• Kaushik Subramanian

Animals in Neuroscience research - Methods and Ethics

Studies on live animals play an important role in neuroscience research. In basic neuroscience, research animals are studied to understand the functioning of the nervous system and the mechanisms involved in the diseases that affect it. In applied neuroscience research, animals are used to develop and test therapies for such diseases. The ultimate aim of both lines of research is commonly to extrapolate results to the human case. When animals are used as models of human diseases – which constitutes the bulk of animal-based neuroscience research. Disease-oriented research in neuroscience includes the study of both psychiatric and neurological disorders. The former consists of disorders of mood and thought associated with either no apparent signs, or at most only minor physical signs in the motor and sensory systems, and includes diseases such as schizophrenia, depression, or anxiety. The latter refers to nervous system disorders that also present somatic signs and include neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s disease, Amyotrophic Lateral Sclerosis, or stroke, and chronic pain. Animal models are used in research into both psychiatric and neurological disorders.

The object is to induce in them conditions which, at least in some aspects, mimic the conditions that researchers aim to understand in humans and for which they wish to develop appropriate treatment.

Some of the most significant discoveries in neuroscience have only been possible thanks to animal research. For instance, 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 (co-morbidities), such as obesity or diabetes, on neurological diseases. 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. Another group of 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.

Despite great advances in basic neuroscience knowledge, the improved understanding of brain functioning has not yet led to the introduction of truly novel pharmacological approaches to the treatment of central nervous system (CNS) disorders. This situation has been partly attributed to the difficulty of predicting efficacy in patients based on results from preclinical studies. To address these issues, we need to critically discuss the traditional role of animal models in drug discovery, the difficulties encountered, and the reasons why this approach has led to suboptimal utilization of the information animal models provide. The discussion focuses on how animal models can contribute most effectively to translational medicine and drug discovery and the changes needed to increase the probability of achieving clinical benefit. Emphasis should be placed on the need to improve the flow of information from the clinical/human domain to the preclinical domain and the benefits of using truly translational measures in both preclinical and clinical testing. Few would dispute the need to move away from the concept of modeling CNS diseases in their entirety using animals. However, the current emphasis on specific dimensions of psychopathology that can be objectively assessed in both clinical populations and animal models has not yet provided concrete examples of successful preclinical–clinical translation in CNS drug discovery. The purpose of this review is to strongly encourage ever more intensive clinical and preclinical interactions to ensure that basic science knowledge gained from improved animal models with good predictive and construct validity readily becomes available to the pharmaceutical industry and clinical researchers to benefit patients as quickly as possible.

Moreover, since most research is intended to benefit humans and not animals, there is no benefit for the research subjects themselves.

Yet, the use of animals for research remains a controversial issue. Most experimental procedures are likely to inflict at least some harm on the animals that are studied. During experimentation, animals may be in relatively limiting conditions, and deprivation of food and water often forms part of behavior testing schedules. Varying degrees of physical or psychological harm can result from the procedures used to induce in animals conditions mimicking the human diseases under study, as well as from the conditions themselves. Distressing or painful interventions may be part of experimental protocols and, not least, most animals are killed at the end of experimental trials. Unlike humans participating as subjects in research, however, animals cannot consent to their own participation. While perhaps few researchers would question the desirability of discovering new ways to prevent, alleviate, or cure human diseases, the question remains: Are we, as human beings, morally justified in using animals as tools for research?

For instance, advances in neuroscience imply that harmful experiments in dogs are unethical. Functional MRI (fMRI) of fully awake and unrestrained dog volunteers has been proven an effective tool to understand the neural circuitry and functioning of the canine brain. Although every dog owner would vouch that dogs are perceptive, cognitive, intuitive and capable of positive emotions/empathy, as indeed substantiated by ethological studies for some time, neurological investigations now corroborate this. There exists an area in the canine brain, enabling dogs to comprehend and respond to emotional cues/valence in human voices, and evidence of a region in the temporal cortex of dogs involved in the processing of faces, as also observed in humans and monkeys. So, we should contend that using dogs in invasive and/or harmful research, and toxicity testing, cannot be ethically justifiable.

These studies show that there exists a striking similarity between dogs and humans in the functioning of the caudate nucleus (associated with pleasure and emotion), and dogs experience positive emotions, empathic-like responses and demonstrate human bonding which, some scientists claim, may be at least comparable with human children.

To combat this, we turn to ‘Animal-free’ alternative methods of neuroscience research as a 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. 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.

Despite successes in some areas of neuroscience as a result of animal testing, 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 individual animal and human brain works. Animal research is still essential for this to happen. 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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