The Ups and Downs of Modelling Mood Disorders in Rodents

David A. Slattery and John F. Cryan

The wide spectrum of disruptions that characterizes major depressive disorder (MDD) and bipolar disorder (BD) highlights the difficulties researchers are posed with as they try to mimic these disorders in the laboratory. Nonetheless, numerous attempts have been made to create rodent models of mood disorders or at least models of the symptoms of MDD and BD. Present antidepressants are all descendants of the serendipitous findings in the 1950s that the monoamine oxidase inhibitor iproniazid and the tricyclic antidepressant imipramine were effective antidepressants. Thus, the need for improved animal models to provide insights into the neuropathology underlying the disease is critical. Such information is in turn crucial for identifying new antidepressants and mood stabilisers. Currently, there is a shift away from traditional animal models to more focused research dealing with an endophenotype-style approach, genetic models, and incorporation of new findings from human neuroimaging and genetic studies. Such approaches are opening up more tractable avenues for understanding the neurobiological and genetic bases of these disorders. Further, such models promise to yield better translational animal models and hence more fruitful therapeutic targets. This overview focuses on such animal models and tests and how they can be used to assess MDD and BD in rodents. Key Words: depression; cognition; animal model; stress; bipolar disorder

Introduction

P

sychiatric disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are multifaceted, heterogeneous diseases and are among the leading

David A. Slattery, PhD, is a researcher at the Department of Behavioral and Molecular Neurobiology, University of Regensburg, Germany. John F. Cryan, PhD, is Chair of the Department of Anatomy & Neuroscience and a professor in the Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. Address correspondence and reprint requests to David A. Slattery, Department of Behavioural and Molecular Neurobiology, Universitaetsst. 31, University of Regensburg, Regensburg, Germany or email david.slattery@ ur.de.

medical and social problems in society. Indeed, MDD affects more than 340 million people worldwide and is predicted to become the leading cause of global disease burden by 2030 (Michaud et al. 2001), while a recent study conducted by the World Health Organization encompassing 24 different countries revealed that after neurological disorders, BD was associated with the greatest loss in work days per year (Alonso et al. 2011). Although there are a number of effective treatment options, they all work with a delayed onset of action and approximately 30–40% of patients do not respond to any therapy. Therefore, there is an urgent need for more efficacious and novel-acting treatments. However, although numerous potential antidepressants, and to a lesser extent mood stabilisers, have been identified in preclinical research, the vast majority have failed to show clinical efficacy (Cryan and Slattery 2007). A number of reasons for this failure rate have been identified, including high placebo response, the lack of objective diagnostic criteria (see Frazer and Morilak 2005 for a review), and the translatability of animal models (see Belzung 2014). In keeping with this, the more traditional paradigms are better referred to as tests of antidepressant activity (Cryan and Holmes 2005; Cryan et al. 2005; Cryan and Slattery 2007, 2010; Geyer and Markou 1995). Although these approaches have undoubtedly advanced our understanding of mood disorders, recent research focus has attempted to design better models, with the ultimate aim to make the findings more translational. However, given that MDD and BD are multifaceted, heterogeneous diseases with multiple symptoms as set out in the current diagnostic manuals (DSM-V and ICD-10; see Cryan and Holmes 2005 and www.dsm5.org for a list of diagnostic criteria), this goal remains challenging. This is compounded by our limited knowledge of the underlying factors that predispose to mood disorders. However, it is clear that genetics and stressful life events are clear players (Wong et al. 2012; Wong and Licinio 2001). In the following review, we discuss animal approaches to study these disorders and highlight their benefits and drawbacks.

What Are the Differences Between a Model and a Test? The distinction between a model and a test is not always made clear and as a result, sometimes a test is called a model.

ILAR Journal, Volume 55, Number 2, doi: 10.1093/ilar/ilu026 © The Author 2014. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: [email protected]

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Abstract

Criteria to Consider When Using/Creating Animal Models of Mood Disorders In a perfect situation, any animal model reflecting a disease would have identical causative factors (construct validity), symptomology (face validity), and treatment modalities ( predictive validity) (Geyer and Markou 1995). However, because the underlying aetiology and causative factors of MDD and BD are poorly understood, it is not feasible to base animal models of mood disorders solely on aetiology (Cryan et al. 2002). Thus, three general strategies to develop animal models have been used: (1) genetic manipulation, (2) selective breeding for behavioural extremes, and (3) environmental, physical, or pharmacological manipulations or a combination of the above (Neumann et al. 2011). Another issue when using animal models is the requirement for repeatability between laboratories, which implies strictly controlling all possible elements of the test. However, even if all factors within different laboratories are controlled as tightly as possible, the results can often be divergent (Crabbe et al. 1999). Additionally, as was shown with the recent modifications introduced to the traditional forced swim test (FST; see below), which provide greater reliability and information, a degree of flexibility is required to allow refinement (Cryan et al. 2002; Lucki 1997). 298

Traditional Animal Models and Tests of Depression Despite the difficulties outlined above, a number of diverse animal models of depression have been widely utilized and many show substantial predictive validity (i.e. antidepressant administration reverses the behavioural parameters assessed). These animal models are often referred to as tests of antidepressant-like activity given that they have all been validated since the introduction of clinically approved medications (Markou et al. 2009). Numerous reviews have been dedicated to these models and their construct validity, which will only be briefly discussed here; thus, the interested reader is directed to these comprehensive articles (Belzung 2014; Berton et al. 2012; Chen et al. 2010; Cryan and Holmes 2005; Cryan and Slattery 2007, 2010; Cryan et al. 2005; Geyer and Markou 1995; Gould and Einat 2007; Hales et al. 2014; Harro 2013; Henry et al. 2010; Joel and Yankelevitch-Yahav 2014; Kokras and Dalla 2014; Kronenberg et al. 2014; McArthur and Borsini 2006; Nestler and Hyman 2010; Perani and Slattery 2014; Pollak et al. 2010; Tanti and Belzung 2010).

FST and Tail Suspension Test (TST) These tests represent the most widely utilized preclinical tests employed in basic research of depression. They are based on the observation that when mice or rats are subjected to an inescapable situation (i.e. cylinder filled with water or suspended by their tail [only mice]) after initial escape-directed behaviour, the animals quickly adopt an immobile posture (Cryan et al. 2005; Petit-Demouliere et al. 2005). This change to immobility is believed to reflect behavioural despair; either a failure to persist with escape-directed behavior or a passive behavior to cease active forms of coping to the stressful stimuli (Cryan et al. 2002; Cryan and Slattery 2007; Slattery and Cryan 2006). It has been repeatedly demonstrated that clinically effective antidepressants, usually given acutely, increase the time that rodents spend in escape-directed behavior (see Cryan et al. 2005; Cryan and Slattery 2007; Petit-Demouliere et al. 2005). However, caution is required when employing these tests, because the readout, immobility, can be easily influenced by interventions that alter locomotor activity, which may lead to false positive or negative findings (Slattery and Cryan 2012). Moreover, the appropriate choice of mouse or rat strain must be employed, because they vary widely in their baseline activity in the FST (Crowley et al. 2005; Slattery and Cryan 2012). A major criticism that has been directed at these two tests is that they do not appear to reflect the clinical situation. However, recent studies have begun to shed light on the underlying circuitries/brain regions that are recruited in the test. Thus, recent data indicate that the hippocampus, infralimbic cortex, and ventral tegmental area to nucleus accumbens pathway and central dopamine signalling are crucial for FSTinduced effects (Airan et al. 2007; Chaudhury et al. 2013; Slattery et al. 2011; Tye et al. 2013; Warden et al. 2012). ILAR Journal

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A model comprises both an independent variable, known as the inducing manipulation, and a dependent variable that is behavioural/neurochemical readout, whereas a test simply comprises the latter variable (Geyer and Markou 1995). As the underlying pathophysiology of MDD and BD is poorly understood, this has had a knock-on effect in choosing independent variables. In recent years, increased clinical experimental evidence has, however, provided preclinical researchers with more information to design the independent variables and, therefore, garner more information about the underlying aetiology of mood disorders. This approach has also been aided by the relatively recent focus on an endophenotype-based approach to study psychiatric disorders. In more detail, this more focused approach attempts to assess only one symptom, or marker, of the disease, thereby using characteristic endophenotypes of diseases and then modelling them independently rather than the whole syndrome (Cryan and Slattery 2007; Hasler et al. 2004, 2005; Slattery and Cryan 2011). This has the benefit of simplifying complex disorders, such as MDD and BD, into individual behaviours, which are more easily measurable in both patients and laboratory animals. Moreover, this approach is akin to preclinical testing, in which only one variable is generally measured and is likely to involve fewer genes (Gottesman and Gould 2003; Gould and Gottesman 2006). However, a number of symptoms of MDD and BD are clearly not measurable in preclinical paradigms, such as recurrent thoughts of death or suicide or excessive thoughts of guilt (see Slattery and Cryan 2011 for more details).

et al. 1998, 1999; Kelly et al. 1997; Song and Leonard 2005). Moreover, a number of the neurochemical adaptations, such as 5-HT hyper-innervation (van der Stelt et al. 2005) and disinhibition of the amygdala are also reversed by chronic antidepressant treatment (Song and Leonard 2005; van der Stelt et al. 2005). Thus, this time frame is more akin to that observed in the clinical situation, which makes bulbectomy an attractive model. More recently, it was shown that peripheral administration of 5-HT2C receptor antagonists for 5 days, but not citalopram, reversed the behavioral phenotype of olfactory bulbectomy, suggesting it may be a suitable model to look for fast-onset of action drugs (Opal et al. 2013). Other serotonergic agents have also been shown to rapidly reverse the bulbectomy-induced phenotype, such as 7 days with 5-HT7 receptor antagonists (Mnie-Filali et al. 2011) and 3 days with a 5-HT4 receptor antagonist (Lucas et al. 2007). Therefore, it would be of great interest to determine whether ketamine would display its fast-acting antidepressant action in this model. However, the fast-acting augmentation of pindolol onto SSRI treatments does not work in this model (Cryan et al. 1998). Moreover, it is performed in only a few laboratories, and it is becoming increasing difficult in a number of countries to receive ethical approval for such an invasive procedure.

Learned Helplessness

Chronic Stress Procedures (Nonsocial)

This model also takes advantage of placing animals in to inescapable situation. However, in this instance rodents are subjected to inescapable shocks and then reintroduced to the same environment, but this time with escape possible. In contrast, the control animals are subjected to escapable shocks each time. A subset of animals will exhibit a reduced number of escape attempts and such a deficit is considered to be indicative of a depressive-like phenotype, which is not related to the shock per se. This can enable comparison of non-helpless and helpless cohorts at a variety of levels (e.g. behavioral, neuronal, and molecular) to assess potential differences underlying their phenotype. Unlike the FST and TST, pharmacological reversal of helpless behavior requires at least 3 to 5 days of antidepressant administration (see Pryce et al. 2011 for more details).

Chronic stress exposure is a well-documented risk factor for MDD and has resulted in the use of a number of chronic mild stress (CMS) paradigms based on the initial discovery by Katz that exposure to severe predictable stressors led to an anhedonic phenotype in rats (Katz 1981). Reducing the severity of the stressors (e.g. social instability, 24-hour light exposure, restraint, food and water deprivation) but prolonging their duration and making them unpredictable resulted in the CMS paradigm. These models are attractive as the depressive-like phenotype provoked by the stress procedure, usually assessed by sucrose preference, can only be reversed by chronic antidepressant treatment (for a comprehensive review of CMS, see Nollet et al. 2013). A potential confound of such studies should be considered, as the sucrose’s calorific content may lead to increased consumption to offset the effect of stress. However, this implies that decreased consumption is reflective of anhedonia, because animals would be more inclined to intake sucrose to gain the increased energy. It is also possible to avoid such a confound by using saccharin instead, because animals prefer it over water and it has no calorific benefit. Finally, due to their complexity and increased number of variables, such protocols are difficult to standardize and can often lead to inconsistent behavioral and physiological, and hence molecular and neuronal, phenotypes.

Olfactory Bulbectomy Unlike humans, the olfactory bulbs constitute a large percentage of the rodent brain and their removal results in multiple long-term alterations in behavior, immune, endocrine, and neurochemical functions (Cryan et al. 2002; Song and Leonard 2005). Importantly, the primary reason for these alterations is not the loss of smell, as administration of zinc sulphate to induce anosmia does not lead to the same phenotype (Song and Leonard 2005). The most consistent behavioral alterations caused by bulbectomy are hyperactivity in a novel, brightly lit, open field arena and deficits in passive avoidance learning, both of which are responsive to chronic, but not acute, antidepressant administration (Cryan Volume 55, Number 2, doi: 10.1093/ilar/ilu026

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Assessing Specific Endophenotypes/Symptoms The majority of the tests and models described above, although showing strong predictive validity, do not, at least on the 299

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Although the FST and TST appear to be similar in construct, it has been shown that different neurobiological substrates underlie them (Cryan and Holmes 2005; Cryan and Slattery 2007). For example, GABAB receptor antagonists and knockout mice have been shown to have antidepressant-like properties in the FST but not TST (Slattery and Cryan 2006). Therefore, studies such as the aforementioned that assess the circuitry and systems that underlie the behavioral and pharmacological correlates of these tests will help to improve their validity and employment. Finally, the recent landmark finding that inactivation of Brodmann Area 25 using deep brain stimulation could alleviate depressive symptoms in treatment-resistant patients (Mayberg et al. 2005) gave rise to the possibility of examining the effects of a similar treatment in an animal model of antidepressant activity. Analogous to the human situation, inactivation of the infralimbic cortex, the rodent correlate of Brodmann Area 25, resulted in an antidepressant-like phenotype in normal rats. More pertinently, this finding could be replicated in rats with an innate high level of depression-related behavior, analogous to the findings in treatment-resistant patients (Slattery et al. 2011). These results show that it is possible to replicate findings from a clinical trial in rodents, and with the development of more sophisticated clinical studies, such reverse translational studies will become more common and informative.

Anhedonia Anhedonia has been used as a behavioral end point for a number of the existing animal models of depression, such as CMS and maternal separation, where sucrose preference is often measured (Slattery et al. 2007). A more recent approach to study anhedonia in rodents is the female urine sniffing test. In this test, males are allowed to freely explore a novel environment where sawdust containing female urine has been placed in one section of the arena. Under normal circumstances, male rodents will spend the majority of the time in the arena investigating the section with the female urine as a sexually motivated-driven behavior. It has been demonstrated that animals that have been subjected to stress will spend less time investigating the female urine and that this can be reversed by antidepressant treatment or exposure to a high-fat diet (Finger et al. 2011; Malkesman et al. 2010). Moreover, it is possible to study anhedonia following particular manipulations, genetic or environmental, utilizing paradigms that were initially used in the field of drug addiction, for example, progressive ratio responding or intracranial selfstimulation (ICSS). Numerous researchers have used such 300

readouts to assess the effect that stress exposure or withdrawal from drugs of abuse (Cryan et al. 2003) has on this endophenotype of depression. Moreover, two recent studies have combined the olfactory bulbectomy model with ICSS. Although we could show that anhedonia was observed immediately after bulbectomy, this lasted only 7 days (Slattery et al. 2007). However, conflicting results were observed in relation to the ability of cocaine and amphetamine to reduce the ICSS response threshold (Romeas et al. 2009; Slattery et al. 2007), which may be due to the different psychostimulants employed. Early-life stress, which has been used to study MDD and anxiety disorders in preclinical research, has recently been shown to affect ICSS responding following social defeat. Thus, rats that underwent maternal separation in early life display an anhdeonic phenotype to repeated social defeat and increased reward enhancing effect to acute amphetamine 1 week after stress termination (Der-Avakian and Markou 2010). Although the use of this model is time and labor intensive, ICSS has the advantage that it can be repeatedly performed in the same animal without habituation or sensitization (such as occurs in other MDD tests). Therefore, it is theoretically possible to use ICSS with animal models that lead to long-lasting anhedonic phenotype to determine not only the dose range of “antidepressants” that are required to alleviate the anhedonia but also whether different drug concentrations have differential temporal time frames. Indeed, it has recently been shown that chronic social defeat stress in both rats (Der-Avakian et al. 2014) and mice (Donahue et al. 2014) leads to a persistent anhedonic phenotype as assessed by ICSS responding. Such information at present is not attainable in other MDD models/tests without resorting to truly large experimental numbers. Thus, more extensive use of the ICSS procedure in preclinical research would provide invaluable insights into the time course of alterations to the brain reward system and anhedonic-like behavior. Studies have also shown that the reward system appears to be hypersensitive in severely depressed patients (Eshel and Roiser 2010; Naranjo et al. 2001; Tremblay et al. 2002, 2005). The hypersensitivity was associated with decreased activity of a number of regions of the reward circuitry as well as cortical regions following drug administration. These findings resemble the findings from recent animal studies revealing increased cocaine preference following chronic stress exposure (Krishnan et al. 2007). Interestingly, in this study, increased brain-derived neurotrophic factor signalling in the ventral tegmental area-nucleus accumbens pathway was found to underlie, at least in part, the depressed phenotype. Taken together, these studies reveal converging evidence from rodent and human studies supporting an alteration in the brain reward system in the aetiology of rodent and human models. Cognitive Processes Another endophenotype that has more recently been studied in relation to MDD is cognitive dysfunction. It has been repeatedly demonstrated that patients can have difficulty in concentrating and display more attention and processing of ILAR Journal

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surface, possess strong face validity (i.e. similar symptoms to the human situation). However, the fact that several symptoms, or symptom clusters, can be modelled in both rodents (and humans) has resulted in a number of newer approaches to study mood disorders in basic research. Thus, rather than attempting to model the whole syndrome, recent approaches have focussed on studying a specific symptom or endophenotype of the disorder. In this case, an endophenotype relates to specific genetic factor, biological substrate, and symptomology (Belzung 2014; Hasler and Northoff 2011). This symptom-, or endophenotype-based, approach has both advantages and disadvantages. Thus, it simplifies the study of multifaceted disorders to its individual components, which are likely to be controlled by fewer genes and more reliable across laboratories but may lead to findings that do not translate to the clinical situation (Cryan et al. 2002; Hasler et al. 2004). However, with regard to this latter potential problem, such an approach may increase our understanding of the aetiology and treatment of specific symptoms such as those that follow that may be beneficial in numerous psychiatric disorders. Alternatively, it is possible that the findings are too specific to a certain symptom and therefore translate to novel treatments that are not effective for MDD/BD. As mentioned above regarding the design of animal models, a number of considerations should be adhered to when following such an approach. Thus, the chosen endophenotype or symptom should be inherently relevant to the disease of interest, and its heritability and centrality to the disorder should also be considered (Cryan and Slattery 2007; Hasler et al. 2004; Slattery and Cryan 2011). Below, we discuss anhedonia and cognitive processing which have been studied in this fashion in relation to MDD. For a more comprehensive review, including other endophenotypes and symptoms, we refer the reader to other reviews (Cryan and Holmes 2005; Cryan and Slattery 2007, 2010).

Social-Stress Based Models Given the evidence purporting social stress to be a risk factor for the development, not only of cardiovascular diseases but also of MDD in vulnerable individuals, recent attempts have focused on the development of social stress paradigms (Berton et al. 2006; Finger et al. 2011; Krishnan et al. 2007; Peters et al. 2013; Reber et al. 2006, 2007). Such paradigms are believed to be more relevant to the human situation than nonsocial stress paradigms (e.g. repeated restraint; Cryan and Slattery 2007; Reber 2012). Social defeat (Berton et al. 2006), chronic subordinate colony housing in mice (Reber et al. 2007), social defeat overcrowding (Finger Volume 55, Number 2, doi: 10.1093/ilar/ilu026

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et al. 2011; Reber et al. 2006) or chronic subordination in tree shrews (Fuchs 2005) have been shown to result in numerous behavioral and physiological consequences, which closely resemble those resulting from chronic stress in humans. These alterations are also believed to persist for a long time after the termination of the stressor. Chronic social defeat was shown to alter anhedonia-type readouts and cocaine and sucrose preference, but interestingly not to alter behavior in traditional tests such as the FST and TST (Krishnan et al. 2007). Such findings demonstrate the need in preclinical models to assess multiple behavioral readouts. In contrast, we recently demonstrated that the chronic subordinate colony housing and social defeat/overcrowding paradigms result in increased anxiety-related, but not depression-related behavior, and that the development of these anxious-like states displays different temporal dynamics in dependence on the chronic stress paradigm (Peters et al. 2013; Slattery et al. 2012). Moreover, we could also reveal by subjecting mice to repeated social defeats across 19 days in either the active or inactive phase that the time of stressor exposure is also critical (Bartlang et al. 2012). These findings highlight the fact that different social stress paradigms lead to varying outcomes, and careful choice must be taken if being established in a new laboratory. A major advantage of chronic social stress paradigms is that the time required for therapeutic efficacy more closely resembles that required for clinical benefit of current antidepressants. Thus, social stress paradigms can provide insight into novel factors involved in the aetiology of stress-based disorders and have enhanced our knowledge of underlying molecular maladaptations caused by chronic stress exposure and continue to so.

Genetic Predisposition As stated above, a substantial barrier in preclinical psychiatric research has been the lack of knowledge regarding the cause and pathophysiology of the illness in humans. Indeed, in specific instances where there has been a very definable cause, such as the triple GGG motif present in Huntington’s disease, there has been success in creating an animal model, which is a transgenic mouse expressing the human huntingtin promoter. Unfortunately, although it is known that genetic factors play a significant role in MDD and BD, to date no gene has been categorically linked with their aetiology. Similar genetic predisposition can also be observed in inbred strains of rats and mice, which show highly divergent behavioral and treatment response profiles (see Jacobson and Cryan 2007 for review). Moreover, identification of target genes can lead to assessment of their causality in a psychiatric disorder via the use of knockout/knockin technology or more recently via application of short-interfering or short-hairpin RNA sequences, or micro RNAs, which selectively down-regulate the target gene (Guo et al. 2010; O’Connor et al. 2012). Additionally, a number of studies are now finding a number of polymorphisms in certain genes, which in some cases are proposed to increase the likelihood of patients to become depressed. A further complication is the fact that such genetic factors interact with environmental factors. For example, in some individuals, MDD appears to 301

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negative stimuli than controls, which is believed to consolidate and prolong the depressive episode (Disner et al. 2011; Elliott et al. 1998, 2004). Although negative bias has not been as widely studied in animal models as other endophenotypes, there is growing evidence that rodents subjected to stress, for example the learned helpless paradigm, show similar negative bias (Enkel et al. 2010; Pryce et al. 2011, 2012; Pryce and Seifritz 2011; Richter et al. 2012). More recently, Robinson and co-workers have developed a model in rats to study affective bias (Stuart et al. 2013). This work is based on the fact that acute, not only chronic, antidepressant treatment can lead to a positive shift in emotion processing in humans (Browning et al. 2010), making it an attractive symptom to study. In this paradigm, rats are given two separate positive experiences of equal absolute value on different days under either neutral conditions or during pharmacological or affective state manipulations. Affective bias is then assessed using a preference test where both positively rewarded substrates are presented together. Using this test, the authors could show that acute antidepressant treatment leads to a positive bias towards the substrate paired with administration, whereas drugs associated with negative bias in humans also lead to a similar phenotype in the rats. Finally, opposite effects of acute social stress and environment enrichment were also shown, suggesting that this model is responsive to both pharmacological and environmental manipulation (Stuart et al. 2013). Another recent study that assessed the role of cognitive processing in depression focussed on the beneficial effects of learned safety (Pollak et al. 2008). The authors define learned safety as “the learning and memory resulting from a conditioned inhibition training procedure,” and it is established using a fear conditioning paradigm in which the conditioned stimulus and the shock are not paired. When mice were then subjected to the FST or a CMS paradigm in the presence of the conditioned stimulus, the observed depressive-like behavior was decreased, findings that required intact hippocampal neurogenesis (Pollak et al. 2008). Thus, it appears that safety signals have antidepressant properties, perhaps by reducing the stressful situation for the individual. Therefore, such studies show that assessment of cognitive (dys)-function in rodent models of depression is possible and that more such studies are required to gain a greater insight into the biological substrates underlying this symptom.

Sex Differences in Modelling MDD Women exhibit a higher susceptibility to stress-related illnesses, such as mood and anxiety disorders, than men in general (Kessler 2003), which is particularly true during their reproductive years (Gutierrez-Lobos et al. 2002). Furthermore, it is apparent that there are sex differences in drug metabolism, which may relate to different effective doses of novel antidepressants between males and females (Kokras et al. 2011). Despite this, most basic studies assessing MDD and BD are performed in males. This is due, in part, to the complexity of studying females given the differences in a number of factors that are observed across the oestrus cycle, for example OXT-R expression (Bale et al. 1995) and HPA axis activity (Atkinson and Waddell 1997). Although traditional tests have been employed to study MDD in females (e.g. FST, TST, sucrose preference test), many other tests are not appropriate (e.g female urine sniffing test). In light of this, it is important to note that forms of stress that are effective in males may not be in females and vice versa (see Hillerer et al. 2012; Perani and Slattery 2014 for reviews). Moreover, corticotropin-releasing factor overexpression, mimicing chronic stress exposure, can lead to a lengthening of the oestrus cycle (Keen-Rhinehart et al. 2009), complicating the choice of appropriate controls. Female rodents tend to exhibit greater HPA axis responses to stress and display less habituation to repeated stress compared with males (see O’Leary and Cryan 2013 for review). Such findings would appear to be in keeping with those in humans showing that women are more susceptible to stress-related illnesses. Indeed, in one of the few studies that have compared males and females, females showed exaggerated FST immobility and differential response to antidepressants (Dalla et al. 2010, 2011), although the phenotype induced by the learned helpless paradigm between the sexes is less clear (Chourbaji et al. 2010; Dalla et al. 2011). There have also been studies that employ the sucrose preference test to assess anhedonia in females following stress exposure, but these have been relatively few (for 302

review see Kokras and Dalla 2014). Therefore, many more studies are required before a clearer picture regarding the utility of such tests for assessing MDD in females is feasible. Furthermore, one of the periods of highest risk for women to develop psychiatric disorders is during the peripartum period such as postpartum depression, which affects 15–20% of mothers (O’Hara and McCabe 2013; Perani and Slattery 2014). A number of risk factors have been identified that may increase the risk of postpartum depression, including the dramatic fluctuation in sex steroids and stress exposure (Bloch et al. 2000, 2005; Brummelte and Galea 2010; Hillerer et al. 2012). Although it is unlikely that a specific rodent model of postpartum depression can be achieved, a number approaches have been utilized to provide a better understanding of its etiology (see Brummelte and Galea 2010; Perani and Slattery 2014 for reviews).

Modelling Treatment-Resistant Depression As stated above, many patients do not respond to any antidepressant therapy currently available, and many responders stop taking the medication due to a number of reasons, particularly because of the side effects of the treatment. Therefore, it is feasible to conceive of animal models that could be utilized to assess the neurobiology and novel treatment options of treatment-resistant depression. We have already mentioned above one such study, where findings from a human study were reverse-translated in to animals (see FST section above) (Slattery et al. 2011). Indeed, similar findings were also observed when rodents received deep brain stimulation in the rodent correlate, the infralimbic cortex, of Broadmann Area 25 that was targeted in the human study (Hamani et al. 2010). Another approach that has been taken is to separate antidepressant responders and nonresponders in a CMS paradigm and assess the molecular characteristics that differ between the groups (Bisgaard et al. 2012; Christensen et al. 2011). Similarly, while many strain differences are observed in FST behavior, it can also be stated that many strains do not respond to antidepressant treatment (Crowley et al. 2005; O’Leary and Cryan 2013). Therefore, such strains can be assessed to determine if alternative or augmentative treatments may restore the antidepressant efficacy of the currently available therapeutics (see O’Leary and Cryan 2013 for review). Finally, in recent years, there has been substantial interest in ketamine, as it has been shown to have rapid antidepressant effects in humans that can last up to 1 week (Niciu et al. 2014; Zarate et al. 2006, 2013a, 2013b), which has been recapitulated in animal models (Beurel et al. 2011; Duman and Aghajanian 2012; Li et al. 2010). By further exploring the mechanism of action of ketamine, novel targets may be uncovered that may be more effective in treatment-resistant patients (Cryan and O’Leary 2010; Naughton et al. 2014; O’Connor et al. 2013).

Modelling Depression in Old Age Similar to the statement above regarding the predilection to perform MDD studies in males, the vast majority of studies ILAR Journal

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be preceded by stress, whereas in the majority of cases such stress does not lead to the development of depression (Kendler et al. 1999). Similar variation to stressors has also been shown in preclinical studies, with some animals displaying high or low behavioral responses. For example, approximately 70% of rats exposed to inescapable stressors subsequently display helpless behavior (Henn and Vollmayr 2005). These observations have formed the basis of a number of selective breeding programs, such as the Flinders Sensitive Line rats and High- versus Low- anxiety-related behavior rodents, which have been extensively reviewed elsewhere (Bunck et al. 2009; Landgraf et al. 2007; Neumann et al. 2011). Such breeding programs have revealed the importance of selectively bred lines for studying the underlying aetiology of a disease, such as depression and anxiety, and also potential novel therapeutic strategies to test in the clinic. Moreover, they show the importance of combining a genetic model with stress exposure, as this is likely to translate to the human situation more accurately.

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Table 1 Animal models/tests of major depressive disorder (adopted from Cryan and Slattery 2007; Slattery and Cryan 2011) Description

FST

Rodents placed in an inescapable container of water swim more following Ease of use, high throughput, responsive to AD, inter-laboratory reliability, antidepressant administration but responsive to acute drug administration, reliant on motor function, and not always responsive to SSRIs

Modified FST

Same as above but swimming and climbing behaviors are separated and increased with serotonergic or catecholaminergic antidepressants, respectively

Ease of use, high throughput, responsive to AD (including SSRIs), inter-laboratory reliability, but responsive to acute drug administration and reliant on motor function

TST

Rodents, chiefly mice, when hung from the tail will adopt an immobile posture. Antidepressant treatment increases the time animals spend in active behaviors

Ease of use, high throughput, inter-laboratory reliability, responsive to antidepressants, but may differ from FST results, responsive to acute drug administration, and reliant on motor function

CMS

Animals are subjected to a variety of unpredictable stressors, which leads Stress exposure increases depressive symptoms in susceptible rodents, requires chronic antidepressant, but has low reliability and throughput to a constellation of symptoms that are reversed by antidepressant treatment

DRL-72

Reinforcement of voluntary responses (e.g. lever presses) with inter-responses longer than 72 s and punishment for incorrect responding. Antidepressant administration improves the number of reinforced trials

Drug-withdrawal paradigms

When animals are withdrawn from drugs of abuse, they display numerous Face validity, responsive to AD, model core symptom of depression, but characteristics that resemble those observed in depression low throughput and expensive

Learned helplessness

Animals exposed to inescapable shocks subsequently fail to escape when Responds to some AD, causes depression-like symptoms, not all animals become helpless, which can enable comparison between helpless and able to. Antidepressant treatment increases the number of escapes; not nonhelpless cohorts, but requires foot-shock all animals develop this helpless behavior

Maternal deprivation

When animals are separated from the mother during early postnatal life, Early-life stress increase MDD likelihood in humans, deficits in reward, but has low reliability and throughput they can develop a number of depression- and anxiety like behavioral characteristics. These behaviors are not present in all animals subjected to this treatment

Olfactory bulbectomy

Removal of the olfactory bulbs causes a constellation of behavioral and neurochemical alterations, which are only reversed by chronic antidepressant treatment

Reward paradigms

It is possible to study anhedonia in animals following other manipulations Respond to some antidepressants, analogous to core symptom of depression, but not well-validated and low throughput by utilizing paradigms that were initially used in the field of drug addiction, for example, progressive ratio responding or ICSS

2014

Animal model/test

Comments

Models cognitive aspect of depression, sensitive to TCAs and SSRIs, but not widely utilized, time-consuming, and may not detect novel antidepressants

Requires chronic AD, translational neurochemical and structural changes, but not utilized and mainly reliant on motor function

Continued

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Rodents form a stable dominant/subordinate relationship with subordinate Face validity, respond to chronic AD treatment, mimic numerous endophenotypes, but low throughput and differences between showing behavioral and neurochemical alterations similar to depressed species have been observed patients. A number of these alterations can be reversed with antidepressant treatment Social stress

Abbreviations: AD, antidepressant; CMS, chronic mild stress; FST, forced swim test; ICSS, intracranial self-stimulation; MDD, major depressive disorder; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TST, tail suspension test.

Enables comparison of susceptible and resistant animals, but low Animals are bred based on their extreme performances in animal tests throughput and expensive (e.g. FST) leading to animals with high and low behavior for the selected trait. These lines can then be used to assess treatment and differences (e.g. molecular) that may underlie the trait Selective breeding / inbred strains

Comments Description Animal model/test

Table 1 Continued

Animal Approaches to Study BD There have also been a number of models and tests employed to gain a better understanding of BD, which affects about 1% of the population and is characterized by a cycling between depressive episodes and mania. Mania reflects periods of irritable mood, elation, and overactivity as set out in the diagnostic manuals (DSM-IV and ICD-10) that last for >1 week (see Table 2). These symptoms may be concurrent with other alterations such as decreased need for sleep, aggressiveness, and poor judgement. There are a number of drugs available for the treatment/prophylaxis of BD, with the mood stabilizers such as lithium, carbamazepine, valproate, and newer options, including lamotrigine and atypical antipsychotics being used. Thus, as for MDD, the lack of definitive biological changes and understanding of the aetiology of BD, as well as its heterogeneity, has hindered preclinical research attempts to investigate this disorder (Chen et al. 2010; Cryan and Slattery 2007; Tanti and Belzung 2010; Young et al. 2011). Therefore, ILAR Journal

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are also performed in young adults. However, the incidence of MDD in adolescence and old age has increased substantially in recent years and, although there is a great body of work assessing the effect of early-life stress and depression (see McClelland et al. 2011; Murgatroyd and Spengler 2011; Pryce and Feldon 2003 for reviews), the field of aged depression has not received as much study. It has been shown, for example, that antidepressants are less effective in older patients (Nelson et al. 1995; Roose et al. 1994). Hippocampal neurogenesis, often implicated in both the pathophysiology of depression and antidepressant efficacy (Santarelli et al. 2003; Snyder et al. 2011) has been shown to both decrease with age and become less sensitive to antidepressant treatment in aged rats (Couillard-Despres et al. 2009; Villeda et al. 2011). Therefore, it is possible to envisage that hippocampal neurogenesis may play a role in depression in old age; although studies are required to reveal a causal link. The traditional tests of depression highlighted above may be of less use to study depression in aged rodents given their reliance on motor activity, but some of the novel approaches, such as assessing affective bias (Stuart et al. 2013), learned safety (Pollak et al. 2008), or social-stress based models may provide a starting point to improve our understanding of the neurobiology of MDD in old age. Another interesting approach in this field is the fact that both aged humans and rodents have elevated immune activation (Kinsey et al. 2008; Shaw et al. 2013) and given the immune hypotheses of MDD (Leonard and Maes 2012; Maes 2008; Miller et al. 2009), immune challenge paradigms may represent a novel approach to study the pathophysiology of old-age MDD. Such studies have important translational value as treatment modalities that are effective in aged animals are likely to reflect the situation in elderly patients to a greater degree. However, there are also challenges to developing such models, including adequately separating the normal cognitive decline due to ageing versus an induced deficit.

Table 2 Description and comments regarding selected animal models/tests of BD

Description

Comments

Drug-induced hyperactivity

Rodents are injected with drugs, which results in hyperactivity

Ease of use, high throughput, responsive to mood stabilizers, inter-laboratory reliability, but reliant on motor function

Sleep deprivation

Rodents are subjected to sleep deprivation (up to 72 h), which induces manic-like behavior

Mimics aspects of BD, responsive to mood stabilizers, but remains to be fully characterized

Social stress

Resident-intruder paradigm is performed for 3 weeks, and administration of mood stabilizers decrease aggressive behavior of resident

Mimics aspects of BD, responsive to mood stabilizers, but remains to be fully characterized

Strain differences

Assess the effect of mood stabilizers across different strains in models of BD

Provides insight into underlying neurobiology, but expensive and not fully characterized

Abbreviation: BD, bipolar disorder.

scientists again have tended to use an endophenotype-based approach to study BD by focussing on several key symptoms associated with BD. The first attempts to model mania in basic research centered around the fact that psychostimulant administration causes hyperactivity in rodents. For example, it has repeatedly been shown that acute lithium administration can reverse amphetamine-induced hyperactivity in rodents, although there are a number of caveats that can affect this behavior, including environmental novelty, circadian rhythm, and chronicity of drug administration. A number of other drugs that lead to hyperactivity have also been employed, such as the adenosine triphosphatase inhibitor ouabain and the dopaminergic agent quinpirole (see Herman et al. 2007; Young et al. 2011 for reviews). Although helpful, assessment of purely locomotor activity can provide only limited information regarding the aetiology of a complex disorder such as BD. Therefore, a number of manipulations have been studied in relation to mania, including sleep deprivation (Szabo et al. 2009) and social defeat stress (Einat 2007b). Such manipulations, while causing hyperactivity, also lead to other symptoms such as increased aggression and changes in sexual activity, as well as molecular alterations in systems that are affected by mood stabilizers such as the glycogen synthase kinase-3 gene (for reviews see Young et al. 2011). As with MDD, genetic studies have been performed to assess mania (Chen et al. 2010; Einat 2007a; Malkesman et al. 2009; Saul et al. 2012), many of which take the form of assessing strain differences or disruptions in circadian rhythms (Roybal et al. 2007). Ultimately, as with MDD, utilization of a variety of approaches will be required to gain a better insight into the underlying pathophysiology of BD.

Conclusions and Outlook Taken together, the findings outlined above and summarized in Tables 1 and 2 reveal the necessity of a multidisciplinary Volume 55, Number 2, doi: 10.1093/ilar/ilu026

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approach to study MDD and BD and show that novel approaches both in the paradigm employed and the readouts are required in basic research. Moreover, they show that at an individual systems level, drug manipulation may give different outcomes in relation to depressive symptomology and therefore, employing numerous models/tests is necessary to reach a conclusive answer. Ultimately, replication of such preclinical findings in a clinical setting is required to validate the findings from basic research.

Acknowledgments The work by D.A.S. was supported in part by the Deutsche Forschungsgemeinschaft (DFG SL141/4-1). The work by J.F.C. was supported in part by Science Foundation Ireland in the form of a center grant (Alimentary Pharmabiotic Centre) under grant number SFI/12/RC/2273 and an Investigator Programme grant (SFI/12/IA/1537), by the Health Research Board of Ireland (grant number no. HRA_POR/2012/32), and by the European Community’s Seventh Framework Programme (grant no. FP7/2007-2013) under grant agreement noumber. 278948 (Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndrome).

References Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K. 2007. Highspeed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317:819–823. Alonso J, Petukhova M, Vilagut G, Chatterji S, Heeringa S, Ustun TB, Alhamzawi AO, Viana MC, Angermeyer M, Bromet E, et al. 2011. Days out of role due to common physical and mental conditions: Results from the WHO World Mental Health surveys. Mol Psychiatry 16:1234–1246. Atkinson HC, Waddell BJ. 1997. Circadian variation in basal plasma corticosterone and adrenocorticotropin in the rat: Sexual dimorphism and changes across the estrous cycle. Endocrinology 138:3842–3848.

305

Downloaded from http://ilarjournal.oxfordjournals.org/ at University of Minnesota Libraries -- Wilson Library on October 14, 2014

Animal model/test

306

Cryan JF, Markou A, Lucki I. 2002. Assessing antidepressant activity in rodents: Recent developments and future needs. Trends Pharmacol Sci 23:238–245. Cryan JF, McGrath C, Leonard BE, Norman TR. 1998. Combining pindolol and paroxetine in an animal model of chronic antidepressant action: Can early onset of action be detected? Eur J Pharmacol 352:23–28. Cryan JF, McGrath C, Leonard BE, Norman TR. 1999. Onset of the effects of the 5-HT1A antagonist, WAY-100635, alone, and in combination with paroxetine, on olfactory bulbectomy and 8-OH-DPAT-induced changes in the rat. Pharmacol Biochem Behav 63:333–338. Cryan JF, Mombereau C, Vassout A. 2005. The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29:571–625. Cryan JF, O’Leary OF. 2010. Neuroscience. A glutamate pathway to fasteracting antidepressants? Science 329:913–914. Cryan JF, Slattery DA. 2007. Animal models of mood disorders: Recent developments. Curr Opin Psychiatry 20:1–7. Cryan JF, Slattery DA. 2010. Animal models of depression – Where are we going? In: Cryan JF, Leonard BE, editors. Experimental Models of Depression and the Mechanisms of Action of Antidepressants. Basal: S. Karger, A.G. Dalla C, Pitychoutis PM, Kokras N, Papadopoulou-Daifoti Z. 2010. Sex differences in animal models of depression and antidepressant response. Basic Clin Pharmacol Toxicol 106:226–233. Dalla C, Pitychoutis PM, Kokras N, Papadopoulou-Daifoti Z. 2011. Sex differences in response to stress and expression of depressive-like behaviours in the rat. Curr Top Behav Neurosci 8:97–118. Der-Avakian A, Markou A. 2010. Neonatal maternal separation exacerbates the reward-enhancing effect of acute amphetamine administration and the anhedonic effect of repeated social defeat in adult rats. Neuroscience 170:1189–1198. Der-Avakian A, Mazei-Robison MS, Kesby JP, Nestler EJ, Markou A. 2014. Enduring deficits in brain reward function after chronic social defeat in rats: Susceptibility, resilience, and antidepressant response. Biol Psychiatry. doi:10.1016/j.biopsych.2014.01.013. Jan 31. [Epub ahead of print] Disner SG, Beevers CG, Haigh EA, Beck AT. 2011. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci 12:467–477. Donahue RJ, Muschamp JW, Russo SJ, Nestler EJ, Carlezon WA Jr. 2014. Effects of striatal deltaFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice. Biol Psychiatry. doi:10.1016/j. biopsych.2013.12.014. Jan 8. [Epub ahead of print] Duman RS, Aghajanian GK. 2012. Synaptic dysfunction in depression: Potential therapeutic targets. Science 338:68–72. Einat H. 2007a. Different behaviors and different strains: Potential new ways to model bipolar disorder. Neurosci Biobehav Rev 31:850–857. Einat H. 2007b. Establishment of a battery of simple models for facets of bipolar disorder: A practical approach to achieve increased validity, better screening and possible insights into endophenotypes of disease. Behav Genet 37:244–255. Elliott R, Ogilvie A, Rubinsztein JS, Calderon G, Dolan RJ, Sahakian BJ. 2004. Abnormal ventral frontal response during performance of an affective go/no go task in patients with mania. Biol Psychiatry 55:1163–1170. Elliott R, Sahakian BJ, Michael A, Paykel ES, Dolan RJ. 1998. Abnormal neural response to feedback on planning and guessing tasks in patients with unipolar depression. Psychol Med 28:559–571. Enkel T, Gholizadeh D, von Bohlen Und Halbach O, Sanchis-Segura C, Hurlemann R, Spanagel R, Gass P, Vollmayr B. 2010. Ambiguous-cue interpretation is biased under stress- and depression-like states in rats. Neuropsychopharmacology 35:1008–1015. Eshel N, Roiser JP. 2010. Reward and punishment processing in depression. Biol Psychiatry 68:118–124. Finger BC, Dinan TG, Cryan JF. 2011. High-fat diet selectively protects against the effects of chronic social stress in the mouse. Neuroscience 192:351–360. Frazer A, Morilak DA. 2005. What should animal models of depression model? Neurosci Biobehav Rev 29:515–523.

ILAR Journal

Downloaded from http://ilarjournal.oxfordjournals.org/ at University of Minnesota Libraries -- Wilson Library on October 14, 2014

Bale TL, Dorsa DM, Johnston CA. 1995. Oxytocin receptor mRNA expression in the ventromedial hypothalamus during the estrous cycle. J Neurosci 15:5058–5064. Bartlang MS, Neumann ID, Slattery DA, Uschold-Schmidt N, Kraus D, Helfrich-Forster C, Reber SO. 2012. Time matters: Pathological effects of repeated psychosocial stress during the active, but not inactive, phase of male mice. J Endocrinol 215:425–437. Belzung C. 2014. Innovative drugs to treat depression: did animal models fail to be predictive or did clinical trials fail to detect effects? Neuropsychopharmacology 39:1041–1051. Berton O, Hahn CG, Thase ME. 2012. Are we getting closer to valid translational models for major depression? Science 338:75–79. Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, et al. 2006. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868. Beurel E, Song L, Jope RS. 2011. Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 16:1068–1070. Bisgaard CF, Bak S, Christensen T, Jensen ON, Enghild JJ, Wiborg O. 2012. Vesicular signalling and immune modulation as hedonic fingerprints: Proteomic profiling in the chronic mild stress depression model. J Psychopharmacol 26:1569–1583. Bloch M, Rubinow DR, Schmidt PJ, Lotsikas A, Chrousos GP, Cizza G. 2005. Cortisol response to ovine corticotropin-releasing hormone in a model of pregnancy and parturition in euthymic women with and without a history of postpartum depression. J Clin Endocrinol Metab 90:695–699. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR. 2000. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry 157:924–930. Browning M, Holmes EA, Harmer CJ. 2010. The modification of attentional bias to emotional information: A review of the techniques, mechanisms, and relevance to emotional disorders. Cogn Affect Behav Neurosci 10:8–20. Brummelte S, Galea LA. 2010. Depression during pregnancy and postpartum: Contribution of stress and ovarian hormones. Prog Neuropsychopharmacol Biol Psychiatry 34:766–776. Bunck M, Czibere L, Horvath C, Graf C, Frank E, Kessler MS, Murgatroyd C, Muller-Myhsok B, Gonik M, Weber P, et al. 2009. A hypomorphic vasopressin allele prevents anxiety-related behavior. PLoS One 4:e5129. Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, Ferguson D, Tsai HC, Pomeranz L, Christoffel DJ, et al. 2013. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493:532–536. Chen G, Henter ID, Manji HK. 2010. Translational research in bipolar disorder: Emerging insights from genetically based models. Mol Psychiatry 15:883–895. Chourbaji S, Pfeiffer N, Dormann C, Brandwein C, Fradley R, Sheardown M, Gass P. 2010. The suitability of 129SvEv mice for studying depressivelike behaviour: Both males and females develop learned helplessness. Behav Brain Res 211:105–110. Christensen T, Bisgaard CF, Wiborg O. 2011. Biomarkers of anhedonic-like behavior, antidepressant drug refraction, and stress resilience in a rat model of depression. Neuroscience 196:66–79. Couillard-Despres S, Wuertinger C, Kandasamy M, Caioni M, Stadler K, Aigner R, Bogdahn U, Aigner L. 2009. Ageing abolishes the effects of fluoxetine on neurogenesis. Mol Psychiatry 14:856–864. Crabbe JC, Wahlsten D, Dudek BC. 1999. Genetics of mouse behavior: Interactions with laboratory environment. Science 284:1670–1672. Crowley JJ, Blendy JA, Lucki I. 2005. Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test. Psychopharmacology (Berl) 183:257–264. Cryan JF, Holmes A. 2005. The ascent of mouse: Advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790. Cryan JF, Hoyer D, Markou A. 2003. Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biol Psychiatry 54:49–58.

Volume 55, Number 2, doi: 10.1093/ilar/ilu026

2014

Kokras N, Dalla C. 2014. Sex Differences in animal models of psychiatric disorders. Br J Pharmacol. doi:10.1111/bph.12710. Apr 4. [Epub ahead of print] Kokras N, Dalla C, Papadopoulou-Daifoti Z. 2011. Sex differences in pharmacokinetics of antidepressants. Expert Opin Drug Metab Toxicol 7:213–226. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, Laplant Q, Graham A, Lutter M, Lagace DC, et al. 2007. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131:391–404. Kronenberg G, Gertz K, Heinz A, Endres M. 2014. Of mice and men– Modeling post-stroke depression experimentally. Br J Pharmacol. doi:10.1111/bph.12775. May 19. [Epub ahead of print] Landgraf R, Kessler MS, Bunck M, Murgatroyd C, Spengler D, Zimbelmann M, Nussbaumer M, Czibere L, Turck CW, Singewald N, et al. 2007. Candidate genes of anxiety-related behavior in HAB/LAB rats and mice: Focus on vasopressin and glyoxalase-I. Neurosci Biobehav Rev 31:89–102. Leonard B, Maes M. 2012. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 36:764–785. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. 2010. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964. Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta S, LambasSenas L, Wiborg O, Haddjeri N, Pineyro G, et al. 2007. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55:712–725. Lucki I. 1997. The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav Pharmacol 8:523–532. Maes M. 2008. The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro Endocrinol Lett 29:287–291. Malkesman O, Austin DR, Chen G, Manji HK. 2009. Reverse translational strategies for developing animal models of bipolar disorder. Dis Model Mech 2:238–245. Malkesman O, Scattoni ML, Paredes D, Tragon T, Pearson B, Shaltiel G, Chen G, Crawley JN, Manji HK. 2010. The female urine sniffing test: A novel approach for assessing reward-seeking behavior in rodents. Biol Psychiatry 67:864–871. Markou A, Chiamulera C, Geyer MA, Tricklebank M, Steckler T. 2009. Removing obstacles in neuroscience drug discovery: The future path for animal models. Neuropsychopharmacology 34:74–89. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. 2005. Deep brain stimulation for treatment-resistant depression. Neuron 45:651–660. McArthur R, Borsini F. 2006. Animal models of depression in drug discovery: A historical perspective. Pharmacol Biochem Behav 84:436–452. McClelland S, Korosi A, Cope J, Ivy A, Baram TZ. 2011. Emerging roles of epigenetic mechanisms in the enduring effects of early-life stress and experience on learning and memory. Neurobiol Learn Mem 96:79–88. Michaud CM, Murray CJ, Bloom BR. 2001. Burden of disease–Implications for future research. JAMA 285:535–539. Miller AH, Maletic V, Raison CL. 2009. Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65:732–741. Mnie-Filali O, Faure C, Lambas-Senas L, El Mansari M, Belblidia H, Gondard E, Etievant A, Scarna H, Didier A, Berod A, et al. 2011. Pharmacological blockade of 5-HT7 receptors as a putative fast acting antidepressant strategy. Neuropsychopharmacology 36:1275–1288. Murgatroyd C, Spengler D. 2011. Epigenetic programming of the HPA axis: Early life decides. Stress 14:581–589. Naranjo CA, Tremblay LK, Busto UE. 2001. The role of the brain reward system in depression. Prog Neuropsychopharmacol Biol Psychiatry 25:781–823.

307

Downloaded from http://ilarjournal.oxfordjournals.org/ at University of Minnesota Libraries -- Wilson Library on October 14, 2014

Fuchs E. 2005. Social stress in tree shrews as an animal model of depression: An example of a behavioral model of a CNS disorder. CNS Spectr 10:182–190. Geyer MA, Markou A. 1995. Animal models of psychiatric disorders. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology–The 4th generation of progress. New York: Raven. p. 787–798. Gottesman II, Gould TD. 2003. The endophenotype concept in psychiatry: Etymology and strategic intentions. Am J Psychiatry 160:636–645. Gould TD, Einat H. 2007. Animal models of bipolar disorder and mood stabilizer efficacy: A critical need for improvement. Neurosci Biobehav Rev 31:825–831. Gould TD, Gottesman II. 2006. Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav 5:113–119. Guo J, Fisher KA, Darcy R, Cryan JF, O’Driscoll C. 2010. Therapeutic targeting in the silent era: Advances in non-viral siRNA delivery. Mol Biosyst 6:1143–1161. Gutierrez-Lobos K, Scherer M, Anderer P, Katschnig H. 2002. The influence of age on the female/male ratio of treated incidence rates in depression. BMC Psychiatry 2:3. Hales CA, Stuart SA, Anderson MH, Robinson ES. 2014. Modelling Cognitive affective biases in major depressive disorder using rodents. Br J Pharmacol. doi:10.1111/bph.12603. Jan 28. [Epub ahead of print] Hamani C, Diwan M, Macedo CE, Brandao ML, Shumake J, GonzalezLima F, Raymond R, Lozano AM, Fletcher PJ, Nobrega JN. 2010. Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol Psychiatry 67:117–124. Harro J. 2013. Animal models of depression vulnerability. Curr Top Behav Neurosci 14:29–54. Hasler G, Drevets WC, Manji HK, Charney DS. 2004. Discovering endophenotypes for major depression. Neuropsychopharmacology 29:1765–1781. Hasler G, Neumeister A, van der Veen JW, Tumonis T, Bain EE, Shen J, Drevets WC, Charney DS. 2005. Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy. Biol Psychiatry 58:969–973. Hasler G, Northoff G. 2011. Discovering imaging endophenotypes for major depression. Mol Psychiatry 16:604–619. Henn FA, Vollmayr B. 2005. Stress models of depression: Forming genetically vulnerable strains. Neurosci Biobehav Rev 29:799–804. Henry BL, Minassian A, Young JW, Paulus MP, Geyer MA, Perry W. 2010. Cross-species assessments of motor and exploratory behavior related to bipolar disorder. Neurosci Biobehav Rev 34:1296–1306. Herman L, Hougland T, El-Mallakh RS. 2007. Mimicking human bipolar ion dysregulation models mania in rats. Neurosci Biobehav Rev 31:874–881. Hillerer KM, Neumann ID, Slattery DA. 2012. From stress to postpartum mood and anxiety disorders: How chronic peripartum stress can impair maternal adaptations. Neuroendocrinology 95:22–38. Jacobson LH, Cryan JF. 2007. Feeling strained? Influence of genetic background on depression-related behavior in mice: A review. Behav Genet 37:171–213. Joel D, Yankelevitch-Yahav R. 2014. Reconceptualizing sex, brain and psychopathology: Interaction, interaction, interaction. Br J Pharmacol. Katz RJ. 1981. Animal model of depression: Effects of electroconvulsive shock therapy. Neurosci Biobehav Rev 5:273–277. Keen-Rhinehart E, Michopoulos V, Toufexis DJ, Martin EI, Nair H, Ressler KJ, Davis M, Owens MJ, Nemeroff CB, Wilson ME. 2009. Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes. Mol Psychiatry 14:37–50. Kelly JP, Wrynn AS, Leonard BE. 1997. The olfactory bulbectomized rat as a model of depression: An update. Pharmacol Ther 74:299–316. Kendler KS, Gardner CO, Prescott CA. 1999. Clinical characteristics of major depression that predict risk of depression in relatives. Arch Gen Psychiatry 56:322–327. Kessler RC. 2003. Epidemiology of women and depression. J Affect Disord 74:5–13. Kinsey SG, Bailey MT, Sheridan JF, Padgett DA. 2008. The inflammatory response to social defeat is increased in older mice. Physiol Behav 93:628–636.

308

a novel chronic psycho-social stress paradigm in mice: Implications and mechanisms. Endocrinology 148:670–682. Reber SO, Obermeier F, Straub RH, Falk W, Neumann ID. 2006. Chronic intermittent psychosocial stress (social defeat/overcrowding) in mice increases the severity of an acute DSS-induced colitis and impairs regeneration. Endocrinology 147:4968–4976. Richter SH, Schick A, Hoyer C, Lankisch K, Gass P, Vollmayr B. 2012. A glass full of optimism: Enrichment effects on cognitive bias in a rat model of depression. Cogn Affect Behav Neurosci 12:527–542. Romeas T, Morissette MC, Mnie-Filali O, Pineyro G, Boye SM. 2009. Simultaneous anhedonia and exaggerated locomotor activation in an animal model of depression. Psychopharmacology (Berl) 205:293–303. Roose SP, Glassman AH, Attia E, Woodring S. 1994. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 151:1735–1739. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, Chakravarty S, Peevey J, Oehrlein N, Birnbaum S, et al. 2007. Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A 104:6406–6411. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, et al. 2003. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809. Saul MC, Gessay GM, Gammie SC. 2012. A new mouse model for mania shares genetic correlates with human bipolar disorder. PLoS One 7: e38128. Shaw AC, Goldstein DR, Montgomery RR. 2013. Age-dependent dysregulation of innate immunity. Nat Rev Immunol 13:875–887. Slattery DA, Cryan JF. 2006. The role of GABAB receptors in depression and antidepressant-related behavioural responses. Drug Dev Res 67:477–494. Slattery DA, Cryan JF. 2011. Animal models of depression – Where are we going? In: Cryan JF, Leonard BE, editors. Depression: From Psychopathology to Pharmacotherapy. Basel: S. Karger AG. Slattery DA, Cryan JF. 2012. Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat Protoc 7:1009–1014. Slattery DA, Markou A, Cryan JF. 2007. Evaluation of reward processes in an animal model of depression. Psychopharmacology (Berl) 190:555–568. Slattery DA, Neumann ID, Cryan JF. 2011. Transient inactivation of the infralimbic cortex induces antidepressant-like effects in the rat. J Psychopharmacol 25:1295–1303. Slattery DA, Uschold N, Magoni M, Bar J, Popoli M, Neumann ID, Reber SO. 2012. Behavioural consequences of two chronic psychosocial stress paradigms: Anxiety without depression. Psychoneuroendocrinology 37:702–714. Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. 2011. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476:458–461. Song C, Leonard BE. 2005. The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev 29:627–647. Stuart SA, Butler P, Munafo MR, Nutt DJ, Robinson ES. 2013. A translational rodent assay of affective biases in depression and antidepressant therapy. Neuropsychopharmacology 38:1625–1635. Szabo ST, Machado-Vieira R, Yuan P, Wang Y, Wei Y, Falke C, Cirelli C, Tononi G, Manji HK, Du J. 2009. Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania. Neuropharmacology 56:47–55. Tanti A, Belzung C. 2010. Open questions in current models of antidepressant action. Br J Pharmacol 159:1187–1200. Tremblay LK, Naranjo CA, Cardenas L, Herrmann N, Busto UE. 2002. Probing brain reward system function in major depressive disorder: Altered response to dextroamphetamine. Arch Gen Psychiatry 59:409–416. Tremblay LK, Naranjo CA, Graham SJ, Herrmann N, Mayberg HS, Hevenor S, Busto UE. 2005. Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry 62:1228–1236. Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, Kim SY, Adhikari A, Thompson KR, Andalman AS, et al. 2013.

ILAR Journal

Downloaded from http://ilarjournal.oxfordjournals.org/ at University of Minnesota Libraries -- Wilson Library on October 14, 2014

Naughton M, Clarke G, OF OL, Cryan JF, Dinan TG. 2014. A review of ketamine in affective disorders: Current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord 156:24–35. Nelson JC, Mazure CM, Jatlow PI. 1995. Desipramine treatment of major depression in patients over 75 years of age. J Clin Psychopharmacol 15:99–105. Nestler EJ, Hyman SE. 2010. Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169. Neumann ID, Wegener G, Homberg JR, Cohen H, Slattery DA, Zohar J, Olivier JD, Mathe AA. 2011. Animal models of depression and anxiety: What do they tell us about human condition? Prog Neuropsychopharmacol Biol Psychiatry 35:1357–1375. Niciu MJ, Henter ID, Luckenbaugh DA, Zarate CA Jr, Charney DS. 2014. Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: Ketamine and other compounds. Annu Rev Pharmacol Toxicol 54:119–139. Nollet M, Le Guisquet AM, Belzung C. 2013. Models of depression: Unpredictable chronic mild stress in mice. Curr Protoc Pharmacol Chapter 5: Unit 5 65. O’Connor RM, Dinan TG, Cryan JF. 2012. Little things on which happiness depends: microRNAs as novel therapeutic targets for the treatment of anxiety and depression. Mol Psychiatry 17:359–376. O’Connor RM, Grenham S, Dinan TG, Cryan JF. 2013. microRNAs as novel antidepressant targets: Converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus. Int J Neuropsychopharmacol 16:1885–1892. O’Hara MW, McCabe JE. 2013. Postpartum depression: Current status and future directions. Annu Rev Clin Psychol 9:379–407. O’Leary OF, Cryan JF. 2013. Towards translational rodent models of depression. Cell Tissue Res 354:141–153. Opal MD, Klenotich SC, Morais M, Bessa J, Winkle J, Doukas D, Kay LJ, Sousa N, Dulawa SM. 2013. Serotonin 2C receptor antagonists induce fast-onset antidepressant effects. Mol Psychiatry. doi:10.1038/ mp.2013.164. Nov 19. [Epub ahead of print] Perani CV, Slattery DA. 2014. Using Animal models to study postpartum psychiatric disorders. Br J Pharmacol. doi:10.1111/bph.12640. Feb 16. [Epub ahead of print] Peters S, Slattery DA, Flor PJ, Neumann ID, Reber SO. 2013. Differential effects of baclofen and oxytocin on the increased ethanol consumption following chronic psychosocial stress in mice. Addict Biol 18:66–77. Petit-Demouliere B, Chenu F, Bourin M. 2005. Forced swimming test in mice: A review of antidepressant activity. Psychopharmacology (Berl) 177:245–255. Pollak DD, Monje FJ, Zuckerman L, Denny CA, Drew MR, Kandel ER. 2008. An animal model of a behavioral intervention for depression. Neuron 60:149–161. Pollak DD, Rey CE, Monje FJ. 2010. Rodent models in depression research: classical strategies and new directions. Ann Med 42:252–264. Pryce CR, Azzinnari D, Sigrist H, Gschwind T, Lesch KP, Seifritz E. 2012. Establishing a learned-helplessness effect paradigm in C57BL/6 mice: Behavioural evidence for emotional, motivational and cognitive effects of aversive uncontrollability per se. Neuropharmacology 62:358–372. Pryce CR, Azzinnari D, Spinelli S, Seifritz E, Tegethoff M, Meinlschmidt G. 2011. Helplessness: A systematic translational review of theory and evidence for its relevance to understanding and treating depression. Pharmacol Ther 132:242–267. Pryce CR, Feldon J. 2003. Long-term neurobehavioural impact of the postnatal environment in rats: Manipulations, effects and mediating mechanisms. Neurosci Biobehav Rev 27:57–71. Pryce CR, Seifritz E. 2011. A translational research framework for enhanced validity of mouse models of psychopathological states in depression. Psychoneuroendocrinology 36:308–329. Reber SO. 2012. Stress and animal models of inflammatory bowel disease– An update on the role of the hypothalamo-pituitary-adrenal axis. Psychoneuroendocrinology 37:1–19. Reber SO, Birkeneder L, Veenema AH, Obermeier F, Falk W, Straub RH, Neumann ID. 2007. Adrenal insufficiency and colonic inflammation after

Volume 55, Number 2, doi: 10.1093/ilar/ilu026

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Wong ML, Licinio J. 2001. Research and treatment approaches to depression. Nat Rev Neurosci 2:343–351. Young JW, Henry BL, Geyer MA. 2011. Predictive animal models of mania: Hits, misses and future directions. Br J Pharmacol 164: 1263–1284. Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA, Luckenbaugh DA. 2013a. A randomized trial of a low-trapping nonselective N-methylD-aspartate channel blocker in major depression. Biol Psychiatry 74:257–264. Zarate CA Jr, Mathews DC, Furey ML. 2013b. Human biomarkers of rapid antidepressant effects. Biol Psychiatry 73:1142–1155. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. 2006. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856–864.

309

Downloaded from http://ilarjournal.oxfordjournals.org/ at University of Minnesota Libraries -- Wilson Library on October 14, 2014

Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493:537–541. van der Stelt HM, Breuer ME, Olivier B, Westenberg HG. 2005. Permanent deficits in serotonergic functioning of olfactory bulbectomized rats: An in vivo microdialysis study. Biol Psychiatry 57:1061–1067. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, et al. 2011. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90–94. Warden MR, Selimbeyoglu A, Mirzabekov JJ, Lo M, Thompson KR, Kim SY, Adhikari A, Tye KM, Frank LM, Deisseroth K. 2012. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492:428–432. Wong ML, Dong C, Andreev V, Arcos-Burgos M, Licinio J. 2012. Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors. Mol Psychiatry 17:624–633.