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Neuromethods

Series Editor
Wolfgang Walz
University of Saskatchewan
Saskatoon, SK, Canada

For further volumes:

http://www.springer.com/series/7657
 Mood and Anxiety Related
Phenotypes in Mice

Characterization Using Behavioral Tests,

Volume II

Edited by

Todd D. Gould
University of Maryland School of Medicine, Department of Psychiatry, Baltimore, USA
Editor
Todd D. Gould
University of Maryland
School of Medicine
Department of Psychiatry
Baltimore, Maryland, USA
[email protected]

ISSN 0893-2336 e-ISSN 1940-6045

ISBN 978-1-61779-312-7 e-ISBN 978-1-61779-313-4
DOI 10.1007/978-1-61779-313-4
Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2011935540

© Springer Science+Business Media, LLC 2011

All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the
publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA),
except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information
storage and retrieval, electronic adaptation, computer software, or by similar or ­dissimilar methodology now known or
hereafter developed is forbidden.
The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified
as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

Printed on acid-free paper

Humana Press is part of Springer Science+Business Media (www.springer.com)

Preface to the Series

Under the guidance of its founders Alan Boulton and Glen Baker, the Neuromethods series
by Humana Press has been very successful since the first volume appeared in 1985. In about
17 years, 37 volumes have been published. In 2006, Springer Science + Business Media
made a renewed commitment to this series. The new program will focus on methods that
are either unique to the nervous system and excitable cells or which need special consider-
ation to be applied to the neurosciences. The program will strike a balance between recent
and exciting developments like those concerning new animal models of disease, imaging,
in vivo methods, and more established techniques. These include immunocytochemistry
and electrophysiological technologies. New trainees in neurosciences still need a sound
footing in these older methods in order to apply a critical approach to their results. The
careful application of methods is probably the most important step in the process of scien-
tific inquiry. In the past, new methodologies led the way in developing new disciplines in
the biological and medical sciences. For example, Physiology emerged out of Anatomy in
the nineteenth century by harnessing new methods based on the newly discovered phe-
nomenon of electricity. Nowadays, the relationships between disciplines and methods are
more complex. Methods are now widely shared between disciplines and research areas.
New developments in electronic publishing also make it possible for scientists to download
chapters or protocols selectively within a very short time of encountering them. This new
approach has been taken into account in the design of individual volumes and chapters in
this series.

 Wolfgang Walz

v
Preface

Preclinical research related to mood and anxiety disorders relies extensively upon mouse
behavioral tests and models. The use of these approaches continues to increase as a greater
number of underlying susceptibility genes are discovered, new targets for medications are
identified, and clinical studies reveal novel neurobiological risk factors.
The rationale for this second volume is straightforward: to include tests that were not
covered in the first volume. This book is meant, therefore, as a complement to Volume I.
Together, the two volumes offer a comprehensive resource for the behavioral approaches
that are valuable for the characterization of mood and anxiety disorder-related behaviors in
mice, and that are utilized in the development of medications that are effective in their
treatment. The contributing authors are world-renowned scientists with broad experiences
in the development and application of mouse behavioral tasks. Each chapter provides a brief
background and review of the test or model as well as a complete and up-to-date protocol
narrative.
The chapters are primarily intended as a resource for scientists actively pursuing or inter-
ested in establishing behavioral protocols in their laboratories and who have prior experience
with studying rodent behavior. However, it will also serve as a reference for those scientists
and practitioners who seek to better understand the behavioral methods used in preclinical
mood and anxiety research. Though the chapters provide an important resource for refer-
ence material and detailed methods, there are a number of subtleties in mouse husbandry,
handling, and testing procedures that cannot be acquired solely from following a book. It is
therefore strongly encouraged that those with limited experience with rodent behavior seek
collaboration with an experienced behavioral neuroscientist to lend a hand in addressing
experimental and analysis issues that will, without a doubt, arise.

Baltimore, USA Todd D. Gould

vii
Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

1 Longitudinal Assessment of Deliberate Mouse Behavior

in the Home Cage and Attached Environments: Relevance
to Anxiety and Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Martien J. Kas, Ilan Golani, Yoav Benjamini, Ehud Fonio,
and Oliver Stiedl
2 Using Behavioral Patterns Across Species in Mood Disorder Research . . . . . . . . . 21
Jared W. Young and Mark A. Geyer
3 Telemetry in Mice: Applications in Studies of Stress and Anxiety Disorders . . . . . 43
Larry D. Sanford, Linghui Yang, and Laurie L. Wellman
4 Modeling Mouse Anxiety and Sensorimotor Integration:
Neurobehavioral Phenotypes in the Suok Test . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Elisabeth Dow, Valerie Piet, Adam Stewart, Siddharth Gaikwad,
Jonathan Cachat, Peter Hart, Nadine Wu, Evan Kyzar, Eli Utterback,
Alan Newman, Molly Hook, Kathryn Rhymes,
Dillon Carlos, and Allan V. Kalueff
5 Assessment of Social Approach Behavior in Mice . . . . . . . . . . . . . . . . . . . . . . . . . 83
Orsolya J. Kuti and Damon T. Page
6 The Mouse Defense Test Battery: A Model Measuring
Different Facets of Anxiety-Related Behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Guy Griebel and Sandra Beeské
7 Novelty-Suppressed Feeding in the Mouse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Benjamin Adam Samuels and René Hen
8 The Four-Plate Test in Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Martine Hascoët and Michel Bourin
9 The Vogel Punished Drinking Task as a Bioassay
of Anxiety-Like Behavior of Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Alicia A. Walf and Cheryl A. Frye
10 A Vogel Conflict Test Using Food Reinforcement in Mice . . . . . . . . . . . . . . . . . . 159
Jeffrey M. Witkin
11 Fear Conditioning and Extinction as a Model of PTSD in Mice . . . . . . . . . . . . . . 171
Georgette M. Gafford and Kerry J. Ressler
12 The “Cut-Off Behavioral Criteria” Method: Modeling Clinical
Diagnostic Criteria in Animal Studies of PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Hagit Cohen, Michael A. Matar, and Joseph Zohar

ix
x Contents

13 Measuring Variations in Maternal Behavior: Relevance

for Studies of Mood and Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Becca Franks, James P. Curley, and Frances A. Champagne
14 Emotionality-Related Consequences of Early Weaning in Mice and Rats . . . . . . . 225
Takefumi Kikusui
15 Separation-Induced Depression in the Mouse . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Richard E. Brown, Alison L. Martin, and Rhian K. Gunn
16 Induction of Persistent Depressive-Like Behavior by Corticosterone . . . . . . . . . . 251
Shannon L. Gourley and Jane R. Taylor
17 The Olfactory Bulbectomised Mouse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Michelle Roche
18 Differential-Reinforcement-of-Low-Rate Behavior
in Rodents as a Screen for Antidepressant Efficacy . . . . . . . . . . . . . . . . . . . . . . . . 287
Lindsay M. Lueptow and James M. O’Donnell
19 The Intracranial Self-Stimulation Procedure Provides
Quantitative Measures of Brain Reward Function . . . . . . . . . . . . . . . . . . . . . . . . . 307
Astrid K. Stoker and Athina Markou
20 The Female Urine Sniffing Test (FUST) of Reward-Seeking Behavior . . . . . . . . . 333
Oz Malkesman
21 Measuring Impulsive Choice Behaviour in Mice . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Claire L. Dent and Anthony R. Isles
22 Assessment of Male Sexual Behavior in Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Jin Ho Park

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
Contributors

Sandra Beeské • Sanofi-Aventis, Chilly-Mazarin, Paris, France

Yoav Benjamini • Department of Statistics and Operation Research,
Tel Aviv University, Tel-Aviv, Israel
Michel Bourin • Neurobiologie de l’anxiété et de la dépression, Faculté de Médecine,
University of Nantes, Nantes, France
Richard E. Brown • Psychology Department and Neuroscience Institute,
Dalhousie University, Halifax, NS, Canada
Jonathan Cachat • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
Dillon Carlos • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
Frances A. Champagne • Department of Psychology, Columbia University,
New York, NY, USA
Hagit Cohen • Israel Ministry of Health Mental Health Center, Anxiety and Stress
Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev,
Beer-Sheva, Israel
James P. Curley • Department of Psychology, Columbia University, New York,
NY, USA
Claire L. Dent • Behavioural Genetics Group, MRC Centre for Neuropsychiatric
Genetics and Genomics, Neuroscience and Mental Health Research Institute,
Cardiff University, Cardiff, UK
Elisabeth Dow • Department of Neuroscience, Connecticut College, New London,
CT, USA
Ehud Fonio • Department of Neurobiology, Weizmann Institute, Rehovot, Israel
Becca Franks • Department of Psychology, Columbia University, New York, NY, USA
Cheryl A. Frye • Department of Psychology, The University at Albany, SUNY, Albany,
NY, USA; Department of Biological Sciences, The University at Albany, SUNY,
Albany, NY, USA; The Center for Life Sciences Research, The University at Albany,
SUNY, Albany, NY, USA; Department of Life Sciences, The University at Albany,
SUNY, Albany, NY, USA
Georgette M. Gafford • Department of Psychiatry and Behavioral Sciences,
Center for Behavioral Neuroscience, Yerkes National Primate Research Center,
Emory University, Atlanta, GA, USA
Siddharth Gaikwad • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
Mark A. Geyer • Department of Psychiatry, University of California San Diego,
La Jolla, CA, USA
Ilan Golani • Department of Zoology, Tel Aviv University, Tel-Aviv, Israel

xi
xii Contributors

Shannon L. Gourley • Department of Pediatrics, Emory University, Atlanta,

GA, USA
Guy Griebel • Sanofi-Aventis, Chilly-Mazarin, Paris, France
Rhian K. Gunn • Psychology Department and Neuroscience Institute,
Dalhousie University, Halifax, NS, Canada
Martine Hascoët • Neurobiologie de l’anxiété et de la dépression, Faculté de
Médecine, University of Nantes, Nantes, France
Peter Hart • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
René Hen • Departments of Psychiatry and Neuroscience, New York State Psychiatric
Institute, Columbia University, New York, NY, USA
Molly Hook • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
Anthony R. Isles • Behavioural Genetics Group, MRC Centre for Neuropsychiatric
Genetics and Genomics, Neuroscience and Mental Health Research Institute,
Cardiff University, Cardiff, UK; Department of Psychological Medicine
and Neurology, Cardiff University School of Medicine, Cardiff, UK
Allan V. Kalueff • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
Martien J. Kas • Department of Neuroscience and Pharmacology, Rudolf Magnus
Institute of Neuroscience, University Medical Center Utrecht, Utrecht,
The Netherlands
Takefumi Kikusui • Companion Animal Research, Azabu University, Sakamihara,
Kanagawa, Japan
Orsolya J. Kuti • Department of Brain and Cognitive Sciences and Picower Institute
for Learning and Memory, Massachusetts Institute of Technology, Cambridge,
MA, USA; UC Davis School of Veterinary Medicine, Davis, CA, USA
Evan Kyzar • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
Lindsay M. Lueptow • Department of Behavioral Medicine and Psychiatry,
West Virginia University Health Sciences Center, Morgantown, WV, USA
Oz Malkesman • Laboratory of Molecular Pathophysiology, Intramural Research
Program, National Institute of Mental Health, National Institutes of Health,
Bethesda, MD, USA
Athina Markou • Department of Psychiatry, School of Medicine, University of
California San Diego, La Jolla, CA, USA
Alison L. Martin • Psychology Department and Neuroscience Institute,
Dalhousie University, Halifax, NS, Canada
Michael A. Matar • Israel Ministry of Health Mental Health Center, Anxiety and
Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev,
Beer-Sheva, Israel
Alan Newman • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
James M. O’Donnell • Department of Behavioral Medicine and Psychiatry,
West Virginia University Health Sciences Center, Morgantown, WV, USA
 Contributors xiii

Damon T. Page • Department of Brain and Cognitive Sciences and Picower Institute
for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA,
USA; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA
Jin Ho Park • Department of Psychology, University of Massachusetts, Boston, MA, USA
Valerie Piet • Department of Cell Biology and Anatomy, Louisiana State University
Health Sciences Center, New Orleans, LA, USA
Kerry J. Ressler • Department of Psychiatry and Behavioral Sciences,
Center for Behavioral Neuroscience, Yerkes National Primate Research Center,
Emory University, Atlanta, GA, USA
Kathryn Rhymes • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
Michelle Roche • Department of Physiology, School of Medicine, National University
of Ireland, Galway, Ireland
Benjamin Adam Samuels • Departments of Psychiatry and Neuroscience,
New York State Psychiatric Institute, Columbia University, New York, NY, USA
Larry D. Sanford • Department of Pathology and Anatomy, Sleep Research
Laboratory, Eastern Virginia Medical School, Norfolk, VA, USA
Adam Stewart • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
Oliver Stiedl • Center for Neurogenomics and Cognitive Research,
VU University Amsterdam, Amsterdam, The Netherlands
Astrid K. Stoker • Department of Psychiatry, School of Medicine,
University of California San Diego, La Jolla, CA, USA; Department of
Psychopharmacology, Utrecht Institute for Pharmaceutical Sciences,
Utrecht University, Utrecht, The Netherlands
Jane R. Taylor • Division of Molecular Psychiatry, Departments of Psychiatry
and Psychology, Interdepartmental Neuroscience Program, Yale University,
New Haven, CT, USA
Eli Utterback • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
Alicia A. Walf • Department of Life Sciences, The University at Albany, SUNY,
Albany, NY, USA
Laurie L. Wellman • Department of Pathology and Anatomy,
Sleep Research Laboratory, Eastern Virginia Medical School, Norfolk, VA, USA
Jeffrey M. Witkin • Psychiatric Drug Discovery, Neuroscience Discovery Research,
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
Nadine Wu • Department of Pharmacology and Neuroscience Program,
Tulane University Medical School, New Orleans, LA, USA
Linghui Yang • Department of Pathology and Anatomy, Sleep Research Laboratory,
Eastern Virginia Medical School, Norfolk, VA, USA
Jared W. Young • Department of Psychiatry, University of California San Diego,
La Jolla, CA, USA
Joseph Zohar • The Chaim Sheba Medical Center, Sackler Medical School,
Tel-Aviv University, Tel Hashomer, Israel
 Chapter 1

Longitudinal Assessment of Deliberate Mouse Behavior

in the Home Cage and Attached Environments: Relevance
to Anxiety and Mood Disorders
Martien J. Kas, Ilan Golani, Yoav Benjamini, Ehud Fonio,
and Oliver Stiedl

Abstract
Understanding behavioral regulation can further progress by developing new approaches that allow
refinement of behavioral phenotypes. The current availability of several thousand different mutant mice
and of human candidate genes for emotional (affective) disorders challenges behavioral neuroscientists to
extend their views and methodologies to dissect complex behaviors into behavioral phenotypes and sub-
sequently to define gene–behavioral phenotype relationships. Here, we put forward multiday automated
behavioral and physiological observations in carefully designed environments to assess evolutionary con-
served behavioral strategies in mice. This offers the opportunity to design experimental setups that allow
the animals themselves to regulate their own behavior, using representations of continuous kinematic
variables, studying the dynamics of behavior (change across time or change across activity); i.e., growth or
decay processes of behavior and concomitant physiological adjustments such as heart rate. The measures
characterizing these processes should have discriminative power (across strains or treatments) and be rep-
licable (across laboratories). Furthermore, cross species genetic studies for these neurobehavioral and
physiological traits may provide a novel way toward identifying neurobiological mechanisms underlying
core features of complex psychiatric disorders.

Key words: Genetics, Physiology, Replicability, Exploration, Psychiatry, Conditioned fear, Heart rate,
Sequences of repeated motion, Dynamics of behavior, Behavioral growth, Arousal

1. Introduction

Behavioral testing in animals is a crucial feature of phenotyping in

neuroscience research. In particular, animal models of human
chronic diseases or behavioral symptoms, such as anxiety and mood
disorders, should be tested in situations where long-lasting stable

Todd D. Gould (ed.), Mood and Anxiety Related Phenotypes in Mice: Characterization Using Behavioral Tests, Volume II,
Neuromethods, vol. 63, DOI 10.1007/978-1-61779-313-4_1, © Springer Science+Business Media, LLC 2011

1
2 M.J. Kas et al.

features (“chronic”) of such behavior are manifested. It implies

measuring the behavior for days rather than minutes. Testing animals
in situations in which the animals respond to novel or transient
stimuli is appropriate for studying “states,” not “traits.” Behavioral
testing is usually based on measuring behavioral responses to envi-
ronmental events that are induced by the experimenter. The fre-
quently used open field test, e.g., is commonly employed to study
general activity and fear-related behaviors in mice and rats (1, 2).
In this test, movements of the animal are monitored up to 1 h after
the animal has been placed in a novel open arena from which it
cannot escape. Additional tests, such as the elevated plus maze (3)
and the light–dark box (4), allow external validity of the observed
open-field behaviors. However, these tests are short-lasting and
depend on individual locomotor activity levels and novelty respon-
siveness of the animal and require human interference. This hampers
their use for determining gene–behavioral phenotype relationships
and stresses the need for new analytical procedures addressing the
complex behaviors. Although some ideas for overcoming these
problems have been put forward, such as improving currently avail-
able tests, using test batteries and increasing test information
density (5, 6), behavioral complexity and gene–environment inter-
actions require new methodologies in this field of research.

1.1. Interacting Behavior is triggered by internal and external motivational signals

Physiological (such as hunger and food availability, respectively) and is guided by
Processes the ability of the animal to execute proper behavioral responses.
For instance, a hungry mouse that searches for new food resources
relies on an efficient exploration strategy in which finding the food
resource in time and taking the risk of being exposed to predators
need to be balanced. Furthermore, in the wild, mice face the risk
of spending more energy to obtain food than this food gives them
in return on any given day. Because exploration for food is influ-
enced by different integrated physiological processes (e.g., energy
balance, motor action, and fear), as well as by environmental factors
(e.g., variations in ambient temperature, in food availability, and in
photoperiod), the design of behavioral laboratory methods that
dissociate the various behavioral components is a challenge and
should focus on ethologically relevant behavior and appropriate
environmental conditions for the species selected for the behav-
ioral studies (7).
Conventional laboratory tests, such as the open-field test,
touch upon different aspects of exploratory behavior, including
locomotor activity and fear-related processes. However, during the
relative short testing episode generally employed, it is impossible
to discriminate between gene function in novelty-induced and
baseline behaviors. For example, mice that lack the dopamine
transporter gene have locomotor activity levels under baseline con-
ditions that are comparable to those in wild-type animals, but they
 1 Longitudinal Assessment of Deliberate Mouse Behavior in the Home Cage… 3

exhibit a 12-fold increase of locomotion following placement in a

novel environment. Although dissociation of novelty-induced and
baseline locomotor behavior in this mutant was observed during a
relative short-lasting testing procedure, the time of day that these
tests are performed can highly influence the outcome of the obser-
vations (8–10). Furthermore, the response to novelty induces a
dynamic transient response whose measurement provides variable
results depending critically on the time interval measured and the
size of the time window sampled. Thus, characterization of gene
functions in exploratory behavior requires behavioral paradigms
that allow dissection of this complex behavior into different
components in view of circadian-induced variations of these
components.

1.2. Interference Executing multiple behavioral tests usually involves experimenter

and Order Effects interference, such as handling or transport of animals (11), and
cues from the experimenter that influences the behavioral perfor-
mance of an animal (12). For example, measuring pain responses in
mice revealed that experimenter effects account for more trait vari-
ability than genotype (13). In addition, problems of replicability
across laboratories such as those reported in (14) could reflect the
effects of forced testing. Mice exposed to a battery of various behav-
ioral tests expressed significant lower levels of locomotor activity in
the open field than mice that were naïve to behavioral testing (15).
These order effects could even be amplified in animals with selec-
tive mutations in genes that are involved in physiological processes,
such as coping strategies to changing environments. Circumvention
of these interfering procedural aspects is required to reduce non-
specific environmental influences on the gene–behavioral pheno-
type relationship. Especially, the adverse impact of the experimenter
as uncontrollable variable or even confounder of experiments
should be taken into consideration.

1.3. Dissection of Studies in the field of biological rhythms have revealed that behav-
Behavioral Phenotypes ioral observations during several consecutive days or weeks in the
home cage of an animal allow reliable assessment of stable behav-
ioral circadian rhythms that are highly sensitive to environmental
signals, such as light and human interference (16, 17). Because
behavioral observations during several days can also dissociate
novelty-induced and baseline behaviors at different phases of the
light–dark cycle, behavioral monitoring in the home cage will sig-
nificantly contribute to the refinement of behavioral phenotypes.
In addition, by carefully designing a home cage environment, with
or without additionally attached compartments or arenas that
addresses different behavioral characteristics of interest, complex
behaviors can be further dissected into behavioral phenotypes with
minimum human interference. In this chapter, we would like to
view recent developments in the fields of behavioral neuroscience
4 M.J. Kas et al.

that uses the home cage and attached compartments as a basis for
the assessment of behavioral exploration strategies in mice.
Integration of longitudinal automated behavioral measures with
physiological measures allows further refinement of these neurobe-
havioral traits. Furthermore, we provide an example on how inter-
species trait genetics using home cage behavioral assessment in
mice offers a basis for identifying novel neurobiological mecha-
nisms underlying anxiety and mood disorders.

2. New Method
Developments
In this chapter we introduce setups used in our own work, which
attempt to separate state from trait anxiety by using side-by-side
the home cage environment for long-term observation that might
be more appropriate for longitudinal studies of trait, and environ-
ments attached to the home cage, which are most appropriate for
the study of how mice manage deliberately novel input, but can
also serve for long-term studies. In addition, we complement the
type of information provided by the common assays and models
with a large set of novel mouse-centered kinematic variables which
imply active management of perceptual input. We suggest three
requirements that should guide us in improving our choice of
behavioral measures: measure kinematic variables that appear to be
actively managed by the animal; demonstrate the discriminative
power of these measures between strains and preparations; and
demonstrate the replicability of these measures across laboratories
(18–20). In what follows we briefly demonstrate what we do to
fulfill these three requirements.

2.1. Segmenting One way to obtain a view on the functional organization of explor-
Behavior into Animal- atory behavior is to examine it in situations involving behavioral
Centered Sequences growth. To study and quantify this growth, we connect the mouse’s
of Repeated home cage through a doorway to a large circular arena for an
Approach-and-Avoid extended period of time, and allow the mouse to explore the arena
Motions at a self-regulated rate (Dimensionality Emergence assay, or DIEM
assay; see (21)). In this setup the familiarity of the mouse with the
environment increases gradually, allowing a correspondingly grad-
ual, stretched out growth of behavior. This process exposes the
elementary building blocks of behavior as they are progressively
added to the animal’s repertoire. The moment-to-moment devel-
opmental dynamics of exploratory behavior discloses its presumed
function: a systematic active management of perceptual input
acquired during the exploration of a novel environment, and active
management of the arousal associated with the acquisition of that
novel input (20, 21).
 1 Longitudinal Assessment of Deliberate Mouse Behavior in the Home Cage… 5

Having access to a technology that allows us to track and

record a time series of locations occupied by a mouse during free
exploration, and having developed analytical methods for quantify-
ing continuous kinematic variables (https://www.tau.ac.il/~ilan99/
see/help/), we segment the path, based on its intrinsic statistical
and geometrical properties, into processes involving approach and
avoidance: repetitive Peep and Hide motions from the home cage
into the arena, repetitive Cross and Retreat motions performed
across the doorway, repetitive Borderline round trips consisting of
outbound–inbound movement along the wall, and repetitive incur-
sions from the wall toward the center of the arena and back to the
wall. All these are examples of what we term “sequences of repeated
motion.” The motions are performed in relation to specific refer-
ence values from which the motion commences and to which it
returns: the inside of the home cage for Peep and Hide, the door-
way for Cross and Retreat, the inside of the home cage plus the
“garden,” an area at the proximity of the doorway, for Borderline
Roundtrips, and the Wall ring in the proximity of the arena wall for
incursions. We further identify a growth of behavior that is mani-
fested through a buildup in the extent of each of these motion
types separately and an increase in complexity through the recruit-
ment of additional sequences of repeated motion that are superim-
posed on previously emerged sequences of repeated motion. We
finally quantify this process by computing the rates of growth in
extent in each of the sequences of repeated motion, and by esti-
mating the complexity of the sequence of sequences.

2.2. Management of A session of free exploration commences with peeping, where the
Perceptual Input as mouse crosses the doorway into the arena, always leaving part of its
Indicated by Buildup body behind the doorway, and retreats back. The Peep and Hide
in Extent in Sequences sequence is followed by a Cross and Retreat sequence, Circle in
of Borderline Place, and Entry Head On, before commencing with the Borderline
Roundtrips Roundtrip Motion sequence, which, in the BALB/c mice, com-
mences strictly near and along the wall until the exhaustion of the
borderline dimension (Fig. 2). The reference area near the door-
way that we term garden is defined algorithmically by plotting a
density of cumulative dwell time across the entire arena. This plot
highlights a two-dimensional Gaussian located by the doorway,
whose boundary defines the “garden” (21).
As illustrated in Fig. 1, Borderline movement builds up in
maximal angular distance from home almost monotonically from
one roundtrip to the next. This increase in borderline roundtrip
amplitude is joined next by the option not to return all of the way
into the home cage, as expressed by the emergence and subsequent
proliferation of Cage skips and Home-related shuttles (blue dots in
Figs. 1 and 2). The simple Borderline Roundtrips turn in this way
into complex ones including one to several home-related shuttles.
The buildup in the Borderline roundtrips in the other direction,
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