Author Archives: Editor

Tail or Tunnel: Handling Methods Influence Mouse Behavior in Cognitive Tasks

  • A study funded by the NC3Rs explored how handling methods influenced mice’s behavior during cognitive tasks
  • Mice were either picked up by the tail or guided into a tunnel, then transferred to the testing arena
  • Mice that were transferred in the tunnel were far more exploratory during the cognitive task
  • Acclimation to handling procedures is important

A new study published today in Scientific Reports shows that the way experimenters pick up mice can affect their behavior during cognitive tasks. The study was funded by the NC3Rs, which is dedicated to replacing, refining, and reducing the use of animals in research and testing. This particular study focused on refinement: identifying optimal handling methods for mice has important implications for both the welfare of the animals and the validity and usability of data that are collected, which could potentially lead to a reduction in the need for animals in future studies.

Image Credit: Jane Hurst, University of Liverpool.

Drs. Kelly Gouveia and Jane Hurst first placed laboratory mice near a new, attractive stimulus – urine from a novel mouse of the opposite sex – that is known to stimulate approach and investigation. The mice were allowed three sessions to grow accustomed to the new scent. Throughout all three sessions, mice were either picked up by the tail (standard laboratory practice, though there is no obvious scientific reasoning for this method) or were guided into a clear tunnel that is both affordable and easily sterilized. (The method is also easy to learn.) Mice were then carried to the test arena either by the tail or in the tunnel and allowed to explore. Gouveia and Hurst report that mice picked up by the tail showed very little willingness to explore the test arena, and therefore investigate the new stimulus, whereas those transported in the tunnel showed much higher exploration and a strong interest in the new scent.

Importantly, Gouveia and Hurst then tested the mice’s ability to discriminate between the (formerly) new scent and a second, different urine stimulus. They report that since the mice picked up by the tail performed so poorly from the start, they did not discriminate between the two scents. However, those transported in the tunnel showed robust and reliable discrimination. These findings are noteworthy not only with respect to the psychological welfare of the animals, but also for the important effects that handling and habituation have on yielding usable, reliable data. With the potential to reduce the stress associated with handling, the tunnel method could reduce the anxiety that mice display upon tail handling – thereby resulting in more species-typical behaviors, such as exploration of a novel, conspecific scent. It could also reduce the uncontrolled variation that exists in animal studies and could ultimately produce more reliable data. Thus, identifying optimal handling techniques has the potential to reduce the number of animals needed in laboratory studies in addition to refining the techniques used to study them and enhance their welfare.

Image Credit: Jane Hurst, University of Liverpool.

It is worth noting that a study by Novak and colleagues (2015) found no difference in cognitive performance between mice that were handled by the tail or by a less invasive method (“cupping” in the experimenter’s hands). Why might no difference have been found in this study? One possibility is that the cognitive task the researchers used was different from the present study (a radial arm maze vs. novel scent), and the arm maze may probe for different behaviors than a novel odor task. Another possibility is that perhaps mice “prefer” the tunnel to both tail handling and cupping, but neither the 2015 nor the present study compared all three methods. Hurst and her colleague Rebecca West did compare all three methods in a 2010 study, however, and found that mice preferred both the tunnel and cupping method to tail handling (as assessed by voluntary interaction time with the experimenter); although the cupping method produced more variable results depending on strain and sex. However, in the Novak study, mice were handled daily for many weeks, whereas in the Hurst & West study they were handled only for nine days. Of course, the most parsimonious explanation is that in every handling study, experimenter interaction is confounded with handling. That is, are the mice acclimating to the experimenters, to the handling procedures, or both?

These questions underscore the need for replication before firm conclusions about optimal handling techniques can be drawn. Nevertheless, the findings published today in Scientific Reports are an important addition to the field of animal welfare, and they emphasize the importance of constant, rigorous studies surrounding welfare issues.

Amanda Dettmer

References:

Gouveia K, Hurst JL (2017) Optimising reliability of mouse performance in behavioural testing: the major role of non-aversive handling. Scientific Reports 7: 44999. doi: 10.1038/srep44999

Hurst JL, West RS (2010) Taming anxiety in laboratory mice. Nature Methods. Oct;7(10): 825-6

Novak J, Bailoo JD, Melotti L, Rommen J, Würbel H (2015) An Exploration Based Cognitive Bias Test for Mice: Effects of Handling Method and Stereotypic Behaviour. PLoS ONE 10(7): e0130718. doi:10.1371/journal.pone.0130718

Weekly Roundup: Ebola vaccine hope for apes, gene therapy for dogs, and research into stroke

Welcome to the second of our weekly roundups. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • The first orally administered vaccine for Ebola developed for the conservation of wild apes, has completed its first and final biomedical research trial for the foreseeable future. The study, published in the journal Scientific Reports, shows that the vaccine was effective and did not induce health complications or lead to signs of stress in the apes. Lead investigator, Peter Walsh statedIn an ideal world, there would be no need for captive chimpanzees. But this is not an ideal world. It is a world where diseases such as Ebola, along with rampant commercial poaching and habitat loss, are major contributors to rapidly declining wild ape populations.Oral vaccines offer a real opportunity to slow this decline. The major ethical debt we owe is not to a few captive animals, but to the survival of an entire species we are destroying in the wild: our closest relatives.

One of the captive chimpanzees in the research trial receiving the oral Ebola vaccination. Credit: Matthias Schnell, Thomas Jefferson University.

  • A new compound, P7C3-A20, has been shown to prevent brain cell death and to promote new cell growth in a rat model of ischemic stroke. Nearly 87% of all strokes are ischemic strokes. Strokes kill 130,000 Americans yearly, with someone in the USA having a stroke every 40 seconds and with a death occurring every 4 minutes.
  • A new gene therapy, which aims to treat the fatal muscle-wasting disease, myotubular myopathy or MTM, has shown considerable success in dogs. Like humans, dogs naturally get this disease as a result of a genetic defect which tends to lead to breathing difficulty and early death. One year after a single gene therapy treatment, the dogs with the condition were indistinguishable from the control group. This offers huge promise for future human therapies for MTM. Results were published in Molecular Therapy.

Image from Science Daily

  • A team of scientists have prevented and alleviated two autoimmune diseases, multiple sclerosis (MS) and type 1 diabetes, in early stage mouse models. Autoimmune diseases affect an estimated 23 million Americans, and this research using mice highlights the importance of animal research in alleviating these debilitating diseases.
  • A new study finds that Lactobacillus, a common bacteria found in yogurt, may be used to alleviate symptoms associated with depression in mice – providing hope for the 7% of the population that experience a major depressive episode at least once in their lifetime. The study was published in Scientific Reports.

Image by Understanding Animal Research.

  • Canadian animal rights group, Last Chance for Animals, has alleged mistreatment of animals at the Contract Research Organisation, ITR Laboratories. The footage was included in a CTV W5 news report. In response to the infiltration video, ITR Labs released a statement saying they had parted ways with a number of technicians seen inappropriately handling animals in the footage. The Canadian Council of Animal Care also released a statement explaining that an inspection of the ITR facilities was now being organized.

300 Voices Speaking out For Research

Speaking of Research has worked hard at collating the animal research statements of hundreds of institutions – that list has now reached 300 institutions spanning eleven countries.

We still need your help to complete list – please check that your institution is on there. We are looking for a web page which clearly states that the institution conducts animal studies (and preferably explains why this is important). Submit your institution through our web form.

The excellent animal research pages of the pharmaceutical, Bayer.

We urge institutions to ensure they have an update to date statement which includes a strong explanation of how and why they conduct animal research, as well as the steps they take to maintain and improve animal welfare. Such information can be bolstered by case studies, statistics, images and videos. So far, only 23 (of 300) institutions have achieved full marks when we’ve rated the information available. See the full list at the bottom.

One thing that becomes apparent is that those institutions scoring highly have created a visible, and easily accessible, section of their website – usually with an easy-to-find URL such as (for UK institutions “.edu” is replaced with “.ac.uk”).

  • institution.edu/animal-research
  • institution.edu/research/animal-research
  • institution.edu/research/using-animals-in-research
  • animalcare.institution.edu
  • animalresearch.institution.edu

URL’s like these not only allow the link to be found (usually through a couple of clicks) easily from the homepage, but they also help when Googling for such information. Institutions try googling “institution animal research” and see what comes up – if your institution does not provide much information, will animal rights groups fill the vacuum?

An infographic from the University of Gronigen’s (NL) Annual Report on animal research

Speaking of Research do not believe there is any excuse for open communication about animal research online. The UK has been leading the way here (over half of the statements receiving full marks are from the UK), in part due to the Concordat on Openness – which most animal research institutions have signed up to – demanding such a statement to be drawn up.

Speaking of Research are willing to work with any institution that wants to improve its web content. We are happy to make recommendations and review drafts (for free). 

The 23 institutions receiving full marks are:

The University of Sheffield website got a 4/4 rating for its information

Weekly Roundup: Death of a pioneer, 2017 Brain Prize, and unsubstantiated claims by PETA

Welcome to the first in a series of weekly roundups. These aim to inform our readers about the many stories that relate to animal research each week.

Do you have an animal research story we should include in next week’s roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • Thomas Starzl the father of organ transplantation has died. Beginning with his work on liver transplantation in dogs in the 1950s, and subsequent refinement of the procedure using livers from pigs and primates, today “more than half of the liver-transplant patients who underwent surgery in 1998 were alive ten years later, and in 2009, almost 50,000 Americans carried a transplanted liver” (Lasker Foundation).” Read more about this here and here.

The father of organ transplantation, Thomas Starzl.

  • 2017 Brain Prize announced – Peter Dayan, Ray Dolan and Wolfram Schultz. Collectively, their work examines the ability of humans and animals to link rewards to events and actions. This research, involving non-human primates, provides valuable insights into motivation to perform both positive and negative behaviour, how those behaviours regulate emotions such as happiness and how dysregulation may affect addictive/compulsive behaviours such as gambling. Read more about this here.

  • An unannounced four-day inspection of the animal research facilities at the University of Pittsburgh found no wrongdoing. The inspection was triggered by unspecified allegations by the animal rights group PETA, though USDA officials could not find evidence corroborating the claims by PETA. This is not the first time we have noted that animal rights groups claims against labs which cannot be substantiated by inspectors. More here.
  • Tasmanian devil cancer is a major threat Tasmanian devils with more than 80% of the population being wiped out since it emerged 20 years ago. Fighting cancer with cancer, and in a culmination of 6 years of research, scientists have managed to achieve a 60% survival rate (3 out of 5). The application of animal research takes all forms, and this is a good example of techniques being developed in the lab on nonhuman animals being used to save other nonhuman animals. More here and here.

Tasmanian devils under threat

  • Ethical deliberation of the killing of wild animals humanely for conservation is considered here. The killing of animals by humans warrants moral and ethical consideration. Animal research can be used to inform such decisions so that they are grounded in sound scientific evidence.
  • In a concerning move, advisors to President Trump suggested removing regulations requiring pharmaceutical companies to perform pre-clinical trials which ensure human safety before bringing them to the market. You can read more about the value of animal research in pre-clinical trials here.
  • The NC3Rs has awarded the 2016 3Rs prize to Daniel Weary who investigated possible refinements to the legislative requirements for rats housed in the laboratory for research. Read more here and here. This prize and this research highlights governing bodies’ and researchers’ dedication to the health and well-being of the animals under their care. Well done, Daniel!

Check back next Friday for another weekly roundup.

Jeremy Bailoo and Justin Varholick

Thomas Starzl (1926-2017) – The man who saved countless humans using animal research

Dr. Starzl, a pioneer in the field of surgery and the “father” of organ transplantation in humans, was the first surgeon to perform a human liver transplant.

The liver is a remarkable organ, although more specifically it is a gland. It is essential to the functioning of the human body and is involved in metabolism, the production of hormones, detoxification — to name a few of its many functions. Unlike some of the other organs in the human body — of which we have two, such as the kidneys — there is no redundancy for the liver. For example, if one kidney fails the other kidney can compensate for the loss of function, and in many cases people with one kidney can live a normal life. In contrast, in cases of liver failure the only way to continue living would be liver transplantation; although in the short term — usually while waiting for a liver transplant — liver dialysis may be used. However, the liver is quite remarkable, and unlike many other organs possesses the capacity to regenerate, even if as much as 50 to 75% of the organ is damaged. Chronic liver disease, lasting more than six months, is debilitating and if not assessed early and treated (where possible) leads to death. It is estimated that over 50 million people are impacted from chronic liver disease.

Dr. Starzl’s work on human organ transplants was based on his earlier fundamental (basic) research in dogs. Unaware then of the potential application to humans, Dr. Starzl was investigating the role of nutrient rich blood and its contribution to liver health. Dr. Starzl formulated this question based on a lecture by Dr. Stuart Welch in 1957, who described an experiment where he had grafted an extra liver into a dog. In this experiment, blood left the grafted liver via the same system as the original liver, while the system bringing blood to the liver was different. Dr. Starzl hypothesized that the reason Dr. Welch’s transplant failed was a consequence of the different blood supply which brought blood to the liver.

Image courtesy of the University of Pittsburgh

In his subsequent investigations, Dr. Starzl developed and refined several liver transplant procedures in dogs — with his first success (survival after the operation) occurring in 1958. Between then and 1963, when the first human liver transplantation occurred, much research was being performed into immunosuppression by Dr. Roy Calne — also in dogs. This research was integral to the organ transplant field. Without understanding immunosuppression, the body would reject the donor organ; rendering the transplant useless. This pioneering work, in conjunction with Dr. Starzl’s own work, led to the first attempt at a human liver transplant in 1963. This first transplant was not successful, with the patient dying during the operation. Subsequent operations also resulted in patient death within a few weeks. However, those deaths provided evidence that the donor liver was able to function in the recipient’s body.

Dr. Starzl continued to refine and update his method, later moving his investigations to pigs — grafts from pigs were better tolerated by the human recipient. Then in 1967, he reopened his program and performed the first successful human liver transplant. Mortality after the procedure decreased over time, and “more than half of the liver-transplant patients who underwent surgery in 1998 were alive ten years later, and in 2009, almost 50,000 Americans carried a transplanted liver” (Lasker Foundation).

In 2012, Dr. Starzl and Roy Calne were honoured with the Lasker Award for their pioneering work in liver transplantation – “an intervention that has restored normal life to thousands of patients with end-stage liver disease”.

Complete liver replacement in the dog. The fact that the recipient was a dog rather than a human is identifiable only by the multi-lobar appearance of the liver. Image from University of Pittsburgh

Dr. Starzl was a brilliant scientist with a prolific career; over 2200 articles, 26 honorary degrees, and thousands of lives helped/saved by his work. We have previously written about this here; discussing him receiving the Lasker award. Similar to that post, we recommend reading about Dr. Starzl and his remarkable life here. We also encourage our readers to reflect upon his work, and the remarkable progress that was made using non-human animals for research. In particular, much of his pioneering work was derived from fundamental research investigating surgical procedures in dogs and his later work, refining the method, involved other non-human animals: pigs and baboons. It is often difficult to estimate the prospective benefit of research performed in non-human animals — but Dr. Starzl’s work is a great example of the potential reach of such research.

Jeremy Bailoo

Winners of 2017 Brain Prize announced – Peter Dayan, Ray Dolan and Wolfram Schultz

The one million Euro Brain Prize, awarded by the Lundbeck Foundation in Denmark, has gone to three neuroscientists for their work understanding the mechanisms of reward in the brain. The winners are:

  • Peter Dayan – Director of the Gatsby Computational Neuroscience Unit, University College of London
  • Ray Dolan – Director of the Max Planck Centre for Computational Psychiatry and Ageing
  • Wolfram Schultz – Professor of Neuroscience and Wellcome Trust Principal Research Fellow at the University of Cambridge

Collectively, their work examines the ability of humans and animals to link rewards to events and actions. This capacity has been a foundation of our survival, but can also be the root of many neurological and psychiatric disorders, such as addiction, compulsive behaviour and schizophrenia. In order for the successful survival and reproduction of a species, an animal must be able to make decisions that avoid danger and bring benefits (such as food, shelter, etc.). T decision-making requires predicting outcomes from environmental clues and previously learned responses. For instance, certain smells may indicate that an animal should prepare to chase prey, or to avoid a fruit item. The brain plays a key role in this decision making and learning, and at the centre of this is the neurotransmitter dopamine.

wolfram-schultz

Wolfram Schultz

In the 1980s, Professor Wolfram Schultz developed a way of recording the activity of neurons in the brain that use dopamine to transmit information. He found that the dopamine neurons would respond whenever a monkey was given fruit juice reward. Schultz then showed the animals different visual patterns; whenever a certain pattern was shown, the monkey would receive a reward. After a time the dopamine neurons began to respond to the visual pattern, rather than the juice reward (response to the juice reward itself declined over time). Conversely, when no reward was given (after the correct pattern was shown), the dopamine neuron activity decreased below normal levels. If the reward was given at another time or was bigger than expected, the dopamine neuron activity would spike (1).  This was the first clear demonstration of the neurological basis of one cornerstone of learning theory in Comparative and Behavioural Psychology; Pavlovian conditioning (2).

Building on Schultz’s work, Peter Dayan found the pattern of activity from dopamine neurons described by Schultz resembled the ‘reward prediction error’.  This signal is the difference between predicted and actual reward resulting from an action or event. It continuously updates according to the result of new events and outcomes. Dayan would go on to work with Schultz to create computational models investigating how the brain uses information to make predictions and how this information is updated when new or contrasting information is presented.

Peter Dayan

Peter Dayan

Schultz explains the reward prediction error and resulting learning in the following analogy:

I am standing in front of a drink-dispensing machine in Japan that seems to allow me to buy six different types of drinks, but I cannot read the words. I have a low expectation that pressing a particular button will deliver my preferred blackcurrant juice (a chance of one in six). So I just press the second button from the right, and then a blue can appears with a familiar logo that happens to be exactly the drink I want. That is a pleasant surprise, better than expected. What would I do the next time I want the same blackcurrant juice from the machine? Of course, press the second button from the right. Thus, my surprise directs my behavior to a specific button. I have learned something, and I will keep pressing the same button as long as the same can comes out. However, a couple of weeks later, I press that same button again, but another, less preferred can appears. Unpleasant surprise, somebody must have filled the dispenser differently. Where is my preferred can? I press another couple of buttons until my blue can comes out. And of course I will press that button again the next time I want that blackcurrant juice, and hopefully all will go well.

Which button to push?

Which button to push?

What happened? The first button press delivered my preferred can. This pleasant surprise is what we call a positive reward prediction error. “Error” refers to the difference between the can that came out and the low expectation of getting exactly that one, irrespective of whether I made an error or something else went wrong. “Reward” is any object or stimulus that I like and of which I want more. “Reward prediction error” then means the difference between the reward I get and the reward that was predicted. Numerically, the prediction error on my first press was 1 minus 1/6, the difference between what I got and what I reasonably expected. Once I get the same can again and again for the same button press, I get no more surprises; there is no prediction error, I don’t change my behavior, and thus I learn nothing more about these buttons. But what about the wrong can coming out 2 weeks later? I had the firm expectation of my preferred blackcurrant juice but, unpleasant surprise, the can that came out was not the one I preferred. I experienced a negative prediction error, the difference between the nonpreferred, lower valued can and the expected preferred can. At the end of the exercise, I have learned where to get my preferred blackcurrant juice, and the prediction errors helped me to learn where to find it.

Professor Ray Dolan’s work has involved imaging the human brain in order to understand the mechanisms for learning and decision-making. Advancing the work of Schultz and Dayan, he showed that the reward prediction error can account for how humans learn, and the role that dopamine plays within it. He has collaborated with Dayan for the past decade to investigate human motivation, variations in happiness, and human gambling behaviour.

Ray Dolan

Ray Dolan

Schultz continues to study both animals and humans, using neuroimaging to study changes in neuron signals in Parkinson’s patients, smokers and drug addicts. The more we understand the process which leads people to take certain actions, the better positioned we are to intervene.

Professor Sir Colin Blakemore (University of London), chairman of the Brain Prize selection committee said,

“The judges concluded that the discoveries made by Wolfram Schultz, Peter Dayan and Ray Dolan were crucial for understanding how the brain detects reward and uses this information to guide behaviour. This work is a wonderful example of the creative power of interdisciplinary research, bringing together computational explanations of the role of activity in the monkey brain with advanced brain imaging in human beings to illuminate the way in which we use reward to regulate our choices and actions. The implications of these discoveries are extremely wide-ranging, in fields as diverse as economics, social science, drug addiction and psychiatry”.

Primate research remains today an invaluable tool for comparative research into human health and disease. While other animals remain useful as models for such investigations, non-human primates are arguably the best species to be used for such investigations due to their remarkable similarity to humans. The research performed by Schultz, and built upon by Dayan and Dolan, highlight this simple fact and perhaps also exemplifies why critical consideration against the use of non-human primates for research is needed. The Brain Prize also shows how animal and non-animal methods are often used together to build our understanding of how the brain works.

Speaking of Research

  1. Schultz, W., 2015, Neuronal Reward and Decision Signals: From Theories to Data, Physiol Rev 95(3)
  2. Schultz, W. et al, 1993, Responses of Monkey Dopamine Neurons to Reward and Conditioned Stimuli during Successive Steps of Learning a Delayed Response Task, Journal of Neuroscience 13(3)

Understanding the animal, not just its parts

A recent article in the Atlantic, “How Brain Scientists Forgot That Brains Have Owners” is making headlines. The journalist claims that in an article published in early February, titled “Neuroscience Needs Behavior: Correcting Reductionist Bias”, fancy new technologies have led the field of neuroscience astray. The original scientific publication does draw attention to an area of neuroscience that neglects behavior, and outlines the importance of measuring behavior and the brain. However, behavior is not necessary in all areas of neuroscience, and adding behavior to some neuroscience studies could be problematic. Furthermore, the overall goal of the scientific publication was only to suggest that the field of neuroscience is lacking in scientists interested in studying the whole brain rather than the just studying the sum of its parts.

The field of neuroscience is diverse. Take for example the 9 themes at the Society for Neuroscience Conference in 2016:

  1. Development
  2. Neural Excitability, Synapses, and Glia [Neurophysiology]
  3. Neurodegenerative Disorders and Injury
  4. Sensory Systems
  5. Motor Systems
  6. Integrative Physiology and Behavior
  7. Motivation and Emotion
  8. Cognition
  9. Techniques [Technologies]

Glancing over these themes it is apparent that many scientists specialize in different types of neuroscience. Thus, some neuroscientists may study behavior and some may not need to study behavior. For example, neuroscientists investigating questions about technologies or neurophysiology may not need to study behavior at all — it depends on the question. Those only interested in the integration of physiology and behavior would study both the brain and behavior. And those studying cognition or motor systems might conduct experiments on behavior without directly measuring the brain. Whether neuroscientists study brain and/or behavior depends on the research questions they are asking.

Although both publications neglected to discuss the diversity of neuroscience, the main theme of the scientific publication was to change the way scientists interested in the integration of physiology and behavior approach their research questions. Too many neuroscientists focus on using as many new technologies as possible, and then use behavior as an afterthought. The issue here is that some of these new technologies are not yet well understood. Thus, scientists’ research questions using these technologies could be misguided.

Furthermore, behavior is a separate area of research on its own and should never be treated as an afterthought. Thus, the authors suggest that neuroscience needs more interdisciplinary scientists who understand and study the relationships between brain and behavior. It needs scientists that can merge all areas of the field.

All neuroscientists however, no matter their specific question, will help advance the field in different ways. And all neuroscientists do not need to study behavior. However, Interdisciplinary scientists in particular may set the stage for understanding the whole animal and how the brain operates within it. Furthermore, these scientists may help increase the translation of research from animal to human.

The problem of neuroscience without interdisciplinary scientists

A possible issue with scientists only studying one part of the animal (i.e. the brain) is that they neglect the rest of the animal. The authors suggest many neuroscientists only interested in the brain use a top-down approach (brain-behavior) to infer how behavior operates — and this is problematic. A recent experiment on understanding a simple computer demonstrates the potential flaws in a top-down approach. Briefly, computer scientists tested whether the processes of three classic videogames could be inferred by only studying the microprocessor that operated the videogames. In contrast to the brain, the scientists already understood how this computer system operates. After much investigation of the hardware of the microprocessor and how it functions, it remained unclear how the processes in the videogames operated. Thus, by using a top-down approach to understand behavior we will not be able to understand the brain

The bigger problem with measuring the brain and inferring behavior without studying behavior is that you are only studying one part of the animal. Consider the blind men and the elephant:

blind-men-and-the-elephant

Quite simply, if I am blind-folded and given an elephant’s ear then I may think it is a fan. For me to understand and determine that I am holding an elephant’s ear, I would need to investigate the whole elephant — beyond a small part and beyond all parts individually. Interdisciplinary scientists study the “whole elephant.”

However, only studying the ear of an elephant isn’t completely problematic. I can measure what it is composed of, stick electrodes in it to see how it responds, pour different chemicals on it to see how it reacts, measure how it grows over time, test it in different scenarios etc. Thus, I can learn many different aspects about this so called fan. However, what I cannot do is infer its function or purpose without considering the whole elephant. Also, I may be unable to determine which findings are related to the potential functions, and which findings are not related to the potential functions.

The elephant and the blind men, also apply to all experiments using animal models for understanding human biology. If I do not investigate or consider the whole “elephant” I may never determine that the “ear” I am looking at has a similar function to “ears” in many other animals. More generally, if I only study neural circuitry in a mouse without considering the mouse as a whole (anatomy, organs, cells, behavior, environment, development, evolution, etc.) then it won’t help me determine how — or if – the neural circuitry may function similarly in the human.

Development is particularly important — and often forgotten — ­when studying the whole animal. You cannot just study the “ear” of the “elephant” at a specific time point in a specific environment because the structure or function may change over time. Consider the development of a frog:

development-of-a-frog

In the tadpole stage the frog has a long tail for swimming and gills for breathing underwater. As it develops into an adult frog, however, the tail is reabsorbed and the frog exchanges its gills for lungs. Developmental context is necessary for understanding the whole animal.

The necessity of neuroscience with interdisciplinary scientists

Interdisciplinary scientists study both neural circuitry and behavior to understand the processes of the brain. However, this does not mean that they study parts of the brain, then study some behaviors, and understand the system. It also does not mean that they take a top-down approach (brain to behavior) or bottom-up approach (behavior to brain) — the choice here should depend on the specific research question. Interdisciplinary scientists study both brain and behavior at the same time. By studying both at the same time they can see how behavior emerges from neural circuitry and how neural circuitry emerges from behavior. The two are dependent on one another, they are not separate.

Consider this optical illusion:

optical-illusion-face-and-candlestick

If I just look at the picture on the left, I might only see a chalice and begin describing all of its visual properties and then infer its function. However, if I look at the picture on the right then it might become apparent that the picture is both a chalice and two people looking at each other. If I have too narrow of a focus — only studying the chalice — then I completely miss understanding that this is an optical illusion. Understanding the whole is important, and one part is not the greater than the other.

However, as mentioned earlier when trying to identify the function of an elephant’s ear, if I do not have a starting point for inferring function or mechanism then I could be asking the wrong questions. This is the point that the authors in the original scientific publication also make. If you do not study the behavior of the animal or process that you are interested in, then you will be asking all the wrong questions concerning neural circuitry. One cannot understand the game of chess by just analyzing all the pieces and the board. You must first observe how the game is played, and then you can determine what makes the pieces and the board important.

This is example of watching chess being played first and then analyzing the pieces and the board, represents a top-down approach. However, as already mentioned, the approach you take is particular to the question you are interested in. Different approaches give you different answers. And in the unknown world of brain and behavior, we may really not know enough to properly infer how something functions.

Regardless, this example of chess also applies to all experiments using animal models. For example, I might have learned how to play chess on a large and heavy wooden board with specially molded iron pieces. And as long as I understand the rules and processes of chess, then I can play chess on any board — be it big or small, plastic or wood, physical or virtual. But if I spend all my time studying the chess pieces and never watching how the game is played, then it might be difficult for me to identify which chess piece does what on a different chess set. Just like it would be difficult for me to determine which brain areas of a mouse might be analogous to which brain areas in a human without measuring behavior.

The authors also explain that multiple neural circuits may be responsible for a single behavior, and a single neural circuit may be responsible for multiple behaviors. This further complicates the issue of studying one part of the animal over the other. Thus, one specific neural circuit does not map to one specific behavior.

neural-activity-in-animals-and-the-behaviours-associated

In conclusion, the neuroscientists who published the original scientific article are correct: behavior is necessary and you must study it if you want to understand the brain. However, all the fancy techniques neuroscientists have developed, independent of behavior, help us ask specific questions about neural circuitry and about behavior. Also, all scientists experimenting on animals —not just neuroscientists — should understand the arguments used in this paper and apply it to their own experiments. This will help us better understand how findings in one species might relate to findings in another, and thus help the translation of all science using animal models.

Justin Varholick