Of mice and men (and brains)

June 4th, 2024

Written by: Lindsay Ejoh

You may have seen news articles or movies of scientists making huge discoveries about the brain by experimenting with mice. Though the prospect of poking and prodding at mice all day may seem unpleasant, mice are the cornerstone of neuroscience research. 35-40% of neuroscience studies published between 1960-2015 years used rodent models¹. That being said, it’s glaringly obvious that humans are very different from mice. So one might wonder… is it worth it? What can and can’t we learn about the human brain from investigating the inner workings of a mouse?

One way to start answering this question is to consider how much DNA mice and humans share, which is  90-97%^{2, 3}!! This genetic similarity may indicate that the fundamental processes that control brain function are very similar in both species. However, sharing 98% of DNA with mice doesn’t mean that we are 98% similar to them. The real question lies in whether mice operate like humans. How do we compare to mice at all of the levels that we study the brain: molecular, cellular, and behavioral? Let’s explore how similar our brains are to our furry friends in each of these categories. 

Molecular Building Blocks 

DNA is the genetic code that determines who we are, but DNA isn’t everything. Our cells use DNA to build cellular machines called proteins that help keep us alive and functioning⁴. Do mice make the same proteins that we do? The answer is mostly yes. The proteins that are needed for cells to function properly, maintain their energy levels, and even sense molecules like drugs in the environment are almost identical in mice and humans. Despite that, the structure of some of these proteins differ between the species^{2, 5}. For example, mouse and human cells can both sense opioid drugs⁶, though the proteins in these cells that detect opioids look and act slightly different between the two. Regardless, both species experience pain relief and can develop dependence for opioid drugs. 

Cellular Level: Communication and Function

Do mouse brain cells “speak the same language as human brain cells”? Turns out, we are very similar to mice in how our cells communicate with each other. Both human and rodent brain cells produce chemicals that they use to “talk” with other brain cells, called neurotransmitters⁸. Neurotransmitters you may have heard of include serotonin, dopamine, and glutamate. Cells can also communicate via hormones that are also shared across mice and humans, like insulin, estrogen, cortisol, and testosterone⁹. These chemicals play critical roles in regulating behavior, mood, and overall brain function in both species. However, not all of our neurotransmitters and hormones are identical. For example, mice are able to recognize pheromones, which humans produce but cannot physically detect. Additionally, mice operate on different reproductive cycles, meaning their hormone levels differ from ours, even if they have the same hormones in their bodies¹⁰. Understanding these variations is important for translating what we learn in mice to human biology. 

Behavior and Disease Manifestation

What behaviors and feelings do humans and mice exhibit? Do we share the same motivations and fears? Is it worth it to study mouse behavior when trying to understand humans? It is no secret that mice exhibit only fundamental behaviors for survival, like seeking food and other rewards, avoiding predators and other dangers, and socializing and reproducing to keep their species going. These behaviors are driven by similar brain regions and neurotransmitters in both mice and humans. Despite these similarities, there are significant limitations. Mice do not exhibit complex behaviors such as abstract thinking, language, and complex social interactions. That makes it challenging to study things like intelligence or certain brain disorders solely using mice. 

For example, scientists have developed ways to capture some of the features of Alzheimer’s disease in mice¹¹. These mice show memory impairments similar to humans, but the extent of memory loss and brain death is often less pronounced in mice. That makes it difficult to use mice to create Alzheimer’s therapies for humans. Additionally, we cannot fully investigate mood disorders like depression in mice, because it is impossible to know exactly how they are thinking and feeling¹². As a result, we are forced to rely on indirect measures of their mood, like measuring how motivated they are to seek rewarding things, to save themselves from harm, or to interact with their peers. Ultimately, many diseases do not manifest the same way in mice as they do in humans, rendering it quite difficult to only rely on mice to develop reliable therapeutics. 

Despite these limitations, studying mice has led to significant advancement in treating human brain disorders. Mouse experiments have helped us develop therapies for Parkinson’s disease¹³, brain stimulation therapies for mood disorders¹⁴, therapies for chronic pain disorders¹⁵, and beyond.

Ethical Considerations

It is vital to think through the ethics associated with studying mice, and animals in general. On one hand, if we do not use mice, then who do we study? Technological advancements in genetic engineering have allowed researchers to develop sophisticated tools to study mice, enabling them to answer complex questions that can’t be studied in any other species. There are ethical and legal guidelines in place to ensure that government-funded animal research is conducted responsibly, minimizing harm and maximizing the amount of knowledge to be gained from each study.

Mice are a stepping stone to help us understand and treat the human brain, but they are not the final answer. Insight gained from mouse studies must be complemented with research in other animal models and carefully translated to human clinical trials. As we continue in our pursuit to understand and treat the human brain, we must consider all of the similarities and differences between species to best bridge the gap between animal and human research. 

References 

1. Keifer, J., & Summers, C. H. (2016). Putting the “Biology” Back into “Neurobiology”: The Strength of Diversity in Animal Model Systems for Neuroscience Research. Frontiers in systems neuroscience, 10, 69. https://doi.org/10.3389/fnsys.2016.00069
2. Breschi, A., Gingeras, T. R., & Guigó, R. (2017). Comparative transcriptomics in human and mouse. Nature reviews. Genetics, 18(7), 425–440. https://doi.org/10.1038/nrg.2017.19
3. Why mouse matters. Genome.gov. (2010). https://www.genome.gov/10001345/importance-of-mouse-genome 
4. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Analyzing Protein Structure and Function. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26820/
5. Hernández, F., Merchán-Rubira, J., Vallés-Saiz, L., Rodríguez-Matellán, A., & Avila, J. (2020). Differences Between Human and Murine Tau at the N-terminal End. Frontiers in aging neuroscience, 12, 11. https://doi.org/10.3389/fnagi.2020.00011
6. Falconnier, C., Caparros-Roissard, A., Decraene, C., & Lutz, P. E. (2023). Functional genomic mechanisms of opioid action and opioid use disorder: a systematic review of animal models and human studies. Molecular psychiatry, 28(11), 4568–4584. https://doi.org/10.1038/s41380-023-02238-1
7. Li, X., Keith, D. E., Jr, & Evans, C. J. (1996). Mu opioid receptor-like sequences are present throughout vertebrate evolution. Journal of molecular evolution, 43(3), 179–184. https://doi.org/10.1007/BF02338825
8. Wong, H. H., Chou, C. Y. C., Watt, A. J., & Sjöström, P. J. (2023). Comparing mouse and human brains. eLife, 12, e90017. https://doi.org/10.7554/eLife.90017
9. Bell M. R. (2018). Comparing Postnatal Development of Gonadal Hormones and Associated Social Behaviors in Rats, Mice, and Humans. Endocrinology, 159(7), 2596–2613. https://doi.org/10.1210/en.2018-00220
10. Ajayi, A. F., & Akhigbe, R. E. (2020). Staging of the estrous cycle and induction of estrus in experimental rodents: an update. Fertility research and practice, 6, 5. https://doi.org/10.1186/s40738-020-00074-3
11. Zhong, M. Z., Peng, T., Duarte, M. L., Wang, M., & Cai, D. (2024). Updates on mouse models of Alzheimer’s disease. Molecular neurodegeneration, 19(1), 23. https://doi.org/10.1186/s13024-024-00712-0 
12. Wang, Q., Timberlake, M. A., 2nd, Prall, K., & Dwivedi, Y. (2017). The recent progress in animal models of depression. Progress in neuro-psychopharmacology & biological psychiatry, 77, 99–109. https://doi.org/10.1016/j.pnpbp.2017.04.008
13. Chu, W. T., Hall, J., Gurrala, A., Becsey, A., Raman, S., Okun, M. S., Flores, C. T., Giasson, B. I., Vaillancourt, D. E., & Vedam-Mai, V. (2023). Evaluation of an Adoptive Cellular Therapy-Based Vaccine in a Transgenic Mouse Model of α-synucleinopathy. ACS chemical neuroscience, 14(2), 235–245. https://doi.org/10.1021/acschemneuro.2c00539
14. van den Boom, B. J. G., Elhazaz-Fernandez, A., Rasmussen, P. A., van Beest, E. H., Parthasarathy, A., Denys, D., & Willuhn, I. (2023). Unraveling the mechanisms of deep-brain stimulation of the internal capsule in a mouse model. Nature communications, 14(1), 5385. https://doi.org/10.1038/s41467-023-41026-x
15. Mao J. (2009). Translational pain research: achievements and challenges. The journal of pain, 10(10), 1001–1011. https://doi.org/10.1016/j.jpain.2009.06.002

Cover photo from Helloi42 on Pixabay