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"Vertical exploration and dimensional modularity in mice"
Yair Wexler, Yoav Benjamini and Ilan Golani (2018)
Royal Society Open Science. 5(3), 180069

Note: we recommend clicking on Video S1, S2, S3, S4, S5 and S6. In the PDF, these labels contain hyperlinks to the videos which unfortunately are not highlighted

Video S1 Video S2 Video S3 Video S4 Video S5 Video S6 Supplementary Figures

Abstract: Exploration is a central component of animal behaviour studied extensively in rodents. Previous tests of free exploration limited vertical movement to rearing and jumping. Here, we attach a wire mesh to the arena wall, allowing vertical exploration. This provides an opportunity to study the morphogenesis of behaviour along the vertical dimension, and examine the context in which it is performed. In the current set-up, the mice first use the doorway as a point reference for establishing a borderline linear path along the circumference of the arena floor, and then use this path as a linear reference for performing horizontal forays towards the centre (incursions) and vertical forays on the wire mesh (ascents). Vertical movement starts with rearing on the wall, and commences with straight vertical ascents that increase in extent and complexity. The mice first reach the top of the wall, then mill about within circumscribed horizontal sections, and then progress horizontally for increasingly longer distances on the upper edge of the wire mesh. Examination of the sequence of borderline segments, incursions and ascents reveals dimensional modularity: an initial series (bout) of borderline segments precedes alternating bouts of incursions and bouts of ascents, thus exhibiting sustained attention to each dimension separately. The exhibited separate growth in extent and in complexity of movement and the sustained attention to each of the three dimensions disclose the mice’s modular perception of this environment and validate all three as natural kinds.

Video 1. The morphogenesis of mouse exploratory behavior along the vertical dimension. The video presents the first 249 ascents performed by a selected BALB/c mouse in the order of their performance, in the course of 3 hours. As illustrated, ascents start with episodes of rearing on the wall, and then they progressively grow in their height and width and in their complexity across the session. The red dot represents the mouse's current location. The current ascent is traced in blue. History is colored in grey. The red line marks the doorway.

Video 2. The morphogenesis of mouse vertical exploration, centered on the point of ascent. The video presents the behavior performed during the same mouse session presented in Video 1, where all ascents are traced on top of each other to highlight the growth in extent and in complexity. The horizontal axis represents the horizontal location of the mouse relative to the point of ascent (in radians, centered at zero). The vertical axis represents the height on the wall. The red dot represents the mouse's current location. The current ascent is traced in blue. History is colored in grey. To illustrate the growth in ascent's width without compressing the initial, relatively narrow ascents, the visualization zooms out at ascent 212 and again at ascent 249.

Video 3. Coverage of the lower circumference (point reference) Borderline movement grow in reference to the to the doorway to the home cage, as demonstrated by a single selected mouse (V04). This strategy involves extending a single trodden section to the left and to the right of the doorway, until eventually the whole lower circumference is covered.

Video 4. Coverage of the upper circumference (linear reference) Ascents grow in reference to the entire lower circumference of the arena, rather than specific points on it, as demonstrated by a single selected mouse (V04). This strategy involves opening numerous separate sections, and then connecting them, until eventually the whole upper circumference is covered.

Video 5. Bouts of ascents and incursions in a BALB/c mouse (early entries) Animation of two successive entries (#29 and #30) of a BALB/c mouse (V01) demonstrate the organization of incursions and ascents in bouts. Bouts of ascents in blue (transitions in light blue), bouts of incursions in red (transitions in pink)

Video 6. Bouts of ascents and incursions in a BALB/c mouse (late entries) Animation of two successive entries (#62 and #63) of a BALB/c mouse (V01) demonstrate the organization of incursions and ascents in bouts. Bouts of ascents in blue (transitions in light blue), bouts of incursions in red (transitions in pink)
"Origin related exploration in animals (work in progress)"
Ilan Golani, Yair Wexler and Yoav Benjamini (2018)
"Origin related exploration in animals (work in progress)"
Ilan Golani, Yair Wexler and Yoav Benjamini (2018)
"Home base"
Ilan Golani and Yoav Benjamini (2018)
"The angular interval between the direction of progression and body orientation in normal, alcohol- and cocaine treated fruit flies."
Anna Gakamsky, Efrat Oron, Dan Valente, Partha P Mitra, Daniel Segal, Yoav Benjamini and Ilan Golani (2013)
PloS one. Vol. 8 (10) , pp. e76257.
Abstract: In this study we characterize the coordination between the direction a fruit-fly walks and the direction it faces, as well as offer a methodology for isolating and validating key variables with which we phenotype fly locomotor behavior. Our fundamental finding is that the angular interval between the direction a fly walks and the direction it faces is actively managed in intact animals and modulated in a patterned way with drugs. This interval is small in intact flies, larger with alcohol and much larger with cocaine. The dynamics of this interval generates six coordinative modes that flow smoothly into each other. Under alcohol and much more so under cocaine, straight path modes dwindle and modes involving rotation proliferate. To obtain these results we perform high content analysis of video-tracked open field locomotor behavior. Presently there is a gap between the quality of descriptions of insect behaviors that unfold in circumscribed situations, and descriptions that unfold in extended time and space. While the first describe the coordination between low-level kinematic variables, the second quantify cumulative measures and subjectively defined behavior patterns. Here we reduce this gap by phenotyping extended locomotor behavior in terms of the coordination between low-level kinematic variables, which we quantify, combining into a single field two disparate fields, that of high content phenotyping and that of locomotor coordination. This will allow the study of the genes/brain/locomotor coordination interface in genetically engineered and pharmacologically manipulated animal models of human diseases.
Annotation: In this paper fruit fly behavior is characterized (phenotyped) in terms of the dynamics of the coordination between the two degrees of freedom available to the fly at the scale of the animal's path – the animal's shift of weight (direction of translation of the animal's center) and the animal's front (the direction the fly is facing). The two drug preparations are used as two phenotypes whose dynamics is compared to the dynamics of intact fly behavior.
"Short and long term measures of anxiety exhibit opposite results."
Ehud Fonio, Yoav Benjamini and Ilan Golani (2012)
PloS one. Vol. 7 (10) , pp. e48414.
Abstract: Animal models of human diseases of the central nervous system, generalized anxiety disorder included, are essential for the study of the brain-behavior interface and obligatory for drug development; yet, these models fail to yield new insights and efficacious drugs. By increasing testing duration hundredfold and arena size tenfold, and comparing the behavior of the common animal model to that of wild mice, we raise concerns that chronic anxiety might have been measured at the wrong time, for the wrong duration, and in the wrong animal. Furthermore, the mice start the experimental session with a short period of transient adaptation to the novel environment (habituation period) and a long period reflecting the respective trait of the mice. Using common measures of anxiety reveals that mice exhibit opposite results during these periods suggesting that chronic anxiety should be measured during the post-habituation period. We recommend tools for measuring the transient period, and provide suggestions for characterizing the post habituation period.
Annotation: This is a twin article, to be read before the "Nature Methods" article "Measuring behavior of animal models: faults and remedies".
"Measuring behavior of animal models: faults and remedies."
Ehud Fonio, Ilan Golani and Yoav Benjamini (2012)
Nature methods. Vol. 9 (12) , pp. 1167-70.
Abstract: Widely used behavioral assays need re-evaluation and validation against their intended use. We focus here on measures of chronic anxiety in mouse models and posit that widely used assays such as the open-field test are performed at the wrong time, for inadequate durations and using inappropriate mouse strains. We propose that behavioral assays be screened for usefulness on the basis of their replicability across laboratories.
Annotation: The absence of a wide perspective in time, space and natural history, and the use of ad hoc measures having no intrinsic (Statistical and/or geometrical) justification yield animal models that have poor translational values for human diseases of the brain.
"The developmental dynamics of behavioral growth processes in rodent egocentric and allocentric space."
Ilan Golani (2012)
Behavioural brain research. Vol. 231 (2) , pp. 309-16.
Abstract: In this review I focus on how three methodological principles advocated by Philip Teitelbaum influenced my work to this day: that similar principles of organization should be looked for in ontogeny and recovery of function; that the order of emergence of behavioral components provides a view on the organization of that behavior; and that the components of behavior should be exhibited by the animal itself in relatively pure form. I start by showing how these principles influenced our common work on the developmental dynamics of rodent egocentric space, and then proceed to describe how these principles affected my work with Yoav Benjamini and others on the developmental dynamics of rodent allocentric space. We analyze issues traditionally addressed by physiological psychologists with methods borrowed from ethology, EW (Eshkol-Wachman) movement notation, dynamical systems and exploratory data analysis. Then we show how the natural origins of axes embodied by the behavior of the organism itself, are used by us as the origins of axes for the measurement of the developmental moment-by-moment dynamics of behavior. Using this methodology we expose similar principles of organization across situations, species and preparations, provide a developmental view on the organization of behavior, expose the natural components of behavior in relatively pure form, and reveal how low level primitives generate higher level constructs. Advances in tracking technology should allow us to study how movements in egocentric and allocentric spaces interlace. Tracking of multi-limb coordination, progress in online recording of neural activity in freely moving animals, and the unprecedented accumulation of genetically engineered mouse preparations makes the behavioral ground plan exposed in this review essential for a systematic study of the brain/behavior interface.
Annotation: We assume that organisms do not move in a haphazard way. Therefore  we first search for the origin established by the organism itself for performing a particular behavior.  Then we follow the organism step by step, measuring its behavior in reference to that origin. This procedure exposes the intrinsic dimensionality, the building blocks, and the developmental dynamics of the behavior. Here, we expose the phenomenology (a la Husserl) of mice experiencing their egocentric and allocentric spaces.
"Validation of the dimensionality emergence assay for the measurement of innate anxiety in laboratory mice."
Apar Jain, Anna Dvorkin, Ehud Fonio, Ilan Golani and Cornelius T Gross (2012)
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. Vol. 22 (2) , pp. 153-63.
Abstract: The open field test is a common tool to measure innate anxiety in rodents. In the usual configuration of this test the animal is forced to explore the open arena and its behavior includes both anxiety and non-anxiety responses. However, the open arena is generally small and allows only limited expression of exploratory behavior. The recently developed dimensionality emergence assay in which an animal is housed in a home cage with free access to a large circular arena elicits graded exploration and promises to serve as a more ethological test of anxiety. Here we examined the predictive validity of this assay for anxiety-related measures in mice. First, we compared their behavior in the presence or absence of access to the home cage and found that mice with access to the home cage exhibited a gradual build-up in exploration of the arena while those without did not. Then we identified behavioral measures that responded to treatment with the anxiolytic drug diazepam. Diazepam altered several classical measures of innate anxiety, such as distance traveled and thigmotaxis, but also led to a dose-dependent acceleration of the build-up as reflected in a significantly reduced latency to attain several exploratory landmarks. Finally, we tested the utility of the dimensionality emergence assay in assessing alterations in innate anxiety reported in mice carrying a knockout allele for the serotonin 1A receptor (Htr1a). Our findings support the validity of the dimensionality emergence assay as a method to extract an expanded repertoire of behavioral measures for the assessment of anxiety in laboratory mice.
"Quantifying the buildup in extent and complexity of free exploration in mice"
Yoav Benjamini, Ehud Fonio, Tal Galili, Gregor Z Havkin and Ilan Golani (2011)
Proceedings of the National Academy of Sciences of the United States of America. Vol. 108 Suppl , pp. 15580-7.
Abstract: To obtain a perspective on an animal's own functional world, we study its behavior in situations that allow the animal to regulate the growth rate of its behavior and provide us with the opportunity to quantify its moment-by-moment developmental dynamics. Thus, we are able to show that mouse exploratory behavior consists of sequences of repeated motion: iterative processes that increase in extent and complexity, whose presumed function is a systematic active management of input acquired during the exploration of a novel environment. We use this study to demonstrate our approach to quantifying behavior: targeting aspects of behavior that are shown to be actively managed by the animal, and using measures that are discriminative across strains and treatments and replicable across laboratories.
"Ten ways to improve the quality of descriptions of whole-animal movement."
Yoav Benjamini, Dina Lipkind, Guy Horev, Ehud Fonio, Neri Kafkafi and Ilan Golani (2010)
Neuroscience and biobehavioral reviews. Vol. 34 (8) , pp. 1351-65.
Abstract: The demand for replicability of behavioral results across laboratories is viewed as a burden in behavior genetics. We demonstrate how it can become an asset offering a quantitative criterion that guides the design of better ways to describe behavior. Passing the high benchmark dictated by the replicability demand requires less stressful and less restraining experimental setups, less noisy data, individually customized cutoff points between the building blocks of movement, and less variable yet discriminative dynamic representations that would capture more faithfully the nature of the behavior, unmasking similarities and differences and revealing novel animal-centered measures. Here we review ten tools that enhance replicability without compromising discrimination. While we demonstrate the usefulness of these tools in the context of inbred mouse exploratory behavior they can readily be used in any study involving a high-resolution analysis of spatial behavior. Viewing replicability as a design concept and using the ten methodological improvements may prove useful in many fields not necessarily related to spatial behavior.
"Knots: attractive places with high path tortuosity in mouse open field exploration."
Anna Dvorkin, Henry Szechtman and Ilan Golani (2010)
PLoS computational biology. Vol. 6 (1) , pp. e1000638.
Abstract: When introduced into a novel environment, mammals establish in it a preferred place marked by the highest number of visits and highest cumulative time spent in it. Examination of exploratory behavior in reference to this "home base" highlights important features of its organization. It might therefore be fruitful to search for other types of marked places in mouse exploratory behavior and examine their influence on overall behavior.Examination of path curvatures of mice exploring a large empty arena revealed the presence of circumscribed locales marked by the performance of tortuous paths full of twists and turns. We term these places knots, and the behavior performed in them-knot-scribbling. There is typically no more than one knot per session; it has distinct boundaries and it is maintained both within and across sessions. Knots are mostly situated in the place of introduction into the arena, here away from walls. Knots are not characterized by the features of a home base, except for a high speed during inbound and a low speed during outbound paths. The establishment of knots is enhanced by injecting the mouse with saline and placing it in an exposed portion of the arena, suggesting that stress and the arousal associated with it consolidate a long-term contingency between a particular locale and knot-scribbling.In an environment devoid of proximal cues mice mark a locale associated with arousal by twisting and turning in it. This creates a self-generated, often centrally located landmark. The tortuosity of the path traced during the behavior implies almost concurrent multiple views of the environment. Knot-scribbling could therefore function as a way to obtain an overview of the entire environment, allowing re-calibration of the mouse's locale map and compass directions. The rich vestibular input generated by scribbling could improve the interpretation of the visual scene.
"High-throughput data analysis in behavior genetics"
Anat Sakov, Ilan Golani, Dina Lipkind and Yoav Benjamini (2010)
The Annals of Applied Statistics. Vol. 4 (2) , pp. 743-763.
Abstract: In recent years, a growing need has arisen in different fields for the development of computational systems for automated analysis of large amounts of data (high-throughput). Dealing with nonstandard noise structure and outliers, that could have been detected and corrected in manual analysis, must now be built into the system with the aid of robust methods. We discuss such problems and present insights and solutions in the context of behavior genetics, where data consists of a time series of locations of a mouse in a circular arena. In order to estimate the location, velocity and acceleration of the mouse, and identify stops, we use a nonstandard mix of robust and resistant methods: LOWESS and repeated running median. In addition, we argue that protection against small deviations from experimental protocols can be handled automatically using statistical methods. In our case, it is of biological interest to measure a rodent’s distance from the arena’s wall, but this measure is corrupted if the arena is not a perfect circle, as required in the protocol. The problem is addressed by estimating robustly the actual boundary of the arena and its center using a nonparametric regression quantile of the behavioral data, with the aid of a fast algorithm developed for that purpose.
"Freedom of movement and the stability of its unfolding in free exploration of mice"
Ehud Fonio, Yoav Benjamini and Ilan Golani (2009)
Proceedings of the National Academy of Sciences of the United States of America. Vol. 106 (50) , pp. 21335-40.
Abstract: Exploration is a central component of human and animal behavior that has been studied in rodents for almost a century. The measures used by neuroscientists to characterize full-blown exploration are limited in exposing the dynamics of the exploratory process, leaving the morphogenesis of its structure and meaning hidden. By unfettering exploration from constraints imposed by hunger, thirst, coercion, and the confines of small cage and short session, using advanced computational tools, we reveal its meaning in the operational world of the mouse. Exploration consists of reiterated roundtrips of increasing amplitude and freedom, involving an increase in the number of independent dimensions along which the mouse moves (macro degrees of freedom). This measurable gradient can serve as a standard reference scale for the developmental dynamics of some aspects of the mouse's emotional-cognitive state and for the study of the interface between behavior and the neurophysiologic and genetic processes mediating it.
"Mouse cognition-related behavior in the open-field: emergence of places of attraction."
Anna Dvorkin, Yoav Benjamini and Ilan Golani (2008)
PLoS computational biology. Vol. 4 (2) , pp. e1000027.
Abstract: Spatial memory is often studied in the Morris Water Maze, where the animal's spatial orientation has been shown to be mainly shaped by distal visual cues. Cognition-related behavior has also been described along "well-trodden paths"--spatial habits established by animals in the wild and in captivity reflecting a form of spatial memory. In the present study we combine the study of Open Field behavior with the study of behavior on well-trodden paths, revealing a form of locational memory that appears to correlate with spatial memory. The tracked path of the mouse is used to examine the dynamics of visiting behavior to locations. A visit is defined as either progressing through a location or stopping there, where progressing and stopping are computationally defined. We then estimate the probability of stopping at a location as a function of the number of previous visits to that location, i.e., we measure the effect of visiting history to a location on stopping in it. This can be regarded as an estimate of the familiarity of the mouse with locations. The recently wild-derived inbred strain CZECHII shows the highest effect of visiting history on stopping, C57 inbred mice show a lower effect, and DBA mice show no effect. We employ a rarely used, bottom-to-top computational approach, starting from simple kinematics of movement and gradually building our way up until we end with (emergent) locational memory. The effect of visiting history to a location on stopping in it can be regarded as an estimate of the familiarity of the mouse with locations, implying memory of these locations. We show that the magnitude of this estimate is strain-specific, implying a genetic influence. The dynamics of this process reveal that locations along the mouse's trodden path gradually become places of attraction, where the mouse stops habitually.
"Estimating wall guidance and attraction in mouse free locomotor behavior."
G Horev, Y Benjamini, A Sakov and I Golani (2007)
Genes, brain, and behavior. Vol. 6 (1) , pp. 30-41.
Abstract: In this study, we estimate the influence exerted by the wall of the Open Field on the trajectory of the mouse. The wall exerts two types of influence on the mouse's path: one of guidance and one of attraction. The guiding influence is expressed by the tendency of mice to progress in parallel to the wall. This tendency wanes with increasing distance from the wall but is observed at large distances from it. The more parallel the mouse is to the wall the higher is its speed, even when distant from the wall. This association between heading direction and speed shows that the mouse controls its heading in reference to the wall. It is also observed in some blind strains, revealing that wall-guidance is not based exclusively on vision. The attraction influence is reflected by movement along the wall and by the asymmetry between speed during movement toward, and during movement away from the wall: sighted mice move faster toward the wall, whereas blind mice use similar speeds in both directions. Measures characterizing these influences are presented for five inbred strains, revealing heritable components that are replicable across laboratories. The revealed structure can lead to the identification of distinct groups of genes that mediate the distinct influences of guidance and attraction exerted by the wall. It can also serve as a framework for the decoding of electrophysiological data recorded in free moving rodents in the Open Field.
"Analysis of the trajectory of Drosophila melanogaster in a circular open field arena."
Dan Valente, Ilan Golani and Partha P Mitra (2007)
PloS one. Vol. 2 (10) , pp. e1083.
Abstract: BACKGROUND: Obtaining a complete phenotypic characterization of a freely moving organism is a difficult task, yet such a description is desired in many neuroethological studies. Many metrics currently used in the literature to describe locomotor and exploratory behavior are typically based on average quantities or subjectively chosen spatial and temporal thresholds. All of these measures are relatively coarse-grained in the time domain. It is advantageous, however, to employ metrics based on the entire trajectory that an organism takes while exploring its environment.

METHODOLOGY/PRINCIPAL FINDINGS: To characterize the locomotor behavior of Drosophila melanogaster, we used a video tracking system to record the trajectory of a single fly walking in a circular open field arena. The fly was tracked for two hours. Here, we present techniques with which to analyze the motion of the fly in this paradigm, and we discuss the methods of calculation. The measures we introduce are based on spatial and temporal probability distributions and utilize the entire time-series trajectory of the fly, thus emphasizing the dynamic nature of locomotor behavior. Marginal and joint probability distributions of speed, position, segment duration, path curvature, and reorientation angle are examined and related to the observed behavior.

CONCLUSIONS/SIGNIFICANCE: The measures discussed in this paper provide a detailed profile of the behavior of a single fly and highlight the interaction of the fly with the environment. Such measures may serve as useful tools in any behavioral study in which the movement of a fly is an important variable and can be incorporated easily into many setups, facilitating high-throughput phenotypic characterization.

"Characterizing Animal Behavior through Audio and Video Signal Processing"
Dan Valente, Haibin Wang, Peter Andrews, Partha P. Mitra, Sigal Saar, Ofer Tchernichovski, Ilan Golani and Yoav Benjamini (2007)
IEEE Multimedia. Vol. 14 (4) , pp. 32-41.
Abstract: This article presents two instances in which multimedia systems and processing have elucidated animal behavior and have been central in developing quantitative descriptions. These examples demonstrate multimedia systems' utility and necessity in developing a complete phenotypic description. We hope that this article will spur interest in this subject in the multimedia community, so more advanced processing techniques will enter the field of quantitative neuroethology. You might have noticed that in our two examples, there was nothing very multimodal about the media techniques used. Both of these systems are transparently unimodal. This speaks to the limited crossover between the multimedia community and the behavioral neuroscientists (or neuroethologists). These examples did show, however, that the neuroscientific community can benefit greatly from incorporating multimedia techniques into their experiments and data analysis. As the walls between these disciplines begin to fall, experimental setups that are truly multimedia will likely appear. Such systems will allow complete phenotypic descriptions of animals in ethologically relevant settings, along with methods for analyzing, manipulating, annotating, and storing the resulting data. Combining these phenotypic descriptions with the corresponding genetic and neural network properties will facilitate the connection of these organization levels and lead to a more thorough understanding of brain functioning.
"Wild mouse open field behavior is embedded within the multidimensional data space spanned by laboratory inbred strains."
E Fonio, Y Benjamini, A Sakov and I Golani (2006)
Genes, brain, and behavior. Vol. 5 (5) , pp. 380-8.
Abstract: The vast majority of studies on mouse behavior are performed on laboratory mouse strains (Mus laboratorius), while studies of wild-mouse behavior are relatively rare. An interesting question is the relationship between the phenotypes of M. laboratorius and the phenotypes of their wild ancestors. It is commonly believed, often in the absence of hard evidence, that the behavior of wild mice exceeds by far, in terms of repertoire richness, magnitude of variables and variability of behavioral measures, the behavior of the classical inbred strains. Having phenotyped the open field behavior (OF) of eight of the commonly used laboratory inbred strains, two wild-derived strains and a group of first-generation-in-captivity local wild mice (Mus musculus domesticus), we show that contrary to common belief, wild-mouse OF behavior is moderate, both in terms of end-point values and in terms of their variability, being embedded within the multidimensional data space spanned by laboratory inbred strains. The implication could be that whereas natural selection favors moderate locomotor behavior in wild mice, the inbreeding process tends to generate in mice, in some of the features, extreme and more variable behavior.
"Activity density in the open field: a measure for differentiating the effect of psychostimulants."
Neri Kafkafi and Gregory I. Elmer (2005)
Pharmacology, biochemistry, and behavior. Vol. 80 (2) , pp. 239-49.
Abstract: Traditional open-field activity measures do not provide a sharp behavioral differentiation across psychomotor stimulants such as d-amphetamine (AMPH) and cocaine (COC) in the mouse. We used Software for the Exploration of Exploration (SEE) to investigate and develop a novel behavioral endpoint to characterize the "structure" of AMPH- and COC-induced locomotor behavior in two inbred strains of mouse, C57BL/6 (B6) and DBA/2 (D2). We suggest a measure we term "activity density" as a means to differentiate the behavioral effects of COC and AMPH. Activity density is defined as the activity divided by the range over which it took place. It characterizes the restriction of behavioral repertoire that does not result merely from inactivity. In both the B6 and D2 mice, AMPH increased activity density in a dose-dependent fashion by restricting the range of activity compared with COC doses producing the same level of activity. While AMPH restricted the range in both genotypes, characterizing the geographical region in which the restriction took place further differentiated the genotypes. The newly developed activity density measure thus provides a more general measure than stereotypy of the path, and can differentiate the effects of AMPH and COC both within and across genotypes.
"Genotype-environment interactions in mouse behavior: a way out of the problem."
Neri Kafkafi, Yoav Benjamini, Anat Sakov, Greg I Elmer and Ilan Golani (2005)
Proceedings of the National Academy of Sciences of the United States of America. Vol. 102 (12) , pp. 4619-24.
Abstract: In behavior genetics, behavioral patterns of mouse genotypes, such as inbred strains, crosses, and knockouts, are characterized and compared to associate them with particular gene loci. Such genotype differences, however, are usually established in single-laboratory experiments, and questions have been raised regarding the replicability of the results in other laboratories. A recent multilaboratory experiment found significant laboratory effects and genotype x laboratory interactions even after rigorous standardization, raising the concern that results are idiosyncratic to a particular laboratory. This finding may be regarded by some critics as a serious shortcoming in behavior genetics. A different strategy is offered here: (i) recognize that even after investing much effort in identifying and eliminating causes for laboratory differences, genotype x laboratory interaction is an unavoidable fact of life. (ii) Incorporate this understanding into the statistical analysis of multilaboratory experiments using the mixed model. Such a statistical approach sets a higher benchmark for finding significant genotype differences. (iii) Develop behavioral assays and endpoints that are able to discriminate genetic differences even over the background of the interaction. (iv) Use the publicly available multilaboratory results in single-laboratory experiments. We use software-based strategy for exploring exploration (see) to analyze the open-field behavior in eight genotypes across three laboratories. Our results demonstrate that replicable behavioral measures can be practically established. Even though we address the replicability problem in behavioral genetics, our strategy is also applicable in other areas where concern about replicability has been raised.
"Extending SEE for large-scale phenotyping of mouse open-field behavior"
Neri Kafkafi (2003)
Behavior Research Methods, Instruments, & Computers. Vol. 35 (2) , pp. 294-301.
Abstract: SEE (Software for the Exploration of Exploration) is a visualization and analysis tool designed for the study of open-field behavior in rodents. In this paper, I present new extensions of SEE that were designed to facilitate its use for mouse behavioral phenotyping and, especially, for the problems of discrimination of genotypes and the replication of results across laboratories and experimental conditions. These extensions were specifically designed to promote a new approach in behavioral phenotyping, reminiscent of the approach that has been successfully employed in bioinformatics during recent years. The path coordinates of all animals from many experiments are stored in a database. SEE can be used to query, visualize, and analyze any desirable subsection of this database and to design new measures (endpoints) with increasingly better discriminative power and replicability. The use of the new extensions is demonstrated here in the analysis of results from several experiments and laboratories, with an emphasis on this approach.
"Darting behavior: a quantitative movement pattern designed for discrimination and replicability in mouse locomotor behavior"
Neri Kafkafi, Michal Pagis, Dina Lipkind, Cheryl L Mayo, Yoav Bemjamini, Ilan Golani and Gregory I Elmer (2003)
Behavioural brain research. Vol. 142 (1-2) , pp. 193-205.
Abstract: In the open-field behavior of rodents, Software for Exploring Exploration (SEE) can be used for an explicit design of behavioral endpoints with high genotype discrimination and replicability across laboratories. This ability is demonstrated here in the development of a measure for darting behavior. The behavior of two common mouse inbred strains, C57BL/6J (B6) and DBA/2J (D2), was analyzed across three different laboratories, and under the effect of cocaine or amphetamine. "Darting" was defined as having higher acceleration during progression segments while moving less during stops. D2 mice darted significantly more than B6 mice in each laboratory, despite being significantly less active. These differences were maintained following cocaine administration (up to 20mg/kg) and only slightly altered by amphetamine (up to 5mg/kg) despite a several fold increase in activity. The replicability of darting behavior was confirmed in additional experiments distinct from those used for its design. The strategy leading to the darting measure may be used to develop additional discriminative and replicable endpoints of open-field behavior.
"SEE locomotor behavior test discriminates C57BL/6J and DBA/2J mouse inbred strains across laboratories and protocol conditions."
Neri Kafkafi, Dina Lipkind, Yoav Benjamini, Cheryl L Mayo, Gregory I Elmer and Ilan Golani (2003)
Behavioral neuroscience. Vol. 117 (3) , pp. 464-77.
Abstract: Conventional tests of behavioral phenotyping frequently have difficulties differentiating certain genotypes and replicating these differences across laboratories and protocol conditions. This study explores the hypothesis that automated tests can be designed to quantify ethologically relevant behavior patterns that more readily characterize heritable and replicable phenotypes. It used SEE (Strategy for the Exploration of Exploration) to phenotype the locomotor behavior of the C57BL/6 and DBA/2 mouse inbred strains across 3 laboratories. The 2 genotypes differed in 15 different measures of behavior, none of which had a significant genotype-laboratory interaction. Within the same laboratory, most of these differences were replicated in additional experiments despite the test photoperiod phase being changed and saline being injected. Results suggest that well-designed tests may considerably enhance replicability across laboratories.
"Rats and mice share common ethologically relevant parameters of exploratory behavior."
D Drai, N Kafkafi, Y Benjamini, G Elmer and I Golani (2001)
Behavioural brain research. Vol. 125 (1-2) , pp. 133-40.
Abstract: Detailed studies of rat exploratory behavior reveal that it consists of typical behavior patterns having a distinct structure. Recently we have developed interactive software that uses as input the automatically digitized time-series of the animal's location for the visualization, analysis, capturing and quantification of these patterns. We use this software here for the study of BALB/cJtau mouse behavior. The results suggest that a considerable number of rat patterns are also present in the mouse. These ethologically-relevant patterns have a significant potential as a phenotyping tool.
"SEE: a tool for the visualization and analysis of rodent exploratory behavior"
Dan Drai and Ilan Golani (2001)
Neuroscience & Biobehavioral Reviews. Vol. 25 (5) , pp. 409-426.
Abstract: The complexity of exploratory behavior creates a need for a visualization and analysis tool that will highlight regularities and help generating new hypotheses about the structure of this behavior. The hypotheses can then be formulated as algorithms that capture the patterns and quantify them. SEE is a Mathematica based software developed by us for the exploration of exploratory behavior. The raw data for SEE are a time series of the animal ‘s coordinates in space sampled at a rate that allows a meaningful computation of speeds. SEE permits: (i) a visualization of the path of the animal and a computation of the dynamics of activity; (ii) a decomposition of the path into several modes of motion (1st gear, 2nd gear, etc.) and a computation of the typical maximal speeds, the spatial spread, and the proportion of each of these modes; and(iii) a visualization of the location in the environment of stopping episodes, along with their dwell time. These visualizations highlight the presence of preferred places, including the animal's so-called home base, and permits a computation of the spatio-temporal diversity in the location of stopping episodes. The software also: (i) decomposes the animal's path into round trips from the home base, called ‘excursions’, and computes the number of stops per excursion; (ii) generates a visualization of the phase space (path+speed, traced in a three-dimensional graph) of any progression segment or list of such segments; and (iii) produces a visualization of the way places in the animal's operational world are connected to each other. SEE also permits the definition and computation of behavioral endpoints across any section of any database of raw data. The range of applicability of SEE to various experimental setups, tracking procedures, species, and preparations is addressed in the discussion.
"Natural segmentation of the locomotor behavior of drug-induced rats in a photobeam cage"
N Kafkafi, C Mayo, D Drai, I Golani and G Elmer (2001)
Journal of neuroscience ldots. Vol. 109 (2) , pp. 111-21.
Abstract: Recently, Drai et al. (J Neurosci Methods 96 (2000) 119) have introduced an algorithm that segments rodent locomotor behavior into natural units of 'staying in place' (lingering) behavior versus going between places (progression segments). This categorization, based on the maximum speed attained within the segment, was shown to be intrinsic to the data, using the statistical method of Gaussian Mixture Model. These results were obtained in normal rats and mice using very large (650 or 320 cm) circular arenas and a video tracking system. In the present study, we reproduce these results with amphetamine, phencyclidine and saline injected rats, using data measured by a standard photobeam tracking system in square 45 cm cages. An intrinsic distinction between two or three 'gears' could be shown in all animals. The spatial distribution of these gears indicates that, as in the large arena behavior, they correspond to the difference between 'staying in place' behavior and 'going between places'. The robustness of this segmentation over arena size, different measurement system and dose of two psychostimulant drugs indicates that this is an intrinsic, natural segmentation of rodent locomotor behavior. Analysis of photobeam data that is based on this segmentation has thus a potential use in psychopharmacology research.
"Statistical discrimination of natural modes of motion in rat exploratory behavior."
D Drai, Y Benjamini and I Golani (2000)
Journal of neuroscience methods. Vol. 96 (2) , pp. 119-31.
Abstract: We analyze the locomotor behavior of the rat during exploration, and show that digitally collected data (time series of positions) provide a sufficient basis for establishing that the rat uses several distinct modes of motion (first, second, third, and sometimes fourth gear). The distinction between these modes is obtained by first segmenting the time series into sequences of data points occurring between arrests (as ascertained within the resolution of the data acquisition system). The statistical distribution of the maximal amount of motion occurring within each of these episodes is then analyzed and shown to be multi modal. This enables us to decompose motion into distinct modes. In one application of this decomposition we show that the ethological ad hoc notion of stopping behavior corresponds to progression without leaving first gear. We do so by showing that the spatial spread of such progressions is confined to a small 20-50 cm range in a 6.5 m diameter arena. This provides a justification for a construct of 'staying in place'. This construct is not defined in terms of position in objective space, but purely in terms of the rat's own behavior. We test the generality of our method by applying it to mouse exploratory behavior.
"Coordination of side-to-side head movements and walking in amphetamine-treated rats: a stereotyped motor pattern as a stable equilibrium in a dynamical system"
Neri Kafkafi, Stavit Levi-Havusha, Ilan Golani and Yoav Benjamini (1996)
Biological Cybernetics. Vol. 495 (6) , pp. 487-495.
Abstract: Rats injected with 5.0 mg/kg (+)-amphetamine perform, at one stage of the drug's influence, rhythmic side-to-side head movements while walking. This makes them an interesting preparation for investigating how stereotyped motor patterns emerge from the coordination of periodic movements. We report here such a pattern we have isolated: the left foreleg and the right hindleg land on the ground as the head reaches the peak of its movement to the right, and vice versa (contra-lateral pattern). We show that this pattern can be explained as a stable equilibrium in a simple, nonlinear dynamical model, similar to models developed for tapping with both hands in human subjects. The model also accounts for sequences of behavior that are not in the contra-lateral pattern, explaining them as a flow of the system back towards the stable equilibrium after a disturbance. Motor patterns that constitute the building blocks of unconstrained behavior are often defined as fixed phase relations between movements of the parts of the body. This study applies the paradigm of Dynamic Pattern Generation to free (unconstrained) behavior: motor patterns are defined as stable equilibria in dynamical systems, assembled by mutual influence of concurrent movements. Our findings suggest that this definition is more powerful for the description of free behavior. The amphetamine-treated rat is a useful preparation for investigating this notion in an unconstrained animal whose behavior is still not as complex and variable as that of the normal animal
"The mobility gradient as an integrating model in the organization of vertebrate mowement"
Ilan Golani (1992)
Behavioral and Brain Sciences. Vol. 15 (02) , pp. 249-266.
Abstract: Ordinary language can prevent us from seeing the organization of whole-animal movement. This may be why the search for behavioral homologies has not been as fruitful as the founders of ethology had hoped. The Eshkol-Wachman (EW) movement notational system can reveal shared movement patterns that are undetectable in the kinds of informal verbal descriptions of the same behaviors that are in current use. Rules of organization that are common to locomotor development, agonistic and exploratory behavior, scent marking, play, and dopaminergic drug-induced stereotypies in a variety of vertebrates suggest that behavior progresses along a “mobility gradient” from immobility to increasing complexity and unpredictability. A progression in the opposite direction, with decreasing spatial complexity and increased stereotypy, occurs under the influence of the nonselective dopaminergic drugs apomorphine and amphetamine and partly also the selective dopamine agonist quinpirole. The behaviors associated with the mobility gradient appear to be mediated by a family of basal ganglia-thalamocortical circuits and their descending output stations. Because the small number of rules underlying the mobility gradient account for a large variety of behaviors, they may be related to the specific functional demands on these neurological systems. The EW system and the mobility gradient model should prove useful to ethologists and neurobiologists.
"Superiority and Inferiority: a Morphological Analysis of Free and Stimulus Bound Behaviour in Honey Badger (Mellivora capensis) Interactions"
YONA YANIV and Ilan Golani (1987)
Ethology. Vol. 74 (2) , pp. 89-116.
Abstract: In analyzing motor behaviour, we use a method of gestalt perception that relies less on intuition and more on rational processes. The elementary building blocks of behaviour in this study are single movements — distinct changes of relation between two adjacent parts of the body. The single movements are performed in groups around specific axes: whole body rotations around the vertical absolute axis, whole body rotations around the longitudinal axis of the body, and whole body rotations around the side-to-side axis of the body. In their full blown form these rotations amount, respectively, to pivoting, rolling and tumbling. During “ritualized fighting”, these rotations are incorporated into the behaviour of the badger in a fixed sequence, yielding a fugue of rotations. “Ritualized fighting” is comprised in the badgers of five higher level (whole body) building blocks: the three whole body rotations, squatting, and forward walking. These building blocks are termed in the present study component-variables. At a still higher level of analysis we reveal the effect of the environment (the moving partner), on the performance of these component-variables. We record continuously the parts of the bodies of the two partners that touch or almost touch each other. In this way, we specify the tactile and visual input which impinges on each of the partners at any one time in the course of the interaction. Then, we examine the effect of the very same input, on the types of response performed by the badgers. This method allows us to assess the freedom of movement, i.e. the number of different responses available to each of the partners when confronted with the same stimulus situation. The five component-variables generate four composite profiles of actual behaviour (the “inferior” female, the “inferior” male, the “superior” female, and the “superior” male). They form a common denominator in all the profiles, but vary systematically in amount, amplitude, and frequency from one profile to the next, yielding a gradient. Part of the gradient was also described in “ritualized fighting” in wolves, and in other species and situations. In wolves and badgers it involves a gradual transition from relative immobility in the most inferior, to extensive mobility in the most superior partner. We show, that the same stimulus situations elicit in the inferior the most fixed response sequences, and in the superior, the most variable ones. Inferiority consists of relative immobility and stimulus bound behaviour; superiority consists of extensive mobility and relatively free behaviour. The difference between fixed response sequences and “voluntary” behaviour is of degree, not of principle.

Supported by European Research Council under the uropean Community’s Seventh Framework Programme, ERC grant 294519 (PSARPS)