Perhaps more than in any other field of biomedical research, it is essential to use animals to understand the functions of the brain, both in basic research and drug testing. Becky Jones looks at why this is necessary and how near we are to finding non-animal methods of study.

The brain is fundamental to all aspects of our health and human diseases, 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.

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.

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.

At present, society’s best hope of finding drugs and other treatments for diseases of the brain rely 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.

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.

Which animals are used in brain research?

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.

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. Mice and rats can also be used to study the effects of additional conditions (comorbidities), such as obesity or diabetes, on neurological diseases.

Zebrafish – 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 they react to stress and depression – and used to test potential treatments or highlight new mechanisms to study in humans.

Monkeys – 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.

While there are understandable ethical worries about using monkeys, they continue to be an important model for studying the function of the brain due to the similarity in structure and composition. As monkeys have very similar brains to humans, we can gain reliable information as to what might be happening in a human one. Much of what we know today about complex behaviour and emotion, vision, and higher cognitive function has been gained from the study of monkeys. Specifically, the prefrontal cortex is more alike between non-human primates and humans than between rodents and humans.

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 mostly closely related to humans – is prohibited.

Animal research and significant discoveries

In order to understand the brain and what happens when things go wrong, it is first necessary to understand what happens in a healthy brain. Over the past 50 years, basic research has helped dramatically improve our understanding of the brain and the nervous system, winning the Nobel Prize for Physiology and Medicine in both 2000 and 2013. Exploring memory, emotion or behaviour, for instance in the brains of zebrafish, gives an insight into how the underlying mechanisms are affected in disease, and allows scientists to find new ways to treat them more accurately.

Some of the most significant discoveries in neuroscience have only been possible thanks to animal research. Here are some recent examples:

Basic Research:

• Scientists at the Netherlands Institute for Neuroscience (NIN), Amsterdam, have created a brain implant that could restore some vision in blind people. The team developed high-resolution implants and then inserted these into the visual cortex – the part of the brain that processes visual information – of two sighted monkeys.
  

Scientists at the Netherlands Institute for Neuroscience (NIN), Amsterdam, have created a brain implant that could restore some vision in blind people. The team developed high-resolution implants and then inserted these into the visual cortex – the part of the brain that processes visual information – of two sighted monkeys.

• Researchers at the Moscow Institute of Physics and Technology, Russia, have shed light on how some genes react to chronic stress by studying zebrafish in stressful situations and were able to treat some of the symptoms using a common antidepressant.
  

• Scientists at Stanford University, USA have been able to switch cells ‘on and off’ within the brain of a living animal, preventing seizures in epileptic mice using optogenetics – a combination of light and genetic engineering to control brain cells.
  

• Using mice, researchers at the German Center for Neurodegenerative Diseases, Berlin, have developed a gene therapy which could help to treat Alzheimer’s disease. The team used a gene editing tool called “zinc fingers” to reduce the levels of tau – a key protein that accumulates in the brain during Alzheimer’s disease.
  

• Researchers from the University of Cambridge, UK have discovered that a ‘cold shock’ protein found in cold water swimmers may prevent brain diseases, such as dementia, having previously identified this in a mouse model.
  

Researchers at the Moscow Institute of Physics and Technology, Russia, have shed light on how some genes react to chronic stress by studying zebrafish in stressful situations and were able to treat some of the symptoms using a common antidepressant.

Scientists at Stanford University, USA have been able to switch cells ‘on and off’ within the brain of a living animal, preventing seizures in epileptic mice using optogenetics – a combination of light and genetic engineering to control brain cells.

Using mice, researchers at the German Center for Neurodegenerative Diseases, Berlin, have developed a gene therapy which could help to treat Alzheimer’s disease. The team used a gene editing tool called “zinc fingers” to reduce the levels of tau – a key protein that accumulates in the brain during Alzheimer’s disease.

Researchers from the University of Cambridge, UK have discovered that a ‘cold shock’ protein found in cold water swimmers may prevent brain diseases, such as dementia, having previously identified this in a mouse model.

Clinical Research:

• Thanks to research in NHPs by Neurolixis, USA, a new drug which combats a side effect of a common Parkinson’s disease treatment, is entering clinical trials. The drug reduced the uncontrolled movement in marmosets with symptoms of Parkinson’s who were receiving a levodopa-based medicine, without affecting the efficiency of the treatment.
  

• Research from Erasmus Medical Center Rotterdam, in the Netherlands, has used non-invasive imaging on mice to identify when arteries become clogged with fatty substances, which can lead to stroke.

Thanks to research in NHPs by Neurolixis, USA, a new drug which combats a side effect of a common Parkinson’s disease treatment, is entering clinical trials. The drug reduced the uncontrolled movement in marmosets with symptoms of Parkinson’s who were receiving a levodopa-based medicine, without affecting the efficiency of the treatment.

Research from Erasmus Medical Center Rotterdam, in the Netherlands, has used non-invasive imaging on mice to identify when arteries become clogged with fatty substances, which can lead to stroke.

Why can’t we replace animals with alternatives?

Animal-free alternative methods of neuroscience research are also an 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 and combined with computer simulations they 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, consisting of only one cell type, or grown in isolation of other tissues, the immune system and blood supply. They also lack the interactions with other organs of the body, particularly important now that we are beginning 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 such as these are often used alongside animal research, where animal studies are used to validate the findings.

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.

The future of neuroscience research

Despite successes in some areas of neuroscience, there is much 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. By continuing to fund and perform this animal research, we can pursue the only realistic way of finding ways to tackle and improve treatments for the range of brain disorders that humans currently suffer in their thousands.

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