Use of animal models in neuroscience research
Sudarshana (Sophie) Banerjee
Global Programs Operations Manager, at Sony Interactive Entertainment (Esports and Competitive Gaming)
Advantages, limitations. Ethics, compassion.
And by the way, we have more in common with fruit flies or zebra fish, than we think.
The utilization of animal models to study human physiology has a long historical tradition, with the earliest recorded instance taking place in 6th century BC. Alcmaeon, a Greek philosopher, is credited with using canines as experimental models to conclude that the optic nerve is connected to the brain.?
The practice of utilizing animal models has greatly contributed to our understanding of disease progression and treatment, and continues to do so. Humans have shared ancestry with various species, leading to similar neurophysiological structures or homology. Animal brains are representative of humans’, though much smaller in size, and with limited circuitry and complexity.?
In pre-clinical trials and early stage testing animal models come in handy because of homologous or similar (but not same) physiological constructs. Animal models without any apparent similarities with humans have also proved invaluable in research. Fruit flies and humans for example, carry commonalities in some 75% of disease causing genes in humans. In zebrafish this similarity is as much as 84%. Zebrafish also have a functional blood brain barrier, akin to humans.??
Advantages of using animal models
There are several advantages of using animal models in understanding diseases of the human brain.?
Most human model research uses in vitro testing, and is limited in scope. For example, isolated tissue cultures can not reproduce the full extent of function, metabolism or interactions when isolated from the body. Animal models can be used for in vivo testing to overcome these challenges. In vivo studies can also be conducted for longer time frames, allowing researchers to study the effects and rate of disease progression across the entire physiology of the animal over time.
Manipulating a gene or protein by mutating, inactivating, or overexpressing can create a disease phenotype in an animal model that mimics a human disease, thus giving researchers the ability to study the underlying disease and perhaps possible treatment protocols under controlled environments.
Researchers can study various molecular mechanisms and disease pathways by finding interacting or binding partners of both multiprotein complexes or individual proteins in animal models to better understand their role in human disease. For example, using techniques like two hybrid screenings (both yeast and bacterial) or co-immunoprecipitation (mouse or drosophila).?
There are other advantages as well. Animal models are easier to access, and investigations are often less expensive. Animals have shorter life spans; making it easier to conduct research across different generations of the same species, or to study disease progression comparatively rapidly. Animal models also lend themselves to genetic modifications, for example, transgenic or knockout mice. Newer imaging technologies like resting-state functional MRI (rsfMRI) are better at offering translation across species as well, further encouraging the use of animal models.
Of course, the choice of animal model depends on the scope and specifics of the neurological disease being studied. For example, here is a representative list of some common animal models and the corresponding research they have been used in:
Rodents: Multiple sclerosis, Parkinson’s disease, Huntington's disease, Alzheimer’s disease, Schizophrenia, Depression, Anxiety, Autism, Epilepsy, Stroke.
Drosophila melanogaster: Alzheimer’s disease, Parkinson’s disease, Huntington's disease, Amyotrophic lateral sclerosis (ALS), Spinal muscular atrophy, neurodevelopmental disorders, sleep patterns, Ataxia-Telangiectasia.
Caenorhabditis elegans: Alzheimer’s disease, Parkinson’s disease, Huntington's disease, Amyotrophic lateral sclerosis (ALS), Spinal muscular atrophy, neurodegeneration, sleep and Circadian rhythms.
Non-human primates: Parkinson’s disease, Alzheimer’s disease, Multiple sclerosis, Stroke, Epilepsy, Huntington's disease, Amyotrophic lateral sclerosis (ALS).
Zebra fish: Epilepsy, Autism spectrum disorders, Depression, Schizophrenia, Alzheimer’s disease, Spinal muscular atrophy, neuronal development and migration, Parkinson’s disease (Along with Medaka fish.).
Success stories?
Parkinson’s disease: Animal models have been used extensively to model Parkinson’s disease. Both early and late onset variations have been studied in zebrafish. (Doyle & Croll, 2022). Zebrafish is an especially effective model because the ventral diencephalon in a zebrafish is homologous to the substantia nigra (Najib et al., 2020), enabling researchers to study neuronal degeneration in the region .?
The effect of acute exposure to neurotoxins like agrochemicals in Parkinson’s disease modeling and progression have been studied in rats and non-human primates (Konnova & Swanberg, 2018).?
Overexpression of the aggregated alpha-synuclein (α-syn) gene in transgenic mice is used to study motor abnormalities and impairments in the dopamine system (Elabi et al., 2021).?
Epilepsy and seizures: Animal models are widespread in the study of epilepsy. These include drug studies for antiepileptic drugs in C. elegans? (Wong et al., 2018).?
Chemical convulsants (pilocarpine, kainic acid) have been used successfully to cause recurrent seizures in rodents, as in temporal lobe epilepsy, with hippocampal models akin to humans with mesial temporal lobe epilepsy (Sharma et al., 2007). Neonatal seizures are most commonly attributed to hypoxic encephalopathy. Researchers have been able to induce hypoxia to investigate the underlying mechanisms of spontaneous seizures in rats. (Sanchez et al., 2001).
Canine models are used to study idiopathic epilepsy, with? status epilepticus being a neurological fate common to both dogs and humans (Loscher, 2022).
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Non-human primates are also used as model organisms in epilepsy pathophysiology and disease progression studies. Given the size of primates, and commonality with human neurology, rhesus monkeys, marmosets, baboons, and pig-tailed monkeys have been used to study clinical manifestations as well as EEG reports of focal and generalized epilepsy (Croll et al., 2019)
Limitations of using animal models
Study outcomes using animal models must take into account that human and animal brains are physiologically disparate; with differences in shape, size, and the complexity of neural circuitry.?
The progression and outcome of diseases may be different based on the species. Animal models can not follow the average human life span of 73.16 years for observability and longitudinal studies, for example. There are also genetic differences to be considered. Differences in physiology explain why animal models have not been widely successful in drug testing, except perhaps cancer therapeutics.??
Spontaneous occurrences of human neurological diseases in animals are few. Neurodegenerative diseases that are primarily caused due to aging, for example. (Jucker, 2010).?
The lack of language and vocalization, complex social interactions, wildly different nutritional profiles, and last but not least cognitive capacity, affect the manifestation of observable symptoms in animal models. Symptoms like hallucinations are harder to study in animals, as they may be spontaneous, even without the presence or absence of sensory inputs triggering any such manifestations.
Environmental factors also play a crucial role in animal models. In laboratory experiments, often under induced symptoms, animals are highly-stressed. Their diet may have been altered. They may have had surgical procedures or even implants. This is especially accurate for non-human primates (Pfefferle et al., 2018). All of this can make experimental data noisy, and extrapolation to human models harder.?
Deducing affect and behavioral modifications either as a cause or effect of neurophysiological changes is not easy even under the best of circumstances, in the absence of diagnostic protocols that use imaging or bloodworks. The subjective nature of symptoms and lack of objective tests, coupled with the fact that animals can not verbally express their feelings adds to the complexity of research (Nestler & Hyman, 2010). A wide variety of disorders listed in the Diagnostic and Statistical Manual of Mental Disorders, even in the fifth edition, rely on phenomenology like behavior and changes in cognition to be diagnosed.
Getting an animal to follow instructions or allow itself to be examined willingly is often not possible; an ataxic cow, for example, may harm the researchers trying to examine the animal (Constable et al., 2017).?
It is small wonder then that we come across research that shows promise in animal models, but the same success is not replicated in clinical practice or drug trials in humans.?
Failures to deliver desired outcomes?
Animal models have yet to provide groundbreaking insights into human neurodegenerative diseases.??
In Alzheimer’s disease research, for example, transgenic mice have been shown to develop cerebral β-amyloidosis as well. However, imaging results have suggested that there are significant differences in human and mice lesions (Jucker, 2010). Non-human primates have not been a successful model for Alzheimer’s research either, the amyloid deposit being much lower (Wisniewski, 1973). In canine or feline models,? the β-amyloid peptide deposition lacks neuritic plaques (Cummings et al., 1996) with low neuronal loss.?
Drug safety is also another area where animal models have not been widely successful (Van Norman, 2019).
Conclusion
The journey of a baby cow from being born in a confined industrial farming environment to being served as a veal cutlet defy compassion. If we can slaughter sentient animals in the name of food, do we draw the line at medical research, where lab conditions are much more humane and are closely monitored by various regulatory agencies?
As of 2015, roughly 192.1 million animals have been used for research purposes. (Taylor & Alvarez, 2019). No statistics can adequately represent the pain and agony a huge number of them may have suffered. What right do we have to force experimentation on another species, that has no way to give informed consent? Can we inflict trauma and pain on animals unable to defend themselves??
Yet, we can not ignore the breadth of human lives saved as a direct result of animal research. What if Pasteur had not experimented with chickens and cholera germs??
Perhaps the answer lies in modern research protocols, encompassing learnings from fields as varied as complexity theory and complex systems, computer science, artificial intelligence, or big data, making the use of animal models slowly but surely irrelevant.?
There is definite promise in newer research using brain on a chip and cerebral organoids. Perhaps research in human iPSC-derived 3D platforms (Plummer et al., 2019) can pave the way to personalized medicine, minimizing the use of animal models except for extraordinary circumstances.
References
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