Abstract
Depression, among other mood disorders, represents one of the most common health problems worldwide, with steadily increasing incidence and major socio-economic consequences. However, since the knowledge about the underlying pathophysiological principles is still very scanty, depression and other mood disorders are currently diagnosed solely on clinical grounds. Currently used treatment modalities would therefore benefit enormously from the development of alternative therapeutic interventions. The implementation of proper animal models is a prerequisite for increasing the understanding of the neurobiological basis of mood disorders and is paving the way for the discovery of novel therapeutic targets. In the past thirty years, since the seminal description of the Forced Swim Test as a system to probe antidepressant activity in rodents, the use of animals to model depression and antidepressant activity has come a long way. In this review we describe some of the most commonly used strategies, ranging from screening procedures, such as the Forced Swim Test and the Tail Suspension Test and animal models, such as those based upon chronic stress procedures, to genetic approaches. Finally we also discuss some of the inherent limitations and caveats that need to be considered when using animals as models for mental disorders in basic research.
| Abbreviations | ||
| 5-HT | = | 5-hydroxytryptamine |
| CFS | = | chronic foot-shock stress |
| EE | = | enriched environment |
| ENU | = | ethylnitrososurea |
| FST | = | Forced Swim Test |
| HPA | = | hypothalamic–pituitary–adrenal |
| ICSS | = | intercranial self-stimulation |
| LPS | = | lipopolysaccharide |
| NIH | = | novelty-induced hypophagia |
| SD | = | social defeat |
| SSRI | = | selective serotonin re-uptake inhibitors |
| TST | = | Tail Suspension Test |
| UCMS | = | unpredictable chronic mild stress |
Key messages
Depression can be modeled in laboratory animals.
Animal models can be used to investigate the pathophysiological mechanisms underlying depression in human patients and to develop novel and evaluate existing antidepressant treatments.
The translational applicability should be considered in the design of new and modulation of existing animal models for depression.
Introduction
Depression (major depressive disorder, major depression, unipolar depression, clinical depression), like most other mental disorders, is currently diagnosed usually on clinical grounds without any reference to etiology or diagnostic biological markers. This is due to the still limited understanding of the underlying pathophysiological mechanisms of the disorder. Depression is one of the leading causes of disability worldwide (Citation1), with significant morbidity (Citation2) and mortality (Citation3). The weight on national economies goes far beyond the actual treatment costs and loss of earnings due to disabilities, since patients diagnosed with this disease are also facing a higher prevalence of somatic conditions, such as heart disease and obesity (Citation4,Citation5). Despite this heavy burden on the public systems, not to mention the harm to and pain of the affected individuals, diagnosis and treatment of depression are still unsatisfactory. The range of currently available therapeutic options is narrow, and standard pharmacological treatment plans, which are successful in less than 50% (Citation6), are often associated with a range of very serious side-effects (Citation7). The lack of objective diagnostic criteria, together with the heterogeneity of the depressive disorder, poses an increased difficulty for the development of valid laboratory animal models. Basic science approaches addressing both the disease and possible therapeutic interventions at the systemic, cellular and molecular levels in adequate animal models are therefore urgently needed in order to develop antidepressants with novel mechanisms of action. Since the seminal first description of the Forced Swim Test as a system to probe antidepressant activity in rodents, by Porsolt et al. in 1977 (Citation8), a variety of new approaches for studying depression-like behaviors in experimental animals has been developed. In this review we describe some of the various strategies that have been used to date to establish animal models and test systems to study the biological mechanisms underlying and/or mediating major depression in humans. Finally, we discuss some of the central questions and important caveats that need to be addressed when using animals to learn about depression in humans.
However, we cannot provide a complete coverage of the ample literature on animal models of mood disorders, which is extensive and substantial, and several outstanding reviews from specialists of the individual areas are available (Citation9–20).
Model versus test
A ‘model’ is defined as any experimental preparation developed for the purpose of studying a condition in the same or a different species. Usually, models are animal preparations that attempt to mimic a human condition, including human psychopathology. As such, a model comprises both an independent variable, known as the manipulation to induce the respective condition, and a dependent variable, which comprises the behavioral/neurochemical/molecular read-out (Citation21). A model can be developed in an attempt to mimic a psychiatric disorder, such as depression, in its entirety, which poses a significant difficulty since it requires reproducing in animals a multi-faceted, complex and even in humans only descriptively defined disease. An alternative approach is based upon the rationale to mimic in the animal model system only individual symptoms associated with the disorder. In this case, specific behaviors/phenotypes which have been consistently observed in patients are being modeled in experimental animals. The particular phenotype must be readily observable, quantifiable and reliably reproducible, while it may not be specific or pathognomonic for the respective condition.
An animal experimental set-up which provides a screening procedure to evaluate the outcome of a particular experimental manipulation is referred to as a ‘test’. As opposed to a model, it comprises only a dependent variable, which is used to measure the efficacy of the manipulation tested. Thus, while a test, as screening procedure, may evaluate the potential existence of depressive-like behavior, a model is determined by its ability to induce, by defined chemical/surgical/genetic or other interventions, precisely this depressive-like phenotype.
Defining validity criteria
When developing and evaluating an animal model, it is essential to refer to its specific purpose since the proposed application determines the criteria used to assess the validity of the respective model. Stringent criteria need to be applied to establish, for any animal model, its validity and utility with regards to the human condition. According to Willner (Citation22), the validity of an animal model is characterized by three different aspects. The animal model should reproduce some of the symptoms of depression observed in humans (face validity). The symptoms in the animal should be mediated by equivalent neurobiological mechanisms as in humans (construct validity). Currently used pharmacological and non-pharmacological treatments for depression should modulate the behavioral changes observed in the animal model (predictive validity). It has to be noted that the validity of the animal model of course also relies on the information available concerning the human disease. Thus, as long as the neurobiological mechanisms underlying depression in people are not clearly understood, it will be difficult to establish an animal model with a high degree of construct validity.
To be successfully used in preclinical research, an animal model additionally has to be relatively easy to carry out by trained personnel (usability) and the behavioral and biochemical/molecular phenotype of the animal model should be highly consistent over time (reliability).
Replicability of results constitutes the foundation of empirical research, and the issue of reproducibility of behavioral phenotypes among laboratories is one of the greatest concerns in behavioral neuroscience. Reproducibility can be defined as the level of agreement between data obtained from the same experiment carried out independently in the same or different laboratories. Standardizing laboratory and testing conditions is essential for providing consistency and comparability of results among different laboratories and over time and for the validation of the model/test used (Citation23). It has to be mentioned that despite enormous efforts to standardize testing conditions, significant variations in the behavioral phenotypes observed in different laboratories carrying out ‘the same’ experiment have been observed, suggesting a major impact of the gene–environment interaction (Citation24,Citation25).
Standardization should not be interpreted as establishment of dogmatic rules but has to be flexible to changes. In fact, practical experience gained from carrying out experiments, even under ‘non-standard’ conditions, may generate essential information about previously not considered aspects and should feed back to enable appropriate adaptation and modification of the ‘standard’ conditions (Citation26). Nevertheless, it has to be kept in mind that the greater the extent of standardization of experimental conditions, the lower the degree of generalizability of the results. If the range of conditions under which a specific hypothesis has been tested is narrow, the applicability of the information obtained across experimental settings or even species becomes more uncertain. External validity, the level up to which a result can be corroborated in various situations, populations, and species (Citation23), is of essential importance when using animal models. It seems pertinent that hypotheses derived from observations in a particular animal model, no matter how reproducible, should be validated under different conditions or by a separate approach in order to justify inferring general principles from observations obtained in this model.
Animal tests: screening procedures developed to detect selectively the effects of pharmacological antidepressants
The first-generation and today still most widely used animal tests for depression have been originally designed to detect most specifically and sensitively behavioral responses to pharmacological antidepressants. These assays—because of their low cost, easy-to-use, and high-throughput options—have become widely accepted as convenient tools to evaluate the efficacy of a large series of substances for antidepressant-like activity. However, they are by themselves of restricted use for investigating the pathomechanisms and pathogenesis of depression (Citation16).
Forced Swim Test (FST)
Originally developed by Porsolt et al. (Citation8), the Forced Swim Test is to date the most popular behavioral test to evaluate depression-like behavior and antidepressant efficacy in rodents. The paradigm is based upon the evaluation of immobility, as a measure of ‘behavioral despair’, which rodents adopt some time after being placed in a beaker filled with water from which they cannot escape. The time spent immobile has been shown to be significantly reduced in the presence of pharmacological and behavioral interventions for depression (see for review e.g. (Citation27,Citation28)). The vast majority of clinically active antidepressants, ranging from tricylic antidepressants (Citation29), such as imipramine or desipramine, and selective serotonin re-uptake inhibitors (SSRIs), such as fluoxetine (Citation29), to novel pharmacological compounds, such as agomelatine (Citation30), an agonist of the melatonergic MT(Citation1) and MT(Citation2) receptors as well as a 5-HT(2C) receptor antagonist, have been found to induce a detectable behavioral effect in the FST. Although anxiolytic substances and antipsychotics do not alter immobility in the FST (Citation31), other behavioral tests may be needed to exclude motor effects or general stimulant activity as confounding factors when evaluating the antidepressant activity of a novel compound or the effects of a genetic manipulation. Moreover, it has to be noted that the FST was originally developed for rats, which are known to be very good swimmers. In contrast, mice are more water-avoidant, and although the FST has been extensively used with mice it has to be taken into consideration that the FST may be more aversive and stressful for mice than for rats.
Tail Suspension Test (TST)
In the Tail Suspension Test (TST), as in the FST, immobility, reflecting behavioral despair, is used as a measured behavioral variable. The TST comprises a technically very simple set-up in which mice are suspended from a horizontal bar by taping the tip of their tail to the bar and the time spent in immobile positions is evaluated. The TST is most widely used in both rats and mice. Comparably to the FST, sensitivity of the TST to all major classes of pharmacological antidepressants, including desipramine, imipramine, atypical antidepressants (bupropion, citalopram), and SSRIs, such as fluoxetine and paroxetine, has been reported (Citation32–34). However, in the last years both the FST and the TST have been substantially questioned as behavioral tests for depression. A major point of criticism raised concerns the fact that both tests represent an acute situation and that they therefore do not mimic the temporal features of onset, persistence, and therapeutic effects of clinical depression in human patients.
Novelty-induced hypophagia (NIH)
The inhibition of feeding in a novel environment constitutes a measure of the anxiety-related component of depression (see for review (Citation10)). In this test, which has been successfully used in mice and rats, the latency to consume a palatable snack and the amount consumed are assessed in a novel cage and compared to the same parameters measured in the home cage. Significant effects of chronic, but not acute or subchronic, treatment with fluoxetine have been described (Citation35). The novelty-induced hypophagia (NIH) test examines the efficacy for antidepressants in the treatment of anxiety but is also a tool to investigate anxiety as a co-morbid manifestation of depression. Considering the high degree of co-morbidity between anxiety disorders and depression, with up to 90% of patients with anxiety disorders experiencing clinical depression at some point in their lifetime, the need for highly specific animal models has been questioned (Citation36). As a matter of fact, it has been proposed that besides specific anxiety and depression paradigms, animal models allowing investigation of shared pathogenic mechanisms, risk factors, and the neurobiological basis for co-morbidity between these disorders, should be actively established (Citation36).
Measurements of anhedonia
Anhedonia, which has been described as ‘markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day’, is one of the core symptoms of depression (Citation37). Anhedonic behavior constitutes an endophenotype of depression which can be reliable reproduced and measured in laboratory animals. However, it has been noted that anhedonia occurs in a large percentage of psychiatric patients, regardless of their diagnosis (Citation38). Impairment in the mesolimbic dopamine system, a major component of the brain reward circuitry, is thought to underlie the anhedonic behavior (Citation39). Several paradigms are available to test anhedonic behavior in rodents; two of the most popular ones are described below.
Sucrose preference. Evaluation of preference for, and consumption of, a 1%–2% sucrose solution in a two-bottle choice setting in comparison to water, is one of the most commonly used rodent models of anhedonia. The physiological preference for the sweet solution has been found to be significantly reduced by chronic stress in rodents, and this reduced consumption of sucrose is assumed to be indicative of a reduction in the rewarding effectiveness of the sweet taste (Citation40) in analogy to the anhedonic behavior described in depressed patients. Treatment with antidepressant drugs, such as citalopram (Citation41) and paroxetine (Citation42), has been shown to inhibit the development of this behavior under conditions of chronic stress and to reverse the existing anhedonic phenotype. Although the reduction in sucrose preference following chronic stress has been first described in the rat there are now a series of studies showing the applicability of this model also to mice.
Intracranial self-stimulation (ICSS). ICSS is a valuable paradigm for studying the properties of the endogenous reward system and to evaluate the rewarding properties of drugs and other natural reinforcers (Citation43). Several brain regions implicated in depression in human patients, such as the hippocampus and the amygdala, are also involved in ICSS responding in rodents (Citation44), making ICSS a suitable tool to evaluate depression-related behavior in a preclinical setting. An important advantage of ICSS is that there is no development of tolerance to the stimulation, and the response can be measured for extended time periods (Citation44). While ICSS has been tested in various animal models of depression (Citation44–46), it can be reliably applied to rats and mice and offers good face and construct validity, its predictive validity remains to be further corroborated.
Homologous models: reconstructing in animals behaviors forming part of the depressive disorder in people
Whereas animal tests are very useful for high-throughput screening of compounds with potential antidepressant activity, they are of limited value for studying the etiological and pathogenetic underpinnings of depression which can only be assessed in bona fide animal models (Citation21). Homologous models are based upon the principle that particular features of human behavior can be reproduced in animals which are mediated by comparable biological mechanisms. We will briefly discuss some of the most commonly used ones.
Chronic stress paradigms
Experience of stressful events, especially when repeated, is one of the major predisposing factors for the development of an ample spectrum of psychiatric conditions, including depression. Hypothalamic–pituitary–adrenal (HPA) axis hyperactivity has been reported in depressed patients and in chronically stressed animals. It has recently been proposed that stress may enhance the occurrence of depression through its negative effects on synaptic plasticity (including neurogenesis), whereas support of synaptic plasticity through antidepressant treatment seems to ameliorate stress-induced dysfunctions.
Unpredictable chronic mild stress (UCMS). The UCMS procedure involves exposing rodents to a series of mild unpredictable stressors in a random order over several weeks. As a result, the animals acquire an anhedonic behavioral state which can be reversed by chronic but not acute treatment with compounds belonging to the most popular classes of antidepressant medications, such as desipramine, imipramine, maprotiline, moclobemide, fluoxetine, and citalopram (Citation13,Citation22,Citation47). Moreover, it has been demonstrated that exposure to UCMS induces a series of persistent neurochemical, neuroimmune, and neuroendocrine changes paralleling those observed in human depression (Citation22). Nevertheless, reservations concerning the reproducibility of the behavioral results obtained have been raised (Citation27,Citation31), thus questioning the reliability of the model. Moreover, there are only a limited number of studies that have used the UCMS model in mice (Citation27), further questioning its applicability with regards to genetically modified animals, which constitute mainly mouse lines.
Social defeat (SD). The SD model involves a form of chronic social stress, which shows similarity to stress-induced psychopathology in humans and can be reversed by chronic but not acute treatment with the pharmacological antidepressant imipramine (Citation48). Also in human patients the clinical effect of antidepressants becomes apparent only after prolonged treatment periods (Citation49). The SD procedure, which has been used in rats as well as in mice, involves the daily exposure to a novel, physically superior aggressor for a defined period of time and results in significantly reduced display of social interaction (social avoidance) and increased anxiety-like behavior of the defeated animal (Citation48,Citation50). However, SD may also relate to psychiatric syndromes other than depression (such as social phobia and post-traumatic stress disorder) and a more complete characterization of the paradigm is needed in order to attribute it to a specific clinical entity.
Chronic foot-shock stress (CFS). Several weeks of daily exposure to mild electric foot-shocks has been found to induce depressive-like behavior in rats in the FST which is accompanied by reduction in neurogenesis and can be reversed by treatment with citalopram (Citation51). In mice, CFS has been found to induce depression-like activity in the FST, but not in the TST (Citation52), pointing towards species-specific sensitivity to this paradigm. While CFS does present with good face and predictive validity, it does not seem to be the most ethologically relevant stress paradigm.
Chronic restraint stress. Chronic restraint stress is induced by placing rodents into a well ventilated transparent tube for several hours per day during 2–3 weeks. As a result, rodents display depressive-like behavior, which can be reversed by drug treatment with reboxetine (Citation53) and desipramine (Citation54) and in conditions of enriched environment (Citation55). Chronic restraint stress causes impairment of hippocampal neurogenesis (Citation55), down-regulation of brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 (Citation53) and alterations in synaptic plasticity markers (Citation54). However, it has recently been proposed that daily exposure to the same kind of stressor at the same time (such as daily restraint stress) is experienced as predictable mild stress, which may actually improve mood and enhance hippocampal neurogenesis in mice (Citation56). Similarly, it has been found that predictable chronic restraint stress reduces learned fear and induces hyperactivity, in contrast to what would be observed in a depression-like phenotype (Citation57). Thus the relevance of this paradigm as animal model of depression is questionable.
Adverse early life events
Adverse early life events have been proposed as a major risk factor predisposing for the development of various psychiatric disorders, including depression (Citation16). Early exposure to stress and absence or dysfunction of the parental protection significantly contributes to mental disease-related susceptibility (Citation16). Various different approaches have been successfully used to study the effects of adverse early life events on the development of psychiatric conditions, including depression, later in life. Below we provide examples of some of the most prominent paradigms, each of which has been described using protocols with variations in the specific conditions applied.
Maternal deprivation. In this model of dysfunctional parenting, the mother is separated from her pups for designated periods of time usually within the first 2–3 postnatal weeks. The consequences of this procedure are two-sided: The offsprings are repeatedly deprived of maternal care during a period critical for physical and mental development. Additionally, as a result of the disrupted parenting situation, the mother's caring behavior becomes stunted resulting in inappropriate attention towards the pups. It has been shown that maternal separation leads to an increase in anxiety and depression-like behaviors in rats (Citation58). Whereas prolonged separations from the mother (3–4 hours daily) have been shown to significantly affect the stress and depression-related behaviors of the offsprings later in life, short-term separations (15 min daily) have been found to be more stressful for the dams (Citation59). The neurobiological aberrations induced in this neonatal stress model are persistent and involve changes in the hypothalamic–pituitary–adrenal (HPA) axis activity (Citation60) together with alterations in the noradrenergic (Citation61) and opioid system (Citation62). Moreover, reduction in the number of neurons, resulting from decreased proliferation and augmented apoptosis of hippocampal neurons, has been described as a result of maternal deprivation in rodents (Citation63,Citation64). Paradoxically, neonatal handling has been observed to result in a reduction of anxiety-related behavior and stress sensitivity (Citation65,Citation66).
The maternal deprivation model is of particular interest for studying the role of early life events for the development of psychopathologies later in life. In fact it has been proposed that the adverse experience leads to hypersensitivity to glucocorticoids, and this prevents structural plasticity and reduces the ability of the hippocampus to respond to stress in adulthood (Citation64). Additionally, an epigenetic effect of maternal separation stress is indicated by the fact that females that themselves have undergone maternal separation as pups are more prone to present with deficient parenting behavior (Citation60,Citation67).
Prenatal stress models. A series of experiments in animals have described the effects of prenatal stress on the developing offspring. Adverse effects on physical and mental development (Citation68,Citation69) and persistent behavioral manifestations have been described as consequences of prenatal stress. Most prominent are increased anxiety and depression-like behavior and enhanced stress sensitivity in the adult life (Citation70), paralleled by chronic alterations in HPA axis activity and alterations in noradrenergic, dopaminergic, and serotonergic signaling (Citation71,Citation72). One of the well documented models of early stress involves prenatal restraint where the pregnant dam is kept for a designated period of time over several days in a well ventilated but tight plastic tube which does not allow any movement. Prenatal restraint has been found to result in long-term neurobiological and behavioral impairments including alterations in feedback mechanisms of the HPA axis, disruption of circadian rhythms and altered neuroplasticity (Citation73). Another procedure which is based upon psychological rather than physical stress consists of the experimental animal having to observe through a transparent wall in a social communication box another animal being electrically shocked. This procedure has been shown to result in altered anxiety and depression-like behavior in the offsprings (Citation74). In general, the prenatal stress model is of high predictive and face validity since several neurobiological and behavioral impairments resulting from prenatal stress resemble those observed in depressed patients (Citation75).
Olfactory bulbectomy
Olfactory bulbectomy (OB), like some other animal models of depression, has gained considerable interest due to the fact that in this model antidepressant effects of pharmacological compounds can be discerned only after chronic but not after acute drug treatment (Citation76,Citation77). Thus, this procedure has been proposed as a suitable tool to investigate the temporal development of antidepressant efficacy, which, in the human population, also becomes apparent only after prolonged treatment duration (e.g. (Citation78)).
Rodents subjected to surgical removal of the olfactory bulbs have been shown to present with increased open-field activity and avoidance-learning deficits, together with endocrine, immune and neurotransmitter systems changes, that parallel many of those seen in depressed patients and which can be reversed by chronic treatments with some antidepressant drugs (Citation17). It has been proposed that these symptoms are caused by a major dysfunction of the cortical– hippocampal–amygdala circuit induced by the bulbectomy and that therefore OB may also serve to investigate some of the pathogenetic mechanisms acting in major depression. This model has been originally developed and is still mostly used in rats, while only a limited number of studies in mice are available (Citation27).
Learned helplessness
‘Learned helplessness’, which has been proposed as a model of ‘stress coping’, describes a collection of behavioral manifestations resulting from experience of stressors which cannot be controlled by the behavioral responses of the subjected individual. It has been found that after being exposed to unpredictable and uncontrollable stressful events, animals do not learn to escape the stressful situation when later probed in a new task in which they are given the opportunity to control the stressor, usually by escape (Citation79). It has to be noted that learned helplessness has been originally developed in rats and was only later translated to mice.
Learned helplessness has been established as a model for depression based upon the fact that behavioral correlates of helplessness are seen as a frequent feature in depressed patients and due to its pharmacological specificity for antidepressant drug treatment. Whereas chronic treatment with imipramine, desipramine, iproniazid, or pargyline and many other antidepressant drugs has been shown to reverse learned helplessness, chronic treatment with anxiolytics or stimulants has no effect (Citation79). However, the model has been the subject of major criticism. The concerns raised are mainly centered on the fact that only a small percentage of animals subjected to the paradigm indeed develop measurable behavioral symptoms of learned helplessness and that on the other hand several strains of mice endogenously present with escape deficiencies which are independent of exposure to uncontrollable stressors (Citation80).
Tackling the genetics of depression in animals: from selective breeding to gene-targeting approaches
Depression can be seen as multifactorial illness in which a series of environmental and genetic factors are potentially interacting in the etiology of the disease (Citation81). The heritable basis of depression is considered as highly complex and of polygenic and epistatic nature (Citation82). As for all other mental disorders, mice have been selected as the model organism of choice in the quest to identify the genetic underpinnings contributing to depression, for several reasons: The majority of the mouse genes have a homolog in the human genome. Moreover, mice are cheap, easy to keep and reproduce fast, thus providing the ideal system for selective breeding. Additionally, the mouse genome is readily accessible by gene-targeting and transgenic techniques and the phenotype of the genetically modified animals can be assessed in standardized behavioral tests. Moreover, gene-targeting approaches in rats have been of limited success so far.
However, the use of genetically modified mice, though extremely valuable, has to be regarded in light of some important caveats: The constitutive mutation of a gene raises the issue of possible compensatory mechanisms which may mask or contaminate results with regard to the functional role of the gene in question. Also, the importance of the genetic background cannot be underestimated, since the most commonly used inbred mouse strains in neuroscience research differ significantly in terms of behavior, including those related to depression (see below).
Genetically modified mice
Mice with genetically modulated levels of a particular protein have been extremely useful in depression research. Since the first attempts to use genetic engineering techniques in mice to understand mental illnesses, more than 80 different strains of genetically modified mice with an assigned depression-related phenotype have been developed (www.informatics.jax.org (Citation82)). Analysis in these mouse strains provides some insight into the role of the specific protein in the pathophysiology of depression, allows testing of the validity of current molecular theories of depression and screening for alternative targets for antidepressant treatment (Citation27). The generation of several of these mouse lines is based upon an already determined importance of the targeted molecule for the pathomechanisms involved in depression. Excellent examples are found in a series of genetically modified mice in which the expression of a protein of the serotonergic system (i.e. 5-hydroxytryptamine (5-HT) transporter, 5-HT1B, 5-HT1A, and 5-HT4 receptors, etc.) is modified. Outstanding original articles and dedicated reviews summarizing the findings obtained with these mice are available ((Citation83–86); see for review e.g. (Citation81,Citation87,Citation88)). Other approaches involve random mutagenesis, for example by the use of ethylnitrososurea (ENU) followed by identification of the affected gene and the exact site of the mutation in mutants with depression-related phenotypes.
Selective breeding
An alternative method to examine the genetic basis for depression-like behavior is represented in selective breeding strategies. Starting out from a large, heterogeneous population of animals, this breeding approach results in the establishment of independent lines of rodents which are differing in terms of depression-like behavior or in sensitivity to antidepressant drugs such as paroxetine (Citation89). After several generations, animals obtained from these breeding schemes have been most successfully used to investigate the genetic, neurochemical, and electrophysiological characteristics associated with the observed depressive phenotype and data obtained from these analyses may give rise to the identification of new elements or pathways related to depression (Citation89–91). So far, selective breeding strategies have been mostly employed using rats. Prominent examples are the Flinders rats (Flinders Sensitive and Resistant lines (FSL and FRL)) which were generated by selective breeding to produce strains with increased (FSL) or decreased (FRL) sensitivity to diisopropylfluorophosphate, an inhibitor of cholinesterase (Citation92). This approach was chosen on the background of reports describing a cholinergic supersensitivity in depressed patients (Citation93). The FSL rats share several behavioral and neurochemical features with people with depression (Citation20,Citation94) and have been most successfully used as a model system in basic research on depression. Another approach involved the selective breeding of Wistar rat lines based upon a high (HAB) and low anxiety-related behavior (LAB) phenotype in the elevated plus maze (Citation95). Reduced hippocampal serotonergic transmission has been found in HAB rats which could be restored by chronic paroxetine treatment (Citation96), making these rat lines an ideal model to study the effects of pharmacological and non-pharmacological therapeutic options in depression.
Animal correlates of non-pharmacological antidepressant treatment in humans
A series of reports have demonstrated equivalent treatment results in groups of patients receiving either traditional pharmacological treatment or psychotherapy (Citation97). Combined pharmaco- and psychotherapy has been recently suggested as the preferred therapeutic modality with superior outcome, particularly in severely and chronically depressed patients (Citation98). Thus, the need for animal models to assess the neurobiological underpinnings mediating a non-drug-based modulation of depression-like behavior has become apparent. These models would allow assessing of the biochemical and molecular correlates of this type of therapeutic intervention and constitute an appropriate test system to determine the effects of non-drug-based treatment and/or combined therapy protocols in a preclinical model.
Enriched environment (EE)
Environmental enrichment has been shown to induce a range of effects in laboratory rodents, both rats and mice (Citation99,Citation100). Several of the neurobiological changes resulting from environmental enrichment resemble those achieved by antidepressant drug treatment, such as the effects of EE on hippocampal dentate gyrus neurogenesis (Citation101,Citation102). Moreover, it has been shown that EE can reverse depressive-like behavior in several animal models (Citation103). However, its effect seems to be independent of hippocampal neurogenesis (Citation104). Although the effects of EE also beneficially affect deficiencies in animal models of other mental disorders, such as Alzheimer's disease, EE nevertheless constitutes an interesting system to explore the interaction between genetic and environmental factors involved in the pathogenesis of depression.
Physical activity
Similarly to environmental enrichment, several signaling pathways typically affected in depression and targeted by antidepressant treatment (such as neurotrophic factors) are modulated in animal models of physical activity (Citation105–107). At the behavioral level, ample evidence supports a role for physical activity as antidepressant treatment in laboratory rodents (both rats and mice) where it has been found to be effective in various models (Citation108–110). Physical activity, such as running, can be easily translated and applied to the human populations thus making the animal paradigm, albeit not selectively modulating depression-like behavior, an epidemiologically relevant tool.
Learned safety
A novel approach to model a behavioral intervention for depression, the learned safety model, has recently been proposed (Citation28). In this model, which is based upon a conditioned inhibition of fear procedure, the conditioned safety signal has been shown to acquire the ability to reduce depression-like behavior in the FST and UCMS-induced reduction in sucrose preference (Citation28). This observed behavioral effect is comparable and additive to the antidepressant activity of pharmacological antidepressants, such as fluoxetine (Citation28). The signaling pathways involved differ from those targeted by antidepressant drugs, thus making learned safety an ideal model to study the interaction between pharmacological and non-pharmacological therapeutic approaches for depression in a preclinical model. To date the learned safety model has not been tested in rats.
Establishing novel animal models to address alternative hypotheses about the pathogenesis of depression
Various exciting new directions, based upon alternative hypotheses about the pathomechanisms underlying the depressive disorder and response to antidepressant treatment, have given rise to the establishment of novel animal models in depression research. Below we discuss examples of some of those novel approaches, while being aware that many other interesting and promising strategies have also been established.
Constant darkness
Depressed patients often present with disruption in the levels and phases of various circadian factors, such as sleep–wake cycles and body temperature (Citation111), and genetic analyses describe an association between variation in circadian genes and depression (Citation112,Citation113). A novel approach to model depression-like behavior in rodents, based upon the relevance of light in the regulation of mood, has been recently described. In rats (Citation114) and in mice (Pollak et al., unpublished paper) light deprivation for a prolonged period of time (constant darkness) has been shown to induce depressive-like behavior. In rats, this depressive-like behavior has been shown to be reversed by treatment with desipramine (Citation114). Although this model still warrants further biochemical and molecular characterization, it is potentially of major relevance in depression research as a model to study the neurobiological mechanisms of a light-dependent component causally related to depression.
Testing the immune theory of depression—the cytokineinduced sickness model
Several lines of evidence support a causative role for cytokines in depression and have given rise to the ‘immune theory of depression’. First, activated immune parameters have been frequently reported in depressed patients (e.g. (Citation11)). Second, patients suffering from a condition involving a dysfunction of the immune system are more prone to develop clinical depression (Citation115). Third, the development of depressive symptoms in patients undergoing therapeutic interventions which are based upon application of cytokines (such as interferon) has been frequently reported to induce depression and significantly affects patient compliance (Citation116). Fourth, sickness behavior, which shows similarities to a series of behavioral features that are also found as part of the symptomatology in human depression, is reliably induced by the activation of the immune system through challenge with lipopolysaccharide (LPS) or direct application of interleukins and can be attenuated by chronic antidepressant treatment (Citation11,Citation117–119). Thus, cytokine-induced sickness in laboratory animals may present a valuable tool to investigate the contribution of the immune system by itself and in interaction with other regulatory systems, to the development of depression. Biochemical and molecular analyses carried out in this model may have the potential to lead to the development of new therapeutic strategies to combat depression in humans.
Gene–environment interactions and the epigenetic basis of depression
Forward genetic research in animal models is primarily based upon inbred strains and selective breeding approaches. Inbred strains show a high degree of variability with respect to behavioral performance, including behavioral patterns linked to emotionality. However, these interstrain differences may not be solely confounded on a genetic basis. It has been described that these strain-related behavioral differences may also result from the influence of environmental factors during development, such as maternal care and early adverse experiences, and their interaction with the genetic background (Citation14). Although stressful life events are good predictors for the development of depression, the exposure to severe stress is of limited consequences if not in combination with existing vulnerability factors (Citation120). Thus, the impact of environmental factors is strongly dependent on the genetic background. One way by which environmental stimuli can interact with the genetic background to induce long-lasting behavioral changes is through stable alterations in gene expression by epigenetic mechanisms, which provides the molecular basis of gene–environment interactions. Persistent modifications of DNA, such as methylation and/or modifications of the surrounding histones, such as through acetylation and deacetylation, may not only affect the development of the disease and its clinical phenotype, but also the response to therapeutic interventions (Citation121). Several outstanding recent reviews summarize the current state of knowledge about the role of epigenetics in the pathogenesis and treatment of depression based upon results from animal experiments and human research (Citation12,Citation121–124). Using existing animal models to explore the epigenetic nature and molecular basis of gene–environment interaction in depression and developing novel models based upon these insights, is one of the promising directions for future basic research in depression.
Limitations and important caveats
Strain, gender, age differences, and the effect of the laboratory environment
Significant differences in performance in the majority of the animal models for depression and in responsiveness to antidepressant treatment among inbred strains of mice have been reported (Citation35,Citation125,Citation126). These strain specificities have to be taken into consideration for all pharmacological and genetic experiments since effects of the genetic background are potentially providing a source of misunderstanding about the observed phenotypes. Additionally, gender, age, and the specific laboratory environment have been proven to present significant and powerful modulators of several behavioral and neurochemical features in mice, including those related to depression (Citation24,Citation25,Citation127) and have to be considered in the design and interpretation of any study.
Translational aspects
One of the major missions for future development of animal models in depression and in neuroscience research in general is to improve the translational value of the applied paradigms. To enhance the confidence in results obtained from preclinical research it is mandatory to bridge the gap between information acquired in animal models and results collected in human subjects. In this regard, one of the great promises for the future lies in the use of functional neuroimaging. Encouraging pioneering examples are available in the field of mood and anxiety disorders where behavioral paradigms successfully used in experimental animals (such as fear conditioning, fear extinction, or learned safety) were applied to humans ((Citation128,Citation129); see for review e.g. (Citation130)), and functional neuroimaging was used to elucidate some of the neural circuitries. These translational approaches are of utmost importance and will constitute one of the most productive directions for the future, since they can enhance the possibility that preclinically active substances will also be effective in patients. Additionally, they experimentally support the claim that observations in the animal model can indeed be representative of the situation in humans. Finally, data obtained in humans importantly complement results from animal models and vice versa.
How do we know that the mouse is depressed?
Needless to say, we will never be able to evaluate how an animal is ‘feeling’ in a particular situation, let alone if this subjective perception of an inner state relates to what we define as ‘depressed’. As a matter of fact, we are far away from being able to define objectively what one of our fellow human beings is experiencing when he reports the feeling of ‘being depressed’. However, we can take advantage of the very similar general neuroanatomy and neurophysiology that spans the inter-species borders to reconstruct in rodents some of the most salient characteristics of human depression. Information obtained from analyses of these animal models can be used to derive measurable and quantifiable parameters which can and have to be validated in the human population. These novel criteria can then be used to expand and redefine our understanding of depression in patients and allow us to design a ‘new generation’ of animal models. To conclude, the task of a valid and instructive animal model is not to answer the question ‘How do we know that the mouse is depressed?’, but to provide information at the cellular, biochemical, and molecular levels that can enhance our understanding about the neurobiological underpinnings of the disease and to address the urgent need to develop alternative therapeutic approaches to treat patients suffering from depression.
Acknowledgements
Dr Monje and Dr Rey are former members of the Centro Internacional de Física—CIF (Bogotá, Colombia) and thank CIF and Colciencias (Colombia) for support.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper
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