You make a great point about the importance of choosing the right animal models in pre-clinical research, especially in neurology. This is because the brain and nervous system are so complex that it's crucial to look for a specific species with similarities in brain structure to help us get results that translate to humans. In addition, it's interesting to think about how technologies like optogenetics and advanced imaging can further enhance our understanding across different models. Balancing scientific relevance and ethical considerations is key in this field.

The most important factor I believe must be how similar their neurological function and structure are to the human neurological system. No matter what the moral behind using each species is, at the end of the day, it all comes out to the fact that their sacrifice are for the purpose of saving human. To obtain translatable results to human being, I believe their is no other important factor than the similarity of such species to the human brain. This does not only ensure that the treatment is applicable to human, but also save meaningless sacrifices on the animals, no matter which species that is. 

I agree that it is critical to choose a model that offers translatability to ensure therapies/devices being tested will actually be safe in humans. However, I would like to bring up the ethical standpoint. While conducting studies, both investigational research and validation studies, researchers sometimes seek to isolate/test specific biomarkers/genes compared to the organism as a whole. Thus, in these cases, a reductionist model (e.g., cell cultures, brain slices, genetically modified rodents targeting a single pathway/gene) is often chosen due to its cost-effectiveness, efficiency, and control offered in terms of genetic tuning. However, to test other hypotheses or validate other therapies, it is argued that these models do not completely encapsulate the complexity of a whole organism. Thus, in my understanding, whole-animal models are introduced at this point (e.g., non-human primates in behavioral research or rodents in Parkinson's disease studies). This, of course, raises ethical concerns, especially as they are higher-order animals. 

Now, with the advent and development of alternatives, such as organ-on-a-chip models, I wonder if some of us think our reliance on animal studies will reduce?

@krish I definitely agree with you that organ on a chip model are slowly reducing our dependence on animal studies. The FDA themselves have also pushed for this, as the FDA Modernization Act 2.0 allows for organ on a chip models to be used in preclinical testing instead of always having to run animal studies, as well also publishing a Roadmap called "Roadmap to Reducing Animal
Testing in Preclinical Safety Studies" that encouraged using methods such as organ-on-a-chip in drug applications. It's still far from a perfect replacement, the Government Accountability Office has stated that there are still challenges with organ on chip models in regard to not enough validation or no single set standard on how they are made and reported on. That's why they recommend it should be used alongside with animal data for now. When there is a breakthrough with organ-on-a-chip research, which animal studies should be dropped first?

FDA Modernization Act 2.0 - https://www.congress.gov/bill/117th-congress/senate-bill/5002
Roadmap to Reducing Animal Testing in Preclinical Safety Studies - https://www.fda.gov/files/newsroom/published/roadmap_to_reducing_animal_testing_in_preclinical_safety_studies.pdf
Government Accountability Office on Organ on a chip - https://www.gao.gov/products/gao-25-107335

I agree that species similarity and ethical considerations are central, but I think another key factor is how well an animal model can replicate not just the structural, but also the functional and behavioral complexity of a disorder. For example, in my own work with autism spectrum disorder (ASD)-induced mice, we looked at how SDF-1α influenced neurovascular interactions. The model was valuable because it allowed us to see changes in both cellular signaling and behavioral patterns, something that in vitro systems alone couldn’t capture. That kind of perspective is important in neurological research, where pathology often spans from molecules to whole-organism behavior.

It's interesting to me how these layers might be integrated in future models; for example, integrating wearable biosensors or sophisticated imaging with genetic rodent models to monitor long-term functional effects. That might help close the gap between complete animal studies and systems like cell cultures. Do you believe that creating models that accurately represent both molecular details and whole-brain function will be the next significant breakthrough in pre-clinical neurology, or will we eventually rely more on alternatives like organ-on-chip?

I agree that choosing the correct animal model is crucial in research especially in neuroscience. Due to the brain being complex, using models that are close to human biology can improve the accuracy of the findings. Rodents are usually used for basic mechanisms but larger animals are used for researching cognitive functions. If the wrong model is picked, the results may not be accurate in humans which is a very negative effect.

Trying to find the right balance between biological relevance and practicality is crucial for selecting a viable animal model (especially in a pre clinical research). When selecting a species, they should be or share as many similar properties and functions to that of humans (considering brain structure, disease progression, etc.). Another area to consider is how easily a model can replicate the disease or problem in question, whether that be through genetic modification or induced conditions. Looking over the history of what animals have been observed before is important, especially seeing past objectives that have or have not worked. Finally, being able to acquire an animal model ethically, while also balancing the cost and feasibility would be crucial.

In addition to the animal model being tested, researchers should also try focusing on subjects with qualities or flaws similar to their target human demographic and whether or not a treatment to that flaw is a good representation of what would happen in a human subject. While it is unfortunate that it always comes down to an animal getting tested on, it is vital to the accuracy and safety for the human population.