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BrainWaves: The Neuroscience Graduate Program Newsletter

Understanding Humans Using Non-Human Animals: A Brief History of Animal Models in Neuroscience

Author: Salina Edwards

“The difference in mind between man and the higher animals, great as it is, certainly is one of degree and not of kind.”

– Darwin, 1874

Bust of Alcmaeon of “Alcmaeon and Pythagoras,” by the sculptor Ludovico Graziani (Celesia, 2012).

Non-human animals have played a fundamental role in advancing the field of neuroscience since its inception. The earliest records documenting the use of non-human animals as models for human anatomy and physiology in research began in ancient Greece (Neziri et al., 2024; Ericsson et al., 2013).


Early comparative science was often observational, aiming to better understand human development and physiology. However, while human cadavers were commonly used for anatomical dissections--frequently drawing a rather large and curious audience--it was not uncommon for deceased animals to be used in their place when human corpses were unavailable. 


Alcmaeon of Croton, an early Greek medical writer, philosopher-scientist, and student of Pythagoras, is often credited as being the first to observe non-human animals and draw comparisons to humans (Celesia, 2012; Ericsson et al., 2013). Using empirical observations, Alcmaeon concluded that the eye is connected to the skull via a channel or path, concluding that principatum esse in cerebro (the governing faculty is in the brain; Celesia, 2013). Alcmaeon is also credited as being the first to use dissection of animals for the purpose of studying anatomy (Singer, 1925). 

Although this early period is known for many significant discoveries (see Table 1), it wasn’t until the Renaissance (14th–17th centuries) that animal modeling transformed the understanding of human physiology.

Table 1. Early Milestones in Animal Modeling. Adapted from Ericsson et al. (2013).

Figure 2. De humani corpus fabrica

During the Renaissance, comparative science flourished. Flemish surgeon and anatomist Vesalius (1514-1564) explored the varying features between human and animal anatomies, often performing live slaughtering lessons on animals for students studying medicine (Yoladi et al., 2023). Vesalius revolutionized the study of anatomy with the publication of his magnum opus De Humani Corporis Fabrica (On the Fabric of the Human Body). This work drew upon his own studies, correcting many of Galen’s errors in anatomy, and is considered one of the most influential books on the subject (Siraisi, 1997; see Fig. 2). 

The division of blood circulation into pulmonary and systemic was first discovered in the 16th century by physicians Servetus and Lusitano (Yoladi et al., 2023). Later, William Harvey conducted a variety of dissections using eels, fish, chicks, and pigeons, leading to the publication of his seminal work De Motu Cordis (Ericsson et al., 2013). In this, Harvey details the entire human circulatory system with great accuracy. His observations of embryonic chicks also led him to pioneer the theory of epigenesis—the development of embryos from a single cell (Ericsson et al., 2013). 

Later, in the 17th century, comparative science took an electric turn: Luigi Galvani, Italian physician, physicist, biologist and philosopher, pioneered the field of animal electricity. In 1780, Galvani applied electricity to a dead, dissected frog’s leg, causing it to twitch (Bresadola, 1998). This discovery also inspired Mary Shelley’s Frankenstein.

The use of animal models in research increased dramatically by the 20th century: 

  • In 1921, Otto Loewi stimulated frogs' hearts using electrical impulses, leaving them beating in an ionic bath. After transferring this same fluid to another heart, he observed it operating similarly. This experiment (which came to him in a dream*) led to the discovery of neurotransmitters. In 1936, he was awarded the Nobel Prize in Physiology or Medicine for his contributions (McCoy & Tan, 2014). 
  • In the 1920s, Edgar Adrian developed the theory of neural communication using an isolated frog nerve-muscle preparation. He showed that signal magnitude is conveyed through the frequency of action potentials rather than their size. Adrian was also awarded a Nobel Prize for his work (Enroth-Cugell, 1993).
  • In the 1940s, John Cade explored the effects of lithium salts on guinea pigs while searching for anticonvulsant drugs (see Fig. 3). He observed that the animals appeared calmer, leading him to experiment with lithium on himself before using it to manage recurrent mania. By the 1970s, lithium had transformed the treatment of manic depression, which previously relied on lobotomies or electroconvulsive therapy (Parker, 2012).
Figure 3. Experiments on guinea pigs. Image from: https://scenicwritersshack.com/2020/05/08/aussie-scientist-john-cade-and-the-discovery-of-lithium/
Today, rodents, including rats and mice, are among the most common mammalian animal species used in neuroscience research (Romanova & Sweedler, 2018). Their widespread use is largely driven by financial feasibility, ease of care, and the extensive body of existing literature utilizing these models. However, reliance on rodents alone can limit the scope of scientific discovery. As a result, some researchers are beginning to urge the field to diversify animal models used in research away from rodents to other species, such as zebrafish, which offer unique advantages to neuroscientific research (Gerlai, 2023). 

Non-human animals have played a pivotal role in advancing our current understanding of humans. As the field of neuroscience continues to progress, the historical contributions of animal models highlight their enduring value in unravelling the complexities of the brain and behaviour.
Footnotes
* "The night before Easter Sunday of [1920] I awoke, turned on the light and jotted down a few notes on a tiny slip of thin paper. Then I fell asleep again. It occurred to me at 6.00 o’clock in the morning that during the night I had written down something important, but I was unable to decipher the scrawl. The next night, at 3.00 o’clock, the idea returned. It was the design of an experiment to determine whether or not the hypothesis of chemical transmission that I had uttered 17 years ago was correct. I got up immediately, went to the laboratory, and performed a simple experiment on a frog heart according to the nocturnal design.” – Otto Loewi
References
Bresadola, M. (1998). Medicine and science in the life of Luigi Galvani (1737–1798). Brain Research Bulletin, 46(5), 367-380. https://doi.org/10.1016/S0361-9230(98)00023-9

Celesia, G. (2012) Alcmaeon of Croton's observations on health. Brain, Mind, and Soul, Journal of the History of the Neurosciences, 21(4), 409-426. https://doi.org/10.1080/0964704X.2011.626265

Enroth-Cugell, C. (1993). EDGAR D. ADRIAN. Contrast Sensitivity, 5, 149. 

Ericsson, A. C., Crim, M. J., & Franklin, C. L. (2013). A brief history of animal modeling. Missouri Medicine, 110(3), 201. https://pmc.ncbi.nlm.nih.gov/articles/PMC3979591/

Gerlai R. (2023). Zebrafish (Danio rerio): A newcomer with great promise in behavioral neuroscience. Neuroscience and biobehavioral reviews, 144, 104978. https://doi.org/10.1016/j.neubiorev.2022.104978

McCoy, A. N., & Tan, S. Y. (2014). Otto Loewi (1873-1961): Dreamer and Nobel laureate. Singapore Medical Journal, 55(1), 3–4. https://doi.org/10.11622/smedj.2014002 

Neziri, S., Köseoğlu, A. E., Deniz Köseoğlu, G., Özgültekin, B., & Özgentürk, N. Ö. (2024) Animal models in neuroscience with alternative approaches: Evolutionary, biomedical, and ethical perspectives. Animal Models and Experimental Medicine. https://doi.org/10.1002/ame2.12487

Parker, G. (2012). John Cade. American Journal of Psychiatry, 169(2), 125-126. https://doi.org/10.1176/appi.ajp.2011.11111697

Romanova, E. V., & Sweedler, J. V. (2018). Animal model systems in neuroscience. ACS Chemical Neuroscience, 9(8), 1869–1870. https://doi.org/10.1021/acschemneuro.8b00380

Singer, C. (1925). The evolution of anatomy: A short history of anatomical and physiological discovery to Harvey: Being the substance of the Fitzpatrick lectures delivered at the Royal college of physicians of London in the years 1923 and 1924. AA Knopf.

Siraisi, N. G. (1997). Vesalius and the reading of Galen’s teleology. Renaissance Quarterly, 50(1), 1-37. https://doi.org/10.2307/3039327

Yoladi, F. B., Burmaoğlu, E., & Palabiyik, Ş. S. (2023). Experimental in vivo toxicity models for alcohol toxicity. The Eurasian Journal of Medicine, 55(1), 82–90. https://doi.org/10.5152/eurasianjmed.2023.23345