GUIDELINES FOR THE CARE AND USE OF MAMMALS IN NEUROSCIENCE AND BEHAVIORAL RESEARCH

Committee on Guidelines for the Use of Animals in Neuroscience and Behavioral Research

Institute for Laboratory Animal Research

Division on Earth and Lifes Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C. www.nap.edu



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GUIDELINES FOR THE CARE AND USE OF MAMMALS IN NEUROSCIENCE AND BEHAVIORAL RESEARCH Committee on Guidelines for the Use of Animals in Neuroscience and Behavioral Research Institute for Laboratory Animal Research Division on Earth and Lifes Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract/Grant No. N01-OD-4-2139 Task Order 90 between the National Academy of Sciences and the National Institutes of Health. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Library of Congress Cataloging-in-Publication Data Guidelines for the care and use of mammals in neuroscience and behavioral research / Committee on Guidelines for the Use of Animals in Neuroscience and Behavioral Research. p. cm. ISBN 0-309-08903-4 (pbk.) — ISBN 0-309-50587-9 (PDF) 1. Neurosciences—Research—Methodology. 2. Laboratory animals. I. Institute for Laboratory Animal Research (U.S.). Committee on Guildelines for the Use of Animals in Neuroscience and Behavioral Research. II. National Academies Press (U.S.) RC337.G85 2003 616.8’0427—dc21 2003011672 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20001; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu Copyright 2003 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON GUIDELINES FOR THE USE OF ANIMALS IN NEUROSCIENCE AND BEHAVIORAL RESEARCH Richard C. Van Sluyters (Chair), University of California, Berkeley, School of Optometry, Berkeley, California Michael Ballinger, Abbott Laboratories, Comparative Medicine, Abbott Park, Illinois Kathryn Bayne, Association for Assessment and Accreditation of Laboratory Animal Care International, Rockville, Maryland Christopher Cunningham, Oregon Health & Science University, Department of Behavioral Neuroscience, Portland, Oregon Anne-Dominique Degryse, Centre de Recherche Pierre Fabre, Laboratory Animal Resources, France Ronald Dubner, University of Maryland Dental School, Department of Oral & Craniofacial Biological Sciences, Baltimore, Maryland Hugh Evans, New York University School of Medicine, Nelson Institute of Environmental Medicine, Tuxedo, New York Martha Johnson Gdowski, University of Rochester, Department of Neurobiology and Anatomy, Rochester, New York Robert Knight, University of California, Berkeley, Department of Psychology, Helen Wills Neuroscience Institute, Berkeley, California Joy Mench, University of California, Davis, Department of Animal Science, Davis, California Randy J. Nelson, Ohio State University, Department of Psychology and Neuroscience, Columbus, Ohio Christine Parks, University of Wisconsin, Madison, Research Animal Research Center, Madison, Wisconsin Barry Stein, Wake Forest University, Department of Neurobiology & Anatomy, Winston-Salem, North Carolina Linda Toth, Southern Illinois University School of Medicine, Division of Laboratory Animal Medicine, Springfield, Illinois Stuart Zola, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia Consultants Terrie Cunliffe-Beamer, Genetics Institute, Andover, Massachusetts Peggy Danneman, The Jackson Laboratory, Bar Harbor, Maine Timothy Mandrell, University of Tennessee, Department of Comparative Medicine, Memphis, Tennessee Randall J. Nelson, University of Tennessee, Department of Anatomy and Neurobiology, Memphis, Tennessee Staff Jennifer Obernier, Study Director Kathleen Beil, Administrative Assistant Marsha Barrett, Project Assistant Norman Grossblatt, Senior Editor

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INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL Peter A. Ward (Chair), University of Michigan Medical School, Department of Pathology, Ann Arbor, Michigan Stephen W. Barthold, University of California, Davis, Center for Comparative Medicine, Davis, California Rosemary W. Elliott, Roswell Park Cancer Institute, Department of Molecular and Cellular Biology, Buffalo, New York Michael F. Festing, University of Leicester, MRC Toxicology Unit, Leicester, United Kingdom Janet C. Gonder, Pinehurst, North Carolina Coenraad F.M. Hendriksen, National Institute of Public Health and the Environment, Central Animal Laboratories, Bilthoven, Netherlands Jay R. Kaplan, Wake Forest University School of Medicine, Department of Comparative Medicine, Winston-Salem, North Carolina Hilton J. Klein, Merck Research Laboratories, Department of Laboratory Animal Resources, West Point, Pennsylvania William Morton, University of Washington, National Primate Research Center, Seattle, Washington Randall J. Nelson, University of Tennessee, Department of Anatomy and Neurobiology, Memphis, Tennessee Emilie F. Rissman, University of Virginia, Department of Biochemistry and Molecular Genetics, Charlottesville, Virginia Lilly-Marlene Russow, Purdue University, Department of Philosophy, West Lafayette, Indiana William S. Stokes, National Institute of Environmental Health Sciences, Environmental Toxicology Program, Research Triangle Park, North Carolina Michael K. Stoskopf, North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina Thomas Wolfle, Cambridge, Maryland Staff Joanne Zurlo, Director Marsha Barrett, Project Assistant Kathleen Beil, Administrative Assistant Ralph Dell, Associate Director Jennifer Obernier, Study Director Susan Vaupel, Editor of ILAR Journal

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Preface Thirteen years ago, a group of 30 some neuroscientists, laboratory-animal veterinarians, and institutional animal care and use committee (IACUC) members gathered at the National Institutes of Health (NIH) in Bethesda, MD, for a workshop sponsored by the National Eye Institute (NEI). The group’s purpose was to draft a set of guidelines to help in the preparation and review of protocols for the use of animals in neuroscience. The result was a 45-page report titled Preparation and Maintenance of Higher Mammals During Neuroscience Experiments. Published by NIH in 1991, the booklet ultimately went through three printings, and NEI distributed over 30,000 copies to IACUCs, veterinarians, and neuroscientists throughout the world. The Red Book, as it came to be known for its bright red cover, was far more successful than any of the participants in that original workshop ever dreamt it would be. In the years since the Red Book first appeared, neuroscience research has changed in a number of significant ways. To begin with, it has grown phenomenally. Attendance at the 1989 annual meeting of The Society for Neuroscience was 13,767. By 2001, it had more than doubled to 28,774. Neuroscience institutes, centers, and departments have sprung up in virtually every major research university. The number of students and faculty engaged in neuroscience research is at an all-time high, as is the number of animals that the researchers use in their studies of the nervous system. Like other fields of biomedical research, neuroscience has embraced the use of transgenic methods; as a result, the number of rodents, especially mice, used in biomedical research has increased enormously. With the advent of modern brain-imaging techniques and advances in operant-

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conditioning methods used to study nonhuman primates, the use of animals in studies of cognitive brain function has risen dramatically. As a result, a number of institutions have formed cognitive-neuroscience centers, where researchers conduct experiments with both human and animal subjects in a two-pronged effort to unravel some of the brain’s more complex functions. Against that backdrop of growth in neuroscience research, the regulatory environment of the use of animals in research has also changed since 1991. The Animal Welfare Act continues to be refined as new policies and regulations are promulgated. In 1996, the National Research Council published the sixth revision of the Guide for the Care and Use of Laboratory Animals, a primary source of animal care and use guidance for researchers, veterinarians, and IACUCs. Compliance with the Guide is mandated by the Public Health Service as a prerequisite for receiving support from the NIH. The Guide is also the standard used by the Association for Assessment and Accreditation of Laboratory Animal Care International to accredit more than 650 animal care and use programs worldwide. The 1996 revision of the Guide reiterates the requirement to use professional judgment, as opposed to rigid engineering standards, in the application of many of its recommendations. The extent to which the Guide relies on professional judgment has substantially increased, as has the expectation that institutions will develop and use performance-based standards to monitor situations in which professional judgment has an impact on animal welfare. The task of the Committee on Guidelines for the Use of Animals in Neuroscience and Behavioral Research was to revise and update the guidance provided by the 1991 Red Book and provide information on best use practices for all mammalian species in neuroscience research, not just the “higher mammals” discussed in the 1991 Red Book. Thus, this report presents new information on the use of rodents, including transgenic models. Similarly, whereas the 1991 Red Book offered only a limited discussion of behavioral techniques, this volume includes an extensive coverage of the use of behavioral methods to study brain function. Specifically, the committee was asked to: (1) identify common research themes in contemporary neuroscience and behavioral research based on input from neuroscience and behavioral researchers most familiar with current standards of practice and veterinarian specialists in laboratory animal medicine; (2) exercise collective, professional judgment in applying current animal care and best use practices to procedures in these areas of research; (3) obtain information about new scientific and responsible use developments used to maintain animals during these experiments; (4) prepare a report to serve as an informational resource to assist researchers, laboratory animal medicine veterinarians, and IACUC members in the interpretation and implementation of current standards of practice and promote the training of animal care specialists in this area. This report, like its predecessor, is intended to provide information and guidance to assist researchers, veterinarians, and IACUCs in interpreting and

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applying current animal-welfare laws, regulations, policies, and guidelines. It is not meant to replace the Guide, nor does it seek to establish policy. It also is not intended to reflect a departure in any way from official animal care and use guidelines. Like the Guide, this report starts with the understanding that a researcher has already decided to use animals in neuroscience research. It is designed to help the neuroscientist prepare an animal-use protocol that provides the information needed by the veterinarian and IACUC that will review it. It is also intended to assist veterinarians and IACUCs in meeting their mandated responsibilities to ensure that complex neuroscience animal-use protocols comply with official animal-welfare regulations and guidelines. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Michael Fanselow, University of California, Los Angeles, Department of Psychology, Los Angeles, California Roy Henrickson, Private Consultant, Point Richmond, California Julian Hoff, University of Michigan, Department of Neurosurgery, Ann Arbor, Michigan Neil Lipman, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, Research Animal Resource Center, New York, New York Eric Nestler, University of Texas, Southwestern, Department of Psychiatry, Dallas, Texas Marek Niekrasz, Northwestern University, Center for Comparative Medicine, Chicago, Illinois Gaye Ruble, Aventis, Inc., Laboratory Animal Science and Welfare Department, Bridgewater, New Jersey David Solomon, University of Pennsylvania, Departments of Neurology and Otolaryngology-Head and Neck Surgery, Philadelphia, Pennsylvania Charles Vorhees, Children’s Hospital Research Foundation, Division of Developmental Biology, Cincinnati, Ohio Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recom-

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mendations nor did they see the final draft of the report before its release. The review of this report was overseen by: Floyd Bloom, Scripps Research Institute, Department of Neuropharmacology, La Jolla, California Marilyn Brown, Charles River Laboratories, Animal Welfare and Training, East Thetford, Vermont Appointed by the National Research Council, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution. No report of this magnitude could be undertaken without the cooperation and expertise of a group of experts, and in this case a special debt of gratitude is owed to the individuals who participated in the workshop that was held, the consultants to the committee, my fellow committee members, and the ILAR staff. Richard C. Van Sluyters, Chair Committee on Guidelines for the Use of Animals in Neuroscience and Behavioral Research

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Contents INTRODUCTION   1 PART I. GENERAL ANIMAL CARE AND USE PRINCIPLES AND CONSIDERATIONS   5 1   REGULATORY AND ETHICAL CONSIDERATIONS   7     US Animal Welfare Act,   7     Public Health Service Policy on Humane Care and Use of Laboratory Animals,   8     Guide for the Care and Use of Laboratory Animals,   8     US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training,   9     Association for Assessment and Accreditation of Laboratory Animal Care International,   9     The 3 Rs,   10 2   PROTOCOL-DEVELOPMENT STRATEGIES   12     Team Approach and Shared Responsibilities,   12     Pilot Studies,   14     Sample Size,   15     Pain and Distress,   15     Using Animal Behavior to Monitor Animal Health,   23     Humane Endpoints,   24     Euthanasia,   26     Experimental Hazards,   29

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3   GENERAL ANIMAL-CARE CONCERNS   30     Training and Supervision,   30     Monitoring Expected and Unexpected Consequences,   31     Animal Husbandry and Nursing Care,   34     Special Environments and Enclosures and Housing of Multiple Species,   36     Surgery and Procedures,   37     Physical Restraint,   46     Food and Fluid Regulation,   49     Genetically Modified Animals,   61 PART II. APPLICATIONS TO COMMON RESEARCH THEMES IN NEUROSCIENCE AND BEHAVIORAL RESEARCH   69 4   SURVIVAL STUDIES   71     Anatomic Studies,   71     Neurophysiology Studies,   73     Imaging Studies,   83     Stem Cell and Gene-Therapy Studies,   86 5   PROLONGED NONSURVIVAL STUDIES   88 6   STUDIES OF NEURAL INJURY AND DISEASE   94     Disease Models,   94     Lesions,   97     Animal Models Involving Pain,   99 7   PERINATAL STUDIES   102     Development of Pain Perception,   102     Anesthesia and Analgesia,   104     Surgery, Postoperative Monitoring, Cannibalism, and Neglect,   106     Identification, Tagging, Tattooing, and Toe Clipping,   107     Regulatory Considerations in Fetal Surgery,   107     Euthanasia,   108 8   AGENTS AND TREATMENTS   109     Pharmacological and Toxicological Agents,   109     Addictive Agents,   114     Physical Agents,   116     Modification of Dietary Nutrients,   117     Exercise,   118     Sleep Deprivation,   120

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9   BEHAVIORAL STUDIES   123     Use of Appetitive and Aversive Stimuli,   123     Behavioral Screening Tests,   129     Neurophysiologic Recording in Awake Behaving Animals,   137     Mood-Disorder Models,   140     Behavioral Stressors,   142 REFERENCES   150 APPENDIXES   175 A SAMPLE SIZE DETERMINATION   175     Experiments to Test a Formal Hypothesis,   175     Defining the Hypothesis to be Tested,   176     Effect Size, Standard Deviation, Power, and Significance Level,   176     Calculating Sample Size for Single-Group Experiments,   177     Calculating Sample Size for Continuous Variables,   177     Calculating Sample Size for Repeat Studies,   178     Sample Size for Time to an Event,   179 B ESTIMATING ANIMAL NUMBERS   181     Estimating Animal Numbers for Breeding Colonies,   181     Estimating Animal Numbers to Develop an Induced Mutant,   187 C BIOGRAPHICAL SKETCHES OF AUTHORING COMMITTEE   191 INDEX   195

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