time or place

How animals are used in research - animal models of memory - understanding memory and hippocampus - rats - Tolman

• trained the animal to remember right and left turns, rats could map out novel route without any practise or reinforcement

• formed a cognitive map, mental maps could serve wider cognitive functions

How animals are used in research - animal models of memory - understanding memory and hippocampus - Morris water maze

• assessed spatial and place learning In rodents

• found that rats without a hippocampus - couldn’t find the submerged platform - no cogntive map formed

How animals are used in research - animal models of memory - understanding memory and hippocampus - Poulter 2019

• various aspects of learning with respect to the shape of the pool, using the walls of the pool

• no hippocampus - can find a beacon, buy if removed can’t learn

homologous region of hippocampus in mammals

• hippocampus has been preserved over mamillian species

• cells very similar across rats and humans,

In vivo extracellular single cell electrophysiology in mice

• in 1960s pioneered single cell recording in live rats

• found the brains positioning system

• forerunner in bridging the gap between psychology and physiology

• place cells - fire for certain locations of the room

Place cells: the units for tolman’s cognitive map

• different place cells become active in different places

• place cells are context specific

• place cells = spatial scaffolding to bind an event, neural map

• long term stability of maps for each environment, new map formed when learning is blocked (learning is required)

place cells - pattern specific - reactive living room example

• you have a learnt map for your living room, if you go to a showroom and see a fire place - that will reactive a subsample of the neurones for your living room that has a fire in

Future of rodent memory experiments - 2-D rodent virtual reality

• with VR able to instantaneously add, subtract or warp sensory input

• With VR you can use a large microscope to image deep brain regions using 2-photon microscopy

how animals are used in research - in disease - in alziehemrs

• alzheimers disease characterised by the presence of 2 neurotoxic proteins (Amyloid B-plaques, Tau Tangles)

• very difficulty to study pathology in humans while still alive

• in transgenic A mixe, it was shown that amyloid B plaque burden was correlated with memory impairment - pave the way for testing new drugs both on brain pathology and memory impairment - CHEN, 2000

how are animals used in research - brain circuit manipulation - understanding the brain circuits of memory using genetic tricks in mice

75% of first 312 dan exonerations in US were victims of faulty eyewitness testimonies - inaccurate memories

• Hippo implicated during recall of both false and genuine memories

how are animals used in research - brain circuit manipulation - understanding the brain circuits of memory using genetic tricks in mice - can we create false memories in the hippocampus - LEARN TECHNIQUE - method

• Optogenetics - inserting light sensitive switches into specific types of cells

• algae that we call the smallest solar panel in the world, can convert light into energy, can use tricks of gene therapy and you can insert these molecules into particular neurones of interest, shine light = switch on or off - can control neuroens

• when we form a memory there’s footprint in memory cells, took the cells activated by light and attached the sensory cell to a memory cell that were formed, can switch on and off.

how are animals used in research - brain circuit manipulation - understanding the brain circuits of memory using genetic tricks in mice - can we create false memories in the hippocampus - LEARN TECHNIQUE - rats

• put rat in a blue box. then footshock in a red chamber while light shone on memory cells foe blue box e.g. when get a shock in the red box, they only thing of the blue box,

• Animal then froze in the blue box, was expecting shock - false memory

Optogenetic definition - learn this

using genetically engineered mice and pulses of light to control the activity of neurons

chemogentics - definition

• allows for the reversible control of neuronal populations using genetically engineered receptors