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123© Калуев А.В., 2004
EXPERIMENTAL MODELING
in anxiety and depression research
ALLAN V. KALUEFF
Medical School, Tampere University Hospital, University of Tampere, Tampere, Finland
Калуев А.В. Экспериментальное моделирование тревожности и депрессии // Психофармакол. и биол. наркол. 2004. Т. 4. № 2-3. С. 663670. Медицинская школа Университета Тампере, Тампере, Финляндия.
Тревога и депрессия обладают огромный влиянием на поведение человека и животных. В настоящей лекции делается междисциплинарный обзор существующих экспериментальных моделей в области тревожно-депрессивного поведения с целью рассмотрения ряда важных аспектов биологической психиатрии данных патологий ЦНС. Понимание нейробиологичес-ких и поведенческих маркеров тревоги и депрессии у животных поможет
специалистам-клиницистам лучше узнать нейробиологическую основу и пророду патогенеза.
t.Ключевые слова: тревога, депрессия, биологическая психиат-■ рия, экспериментальные модели.
Kalueff A.V. Experimental modeling in anxiety and depression research // Psychopharmacol. Biol. Nar-col. 2004. Vol. 4. № 2-3. P. 663-670. Medical School, Tampere University Hospital, University of Tampere, Tampere, Finland.
Anxiety and depression have dramatic impact on human and animal behaviours. We take an interdisciplinary
approach and review the existing experimental models of anxiety and depression in order to promote further understanding of «biological» aspects in biological psychiatry of anxiety and depression. The present lecture provides a comprehensive overview of the existing neurobehavioural markers and models of anxiety and depression. Knowledge of neurobehavioural aspects and theories behind animal experimental disorders described in the present paper will assist health professionals to better understand the biological nature and causes of anxiety and depression.
fKey words: anxiety, depression, biological psychiatry, experimental models.
INTRODUCTION
Stress is known to play the main role in pathogenesis of mental disorders including anxiety and depression [1-4]. According to McKinney [1], we use animal models as «experimental preparations developed in one species for the purposes of studying phenomena occurring in another species». Over the past decades, there has been intensive study of a variety of neurobiological aspects of depression and anxiety and it is now widely recognized that anxiety and depression are associated with definite specific biological changes. Mice and humans share more then 90% of their genes, and animal models seem to be a useful tool in bio-medical sciences, as evidenced by a notable increase in the number of active laboratories working in the field. Animal models are particularly of help in cases where the impact of stress cannot be studied in humans because of ethical and other like reasons. However, the choice of which biological correlates to study is not easy. Problems with animal models of human psychic disorders include i) the difference between human’s and non-human’s nervous systems, ii) the difficulty in determining analogous behaviours among species and iii) the need
in extrapolation of results from animals to humans. Such problems most likely reflect a significant difference in ethiology and complexity of anxious or depressive behaviours. In addition, the data derived from animal models are of value only to the extend that the models are valid [2], and the level of the disorder in animals may not be the level of the disorder in humans we want to model.
Today our understanding of how anxiety and depression occur in the brain is still quite limited despite the tremendous progress made in this field since 1950 s. In order to further promote cooperation between basic and clinical science, here we focus on a comprehensive and systematic approach to the existing neurobehavioural markers and experimental models of anxiety and depression.
GENERAL CONCEPTS
Behavioural repertoire of animals has long been used to detect effects on, and impact of, anxiety and depression [1, 3, 4]. A number of models, based on animal emotional reactivity, have been designed and proven to be bidirectionally sensitive to stressful
Table 1.
Animal models in the study of anxiety and depression
I. Depression: Acute: 1) Pharmacologic: Reserpine- or clonidine-induced depression
2) Stress-evoked: Porsolt test (forced swimming) behavioural despair task, tail suspension test, inclined/vertical screen test
Chronic: 3) Stress-evoked Learned helplessness (unsignalled inescapable shock) Vogel and Gellert tests
4) Social disruption: Maternal or peer separation, Social defeat, altered group hierarchy Reduced submissive behaviour
5) Chronic stress-evoked depression models (see also p. 7)
6) Sensory models: Olfactory bulbectomy
Long-term ZnSO4-induced anosmia
7) Anhedonic models Willner’s test (sucroze consumption), Hedonic behaviour suppression [2]
II. Anxiety: Acute: 1) Pharmacologic: Convulsant- or stimulant-induced anxiety
2) Stress-evoked: «Forced» single-factor (novelty) or multi-factor tests (eg. novelty + + aversion): elevated plus or zero-maze, light-dark box, holeboard, inclined or vertical screen test, seed seeking behaviour in hamsters, shock-probe defensive burying, etc.
Free exploration paradigm
3) Social models: Social interaction (File’s) paradigm
Chronic: 4) Stress-evoked: Learned anxiety (Geller conflict test), Chronic forced exposure to acute stressors
5) Social models: Chronic social defeat test*
6) Prenatal stress-evoked «state» anxiety models
7) Sensory models: Short-term ZnSO4-induced anosmia*, Exposure to novel or predator odors, Amputation of vibrissae
8) Innate anxiety: Selected «high-anxiety» strains
III. Transitory models: Initially anxiety then depression Anosmia-induced anxiety-depressive symptoms [13], partition test
IV. Combination models: Anxiety and depression states to be measured simultaneously **
V. Comorbidity models: Allows to model anxiety or depression in comorbidity with other psychiatric illnesses (eg. addiction, see [14] for details, epilepsy, etc)
Comments: *See [8] for details. ** Porsolt’s swim and tail suspension depression tests are also sensitive to some anxiolytic actions.
manipulations, including those of anxiety and depression [5], see Tables 1 and 2. Many of these models have been successfully used to test new anxiolytics or antidepressants and understand the underlying neural mechanisms [2, 3, 4] by simple, rapid and inexpensive ways of evaluating an animal’s condition (Table 3). Substantial progress has been made in our understanding which stressors may affect behaviour and how. However, there are several key
questions in this field we still have to answer. Can we really distinguish animal anxiety and depression? Do we have reliable neurobehavioural tools to assess anxiety and depression in animals? And, finally, do we always provide correct interpretations of behavioural changes seen in experiments? The paper will review the traditional animal models of, and discuss neurobehavioural approaches to, experimental anxiety and depression.
Table 2.
Summary of animal conditioned response-based models [15]
Two way avoidance conditioning test «Shuttle box» Rate of acquisition response
Accoustic startle Contraction in response to loud noise
Foot shock induced freezing Contraction in response to conditioned stimuli
Fear-potentiated startle Contraction in response to loud noise in conjunction with loud noise
Geller (Geller-Seifnert) conflict test Frequency of conditioned response coincidental to an electrical shock
Vogel conflict test Frequency of conditioned licking coincidental to an electrical shock
Table 3.
Principal behavioural profiles in experimental models of anxiety and depression
Behavioural indices Anxiety Depression
General locomotion Activated Inhibited*
Exploration Decreased Decreased
Self-grooming Activated (frequency) Activated (duration)
Immobility Activated (freezing) Activated (despair)**
Defecation, urination Activated ?
Aggression Activated Activated
Self-aggression 0 Activated
Transitions between behaviours Increased Decreased
Risk assessment Increased or decreased *** Decreased
Some other «specific» behaviours Activated**** 0 ?
Comments: ? means unclear or inconsistent effects, 0 means no effects. *activated in the open field in olfactory bulbectomy model of depression. **in Porsolt’s swim and tail suspension tests. ***depending on the model. **** e.g. seed finding, shock-probe defensive burying, etc., see [10] for details.
Classification of experimental animal anxiety and depression is a difficult task. Animal anxiety and depression taxonomy can be based on the nature and type of stressors employed (Tables 1, 2), with the continuum of animal models used in psychiatric research ranging from «basic» animal assays to sophisticated homologous models [6]. The former are based on animal behaviours that do not need to be similar to human symptoms while the latter share
some functional similarity with human behaviour. Depending on the aim of research, on can use simple models that utilize relatively primitive manipulations, complex models which incorporate both neurobehavioural and behavioural/cognitive aspects, or hybridic models that mechanically combine two working simple models in one new [7, 8], see also an example in [9]. Experimental anxiety and depression can be acute, sub-chronic and chronic (the latter is crucially important, for example, for modelling depression where behavioural symptoms persist for a period of weeks [2]). The models can be inducing pathology (e.g. by drugs, targeted gene mutations, brain lesions/stimulation or stressful external factors) and measuring pathology (in terms of behavioural and physiological reactions). Other classification considers the models as state or trait, as well as those based on unconditioned or conditioned response [10, 11].
Some authors [12] suggest that anxiety models can be based on: i) exploratory behaviours, ii) social behaviours, iii) defensive behaviours, iv) novelty responses, v) conditioning (active/passive avoidance), vi) suppression of hedonic behaviour, vii) conditioned fear. In addition, there are numerous models of anxiety and depression based on prenatal and neonatal manipulations, including acute and chronic exposure to various stressors or different psychotropic drugs (see [6] for a detailed and updated review). As expected, such experience resulted in long-term behavioural and neurobiological changes similar to those seen in humans having early life stress.
Models of anxiety and depression can be «natural» (based on measuring natural animal behaviours) or «artificial» (utilizing behaviours not normally seen in natural conditions), Tables 1 and 2 [8, 10]. Natural animal models aim to reproduce behavioural and pathological aspect of the disorder, to investigate the neurobiological mechanisms that are not easily amendable to study in humans, and allow a reliable evaluation of a number of external factors including pharmacological agents [11]. Such ethologically based paradigms are more sensitive to stress compared to «artificial» animal conditioned behaviour models which usually use strong and often painful stressors (Table 4). Clearly, the stressfulness of the test has to be taken into account when analysing the behaviour, as it may significantly affect behavioural performance. Since extreme stressors suppress general activity and result in non-specific alterations in animal performance [7, 8], our paper will now focus on the first group of models, more relevant to assess the nature of anxiety and depression.
PRINCIPAL METHODOLOGICAL ISSUES
Papers dealing with modification, validation or refinement of the existing models and introducing the
Table 4.
Major behavioural measures in experimental models of anxiety and depression
Tests Neurobehavioural parameters Anxiety Depres sion Ref.
Open field (circular, square or Defecations/urinations number and duration + -
rectangular open lit arenas) Total distance traveled or squares crossed - + *
Speed of movements + -
Distance in the inner area -
Number of squares crossed in the inner area - +
Distance in the outer area - +
Self-grooming latency - - [20, 26,
duration + +? 31, 32]
frequency + **
% of interrupted (aborted) or incorrect groomings + +
Average duration of a single grooming -
Stretch Attend postures + -
Latency of the 1st and the 2nd visits to the central area + ?
Latency to leave the central area + ?
Open field with novel objects Approach latency + 0 See [20]
Number of contacts - 0 for a
Duration of exploration of the novel object - 0 review
Elevated plus maze (plus-shaped Latency to leave the centre +
maze) Total arms entries (4 paws criterion) a -
Enclosed arms entries +
Open arms entries (4 paws) and rears (2 paws) -
Time spent in the open arms -
Time spent in the enclosed arms +
% Open arms entries - [17, 26,
% Time spent in the open arms - 31, 33)
Head dips -
Defecations, urinations + +
Self-grooming latency + -
duration + +
frequency + -
Central platform crossings and time spent - ?
Hole board test (open field Head dipping (hole poking) - ?
arena with «exploratory» holes latency + +
in the floor) number, duration - - [20, 26, O I i
Defecations, urinations, total distance traveled/squares as in as in
crossed, distance/squares crossed in the inner area, the the 31]
distance in the outer area, self-grooming, rears. open open
field field
Light/dark box (two boxed Light box entries number (4 paws criterion) - -
interconnected with a sliding Light box time spent - -
door) Light box rears number (2 paws criterion) - -
Duration of light box rears - - [21, 31]
Latency of the first rear and entry - -
Vertical activity in the light box (c) + ?
Urinations, defecations, grooming + ?
Exploration of novel objects Number of approached and contacts - -
Duration of contacts - - [31, 34]
Latency of the first approach/contact + +
Free exploratory paradigm Number of entries to the novel compartment - ?
Time spent in the novel environment - ? [35]
Latency to enter the novel compartment + ?
Stretch attention, rearing to the novel box - ?
Porsolt’s swim test (water tank) Immobility latency (until first floating) ? -
Immobility duration in the water tank ? + [24, 31]
Swimming average speed and distance - -
Olfactory bulbectomy Behavioral hyperlocomotion in the open field - + [37]
Aggression + [3 7]
Tail suspension test Immobility latency +? +
Immobility duration +? + [31, 38]
« Tail-climbing» - -
Inclined screen retention test Time spent on the screen (falling latency) - - [31]
Urinations, defecations + - (?) [31]
Pinch-induced catalepsy Duration of catalepsy +? +? [3Q]
Required number of pinches +? +? [39]
Stress-induced hyperthermia The amplitude of hyperthermia + ? [40 41]
The duration of hyperthermia + ? [40, 41]
Hyponeophagia Latency to start eating + ? [15]
Comments: + means activation of a behavioural pattern, — means inhibition of a behavioural pattern, ? means unclear or inconsistent effects. *in olfactory bulbectomy depression model. **Different effects of anxiety (shortening, reversals) and depression (prolonged, stereotypic).
Table 5.
Summary of validity of animal models of anxiety and depression
Validity Impor tance Brief description
Major
Face Reflects phenomenological similarities (isomorphism) between the model and human pathology to be modeled
Predic- tive + Based on ability to predict drugs or manipulations effective in animal models to be effective in humans. May be limited to the drugs or manipulations it has been designed for.
Construct ++ Based on similar theoretical rationale (homology) behind the pathology in animals and humans. May be limited to the extend of our knowledge of pathological mechanisms
Addi- tional
Discrimi- nant Degree to which a test measures aspects of a phenomenon that are different from other aspects of the phenomenon that other tests assess
Conver- gent Degree to which a test correlates with other tests to measure the same construct
Ethiolo- gical — Degree of similarity of ethiology of animal and human states
Genetical + Degree of similarity of the genes involved in anxiety or depression induced in a particular test
Comments: — not important, + important, ++ critically important.
new experimental paradigms are reported with astonishing frequency. Are animal anxiety and depression a good approximation of human disorders? Which tests are good models of anxiety or depression? Which particular subtypes of anxiety of depression they model? — these questions are relatively rarely asked, but are fundamentally important. The use of nearly all animal models from all groups has been extensively critisized in the literature. First, one has to keep in mind that many clinically important symptoms, especially cognitive-based, of anxiety and depression can not be directly modeled in animals. Second, it appears that serious modelling problem is that the measures are confounded and reflect changes in general activity, exploration and anxiety-depression levels [16, 17, 18, 19]. Sometimes poor correlation between different behavioural measures taken in the same test, or the same measures taken in several different tests, is another problem [8]. For example, demonstrate that anxietylike behaviour detected by using the plus-maze test is not detectable by using the two compartment exploratory test or the inner segment ambulation scoring in the open field-test. Furthermore, grooming
and defecation can often be seen as the only behaviours that change in the tests designed to measure anxiety behaviours, not grooming, urinations and defecations [20, 21]. Scoring of defecation (for years used as «emotionality index») often fails to correlate with any of the parameters in rodent anxiety models [8]. The simplest task — distinguishing between horizontal exploration and locomotion in the open field, often mistakenly used synonymously in the literature — is also open for further elaboration [22]. Thus, since it is difficult to interpret a subjective anxiety or depression level based on a single behavioural measure, proper understanding of animal state is only possible through assessment of interaction between behavioural and physiological variables in the multivariate analysis [23]. Also importantly, various forms of psychopathologies in animals and humans can be characterized as context-regulation disorders. This means that subjects may sometimes produce «normal» behaviour in inappropriate contexts. As such, a special research on behavioural contexts may be needed in the field of animal anxiety or depression biological psychiatry.
It is important to remember that animal emotional behaviour is not just «plus» or «minus». It is composed of several dimensions including anxiety, exploration, locomotion, risk assessment, general arousal and coping [24]. These dimensions interact with each other and cognitions, giving us a mosaic picture of animal or human behaviour. That is why traditional quantitative behavioural methods (i.e. latency, frequency and duration parameters and their spatial, temporal or sequential patterns) of animal stress are now combined with sophisticated analysis to assess «not just the presence or absence of these behaviours, but also whether or not the ... acts, postures and gestures are fully developed in intensity, latency and patterning» [25]. In this context, trivial rather than relevant relationships among certain behaviour indices taken from the same test and common low correlations among variables apparently measuring the same phenomena in different models of anxiety or depression [26]. Because not all significant and robust behavioural changes are, in fact, meaningful parameters for assessment of animal anxiety and depression, there is a need for clear-cut measures that will be resistant to experimental conditions or apparatus design of particular laboratories but show reliable and predictable changes following experimental manipulations affecting anxiety and depression states (Table 4).
However, here appears a new cluster of issues. First, can one model different subtypes of anxiety and depression? Distinct subtypes of anxiety can be modeled in the same test as suggested in [27] for the elevated plus maze (single vs. repeated testings). Second, although depression and anxiety are considered to be separate entities according to current diagnostic classifications, in clinical practice these two
conditions are often seen to co-exist. «Ideal» modeling of anxiety or depression in animals presumes that in order to achieve better results we model either pathology separately. The important problem now is whether animals may possibly have comorbidity of depression and anxiety. Theoretically we see no reasons for excluding such cases, and they indeed may represent certain interest for the researchers. Relatively few studies of that kind have been conducted and there is a great need in developing specialized models which will allow to detect and study putative comorbidity states in animals. This can be an important and fruitful direction for future studies in biological psychiatry.
Another key question to be asked here is whether we need a single model to be differentially sensitive to anxiety and depression. In other words, can we model several pathologies that develop one by one, in the same experimental test? From neurobehavioural perspective, such «combinational» models can be extremely useful and require future elaboration, and some promising approaches already come from neurogenetics. For example, Wistar-Kyoto rats have been recently suggested as an animal model of anxiety and depression [28] since they demonstrate frequent anxiety-like freezing and also depressive-like swim immobility. Gass et al. [29] suggested that mice with targeted mutations of gluco/mineralocorticoid receptors are the model of anxiety and depression. Perhaps, encouraging can be recent results obtained in high-anxiety HAB rats [24], considered to be a reliable model of trait anxiety and depression. Thus far, measuring comorbidity of anxiety or depression with other pathologies (addiction, etc), or measuring these states occurring consequently, may present an important field of research. It is, however, critical to ensure that all such models are being thoroughly validated.
VALIDITY AND RELIABILITY OF THE MODELS
The discussion focusing on different aspect of animal models validity is key in biological psychiatry. Validation is defined as the process by which the reliability and relevance of a method are established for specific purposes. Reliability is characterized by the reproducibility of a test within and between laboratories and over time. Since numerous differences exist between laboratories, good reproducibility at least between the same laboratory has to be established [24]. At present, three principal and some additional validity criteria have been formulated and substantiated for animal models of anxiety and depression, including predictive, construct, concurrent or convergent, discriminant, ethiological and face validity [7, 30], see also Table
5. In addition, genetical validation based on behavioural phenotyping approach, is becoming
increasingly important [15]. A «behavioural phenotype» refers to the specific and characteristic behavioural repertoire exhibited by animals with a specific genetic/chromosomal disorder [15]. As such, finding sets of «anxiety» or «depression» chromosomes involved in traditional experimental models in some cases will assist in genetical validation of novel putative models of anxiety or depression. However, the question as for whether certain behaviours shall be a part of behavioural phenotype, is far from being clearly understood. In animal models, as in the clinic, an association between behaviour and syndrome, and between the syndrome and the gene, is not always clear-cut and linear.
On validity basis, animal models can be classified as correlational (based on predictive validity), isomorphic (based on face validity) and homologous (based on construct validity). A model shall fulfill all 3 criteria in order to be good model [42, 43] which means to be correlational, isomorphic and homologous at the same time. However, this situation is not seen in animal modeling very often. For example, traditional models of depression such as Porsolt’s swim and tail suspension tests lack face and construct validity but are extremely good at predictive validity [43]. Despite the fact that some animal models have poor construct and predictive validity, and there is a disconnect between predictive validity and face validity [11], construct validity seems to be the most important for the animal model of anxiety and depression.
CONCLUSION
As it was mentioned earlier, all animal models are generally seen as an attempt to reproduce a psychiatric disorder in a laboratory animal [1]. However, since the symptoms of psychiatric disorders are often being revised and their pathogenesis revisited [30, 44, 45], some caution is needed before claiming or using an animal model of anxiety or depression. With this in mind, we shall always remember that, as McKiney [46] incredibly timely and rightly notes, generating the perfect animal model does not represent a separate goal of research in biological psychiatry, rather the model and its constant evolution represents an integral part of biological psychiatry. And, of course, modelling proceeds most effectively when psychiatrists who are experts in the phenomena in question join forces with neuroscientists who know and understand available modelling tools [47]. Today, with the growing number of medical professionals being involved in basic research, and neuroscientists being heavily involved in clinically-oriented studies, an interdisciplinary view of anxiety and depression research, linking human data to animal experimentation, is becoming extremely important.
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