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Topics: Animal Subjects

A guide that provides information and resources on teaching responsible conduct of research that focuses on the topic of animal subject use. Part of the Resources for Research Ethics Education collection.

What is Research Ethics

Why Teach Research Ethics

Animal Subjects

Biosecurity

Collaboration

Conflicts of Interest

Data Management

Human Subjects

Peer Review

Publication

Research Misconduct

Social Responsibility

Stem Cell Research

Whistleblowing

Descriptions of educational settings , including in the classroom, and in research contexts.

Case Studies

Other Discussion Tools

Information about the history and authors of the Resources for Research Ethics Collection

Fundamental Questions

Humans have often used non-human animals for basic and biomedical research, but also for companionship, supporting those with disabilities or suffering from stress, protection, sources of medicine and clothing, entertainment, transportation, and food. Although the focus of this discussion is the use of animals in research, two fundamental questions are relevant to any use of animals:

• Is the use beneficial ?
• Even if beneficial, are some uses of animals unacceptable ?

Nominal Guidelines

Opinions among scientists, philosophers, and the general public about how to answer these questions are widely divergent . However, at a minimum, scientists should always take the question of animal use seriously:

Critically evaluate the decision to conduct research with animal subjects Both the spirit of regulations and good science requires thoughtful consideration as to what defines acceptable use of animals .

Comply with regulations No use of animals for the purposes of research, teaching, or testing should commence that is not explicitly part of an approved protocol .

Protect animal welfare Researchers have a responsibility to protect animals from all unnecessary suffering or pain .

Promote responsible use of animal subjects Researchers have a responsibility as mentors, as peers, and as trainees to initiate discussion, identify relevant regulations, and promote responsible studies involving animal subjects.

Without the use of animals and human beings, it would have been impossible to acquire the important knowledge needed to prevent much suffering and premature death not only among humans, but also among animals. Albert Sabin, Developer of Polio Vaccine (Sabin, 1992) Virtually every major medical advance for both humans and animals has been achieved through biomedical research using animal models to study and find a cure for disease, and through animal testing, to prove the safety and efficacy of a new treatment. C. Everett Koop, U.S. Surgeon General, 1982-1989 (UCSD, 2001)

Is Animal Research Useful?

The merits of animal research are widely accepted by scientists and largely appreciated by the general public:

• Biomedical research institutions, professional societies, and research scientists share an understanding of tremendous value gained from animal studies (e.g., FASEB, 2015).  
• Polls of the general public historically have shown strong support for biomedical research with animals (Saad, 2010), although more recent polls suggest that the public is becoming more evenly divided (Funk and Rainie, 2015).

That said, the recognition of the benefits of animal research will depend greatly on precisely what question is being asked:  

It would appear that people’s attitudes toward experiments involving animals are likely to change depending on the beneficiary, purpose or necessity of the research. (Ormandy et al., 2014)

For example, it is likely that someone who expresses general misgivings about animal research, but perceives the value of vaccines, will prefer that those vaccines be first tested for safety before being used in their children.  

Is Animal Research Conducted Responsibly?

Foundations of Responsible Research

Animal research has tremendous utility because an understanding of the complex interactions of molecular, biochemical, and physiological mechanisms ultimately depends on studies in intact, living organisms .

• The scientific enterprise and the integrity of research depend on the responsible, humane treatment of animal subjects .  
• To be performed, such studies depend on many genetic and environmental controls that are difficult, if not impossible, to achieve in studies with humans-- yet the studies only have value if these controls are carefully maintained .  
• Furthermore, an experimental design that results in pain or suffering often decreases, if not eliminates, the scientific value of the experiment .  
• Irresponsible or inhumane treatment of animals harms the reputation of scientific institutions, endangers funding, and threatens the public image of science.

Failures of Responsible Research

While researchers typically recognize the need for responsible use of animals, poorly trained or inexperienced investigators may, for example:

• perform studies that deviate from approved protocol  
• provide inadequate care or feeding for animal subjects  
• leave animals poorly attended during recovery from anesthesia and surgery.

Although these lapses may occur rarely, they are never acceptable. It is hoped that the conduct of most researchers is principled and responsible, but this is not always the case. One of the most important early experimental scientists was Claude Bernard. Despite his fundamental and important contributions to science, his words suggest someone who did not recognize the suffering of the subjects of his research:  

To translate and paraphrase Bernard 1 , The physiologist is not a worldly man. He is a scientist seized and absorbed by scientific inquiry. He no longer hears the cries of the animals. He no longer sees the flow of the blood. He only sees his idea and the systems that conceal from him the questions he seeks to answer. (Bernard, 1865)

In this context, it is noteworthy that some instances of animal abuse have been far worse than inadequate care or feeding.  

In 1984, head injury studies conducted with baboons at the University of Pennsylvania were found to exemplify the worst fears of those opposed to animal research. In studies with restrained baboons, researchers were testing the effects of rapid, traumatic head injury. Some of those researchers made comments suggestive of a callous, if not sadistic, attitude toward the experimental subjects. Videotapes documenting these abuses were obtained by an animal rights organization and were aired on national television .

Despite the potential importance of what might be learned, such incidents reflect badly not just on one group of researchers, but on all of research. Investigators who are irresponsible risk not just their own research project, but also the research of others at the same institution. Potentially, they also risk the public's willingness to support or allow any research with animal subjects .  

Opposition to Animal Research

The support for biomedical research is tempered in part by widespread misunderstanding about the general nature of research, and research with animals in particular, but also an impassioned opposition, by some groups, to any use of animals. Arguments against the use of animals in research can broadly be divided into those that focus on the rights of animals and those that emphasize a utilitarian calculation to balance net benefits and harms. Rights Some in the animal rights movement rely on carefully reasoned, philosophical arguments that humans do not have the right to use animals for experiments (e.g., Regan, 1983), even if such studies might contribute important new knowledge about physiology or the mechanisms of disease in both humans and animals. Utilitarian Other opponents of animal research focus more on balancing benefits and harms (e.g., Singer, 1975). The focus in this case is on claims that:

• Animals suffer needlessly in research  
• Current medical advances were or could have been derived without the use of animals  
• Animal research has provided no useful data  
• There are negative consequences of animal research for humans (e.g., Greek and Greek, 2002).

While compelling arguments have been made to diminish the case made by Singer (Russell and Nicoll, 1996), it is important to remember that the principle of "the greatest good," is of paramount importance to Singer, who has even gone on record as saying studies in non-human primates for the purpose of Parkinson's Disease research could be defensible (Crowley, 2006). This is clearly contrary to the typical Rights argument.  

Scientific Community Concerns about Animal Research

Singer is not the only one to have questioned the unmitigated value of animal research. Frances Collins, director of the National Institutes of Health since 2009, noted:  

The use of animal models for therapeutic development and target validation is time consuming, costly, and may not accurately predict efficacy in humans (Collins, 2011)

John Ioannidis, a widely respected Stanford Professor of Statistics, Medicine, and Health Research and Policy, concluded from systematic reviews of the animal research literature that (Ioannidis, 2012):  

Limited concordance exists between treatment effects in preclinical animal experiments and clinical trials in human subjects. [It is] nearly impossible to rely on most animal data to predict whether or not an intervention will have a favorable clinical benefit-risk ratio on human subjects

This is consistent with an increasing body of literature noting a dismaying lack of reproducibility of published research (Prinz et al., 2011; Begley and Ellis, 2012). However, this doesn't necessarily mean that animal models per se are the problem. First, not all uses of animals in research are the same:  

Animal models vary in their capacity for predicting efficacy or safety in humans (Greaves et al., 2004). Just as there are cases in which correlations are strong (e.g., lethal doses for anticancer drugs in mice with maximum tolerated dose in humans or that dogs can be better predictors "of human adverse effects than rodents or, surprisingly, monkeys"), there are others which have little correlation (e.g., rodents appear to be poor predictors of subjective adverse neurological reactions in humans).

Further, as pointed out by Ioannidis (2012), there are at least two reasons that research with animals might not be reliable:  

Potential explanations for the failure of animal models to capture treatment effects in humans can be placed into two categories: First, both the human and animal results are accurate, but human physiology and disease are not adequately captured by animal models . Second, the animal literature is susceptible to biases in the study design, to reporting biases that distort the published evidence, or both. Indeed, although the scientific literature related to human clinical trials suffers from biases.  

Regulations and Guidelines

Enhancing the quality of animal studies will directly improve a quarter of the biomedical literature and may also benefit much of the other three-quarters that have an interface with animal research. Efforts are needed to minimize publication and other selective-reporting biases. Study design, conduct, and reporting can be improved—for example, by using the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines [Kilkenny et al., 2010] (Ioannidis, 2012)  

Roots of Regulation

Except for a set of guidelines for animal use recommended by the National Institutes of Health (NIH) in 1935, animal research in the United States was conducted with little public attention and virtually no oversight until the 1960s. This changed with a report titled "Concentration Camps for Dogs", published in Life magazine in 1966, documenting brutal conditions and lack of care by suppliers of dogs to research laboratories (Cosgrove, 2014):

• Within the year, the first Animal Welfare Act was written and approved, calling for regulatory oversight of the suppliers of some animals.
• Within the next few years, the government and researchers approved further guidelines and regulations to reduce the risk that the privilege of working with animal subjects would be abused .
• One of the most important outcomes was the NIH Policy for Animal Care and Use for institutions supported by the Public Health Service (PHS).

Regulations

The use of animal subjects is covered by numerous regulations. Although many federal agencies have relevant regulatory controls, the two most important for biomedical research are the Public Health Service (PHS) and the  United States Department of Agriculture (USDA) . Institutions are charged with implementing federal regulations primarily through the Institutional Animal Care and Use Committee (IACUC) :

• Public Health Service The Health Research Extension Act of 1985 ('Animals in Research') is the legislative basis for PHS policy on use of animal subjects. The policy covers uses of living vertebrate animals for any PHS-supported research, research training, and biological testing (PHS agencies include but are not limited to the National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), and Food and Drug Administration (FDA)).  
• United States Department of Agriculture Animal Welfare Regulations, and specifically the Animal Welfare Act (AWA), are implemented by the Animal and Plant Health Inspection Service (APHIS) of the USDA. The AWA, first enacted in 1966 and amended periodically, covers the sale, handling, transport, and use of warm-blooded, vertebrate animals. At present, birds, rats, and mice that are bred for research, but not those that are wild, are specifically exempted from the Animal Welfare Regulations. The AWA, as amended in 1985, incorporates a variety of requirements to promote animal welfare, including minimization of pain and distress, consideration of alternative procedures, definitions of institutional responsibilities, and the establishment of IACUCs. In addition, institutions, businesses, or individuals covered under the AWA must be licensed or registered with APHIS. Facilities are inspected on an unannounced basis, and if deficiencies are not corrected by the subsequent inspection, consequences could include fines, or the suspension or revocation of licensing to use animals.  
• Institutional Animal Care and Use Committee Although institutions are subject to federal oversight and inspection, day-to-day responsibility for complying with federal regulations is largely located within the IACUC. Under PHS policy, institutions are granted provisional responsibility for self-regulation after approval of an Animal Welfare Assurance by the Office of Laboratory Animal Welfare (OLAW). If the institution fails to meet its regulatory responsibilities, then OLAW can restrict or withdraw the assurance.

There is no presumption that animals may be sacrificed for research. Use of animals should only be considered if there is a legitimate scientific advantage to doing so, and even then the harm should be as little as possible. Replacement, Reduction, and Refinement Russell and Burch (1959) proposed three specific strategies for minimizing the pain and distress to animal subjects:

• Replacement : When possible, conscious animals should be replaced with unconscious or insentient material in research, and higher animals should be replaced with lower ones.  
• Reduction : Fewer animals should be used if doing so will not compromise the significance or precision of a study.  
• Refinement : Procedures should be designed so as to minimize the incidence and severity of harm to the animal subjects.

These strategies have an ethical basis, but they also have practical advantages . Research with animal subjects is expensive. If experiments can be conducted, for example, with mice rather than monkeys, with fewer animals, or without animals altogether, then the cost of those studies will generally be reduced.  

ARRIVE Guidelines

Even if a case can be made that research is consistent with the principles of reduction, replacement, and refinement, the research cannot be considered ethical if it doesn't also adhere to minimal precautions to favor research that will be reproducible . A widely accepted set of such guidelines are those noted above for Animals in Research: Reporting In Vivo Experiments (Kilkenny et al., 2010).

Case Study 1

Your colleague, Dr. Jay Mahata, is an NIH supported investigator who has an established collaboration with a field biologist, Dr. Ellen Yu, in another state. Dr. Yu does not receive any grant support for her research. Dr. Mahata sometimes receives blood and other tissue samples for analysis from the wild rodents that Dr. Yu traps for her research. Dr. Mahata has asked you to read his latest IACUC protocol prior to its formal submission. You know about his collaboration with Dr. Yu but note that it is not mentioned in the protocol. When you ask Dr. Mahata about this he says that he "does not have to report this activity to the IACUC because there are not any animal welfare concerns involved". He points out to you that he does not sacrifice the rodents or collect the blood and tissues. He maintains that the relevant animal welfare concerns are between Dr. Yu and her institution. Lastly, he suggests that because the NIH does not support her work, it does not have to conform to the same guidelines to which his own work is subject.

© ASM Press, 2000, Scientific Integrity by F.L. Macrina, used with permission.

Case Study 2

You are beginning a new post-doctoral position at the same time that your mentor is moving her laboratory into a new building. She is obsessive about animal care and wants to ensure that the colony of animals to be established in the new facility is healthy. You are assigned the task of developing a system of "sentinel" animals to monitor the health status of all new incoming shipments of animals as well those in the established animal colony. You establish a system that involves selected animals being sacrificed on a regular basis and screened for the presence of specific pathogens by a contract laboratory. Because these animals are not being used for research do you have to submit a protocol to the IACUC to cover these activities?

© ASM Press, 2000, Scientific Integrity by F.L. Macrina, used with permission

Case Study 3

You are a graduate student working on a project that involves administering nerve toxins directly into the cerebrospinal fluid of rats by using a special infuser connected to tubing that you have surgically implanted into the base of each rat's skull. Administering different nerve toxins to block specific effects of different types of drugs will help determine how the drugs work. After surgery, the nerve toxin is given, then a few days later the investigational drug is given to determine whether it will have an effect. This protocol has been approved by the Institutional Animal Care and Use Committee (IACUC) and is being funded by a grant from the Department of Defense. Over the past few weeks, you have carefully implanted a catheter into the base of each rat's skull, then infused the specified amount of nerve toxin. When you go to the vivarium to bring the rats to the lab to administer the investigational drugs, you find that a number of the rats are paralyzed or dead. You did not expect this. The lab director is currently out of town, so you go to the lab's senior graduate student, Tom, for advice. Tom will be able to complete his dissertation writing when this experiment is done and he has made it clear that he wants this experiment to run without delay. You ask him whether you should stop the experiment to determine why some of the rats are dead or paralyzed. He responds that stopping the experiment now would waste several weeks of work and delay completion of his dissertation. Stopping now may mean having to start over later and could result in using even more rats. He further explains that the IACUC might even prohibit restarting the experiment, so the rats would have died for nothing because the data would have to be obtained another way. He suggests that the paralysis and death of some of the rats may be due to your inadequate experience performing rat surgery or infusions, so further practice by continuing this experiment may result in better outcomes for the rest of the rats on which you perform surgery.

What do you do now? Do you continue performing surgery and infusions on the rats, knowing that more rats may be harmed? Do you stop the experiment and inform the IACUC, which risks earning the disfavor of Tom, with whom you have to work? How would you explain each course of action to the IACUC?

• Discuss the benefits of using animals in biomedical research and list at least three different studies that could be accomplished only with the use of animal subjects.
• To what extent does your field of work depend on the use of animal subjects? To what extent is your work intended to benefit both humans and other animals?
• Describe at least one instance in which abuse of animals in research resulted in public concern about the use of animals in research. Identify federal regulations that were apparently direct responses to such abuses.
• Define the terms replacement, reduction, and refinement in the context of research with animal subjects.
• What are the responsibilities of an IACUC?
• In your institution, what minimal changes (e.g., increase in number of animals) to your protocol require review and approval of the IACUC? What changes are of a magnitude to require submission, review, and approval of a new protocol?
• If you observed another investigator abusing the privilege of animal use, who should be notified?
• Describe your criteria for the acceptable use of animals. Consider the importance and likelihood of benefits to be obtained, the nature of the species to be used (e.g., invertebrates versus vertebrates, primates versus non-primates, dogs or cats versus rats or mice), the number of animals to be used, and the extent of likely pain or suffering.
• What forums are available in your institution to examine the ethical and/or legal ramifications of animal use? What, if anything, can you do to promote such discussion?
• OEC Animal Subjects Bibliography A bibliography of books, online resources, and articles on all aspects of animal use in research.  

Cited Sources

• Begley CG and Ellis LM (2012): Drug development: Raise standards for preclinical cancer research . Nature 483:531–533.
• Bernard C (1865):  An Introduction to Experimental Medicine (translation of Introduction à l'étude de la médecine expérimentale translated by HC Greene, A.M.)
• Collins FS (2011): Reengineering Translational Science: The Time Is Right. Science Translational Medicine 3(90):90cm17
• Cosgrove B (2014): ‘Concentration Camps for Dogs’: Revisiting a Grisly LIFE Classic . Time.
• Crowley W (2006): Peter Singer defends animal experimentation . Will & Testament: William Crowley's Blog, BBC.
• FASEB (2015): Animal Research Saves Lives.
• Funk C, Rainie L (2015): Chapter 7: Opinion About the Use of Animals in Research . Pew Research Center. July 1, 2015.
• Greaves P, Williams A, Eve M (2004): First dose of potential new medicines to humans: How animals help. Nat. Rev. Drug Discov. 3:226–236. doi:10.1038/nrd1329 pmid:15031736
• Greek CR and Greek JS (2002): Sacred Cows and Golden Geese: The Human Cost of Experiments on Animals. Continuum International Publishing Group.
• Ioannidis JP (2005): Why most published research findings are false. PLoS Med. 2, e124 (2005). doi:10.1371/journal.pmed.0020124 pmid:16060722
• Ioannidis JPA (2012): Extrapolating from Animals to Humans. Science Translational Medicine 4(151):151ps15
• Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010): Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol. 8, e1000412 (2010). doi:10.1371/journal.pbio.1000412 pmid:20613859
• Ormandy EH, Schuppli CA (2014): Public Attitudes toward Animal Research: A Review. Animals 4(3):391-408; doi:10.3390/ani4030391
• Prinz F, Schlange T, Khusru Asadullah K (2011): Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov 10(9):712.
• Regan T (1983): The Case for Animal Rights. University of California Press, Berkeley, CA.
• Russell SM, Nicoll CS (1996): A dissection of the chapter "Tools for Research" in Peter Singer's Animal Liberation. Proc Soc Exp Biol Med. 211(2):109-38.
• Russell WMS, Burch RL (1959): Principles of Humane Animal Experimentation. Charles C. Thomas, Springfield, IL, Also available in parts at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc
• Saad L (2010): Four moral issues sharply divide Americans . Gallup, May 2, 2010.
• Sabin A (1992): Winston-Salem Journal. March 20, 1992.
• Singer P (1975): Animal Liberation. Distributed by Random House, New York.
• UCSD (2001): The Importance of Animal Research to Medical Discovery. UCSD Perspectives Summer 2001, p. 22.
• 1 Bernard C (1865): Le physio­logiste n'est pas un homme du monde, c'est un savant, c'est un homme qui est saisi et absorbé par une idée scientifique qu'il poursuit : il n'entend plus les cris des animaux, il ne voit plus le sang qui coule, il ne voit que son idée et n'aperçoit que des organismes qui lui cachent des problèmes qu'il veut décou­vrir.

The Resources for Research Ethics Education site was originally developed and maintained by Dr. Michael Kalichman, Director of the Research Ethics Program at the University of California San Diego. The site was transferred to the Online Ethics Center in 2021 with the permission of the author.

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This material is based upon work supported by the National Science Foundation under Award No. 2055332. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

Animal Subjects

• Biosecurity
• Collaboration
• Conflicts of Interest
• Data Management
• Human Subjects
• Peer Review
• Publication
• Research Misconduct
• Social Responsibility
• Stem Cell Research
• Whistleblowing
• Regulations and Guidelines

Fundamental Questions

Nominal guidelines.

Without the use of animals and human beings, it would have been impossible to acquire the important knowledge needed to prevent much suffering and premature death not only among humans, but also among animals. Albert Sabin, Developer of Polio Vaccine (Sabin, 1992) Virtually every major medical advance for both humans and animals has been achieved through biomedical research using animal models to study and find a cure for disease, and through animal testing, to prove the safety and efficacy of a new treatment. C. Everett Koop, U.S. Surgeon General, 1982-1989 (UCSD, 2001)

Is Animal Research Useful?

It would appear that people�s attitudes toward experiments involving animals are likely to change depending on the beneficiary, purpose or necessity of the research. (Ormandy et al., 2014)

Is Animal Research Conducted Responsibly?

To translate and paraphrase Bernard*, The physiologist is not a worldly man. He is a scientist seized and absorbed by scientific inquiry. He no longer hears the cries of the animals. He no longer sees the flow of the blood. He only sees his idea and the systems that conceal from him the questions he seeks to answer. (Bernard, 1865)

In 1984, head injury studies conducted with baboons at the University of Pennsylvania were found to exemplify the worst fears of those opposed to animal research. In studies with restrained baboons, researchers were testing the effects of rapid, traumatic head injury. Some of those researchers made comments suggestive of a callous, if not sadistic, attitude toward the experimental subjects. Videotapes documenting these abuses were obtained by an animal rights organization and were aired on national television .

Opposition to Animal Research

Scientific community concerns about animal research.

The use of animal models for therapeutic development and target validation is time consuming, costly, and may not accurately predict efficacy in humans (Collins, 2011)

Limited concordance exists between treatment effects in preclinical animal experiments and clinical trials in human subjects. [It is] nearly impossible to rely on most animal data to predict whether or not an intervention will have a favorable clinical benefit-risk ratio on human subjects

Animal models vary in their capacity for predicting efficacy or safety in humans (Greaves et al., 2004). Just as there are cases in which correlations are strong (e.g., lethal doses for anticancer drugs in mice with maximum tolerated dose in humans or that dogs can be better predictors "of human adverse effects than rodents or, surprisingly, monkeys"), there are others which have little correlation (e.g., rodents appear to be poor predictors of subjective adverse neurological reactions in humans).

Potential explanations for the failure of animal models to capture treatment effects in humans can be placed into two categories: First, both the human and animal results are accurate, but human physiology and disease are not adequately captured by animal models . Second, the animal literature is susceptible to biases in the study design, to reporting biases that distort the published evidence, or both. Indeed, although the scientific literature related to human clinical trials suffers from biases.

Enhancing the quality of animal studies will directly improve a quarter of the biomedical literature and may also benefit much of the other three-quarters that have an interface with animal research. Efforts are needed to minimize publication and other selective-reporting biases. Study design, conduct, and reporting can be improved�for example, by using the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines [Kilkenny et al., 2010] (Ioannidis, 2012)

Roots of Regulation

Regulations, discussion questions.

• Discuss the benefits of using animals in biomedical research and list at least three different studies that could be accomplished only with the use of animal subjects.
• To what extent does your field of work depend on the use of animal subjects? To what extent is your work intended to benefit both humans and other animals?
• Describe at least one instance in which abuse of animals in research resulted in public concern about the use of animals in research. Identify federal regulations that were apparently direct responses to such abuses.
• Define the terms replacement, reduction, and refinement in the context of research with animal subjects.
• What are the responsibilities of an IACUC?
• In your institution, what minimal changes (e.g., increase in number of animals) to your protocol require review and approval of the IACUC? What changes are of a magnitude to require submission, review, and approval of a new protocol?
• If you observed another investigator abusing the privilege of animal use, who should be notified?
• Describe your criteria for the acceptable use of animals. Consider the importance and likelihood of benefits to be obtained, the nature of the species to be used (e.g., invertebrates versus vertebrates, primates versus non-primates, dogs or cats versus rats or mice), the number of animals to be used, and the extent of likely pain or suffering.
• What forums are available in your institution to examine the ethical and/or legal ramifications of animal use? What, if anything, can you do to promote such discussion?

Case Studies

• Russell WMS, Burch RL (1959): Principles of Humane Animal Experimentation. Charles C. Thomas, Springfield, IL, Also available in parts at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc
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• Site Feedback

2. Psychological Research

Learning objectives.

By the end of this section, you will be able to:

• Discuss how research involving human subjects is regulated
• Summarize the processes of informed consent and debriefing
• Explain how research involving animal subjects is regulated

Today, scientists agree that good research is ethical in nature and is guided by a basic respect for human dignity and safety. However, as you will read in the feature box, this has not always been the case. Modern researchers must demonstrate that the research they perform is ethically sound. This section presents how ethical considerations affect the design and implementation of research conducted today.

RESEARCH INVOLVING HUMAN PARTICIPANTS

Any experiment involving the participation of human subjects is governed by extensive, strict guidelines designed to ensure that the experiment does not result in harm. Any research institution that receives federal support for research involving human participants must have access to an institutional review board (IRB) . The IRB is a committee of individuals often made up of members of the institution’s administration, scientists, and community members ( [link] ). The purpose of the IRB is to review proposals for research that involves human participants. The IRB reviews these proposals with the principles mentioned above in mind, and generally, approval from the IRB is required in order for the experiment to proceed.

An institution’s IRB meets regularly to review experimental proposals that involve human participants. (credit: modification of work by Lowndes Area Knowledge Exchange (LAKE)/Flickr)

An institution’s IRB requires several components in any experiment it approves. For one, each participant must sign an informed consent form before they can participate in the experiment. An informed consent form provides a written description of what participants can expect during the experiment, including potential risks and implications of the research. It also lets participants know that their involvement is completely voluntary and can be discontinued without penalty at any time. Furthermore, the informed consent guarantees that any data collected in the experiment will remain completely confidential. In cases where research participants are under the age of 18, the parents or legal guardians are required to sign the informed consent form.

Link to Learning

Visit this website to see an example of a consent form.

While the informed consent form should be as honest as possible in describing exactly what participants will be doing, sometimes deception is necessary to prevent participants’ knowledge of the exact research question from affecting the results of the study. Deception involves purposely misleading experiment participants in order to maintain the integrity of the experiment, but not to the point where the deception could be considered harmful. For example, if we are interested in how our opinion of someone is affected by their attire, we might use deception in describing the experiment to prevent that knowledge from affecting participants’ responses. In cases where deception is involved, participants must receive a full debriefing upon conclusion of the study—complete, honest information about the purpose of the experiment, how the data collected will be used, the reasons why deception was necessary, and information about how to obtain additional information about the study.

Unfortunately, the ethical guidelines that exist for research today were not always applied in the past. In 1932, poor, rural, black, male sharecroppers from Tuskegee, Alabama, were recruited to participate in an experiment conducted by the U.S. Public Health Service, with the aim of studying syphilis in black men ( [link] ). In exchange for free medical care, meals, and burial insurance, 600 men agreed to participate in the study. A little more than half of the men tested positive for syphilis, and they served as the experimental group (given that the researchers could not randomly assign participants to groups, this represents a quasi-experiment). The remaining syphilis-free individuals served as the control group. However, those individuals that tested positive for syphilis were never informed that they had the disease.

While there was no treatment for syphilis when the study began, by 1947 penicillin was recognized as an effective treatment for the disease. Despite this, no penicillin was administered to the participants in this study, and the participants were not allowed to seek treatment at any other facilities if they continued in the study. Over the course of 40 years, many of the participants unknowingly spread syphilis to their wives (and subsequently their children born from their wives) and eventually died because they never received treatment for the disease. This study was discontinued in 1972 when the experiment was discovered by the national press (Tuskegee University, n.d.). The resulting outrage over the experiment led directly to the National Research Act of 1974 and the strict ethical guidelines for research on humans described in this chapter. Why is this study unethical? How were the men who participated and their families harmed as a function of this research?

A participant in the Tuskegee Syphilis Study receives an injection.

Visit this website to learn more about the Tuskegee Syphilis Study.

RESEARCH INVOLVING ANIMAL SUBJECTS

Many psychologists conduct research involving animal subjects. Often, these researchers use rodents ( [link] ) or birds as the subjects of their experiments—the APA estimates that 90% of all animal research in psychology uses these species (American Psychological Association, n.d.). Because many basic processes in animals are sufficiently similar to those in humans, these animals are acceptable substitutes for research that would be considered unethical in human participants.

Rats, like the one shown here, often serve as the subjects of animal research.

This does not mean that animal researchers are immune to ethical concerns. Indeed, the humane and ethical treatment of animal research subjects is a critical aspect of this type of research. Researchers must design their experiments to minimize any pain or distress experienced by animals serving as research subjects.

Whereas IRBs review research proposals that involve human participants, animal experimental proposals are reviewed by an Institutional Animal Care and Use Committee (IACUC) . An IACUC consists of institutional administrators, scientists, veterinarians, and community members. This committee is charged with ensuring that all experimental proposals require the humane treatment of animal research subjects. It also conducts semi-annual inspections of all animal facilities to ensure that the research protocols are being followed. No animal research project can proceed without the committee’s approval.

Ethics in research is an evolving field, and some practices that were accepted or tolerated in the past would be considered unethical today. Researchers are expected to adhere to basic ethical guidelines when conducting experiments that involve human participants. Any experiment involving human participants must be approved by an IRB. Participation in experiments is voluntary and requires informed consent of the participants. If any deception is involved in the experiment, each participant must be fully debriefed upon the conclusion of the study.

Animal research is also held to a high ethical standard. Researchers who use animals as experimental subjects must design their projects so that pain and distress are minimized. Animal research requires the approval of an IACUC, and all animal facilities are subject to regular inspections to ensure that animals are being treated humanely.

Self Check Questions

Critical thinking questions.

1. Some argue that animal research is inherently flawed in terms of being ethical because unlike human participants, animals do not consent to be involved in research. Do you agree with this perspective? Given that animals do not consent to be involved in research projects, what sorts of extra precautions should be taken to ensure that they receive the most humane treatment possible?

2. At the end of the last section, you were asked to design a basic experiment to answer some question of interest. What ethical considerations should be made with the study you proposed to ensure that your experiment would conform to the scientific community’s expectations of ethical research?

Personal Application Question

3. Take a few minutes to think about all of the advancements that our society has achieved as a function of research involving animal subjects. How have you, a friend, or a family member benefited directly from this kind of research?

1. In general, the fact that consent cannot be obtained from animal research subjects places extra responsibility on the researcher to ensure that the animal is treated as humanely as possible and to respect the sacrifice that the animal is making for the advancement of science. Like human research, the animals themselves should also receive some of the benefits of the research, and they do in the form of advanced veterinary medicine, and so on.

2. The research should be designed in such a way to adhere to the principles described in this section depending on the type of study that was proposed.

• Psychology. Authored by : OpenStax College. Located at : http://cnx.org/contents/[email protected]:1/Psychology . License : CC BY: Attribution . License Terms : Download for free at http://cnx.org/content/col11629/latest/.

Frequently Asked Questions

Why use animals in research?

Animal research is essential for three basic purposes:

• To explore basic biology
• To develop treatments for diseases and disabilities
• To promote health and safety for animals, people and the environment

Why can’t you replace animals with a computer?

Humans, like all animals, are extremely complicated. Drug development, for example, shows the difficulty of finding an accurate alternative. Many drugs are discovered because a chemical compound does something useful in a laboratory dish, but that discovery is followed by a long process of trial and error: first with simple animals, then with more advanced ones. Even the drugs that do reach human trial often either fail to work or have unacceptable side effects, often discovered first through testing on animals.

It’s true that some drugs and diseases “work” one way in mice and another in people; but if animal research can be misleading, computer-based research is likely to be even more difficult. When so much is unknown, how could we possibly program a computer to test drugs and procedures? To put it another way: we will not be able to do all our health and biology research in computers until we have nothing left to learn about health and biology.

Do your researchers look at alternatives to using live animals?

Yes. Following the federal Animal Welfare Act, the UW–Madison Researcher’s Guide to Animal Care and Use specifies that investigators consider alternatives to animal use, as part of its commitment to humane research:

• Replacement; using non-animal alternatives, such as cell culture, or choosing a species lower on the phylogenetic tree (mice instead of monkeys)
• Reduction; using the smallest number of animals necessary for valid scientific results
• Refinement; choosing procedures that minimize pain and distress.

Can you reduce your use of animals by doing something else?

Yes, and we are. For example, two types of stem cells (embryonic and induced pluripotent) are producing human cells that are already being used to test candidate drugs for toxicity. These stem cells are routinely used to produce human heart muscle cells, and because heart toxicity can be lethal, this process will save the lives of both animals and people. Other projects are looking into computer simulations of various sorts that can help reduce the need for research animals.

The federal government is looking into alternatives to animal research .

Who regulates animal research on campus?

Both federal and university bodies regulate research using vertebrate animals:

• U.S. Department of Agriculture .
• Office of Laboratory Animal Welfare, National Institutes of Health .
• Food and Drug Administration .
• Animal research at UW–Madison is overseen by five animal care and use committees, with assistance from the Research Animal Resources Center .

How is an animal research proposal approved?

Animal research is described and governed by a “protocol,” a description of the project that constitutes a contract between the principal investigator and the UW–Madison Animal Care and Use Committee (ACUC).

The review and approval for an animal care and use protocol follows these steps:

• Protocol application is prepared by the investigator and submitted to the Research Animal Resource Center (RARC), which assigns the protocol to the appropriate Animal Care and Use Committee for review.
• The ACUC can approve the protocol as is, approve it pending answers to certain questions, or require substantial revision.
• RARC staff communicates the ACUC’s approval or request for further information/revision to the Investigator.
• Research can begin after the protocol is approved.

Prior to making any significant change to the protocol, investigators must get approval of the relevant ACUC.

Who uses animals in research on campus?

A wide variety of UW–Madison researchers, including veterinarians, medical doctors, scientists and students at all levels of the university, are involved in animal research. Everybody involved in animal research must be trained in animal regulations and care, and have the necessary skills and training. Also, the research must be carried out in licensed premises meeting strict standards and subject to regular inspection.

Is it ethical for humans to experiment on animals?

The wide range of students, faculty and scientists at UW–Madison who use animals in research believe that the use of animals in medical research is ethical when performed under strict regulation, in situations where practical alternatives do not exist. The ethical decision amounts to a trade-off between the harm that may be done to the animals and the benefits to suffering patients, today and in the future. The vast majority of biomedical scientists believe that the abolition of animal research is an unrealistic position.

While we respect the viewpoint of those who oppose research on animals, we feel that the potential benefits to human welfare, animal welfare and basic knowledge about life are too important to not do the research. An argument can be made that refraining from this research would actually be unethical.

Do research animals ever get adopted?

The University of Wisconsin–Madison has a long-standing policy on research animal adoption. It allows UW–Madison to put animals up for adoption with the approval of the university’s veterinarians and after consideration of a number of factors. These are addressed in the institution’s full policy, which can be found here: https://www.rarc.wisc.edu/iacuc/acapac/2012-049-v_laboratory_and_teaching_animal_adoption.html

To be eligible for adoption, animals must no longer be needed by the university for research or teaching. Animals must also be healthy and must have a suitable temperament and long-term health status to be a pet, as determined by university research animal veterinary staff.

UW–Madison policy does not permit adoption of nonhuman primates. With few exceptions, this is primarily because the animals continue to be needed for research. The national primate centers funded by the National Institutes of Health maintain stable animal colonies that are studied across the lifespan. Health research at these centers includes studies of aging and diseases associated with age, such as Alzheimer’s disease and cognitive decline. Thus, older animals contribute to scientific studies.

The centers also maintain valuable tissues and cells from animals that are humanely euthanized. Those tissues are critical to a wide range of scientific studies and are shared with scientists around the world. This helps answer important scientific questions about human and animal health, but also likely reduces — through collaboration and sharing — the overall number of non-human primates in research.

UW–Madison may consider retirement of non-human primates only in the event they are no longer needed for research, only if the facilities receiving them can assure high-quality care, and only to facilities with a demonstrated ability to protect the animal’s wellbeing and health by providing stable care over the course of its lifetime. Any such facilities would necessarily be subject to regulation and monitoring by the United States Department of Agriculture on a permanent basis.

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• Animal Model Exp Med
• v.1(2); 2018 Jun

Environmental enrichment and mouse models: Current perspectives

Kathryn bayne.

1 AAALAC International, Frederick, MD, USA

The provision of environmental enrichment to numerous species of laboratory animals is generally considered routine husbandry. However, mouse enrichment has proven to be very complex due to the often contradictory outcomes (animal health and welfare, variability in scientific data, etc.) associated with strain, age of the animal when enrichment is provided, gender of the animal, scientific use of the animal, and other housing attributes. While this has led to some suggesting that mice should not be provided enrichment, more recently opinion is trending toward acknowledging that enrichment actually normalizes the animal and data obtained from a mouse living in a barren environment are likely not to be representative or even reliable. This article offers an overview of the types of impact enrichment can have on various strains of mice and demonstrates that enrichment not only has a role in mouse husbandry, but also can lead to new areas of scientific enquiry in a number of different fields.

1. INTRODUCTION

The laboratory mouse is a ubiquitously used research subject whose genetics, anatomy, physiology, immunology, and behavior have been studied in detail for generations. Thus, it would seem that providing a housing environment that is species‐appropriate would be a simple matter. However, it would be a serious mistake to approach mouse enrichment as a one‐size‐fits‐all husbandry procedure. The laboratory mouse is still considered behaviorally similar to wild mice in many dimensions 1 (p150) , though it differs somewhat from the wild‐type ancestor in its behavior, with running behavior and open‐field freezing behavior, and a general higher level of activity more evident in wild‐type mice than the laboratory bred animals. 2 Over decades of purposeful breeding, a variety of characteristics (eg, ease of handling) were either deliberately or inadvertently introduced into the behavior profile of the laboratory mouse. Today, the increasing trend in the use of transgenic mice has only amplified the diversity of traits being bred for, and thus, the potential exists for both extant and subtle differences in mouse behavior and their response to their environment.

The behavioral breadth of the species may help to account for the fact that the literature is replete with contradictory findings and diverse conclusions about the potential benefits and unexpected consequences from providing enrichment to laboratory mice. Indeed, an argument has been made that enriched animals produce different results; enrichment may increase between‐subject variability; and enrichment may reduce replicability across laboratories. 3 (p47‐48) A simple response to these arguments could be that animals should not be provided enrichment. But, a counter‐argument has been made that, as expected, the enriched animal model is different in many ways from the animal model living in a barren environment. 3 (p47) Indeed, it is not logical to accept the notion that animals that are stressed due to environmental inadequacies are, in fact, a better research model, especially considering the fact that the normal state of the animal (and the human for which it is serving as a model) live in complex, stimulating environments. Given this, she suggests that the external validity of research animals living in minimalistic environments may not be as robust as is assumed.

Contradictions in results in the enrichment literature clearly signal both inadequate objective information regarding the (possibly changing) behavior of the mice we use in research and the need for additional basic studies to better characterize the animal model as its genome is modified. The reality is that mouse enrichment programs are complex; must be thoroughly researched; and the enrichment should be implemented based on input from the investigator, the veterinarian and husbandry personnel.

2. IMPLEMENTING ENVIRONMENTAL ENRICHMENT

2.1. the goal of enrichment.

Environmental enrichment has been variously defined, but generally includes the goal of improving the welfare of the animal through the thoughtful inclusion of social and nonsocial features to the cage environment. More than 10 years ago, enrichment was described as “any modification in the environment of the captive animals that seeks to enhance its physical and psychological well‐being by providing stimuli meeting the animals' species‐specific needs”. 4 More recently, the aim of enrichment has been described as a method “to enhance animal well‐being by providing animals with sensory and motor stimulation, through structures and resources that facilitate the expression of species‐typical behaviors and promote psychological well‐being through physical exercise, manipulative activities and cognitive challenges according to species‐specific characteristics”. 5 In some cases, the objective of enrichment is to increase the expression of certain behaviors while in other cases, reduction of specific behaviors is intended. For example, reduction in the expression of stereotypic behaviors may be a goal which is achieved by providing resources such as a shelter. 6 In all instances, the provision of enrichment should not negatively impact the health and safety of the animal.

There are several general characteristics of nonsocial enrichments that are desirable and may drive the selection process among enrichment choices. Primary among these is that ideally there should be demonstrated value derived from the enrichment technique in enhancing the welfare of the animal. 7 Optimally, this evidence should be contained in the peer‐reviewed literature and the results of the published data should be able to be extrapolated to the specific context of the institution considering implementing that type of enrichment. It is worthy to note that enrichment is typically intended to improve animal welfare over some established baseline. Often, the wild counterpart of the laboratory animal is held up as the standard for comparison. However, this comparison may be flawed due to the significant changes that have occurred in the laboratory mouse following generations of targeted breeding.

One reasonable approach is to base welfare assessments on a composite of types of mice that evidence similar behaviors, responses to experimental challenges, or fragility. In this manner, groupings of strains or lines of mice would be made and common approaches to assessing welfare would be applied. Needless‐to‐say, the success of such a strategy would be dependent on the accuracy of groupings of mice and, of necessity, relies on the availability of information to make these judgments. In some circumstances, behavioral phenotyping scoring systems facilitate the description of behaviors of transgenic and knockout mice. These systems typically involve analysis of a battery of responses to stimuli and resting activities, 8 as well as physical characteristics (eg, bald patches). This tool may aid in the grouping of mice for determination of when an animal differs from its prototype, which could be an indicator of altered welfare. In the absence of an obvious metric for assessing the welfare of the diverse range of mice used in research, there may be an inclination to rely on the wild‐type mouse or on an inappropriate laboratory strain or line as the basis for comparison. While progress has been made in identifying pain and distress in mice (eg, the mouse grimace scale, 9 changes in activity 10 as well as changes in behaviors such as flinching, writhing, rear leg lift, and press 11 ), strain differences continue to plague making some of these strategies broadly utilitarian, and the value of systems based primarily on behavior change for animals in a prolonged state of compromised welfare (eg, chronic pain) has not been determined. 12

2.2. Common types of mouse enrichment

2.2.1. nests.

Nesting behavior appears to be an activity that is well preserved from wild‐type progenitor mice. 1 (p150) The provision of nesting material to caged mice has received widespread support because there appears to be a strong motivation for individual mice to build nests (even among nonbreeding mice), it can enhance pup survivability, it is a behavior that is commonly performed by numerous strains of mice, and it offers the opportunity for mice to better thermoregulate in their environment. 13 , 14 Numerous studies have assessed the relative merits of different kinds of nesting material, including commercially available Nestlets™, paper strips, tissue or paper towel, cotton string, wood wool, and wood shavings. The value of the nesting material to the mouse has also been critically evaluated, using the complexity or architecture of the nest as a metric for the quality of the nesting material provided 15 , 16 (p29) or the mouse's willingness to work to access nesting material. 17 Some kinds of nesting material (eg, corn husks) reduce aggressive behavior in a line of BALB/c mice, as indicated by reduced wounding of the animals, 18 possibly due to the availability of areas to escape from aggressive animals. Clearly, the type of nesting material impacts this welfare benefit, as aggression was decreased in 7‐week‐old male BALB/c mice provided tissue torn in strips 19 (p71) , though intracage fighting was not reduced by providing wood wool as nesting material to BALB/c and C57BL/6J mice 20 and actually increased fighting in NIH/S male mice. 21 Yet, there is evidence that some strains of mice, such as BALB/c and CD‐1 mice, show reduced signs of stress, to include lower urine corticosterone levels and heavier thymuses, if they are provided nesting material and if the nest is transferred during cage cleaning procedures. 22 Although there are contradictions in the literature regarding optimal nesting material (eg, paper strips 16 vs tissue or paper towel 23 ), an important consideration is the planned use of the mice. For example, a tissue nesting material can be a confounding variable for studies of allergic asthma in BALB/c mice, resulting in increased total cell number, eosinophil number, and IL‐13 concentration in bronchoalveolar lavage fluid as compared with nonenriched control animals. 24 Cautions have been made regarding some types of nesting material that can entangle the limbs of pups. 25 More recently, the provision of a nest‐building material is considered an important element of the mouse's cage environment. 16 (p26) The manifestation of nest‐building behavior by mice is considered a reliable indicator of health and welfare, with its absence reflecting pain or discomfort in the mice. 26

2.2.2. Nest boxes/Shelters

As a prey species, wild‐type mice will attempt to flee and hide from predators and it may be that laboratory mice retain this fear response behavior. For example, laboratory mice may exhibit aggression to handlers if startled or fearful, and thus the provision of shelters has been suggested to reduce the mouse's fear response. 27 The inclusion of shelters or nest boxes has been evaluated as a single enrichment and in association with other enrichments (eg, nesting material, running wheels). As has been demonstrated by investigations into other forms of enrichment, varying results have been obtained on the merits of providing shelters, depending on the strain of mouse, whether nesting material was also present, the number of openings in the nest box, and the material from which the nest box or shelter was constructed (eg, metal, plastic, wood, paper product). In fact, the material of which the nest box is constructed has been proposed as a significant factor in preferences expressed by mice. 28

In some cases, the shelter provided is a tube (perforated along the sides of the tube or nonperforated), while in others it is designed to function more specifically for nesting. Partitioning the cage space up with structures like shelters allows mice to separate areas for feeding, resting, and urination/defecation, thereby aiding mice in controlling their environment, such as exposure to illumination. 29 The location of a tube‐shaped shelter within the cage may vary, being situated either directly on the cage floor or suspended from the cage wall. Indeed, the location of the nest box has been shown to be important in individually ventilated cages, with nest boxes placed on the floor preferred by female Crl:CD1 (ICR) mice, the majority of whom also moved the nest box toward the front of the cage, under the food hopper. 30 Proposed reasons for this strong trend included the reduced ventilation exposure and/or reduced illumination exposure for mice if the nest box was moved under the feeder. But, there are strain‐dependent responses to tubes, as individually housed male TO mice do not use a tube for sleeping if sawdust is made available as bedding in the cage. Rather, these mice used the tube for refuge and as a latrine. 31

Recently, it has been shown that the number of days of survival of Tabby jimpy mice was increased in those animals provided a nest box constructed of paper boxes. 32 These animals also had a higher weaning rate, had a statistically significant higher weaning weight, and developed few abnormal jumping behaviors. This type of nest box allowed the dams to create additional holes and to use the shredded paper as a component in their nest‐building activity. Male BALB/c mice also had increased longevity if they had access to a shelter. 33 However, it should be noted that for some strains of mice, inclusion of a nest box or shelter has been implicated with increased aggression levels in animals 19 (p74) , though this is not always the case. 34 (p367) Yet, mice living in cages containing a nest box, nesting material, chew blocks, and a running wheel consumed less of the anxiolytic agent than mice in standard cages and spent less time performing bar‐related behaviors and bar‐circling stereotypies. 35

3. EFFECTS OF ENRICHMENT

3.1. effects on the animals.

One of the challenges associated with cataloguing the effects of environmental enrichment on mice is that reports of effects from studies using “enrichment” may be confounded by the fact that the items provided in the cage to increase structural complexity were not objects that actually enhanced the welfare of the animals. Clearly, semantics play a role in this problem as any addition to the cage environment seems to be automatically labeled as an enrichment, whether the definition of enrichment is achieved or not. Many preconceived notions about the benefits of certain cage structures must be discarded as evidence mounts regarding their value as true enrichments. Further complicating the picture is the variability among strains of mice in terms of responses to enrichment items or structural additions to the cage environment. For example, the number of litters produced by female mice living in enriched or standard housing can vary due to the presence of enrichment. 1 (p157) In these studies, the enriched cages included a ladder and jar with nesting material, while the standard cage had bedding. BALB/c and Swiss Webster females produced significantly fewer litters ( P  < .001) and had fewer pups per litter when housed in the enriched cage as compared to the standard cage. However, CB17‐Prkdc scid , B6D2F2, and ICR mice did not show any difference in number of litters or pups per litter when housed in standard or enriched cages. There are also striking gender‐dependent immunological differences in BALB/c and Swiss Webster mice. Specifically, females of these 2 strains (but not males) demonstrated significantly lower levels of thymocytes when living in an enriched cage as compared to the standard cage. In addition, the age at which the mouse is exposed to the enrichment and the duration of exposure may influence the effect on the animal. 36 , 37 (p95)

An understanding of the effects of providing an enriched or stimulating environment to rodents has roots in studies done with rats and assessing effects of handling and maze training on brain chemistry and anatomy. 38 Since then, the body of information regarding the influence of cage complexities on the mouse has grown considerably and new findings continue to be published. These findings can generally be categorized into effects on the behavior or biology of the animals, often described in the context of changes in a specific animal model.

3.1.1. Behavior

The standard cage provides limited scope for the expression of species‐appropriate behaviors in the laboratory mouse. Therefore, it is not unexpected that the addition of complexities to the cage environment evokes a change in behavior. It has been theorized that exposure to enriched environments early in the postweaning period may offset the expression of some abnormal behaviors, such as stereotypy, in animals subsequently housed in more limited environments, 39 though minimal effects were observed in mice provided an enriched cage preweaning on adult behavior. 37 (p95) General activity level, which in some studies is dissected into the more specific behaviors of exploration and locomotion, as well as sleep, stress or anxiety related behaviors (sometimes referred to as emotionality), social behaviors, appetitive behavior, and grooming are among the parameters evaluated when one or more objects is introduced to the cage environment. Results vary among strains, gender, and type of object(s) introduced. The data converge in demonstrating increased activity, frequently expressed as exploratory behavior in the home cage, 40 but an inhibition of exploration in experimental settings, with some gender differences, such as an open‐field test or elevated T‐maze; 41 , 42 , 43 increased aggression between animals with many types of enrichment 19 , 44 (p74) , though not in the ABG inbred strain which is known to be very docile; 45 and often a reduction in time spent sleeping. 46

3.1.2. Neurological effects

Morphological changes to the brain are perhaps among the most well‐known effect of enrichment on rodents. The brain evinces numerous responses to environmental complexity. 47 Typically, greater cerebral weight and length, as well as increased cortical depth, are measured in rodents living in an enriched environment. 48 , 49 Recently, the specific regions of the rodent brain affected by living in an enriched environment have been determined. In the hippocampus, CA1 and dentate gyrus cells were affected; however, changes were not observed in layer V pyramidal neurons of the cerebral cortex or in the spiny neurons in the striatum. 50 (p57) When the histological changes in the brains of rats provided with social and inanimate enrichments have been compared with rats that are socially housed without inanimate enrichments, the number of oligodendrocytes and astrocytes in the occipital cortex have reflected an increase in the former group. With rats that were handled daily, only the number of astrocytes increased. 51

Increases in dendritic spines and branching, synaptic connections, and neural cell size have long been recognized to result from enriching the environment of rodents. 52 , 53 Initially, these effects on brain morphology cannot be attributed to the enriching effects of social housing, but rather appear to be related to the presence of the inanimate enrichments 54 , 55 and, more specifically, to direct contact with the inanimate enrichments. 56 Although enriched mice move longer distances and spend more time in the center of an open‐field testing apparatus, 57 increased activity associated with exercise (eg, a running wheel) and exploration may not be responsible for the histological changes in the brain. 50 (p57)

An examination of gene expression in the brain, relative to the availability of enrichment items in the home cage, reveals that enrichment affects the expression of several genes that regulate neuronal structure, synaptic signaling, and brain plasticity 58 which have a role in learning, memory, and age‐related memory deficits through upregulation of certain neural proteins. In fact, the transgenic R6/1 and R6/2 mice, which are used to model Huntington's disease—a genetic disorder that results in motor dysfunction, dementia, and death—exhibit less decline in select motor function tasks and delayed loss of cerebral volume in those transgenic mice living in an environment that includes both social and inanimate enrichment. 59 , 60 (p238) Similarly, female mutant mice used to study Rett syndrome had enhanced motor skills and learned tasks at the same level as normal mice if they lived in an enriched environment. 61 These effects were correlated with upregulated brain‐derived neurotrophic factor (BDNF) in the female mice (though not the males). Increased striatal expression of BDNF, along with an increase in striatal levels of delta‐Fos B and a decrease in striatal levels of the dopamine transporter, also results in increased resistance to the neurotoxic effects of MPTP in mice. 62 Housing Alzheimer's disease transgenic mice in an enriched environment results in significantly reduced levels of amyloid deposition and cerebral β‐amyloid peptides, two hallmarks of the disease in human patients and the mouse model. 63 This has been attributed to increased activity of a β‐amyloid degrading endopeptide, neprilysin which is elevated in the brains of enriched mice. Other effects on the nervous system have been observed after an exposure of 10 days duration of enrichment to 16‐week‐old C57BL/6 mice that had streptozotocin‐induced diabetes. The enrichment exposure resulted in neural cell proliferation, differentiation, and retention; vascularization of the dentate gyrus; and enhanced dendritic complexity of hippocampal neurons. 64 Recent evidence suggests that the mode of action for enrichment on slowing the course of the disease is mediated through reducing protein deficits in the brain, 65 because nonenriched mice have significant decreases in BDNF as well as reductions in dopamine levels. Not only is BDNF higher in the brains of enriched animals, but so too are nerve growth factor and neurotophin‐3 proteins. 66 It has been proposed that standardization of housing conditions should be considered in therapeutic trials. 60 (p235) However, the survivability of R6/2 mice was improved whey they were used in behavioral testing as a means of providing enrichment (rather than housing them in enriched cages). 67 So, it appears that there are a number of potential confounding variables, some of which may not have even been identified to date, that can alter the course of experimentally induced or modeled disease research.

In rodents, a septal lesion produces a phenomenon known as septal rage, which is characterized by hyperemotionality and aggressiveness by the rodents. Enriched mice have been shown to be less “reactive” than nonenriched mice, and mice living first in an enriched environment and later transferred to the nonenriched environment showed an immediate increase in reactivity. 68 Thus, it appears that enrichment may also modulate the emotionality of some mice.

A discussion of possible neurological changes would not be complete without mentioning the effects of enrichment on memory and learning because these effects reflect a functional change that can occur in rodent brains concomitant to the anatomical changes already described. Learning rate is enhanced across a variety of tests in enriched BXSB mice, with and without ectopic cell clusters in the neocortex. 69 Additionally, spatial memory is positively affected by an enriched environment, 70 , 71 even when the enrichment is provided to the animals when they are adults. 72 For example, mice living in enriched cages exhibited faster and better learning and search strategies in a water maze. 73 The effect on memory in the mouse model of post‐traumatic stress disorder is complex, 74 but appears to contribute to retention of the memory when a situational reminder of the trauma was sufficiently long (ie, 10 minutes), but had no effect when the situational reminder was shorter (ie, 1 minute). Although the precise mechanism of the memory enhancement has not been identified fully, recent evidence suggests that enrichment affects cAMP‐dependent protein kinase long‐term potentiation in the hippocampus. 75 Huang and colleagues have demonstrated that Neurogranin (Ng +/+ and Ng +/− ) mice show enhanced long‐term potentiation in the hippocampus and performed significantly better in a Morris water maze as compared to controls, though Ng −/− mice did not. 76 In addition, Ng +/− mice showed improved performance in a radial maze test. The authors suggest that enrichment causes a significant increase in hippocampal Ng levels. More recent research has demonstrated that an enriched environment may result in enhancing memory by accelerating the activity of the medial prefrontal cortex, which has a role in processing spatial memories, and results in the recruitment of additional cortical areas into the network sustaining spatial memories. 77

3.1.3. Organ weights

Organ weights also appear to be influenced by the presence of environmental enrichment in the cage, for example, the heart, liver, kidney, adrenal, spleen, and uterus of three inbred strains of mice (BALB/c, C57BL/6, and A/J) living in enriched and nonenriched cages. 78 (p415) In comparisons with control animals, they found that the weights of the spleen from enriched animals were slightly, but not significantly, increased; and the weights of the adrenal from enriched animals were slightly, but not significantly, decreased. However, no significant differences in the organ weights (kidneys, liver, heart, spleen, testes, prostrate, adrenals, thyroid and parathyroids, pituitary, and brain) were observed in CD‐1 mice provided a gauze pad in the cage as an enrichment compared with mice without a pad or in male Swiss albino mice provided a nest box and cotton. 79 , 80 Similarly, no increase in organ weights was detected in C57BL/6JIcoU or BALB/cAnCrRyCpbRivU mice enriched with objects or enriched with nesting material. 81 A more recent study of B6C3F1/N mice further confirmed no significant increase in organ weights (liver, spleen, thymus, adrenal glands, lung, kidneys, and gastrointestinal tract) of either male or female mice when they were provided with nesting material (Crink‐l'Nest TM ). 82

3.1.4. Physiological changes

The cardiovascular system and hematology of mice from enriched and nonenriched environments have also been assessed. A nonsignificant decrease in red blood cell count and hematocrit and a nonsignificant increase in hemoglobin has been recorded in enriched mice (BALB/c, C57BL/6, and A/J) compared with nonenriched controls. 78 (p414) This same study also demonstrated a nonsignificant increase in the level of white blood cells in enriched C57BL/6 and A/J mice, but not in enriched BALB/c mice.

The mechanism for wound repair and lifespan extension in a mouse model with colon cancer has been elucidated. 83 Mice with a Tcf4 Het/+ ‐ and Apc Min/+ ‐mediated colon tumorigenesis that were provided environmental enrichment had improved survival by eliciting a wound repair process (revascularization, plasma cell recruitment and IgA secretion, replacement of glandular tumor tissue with pericytes, and normalizing the microbiota). Male mice had reduced expression of circulating inflammatory cytokines and induced nuclear hormone receptor signaling, which are related to wound healing.

The effect of enrichment in the environment has been measured for several other physiological parameters. Higher levels of testosterone and immunoglobulin G levels have been detected in enriched mice compared with control animals, although there is some strain variability in these findings. 34 (p370) However, no difference in corticosterone (or thyroxine) levels was observed in enriched vs nonenriched DBA/2 mice. 84 Enrichment items are not the only environmental factors that have the potential to influence the physiology of a mouse. For example, the depth and type of bedding placed in the cage influence body temperature. 85 (p64) Mice housed in deep wood bedding were noted to have a significantly higher temperature than comparable mice housed on a layer of beta chips or thin wood bedding, although this difference was time dependent because it was observed only during the daylight hours. Such a difference in body temperature based on bedding depth and type would be of concern in toxicological studies in which determination of the endpoint is based in part on the animal's body temperature. 85 (p67)

3.1.5. Effects on cancer development

A pattern has been observed over the last several years that environmental enrichment negatively impacts several types of cancer growth. These findings are yielding new avenues of exploration for cancer treatment. One pathway for this beneficial effect is proposed to be upregulation of hypothalamic BDNF which, in turn, downregulates leptin production in adipocytes via sympathoneural β‐adrenergic signaling. 86 They have demonstrated that mice living in enriched environments have reduced susceptibility to melanoma and colon cancer. The activation of the hypothalamic–sympathoneural–adipocyte (HSA) axis is influenced by environmental enrichment, perhaps in part due to the reduction in serum leptin levels following exposure to environmental enrichment. This same effect has been demonstrated using a mouse model of breast cancer. 87 Specifically, enrichment delayed onset of the cancer through a reduction in leptin levels. Enrichment consisting of inanimate objects, social stimulation and exercise was found to inhibit pancreatic cancer growth in both subcutaneous and orthotopic models. 88 (p3) The same impact on BDNF was observed as had been reported by other laboratories, and it was observed that enrichment induced differential expression (downregulated) of genes, mostly located in the mitochondria of the tumors. Inhibition of mitochondrial metabolic genes may promote cancer cell death. 88 (p5) A third potential pathway for cancer development has been illuminated. They demonstrated that C57BL/6 mice housed in an enriched environment that received transplanted murine or human glioma cells had reduced tumor volume and longer survival time, as well as increased resistance to developing the tumor. 89 (p7) Indeed, interleukin‐15 (which increases natural killer cell activity) and BDNF are key to this effect because levels are increased in the brains of enriched mice and they have a tumor‐reducing effect. 89 (p3,5)

3.2. Is enrichment beneficial or a confounding variable?

The scientific literature provides abundant evidence that the welfare of laboratory mice may be seriously impaired by housing them in barren standard laboratory cages, and their welfare may be improved significantly by providing adequate environmental enrichment. Signs of poor welfare in barren standard cages include abnormal behaviors such as stereotypies (eg, bar‐mouthing, jumping, circling) and compulsive behaviors such as barbering, elevated stress hormone levels, fearful and anxiety‐like behavior, anhedonia and impaired thermoregulation. Attenuating these adverse effects through appropriate environmental enrichment is likely to improve not only the animals' well‐being, but also the scientific validity of a wide range of experiments conducted with them. 90 Abnormal behavior, stress, fear and anxiety, and impaired thermoregulation are all confounding variables that may adversely affect the outcome of animal experiments and potentially also increase variation in the data. It therefore appears that providing suitable enrichment is in the best interest of both the animals and the research conducted with them, supporting Trevor Poole's famous quote that only “happy animals make good science”. 91

Nevertheless, environmental enrichment is still far from being a standard husbandry procedure in most mouse facilities. Ironically, one reason for this reluctance is the concern that environmental enrichment itself could be a confounding variable which adversely affects the scientific validity of animal experiments. In particular, it has been argued that environmental enrichment might disrupt environmental standardization in ways that are detrimental to the precision and reproducibility of results from animal experiments. 92 If true, this would mean that environmental enrichment creates a conflict between the welfare of the animals and the validity of the research, and that the benefits of enrichment in terms of better animal welfare need to be measured against its costs in terms of poorer scientific validity to achieve an optimal compromise. However, this perspective is likely a result of the ambiguity of the term “enrichment”, which has been defined in diverse—and sometimes inaccurate—ways. The key is to provide “beneficial” enrichment to the animals, distinguishing these as species‐relevant approaches that improve welfare, rather than simply putting any item into a cage and referring to it as “enrichment”. Indeed, these latter items can be referred to as “pseudo‐enrichments”. 93 Based on an evaluation of multiple laboratories to assess the effect of enrichment on variation in behavioral endpoints and reproducibility of behavioral differences in three strains of mice, it has been determined that within group variability contributed an average of 60% of total variability and was unaffected by enrichment. 94 Thus, nonenriched cage environments fail to reduce individual variability in behavioral endpoints.

4. CONCLUSIONS

The scientific evidence overwhelmingly supports the use of enrichment to improve the welfare of mice used in research. However, the type of enrichment used must be biologically relevant, safe for the animal, improve the animal's welfare, and not interfere with the scientific measures taken from the animals. When these criteria are met, the data produced by the animal will be more valid and reliable. Of note, use of environmental enrichment has led to new areas of scientific enquiry.

CONFLICT OF INTEREST

Bayne K. Environmental enrichment and mouse models: Current perspectives . Animal Model Exp Med . 2018; 1 :82‐90. 10.1002/ame2.12015 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]