Why are animals used
in brain research?
Perhaps more than in any other field of biomedical research, it is essential to use animals in research studies to understand the functions of the brain, both in basic research and drug testing. This EARA feature looks at why this is necessary and where non-animal methods are currently being used.
The brain is fundamental to all aspects of our health and the diseases we suffer – as it links all the organs and systems in our body – yet it is the organ we know the least about, in part due to its vast complexity. And because of this complexity, the treatments that we currently have for brain diseases are often aimed at non-specific targets, and can come with many side effects.
Brain disorders can include any problem with the brain and spinal cord, including mental health and sensory disorders. However, one of the greatest challenges in neuroscience research is tackling neurodegenerative diseases such as dementia and Parkinson's disease, which currently affect tens of millions of people across Europe. As the proportion of the elderly in Europe increases, it is vital that the most effective methods of research are used to combat this challenge.
It is estimated that brain disorders may cost as much as 45% of Europe's annual health budget (800bn euro) and large-scale brain research is now underway, investing billions of dollars and euros, to fund the Human Brain Project in Europe and the Brain Activity Map Project (BRAIN Initiative) in the USA.
At present, society’s best hope of finding drugs and other treatments for diseases of the brain relies on research using animals. While non-animal methods of study have made progress in some fields of biomedical research, their use in neuroscience remains extremely limited due to the complex and interconnected structure of the brain. In most cases, a living and behaving organism remains the only viable model to study the brain in action.
The European Brain Council, which represents scientific societies, patient organisations, professional societies and industry partners, recently expressed its support for the continued use of animals in neuroscience research.
While we wait for alternative methods of study to emerge it is therefore essential to continue to develop better animal models and ensure the highest standards of animal welfare.
‘In the absence of scientifically valid methods that can replace particular animal procedures, phasing out the use of animals in medical research would have major consequences and impact the quest to improve the quality of life of the many citizens affected by brain conditions, neurological and mental alike’.
European Brain Council – statement on animal research, 2023
Researcher with rats (Credit: Radboud University)
How are animals used to study brain diseases?
In order to understand the brain and what happens when things go wrong, scientists first need to understand what happens in a healthy brain. Over the past 50 years, basic research using animals has helped to dramatically improve our understanding of the brain and the nervous system, winning several Nobel Prizes for Physiology and Medicine, including:
In 2000, for the discovery of dopamine that transmits signals in the brain and is involved in diseases such as Parkinson's, using animals including mice and rats.
In 2013, for understanding how proteins are transported in cells, using hamsters, mice and rats.
In 2014, for the discovery of cells involved in a 'positioning' system in the brain, using rats.
Here are some of the ways in which animals have contributed to a new or improved understanding and treatment of different brain disorders.
Mice are crucially needed for studying the common hallmarks and symptoms of dementia, and the ways to prevent the disease. Researchers at the Institute of Biomedicine of Seville, and Pablo de Olavide University, Spain, used mice to show how the accumulation of a specific protein in the brain can cause the memory loss seen in patients with Alzheimer's disease.
Researchers at the California National Primate Research Center (CNPRC), USA, developed a model for early-stage Alzheimer’s in monkeys. Monkeys are also important for studying these types of disorder because of the high similarity of human and monkey brains – see Which animals are used in brain research?
For Parkinson’s disease, strategies to protect against its progression, or symptoms, have been underpinned by animal studies. A study at the University of Geneva, Switzerland, used both mice and fruit flies to identify a gene that can protect against the disease, while research in monkeys showed that motor co-ordination can be improved through a method of infusing dopamine into the brain at the University of Lille, France.
Mice have been used to study depressive behaviours and symptoms, which in turn can help to identify targets in the brain for drugs that reduce the effects of depression. For example, research in mice and cells at EARA member the University of Helsinki, Finland, found that the psychedelic drugs LSD and psilocin can be used as antidepressants without triggering hallucinations.
Larger animals like sheep are proving to be important for studies of Huntington’s disease because their brains more closely resemble humans’ than those of mice, in terms of size and complexity, for example. Read more in this feature by EARA member Understanding Animal Research.
A wide range of animals have contributed to our understanding of autism, including zebrafish, to understand its symptoms, as well as roundworms and fruit flies to look at gene mutations linked to the disorder, and even fish and frogs.
Treatment of paralysis caused by injury or disease has benefited from studies in mice, for example at Ruhr University Bochum, Germany, which stimulated the spinal cord of paralysed mice to allow them to walk again, and in the testing of a drug designed to regrow nerves, at EARA member the University of Padua, Italy.
Animal research can provide insights into both how brain damage can occur and how to stop it. A group at the Institute of Science and Technology Austria found that starving the brain of certain dietary nutrients can impact brain development in mice, while in zebrafish, a team at Ludwig Maximillian University, Germany, were able to prevent the damage caused by brain scarring. Scientists activated existing immune cells in the brain called microglia, to study their effects – microglia are key to forming scar tissue.
The link between the nervous system and digestive system has been investigated in mice, for example at EARA member the Champalimaud Foundation, Portugal, which looked at feeding behaviour in mice to provide insights into understanding and treating obesity.
These findings can help in the development of novel compounds that could in the future be used to treat depression in humans without causing the hallucinations typical of psychedelics.
Prof Eero Castrén, Helsinki
Mouse wearing an electrophysiological implant for recording brain activity Mice in a maze (Credit: Radboud University)
Neuroscience breakthroughs & discoveries using animals
These include attention deficit hyperactivity disorders (ADHD), autism spectrum disorder, intellectual disability.
These include blindness and other vision issues, hearing or sensory problems, including paralysis.
It is essential to demonstrate the functionality and safety of these implants in experimental animals before trying them out in humans.
Our experiments in monkeys were essential to demonstrate that the visual cortical prosthesis can support the perception of shapes such as letters.
Prof Pieter Roelfsema, NIN
Other neurological disorders
This includes sleep disorders, epilepsy, and brain tumours.
Which animals are used in brain research?
Some of the most significant discoveries in neuroscience have only been possible thanks to animal research. Here are some examples:
In what marks the cusp of first-generation treatments for Alzheimer's disease, a monoclonal antibody treatment developed by US pharmaceutical company Eli Lilly, using mouse antibodies, that modifies the disease itself, has shown success in a clinical trial at slowing brain decline in Alzheimer's patients.
A team at the German Center for Neurodegenerative Diseases developed a gene therapy that could help to treat Alzheimer’s disease by reducing the levels of tau – a key protein that accumulates in the brain.
Researchers from the University of Cambridge, UK, discovered that a ‘cold shock’ protein found in cold water swimmers may prevent brain diseases, such as dementia, having previously identified this in mice studies.
A study at the Institut National de la Recherche Scientifique, Canada, was able to visualise the motor deficits in amyloid lateral sclerosis (ALS is the most common type of motor neurone disease), by imaging zebrafish. Meanwhile, international prize-winning research on how the nervous system controls movement used mice to understand how it can go wrong in not only ALS, but other brain conditions like Parkinson’s.
Thanks to research in monkeys by Neurolixis, USA, a new drug combatting a side effect of a common Parkinson’s disease treatment entered clinical trials in 2020. The drug reduced uncontrolled movement in marmoset monkeys, with symptoms of Parkinson’s, who were receiving a medicine that treats muscle stiffness and tremors, without affecting the efficiency of the treatment.
By using rats, researchers led by EARA member the Max Planck Institute (MPI) for Biological Cybernetics, Germany, were able to map cognition in the animals' brains to better understand the abnormalities linked to schizophrenia. Another study at the MPI of Neurobiology (now the MPI for Biological Intelligence) looked at mice to understand the body-brain interactions on the regulation of emotion and fear.
Scientists from the University of Hong Kong and Guangdong University of Chinese Medicine, China, used eye stimulation as a successful treatment for depression in mice.
A study at EARA member Ghent University, Belgium, found that dogs with anxiety have similar behaviours and brain changes as humans with the condition, which could lead to better treatments for both humans and animals.
Research at University College of Cork, Ireland, has investigated how signals between gut bacteria and the brain can influence the behaviour and emotions of mice, which could help to understand anxiety or depression in people.
Using gene editing, a study led by the Institute of Science and Technology Austria (ISTA), looked at the effect of ‘starving’ the brain of essential amino acids in mice, and found that the animals had smaller brains than healthy mice, which was also linked to behavioural changes similar to those seen in neurodevelopmental disorders such as autism.
Researchers at University College London, UK, are working to develop a mouse model of ADHD to study the common features of the condition, including behaviour, and to identify ways to treat both symptoms and the underlying condition in people.
Scientists at the Netherlands Institute for Neuroscience (NIN), Amsterdam, created a brain implant that could restore some vision from blindness. The team developed high-resolution implants and then inserted these into the visual cortex of two sighted monkeys – the part of the brain that processes visual information.
Swiss researchers have developed an implant that allows patients with a complete spinal cord injury to stand and walk again. The device by École Polytechnique Fédérale de Lausanne (EPFL), and Centre Hospitalier Universitaire Vaudois were based on years of studies using monkeys and rats.
Meanwhile, researchers at the University of Pittsburgh and Carnegie Mellon University, both USA, tested a technology that enabled one patient to move their arm again after it was paralysed by a stroke. This breakthrough involved studies in animals such as rats and monkeys to investigate how to repair spinal cord injuries.
Brain conditions can be linked to sleep disorders, as shown in research at the University of Queensland, Australia, which found that a condition called sleep apnoea was associated with a higher risk of developing Alzheimer’s disease.
Scientists at Stanford University, USA, successfully switched cells ‘on and off’ within the brains of mice, preventing seizures from epilepsy using optogenetics – a combination of light and genetic engineering to control brain cells.
A study in mice at EARA member the University of Zurich, Switzerland, has allowed for the testing and refinement of treatments for aggressive brain tumours by showing that a protein-antibody combination treatment can slow or reverse the growth of cancer cells.
Mice and rats
The most commonly used animal species in neuroscience research are mice and rats, as the complexity of their brains is similar enough to humans to give a good overview of brain processes. Mice can also be genetically modified with relative ease, meaning that researchers can look at the effect of individual genes on the way disease progresses.
Read more about the role of mice in research in our EARA feature.
As mice and rats have a shorter life span than other mammals, it is possible to use them to study diseases over a longer period of time, or in ageing animals. These rodents can also be used to look at the effects of additional conditions (comorbidities), such as obesity or diabetes, on neurological diseases, as well as how molecules such as sex hormones can impact the brain and behaviour – see our #TransparencyThursday with Dario Aspesi, at the University of Guelph, Canada (below).
Zebrafish are also becoming more widely used for neuroscience research. Observational studies, combined with the ability to see the molecular changes in the brain and firing neurons, are ongoing to understand how these animals react to stress and depression – and used to test potential treatments or highlight new mechanisms to study in humans.
Because zebrafish also possess the ability to regenerate their tissue and organs,, for example when they become damaged, these fish are also providing insights into how to repair the brain after injury, trauma or infection.
Read more in our EARA feature on zebrafish in research.
Having such a close genetic relationship to humans, monkeys are one of the most valuable animal models used in research. Less than one per cent of the animals used in research in the EU are monkeys, however their impact in providing the most reliable information for what is happening, or what is going to happen, in humans cannot be underestimated.
All animal experiments are strictly regulated and reviewed by ethical committees before they are allowed to proceed and the use of monkeys in research is only permitted when there is no other animal or non-animal model that could provide the same answer. In addition, in Europe, research with great apes such as chimpanzees – the animal that is the most closely-related to humans – is prohibited.
While there are understandable ethical worries about using monkeys, they continue to be an essential model for studying the function of the brain due to the similarity in structure and composition with humans. Much of what we know today about complex behaviour and emotion, vision, and higher cognitive function has been gained from the study of monkeys – as well as insights into how to treat these functions when they go wrong, such as in vision loss and paralysis or stroke. Specifically, the prefrontal cortex is more alike between non-human primates and humans than between rodents and humans.
Read more in our EARA feature on monkeys in research.
Opponents of animal research claim it is old-fashioned and out-dated, but animal studies played an absolutely vital part in this new method of drug development.
Kirk Leech, EARA executive director
Among these disorders are Alzheimer’s disease, dementia, Huntington's disease, motor neurone disease, multiple sclerosis and Parkinson’s disease.
These include anxiety, depression, eating disorders, drug addiction and schizophrenia.
At this moment in time, all evidence indicates that NHPs will continue to play a crucial role in the development of better medical care for patients, as they have done in the past in neuroscience and numerous other domains of medicine.
'Visualizing advances in the future of primate neuroscience research' (Current Research in Neurobiology2023)
[Research with monkeys] is critical to the nation’s ability to respond adequately to public health emergencies and carry out high-impact biomedical research.
Marmosets (Credit: Ernst Strüngmann Institute for Neuroscience)
Heather Rendulic cutting a steak by herself after being paralysed by a stroke (Credit: University of Pittsburgh)
Gene expression maps of the zebrafish brain (Credit: MPI for Biological Intelligence)
Care of animals in brain studies
Rats in arms of handler (Credit: Radboud University)
The use of animals in all areas of biomedical and scientific research is tightly regulated in the EU and many other parts of the world, to ensure that animal research only takes place when there is sound scientific justification and no other viable method is available.
A high standard of animal welfare benefits not only the animal, so that they are kept in an environment that minimises stress and, where possible, can mimic natural conditions, but also to maximise reliable results in studies.
All researchers who use animals must follow the principles of the 3Rs (replacement, reduction, refinement), while alternative methods to complement animal research are increasingly being developed. However, for brain and neuroscience research, such alternatives are still very limited compared to other research areas, and are not yet able to mimic the complexities of living brains – see the next section for more information on alternatives in brain research.
This documentary video (below) from EARA member the Ernst Strüngmann Institute for Neuroscience (ESI), Germany, highlights the essential importance of marmoset monkeys to brain research, and demonstrates how they are housed, cared for and trained at ESI, by inviting viewers into its animal facilities and laboratories.
Why can't we fully replace animals with alternatives?
Animal-free alternative methods of neuroscience research are also a very important way to study the brain. Organoid 'mini-brains' enable researchers to test the effects of some drugs, and can provide an insight into how the brain develops.
For example, researchers at Stanford University, USA, were able to transplant human brain organoids into rats and showed the different cell types had become integrated in the animals’ brain. This paves the way for an improved understanding of brain development and disorders, although such developments also bring about new ethical issues.
Combined with computer simulations, organoids can offer a snapshot of how cells act and develop at any given time. The EU Commission Joint Research Centre has published a collection of over 550 non-animal models used for studying neurodegenerative diseases.
However, these cell-based methods are often of limited use, as they consist of only one cell type, grown in isolation of other tissues, the immune system and the blood supply. They also lack the interactions with other organs of the body, particularly important now that we are starting to understand more about the relationship of the brain with the gut, heart, and lungs.
It is more difficult therefore to predict how a change in one cell type might affect another organ – particularly important when studying the brain. Cells also cannot respond to an external event, such as lack of sleep or feelings of anxiety, which can affect the way the body might respond.
Indeed, cell-based methods are often used alongside animal research, where animal studies are used to validate the non-animal findings. A review of more 13,000 abstracts on Alzheimer's and Parkinson's disease studies has shown how reliant the field still is on animal studies.
Human-focused research can also be a useful tool for understanding behaviour. Non-invasive technologies such as MRI scans can be used to map out brain activity and link it to certain actions or human responses. However, this is mostly observational, and offers no link to the mechanisms or cellular changes that cause these effects. And of course, ethical constraints and data protection laws can also restrict this type of research.
… an abrupt stop to animal experiments would significantly cripple the Alzheimer’s and Parkinson’s research fields. A move towards animal-free research is simply unrealistic.
Prof Patrik Verstreken, VIB-KU Leuven
Human brain organoids (Credit: MPI for Molecular
The future of neuroscience research
Despite successes in some areas of neuroscience, there are huges areas of the brain that we still need to understand to develop more effective treatments and cures. Thanks to basic research using animals, unexpected discoveries have been unearthed which have strengthened our knowledge of how the brain works, and what happens when things go wrong.
As it stands, there is no foreseeable way in which we can continue to discover and deliver life-changing neuroscience research without the use of animals. While alternatives can provide some understanding and reduce some need for animals, in order to develop accurate alternative models, we first need to understand how the brain works. Animal research is still essential for this.