Relevance of Rodent Models of Depression in Clinical Practice: Can We Overcome the Obstacles in Translational Neuropsychiatry?

Relevance of Rodent Models of Depression in Clinical Practice: Can We Overcome the Obstacles in... The diagnosis of a mental disorder generally depends on clinical observations and phenomenological symptoms reported by the patient. The definition of a given diagnosis is criteria based and relies on the ability to accurately interpret subjective symptoms and complex behavior. This type of diagnosis comprises a challenge to translate to reliable animal models, and these translational uncertainties hamper the development of new treatments. In this review, we will discuss how depressive- like behavior can be induced in rodents, and the relationship between these models and depression in humans. Specifically, we suggest similarities between triggers of depressive-like behavior in animal models and human conditions known to increase the risk of depression, for example exhaustion and bullying. Although we acknowledge the potential problems in comparing animal findings to human conditions, such comparisons are useful for understanding the complexity of depression, and we highlight the need to develop clinical diagnoses and animal models in parallel to overcome translational uncertainties. Keywords: RDoC, stress, resilience, vulnerability Introduction One of the greatest challenges of our society is to prevent and research is hampered by the fact that the psychiatric diagnos- treat mental disorders. Despite major breakthroughs in neuro- tic procedure is open for subjective interpretation of reported science, only limited progress in the treatment of mental disor- symptoms and that it lacks objective measures of behavior or ders has been made in the last 30 years. This can be explained biomarkers. Regarding depression, the collection of disparate partly by a lack of compatibility between neuroscience and clin- symptoms is particularly troublesome (Spitzer et al., 1978). The ical practice. wide variability of symptoms and clinical presentations among The diagnosis major depression was introduced in the mid- subtypes of depression clearly indicates that depression is not a 1970s and incorporated in the third edition of the American homogenous disorder but is actually a spectrum of related dis- Psychiatric Association’s Diagnostic and Statistical Manual orders (Lux and Kendler, 2010). of Mental Disorders (DSM) (Spitzer et  al., 1978). Since then, We argue that animal models are necessary for understand- the diagnostic system has been improved and advances have ing the neurobiology of the disease. However, it is futile to seek been made, including increased awareness of mental health one single animal model for the diagnosis depression. Instead, issues and the development of specific forms of psychother - we should use various animal models, where depressive-like apy. However, the translation between clinical work and animal behavior has been induced in different ways, to learn more about Received: May 31, 2017; Revised: February 22, 2018; Accepted: 13 April 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 1 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 2 | International Journal of Neuropsychopharmacology, 2018 the mechanisms underlying the psychiatric conditions they What do we talk about when we talk about model (Table 1). When we compare animal models with clinical depression in rodents? conditions, we need to use less well-established clinical descrip- The translational uncertainties described above, including the tions. These conditions are often associated with an increased lack of functional biomarkers for major depression, compli- risk of developing major depression (Figure 1), but are not major cate the definition of an animal model of depression. Thus, the depression per se. It becomes clear that the animal models are evaluation of the model needs to be based on clinically relevant not diagnostic models, but rather models of risk and vulnerabil- symptoms, and these symptoms must be detectable and quan- ity factors of depression. Importantly, this is not a drawback of tifiable in the animals’ behavior. In this text we refer to “tests” the animal models, but again illustrates that the current diag- as behaviors that can be evaluated, whereas an “animal model” nostic system is neither compatible with neuroscience nor is it is an animal that has been manipulated as to score higher in sufficient to describe the underlying mechanisms of depression. these tests. We will also discuss how these weaknesses can be overcome. Table 1. Animal Models of Depression Based on their Mode of Induction as well as Functional Characteristics Animal Model References Induction Possible Disease Relevance Stress-Induced Chronic mild stress Katz, 1982; Willner et al., 1987 Unpredictable repeated stress Studying of risk-factors for burn-out Unescapable stress Maier, 1984; Telner and Acute, intense stress Possible overlapping mechanisms between Singhal, 1984 PTSD and depression Social defeat Golden et al., 2011; Forced to subordination Bullying as riskfactor for depression Krishnan and Nestler, 2011 Social isolation Grippo et al., 2007; Djordjevic Individual housing et al., 2012 Maternal separation Matthews and Robbins, 2003; Maternal separation Early separation/insecure attachment as Vetulani, 2013 riskfactor for depression Selectivly Bred FSL Gómez-Galán et al., 2013; Sensitivity to cholinergic agents Tests for antidepressant treatments Overstreet and Vulnerability for stress Wegener, 2013 Wistar-Kyoto Paré, 1989; Sensitivity to hypertension Vulnerability for stress Solberg et al., 2001; β-blockers effect on behavior Nam et al., 2014 Other selectively bred Sensitivity to stress, anxiety, Vulnerability factors and risk-behavior models subordination… associated with depression Genetic Manipulations SERT-KO Lira et al., 2003 Total knock-out of serotonin Increased anxiety, serotonergic syndrome, transporter NET-KO Haenisch and Bönisch, 2011 Total knock-out of noradrenaline Protective against depression transporter BDNF modification Kaufman et al., 2006 Knock-out of BDNF or TrkB Study of antidepressant effects vGlut1-KO Garcia-Garcia et al., 2009 Total knock-out of vesicular Depressive-like behavior glutamate transporter Vulnerability to depression DISC1 KO Shen et al., 2008 Total knock-out of DISC1 Overlapping symptoms between schizophrenia and depression Other transgenic Renoir et al., 2013 Specific genetic deletions in Systemic studies on vulnerability to animals targeted organs depression Network Alterations Stimulation of raphe Warden et al., 2012 Optogenetic activation of PFC The role of serotonin in depression nucleus projections to Raphe Nucleus Inhibition of VTA Tye et al., 2013 Optogenetic inhibition of VTA The role of dopamine in depression projections to Nucleus Neuronal activity pattern as vulnerability to Accumbens depression D2 receptors in basal Francis et al., 2014  Targeted modification of Dopamine pharmacology to treat ganglia Dias et al., 2014 D2-containing neurons in the depression striatum Striatal microcircuit involvement in depression Stimulaion of central Tye et al., 2011 Optgenetic activation of central Protective against development of amygdala nucleus of amygdala depression Stimulation of Hsu and Wang, 2014 Optogenetic activation of habenula Reinforcement and aversion in depression Hanbenula Neuroinflammation LPS injection Yirmiya, 1996 Stimulation of inflammation Relationship inflammation - depression Injections of IL6, IL1 or Fleshner et al., 1995; Stimulation of specific inflammatory Relationship inflammation – depression kynurenine Smagin et al., 1996 pathways Systemic signals involved in depression Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 Söderlund and Lindskog | 3 an animal model or the response to a drug; in particular, tests for memory and anxiety are commonly used (Lapiz-Bluhm et al., 2008). Stress-Induced Models of Depression In humans, depression can occur in the absence of any not- able life stressor, while conversely many individuals who are exposed to chronic life stressors never develop clinical depression (Feder et  al., 2009). Nevertheless, many patients with depression often describe stress-inducing life events as contributing factors, and stress is commonly used to induce depressive-like behavior in animals (Slattery and Cryan, 2017). Studies using these stress-induced models of depression have generally reported an increase of plasma corticosterone, and the depressive-like behavior is not elicited when the stress response is reduced (such as in adrenalectomized or genetic- ally modified animals; Keeney et al., 2006; Goshen et al., 2008) . Likewise, major depressive disorder has been associated with increased production of corticotropin-releasing hormone and cortisol as well as increased size of the pituitary and the Figure  1. Scheme of exposures (arrows) and vulnerabilities (circles) that adrenals, indicating a general increased activity of the hypo- increase risk of depression. By combining risk factors for depression identified thalamic–pituitary–adrenal axis (Dinan, 1994) together with in the clinic with specific neurobiological manipulations in animal models, we will achieve a better understanding of the pathophysiology of depression. possible glucocorticoid receptor resistance and defective nega- tive feedback (Pariante, 2004). The best established and most commonly used tests for depressive-like behavior in animals have been developed for Chronic Stress predictive value; that is, an animal’s response to a given treat- ment can predict if the treatment will have an antidepressant The most common model, and one of the best-validated, is effect in humans. The Porsolt swim test (Porsolt et  al., 1977) the chronic mild stress model (Katz, 1982; Willner et  al., 1987) and the tail suspension test (Cryan et  al., 2005) measure an in which animals are subjected to stressors several times a animal’s struggle to escape an unpleasant situation (i.e., being day at unpredictable time points. This protocol minimizes the in water or hanging upside-down, respectively), and these impact of acute stress, as each intervention (loud noise, tilting tests are commonly used by the pharmaceutical industry to of the cage, wet bedding, etc.) causes only moderate stress. One predict how patients will respond to a given antidepressant major advantage of the chronic mild stress model is long-last- drug. It can be argued that these tests also have face value, as ing effects allowing investigation of long-term administration of a decreased struggle can be interpreted as a lack of motivation antidepressant drugs. Although this model has a reputation of or despair—behaviors that are common among patients with being unreliable, a recent survey suggested that the unreliability depression. may not be worse in this model compared with other depression Another commonly used test for depression is to measure models (Willner, 2017). anhedonia (a loss of the ability to derive pleasure from an activ- By design, the chronic mild stress model could be viewed as ity that usually produces pleasure) by comparing how much an resembling exhaustion disorder, in humans caused by difficul- animal prefers sweetened water to unsweetened water. A  lost ties in coping with life and occupational stress. Exhaustion dis- preference for sweet water is interpreted as anhedonia, a depres- order is characterized by a long prodromal phase that can include sive symptom (Willner et  al., 1987). To avoid any possible bias reduced energy and increased emotional instability, eventually due to metabolic factors, anhedonia can be tested more directly progressing to an acute phase that includes exhaustion, hope- using a self-stimulating paradigm where a stimulating electrode lessness, and apathy. Recent studies suggest that exhaustion is implanted in a brain area mediating reward. The animal can disorder is separate from anxiety and major depression (Besèr then self-stimulate by pressing a lever or poking its nose into a et  al., 2014), whereas others report considerable comorbidity hole; a decreased propensity to self-stimulate is considered to between exhaustion disorder and major depression (Glise et al., reflect anhedonia (Vogel et al., 1986). 2012). This may indicate either that exhaustion corresponds to A newly developed test is aiming for another core symp- one aspect of depression or that exhaustion increases the risk tom in depression: negative bias. In this test the propensity of depression. Regardless of the interpretation, the chronic mild for a rat to choose a reward rather than to avoid something stress animal model is an important tool for understanding the unpleasant is measured (Hales et  al., 2014). Other tests that relationship between depressive-like behavior and sustained, are gaining in popularity are based on natural behaviors, such unpredictable stress. as social interaction and/or the motivation to explore, rather than examining the response to a given stimulus or stressful Acute Stress situation. For example, our group and others have shown that Another well-characterized model of depression displaying a decreased exploratory behavior is associated with a depres- sion-like phenotype (Kasahara et  al., 2007; Li et  al., 2010; wide variety of depressive-like behavior is the learned help- lessness model. This model is based on repeated exposure to Gómez-Galán et  al., 2013; Magara et  al., 2015). Several auxil- iary tests can be used to obtain a more complete evaluation of an inescapable acute threat, such as a foot-shock or a pinch to Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 4 | International Journal of Neuropsychopharmacology, 2018 the tail in a box where the animal learns that it has nowhere Neurobiological Models of Depression to escape (Maier, 1984; Telner and Singhal, 1984). Social defeat can be considered a variant of the learned helplessness model, Selectively Bred Animal Models where the stressor is chosen to be innate to the rodent, namely Selectively bred animal models are used to study depression, subordination to a dominant peer (Golden et al., 2011; Krishnan with the 2 most commonly used being the Flinders sensitive line and Nestler, 2011). Typically, animals are put as intruders in (FSL) and the Wistar-Kyoto line. The FSL rat was selectively bred the home cage of a large dominant male and thus forced to for sensitivity to acetylcholinesterase inhibitors (Overstreet subordination. et  al., 1986) and displays several depressive-like behaviors, In addition to being well characterized models for depres- including increased immobility time in the Porsolt’s swim test, sion, the learned helplessness model, as well as the social decreased cognition, and increased anxiety (Gómez-Galán et al., defeat model, produce physiologic and behavioral symptoms 2013; Overstreet and Wegener, 2013). Thus, one could hypothe- that models aspects of PTSD (Pulliam, 2010; Schöner, 2017). size that an increased sensitivity in the acetylcholine system The exposure to an inescapable acute threat, as in the learned is associated with depressive-like symptoms, although FSL helplessness model, corresponds to the first DSM criterion for rats also have deficiencies in many other systems, including posttraumatic stress disorder (PTSD). Interestingly, situations of dopaminergic and glutamatergic transmission (Overstreet and power imbalance such as workplace bullying, often including Wegener, 2013). sexual harassment, are also associated with an increased risk The Wistar-Kyoto line was developed as a control group of development of PTSD (Spence Laschinger and Nosko, 2015) for hypertensive rats and was subsequently found to have as well as depression (Lund et  al., 2009). Moreover, patients increased stress responses, altered sleep patterns, and depres- exposed to trauma or stressful events often exhibit anhedonia sive-like behavior in the Porsolt’s swim test (Paré, 1989; Solberg and dysphoric symptoms (among others) rather than anxiety- et al., 2001; Nam et al., 2014). These rats have a mixed response or fear-based symptoms. The learned helplessness and social to antidepressants and have been selectively bred further to defeat models may thus be useful tools to study how differ- establish lines of “more immobility” and “less immobility,” ent types of acute, severe stress affects the risk of acquiring which respond differently to antidepressants (Will et al., 2003; depressive-like behavior. Andrus et al., 2012). Although we still do not understand the underlying mecha- Social Stress nisms of depressive-like behavior in the FSL and Wistar-Kyoto lines, the transmitter systems used for selection in the devel- Another way to use social stress in animal models is social iso- opment of these two lines are paralleled with observations in lation. Individual housing for 4 weeks has been shown to induce human depression. Cholinergic signaling, which was the tar - depressive-like behavior (Grippo et  al., 2007; Djordjevic et  al., get system in the development of the FSL rat, regulates social 2012). A specific form of social isolation is maternal separation, stress, anxiety, and depressive-like behavior (Mineur et  al., another commonly used model of depression (Matthews and 2013). The adrenergic system, which regulates blood pres- Robbins, 2003; Vetulani, 2013). In this model, the lactating dam sure and was targeted in the development of the Wistar-Kyoto is taken out of the cage for about 3 hours every day from the sec- rats, has not been primarily associated with depression, and ond to the twelfth day postpartum. This treatment is complex results obtained from clinical trials using antihypertensive and goes beyond pure isolation (Lehmann and Feldon, 2000), drugs vary. Although ß-blockers, and propranolol in particular, and it leads to depressive-like behavior that persists into adult- have been found to be associated with depression, it has been hood. This agrees with the fact that childhood separation and argued that the behavioral changes associated with propran- parental neglect can lead to long-lasting attachment insecurity olol do not resemble classic depressive syndrome (Patten and in humans (Waters et al., 2000). Both attachment insecurity and Barbui, 2004). early separation have been associated with depression (Roberts In addition to the well-characterized FSL and Wistar-Kyoto et al., 1996; Otowa et al., 2014), and emotional dysregulation has lines, several groups have bred animals selecting for a specific been proposed as the link between these triggering events and depression-like behavior. In addition to the behaviors that they depression (Malik et al., 2015). were selected on, these animals show disturbed sleep pattern, increased plasma corticosterone, and reduced levels of base- Vulnerability to Stress line serotonin and brain-derived neurotrophic factor (BDNF) (El Yacoubi et al., 2003; Will et al., 2003; Gersner et al., 2014). In addition to these commonly used models of stress-induced Selectively bred models can focus on one particular behav- depression, many other paradigms of stress have been used. ior among the depressive-like symptoms, thus allowing study Nevertheless, we still lack a comprehensive picture of how of the neurobiology or potential treatment of that particular different depression-triggering mechanisms are induced by construct. In contrast to models where selection is based on a different modalities of stress, or differences in when, and for known mechanism, models based on a specific behavior allow how long, stress is applied. Comparing different stress-induced us to discover unexpected mechanisms of relevance to depres- models will help us to get a clearer picture of the differential sion. The drawback of the unknown etiology is that it does not effect of different types of stress and its timing. Experimental allow us to draw causative conclusions. animal models can also be studied to identify factors of vulner- ability and resilience to different types of stressors (Dias et al., 2014). Vulnerability factors and environment may interact to Genetic Models produce depression, as has been shown for a specific serotonin transporter allele that renders an individual more sensitive or Twin studies suggest that the genetic contribution to depression less sensitive to stressful life events (Caspi et  al., 2010; Wang ranges from 10% to 50% (Silberg et  al., 1990; Edvardsen et  al., et al., 2011). 2009), and several genes have been associated with depression; Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 Söderlund and Lindskog | 5 however, no gene has emerged as the main gene underlying the in the ventral tegmental area‒nucleus accumbens connection disorder (Flint and Kendler, 2014). The lack of conclusive genetics can reduce or increase depressive-like behavior, respectivly (Tye data in animal models and human patients can have two pos- et al., 2013), and phasic firing of these projections increases sus- sible explanations: either depression is a highly complex trait, or ceptibility to social stress (Chaudhury et al., 2013). Stimulating depression is not actually one disease but rather a disease spec- the dopamine D -receptor expressing neurons in the basal trum that can be induced by a wide variety of biological causes ganglia increases the resilience to developing depressive-like (Andrus et al., 2012; Gómez-Galán et al., 2016). behavior, whereas activating the D -receptor expressing neu- Nevertheless, attempts have been made to use genetic mod- rons increases the vulnerability (Francis et  al., 2015), suggest- ifications in mice to study depression, and the serotonergic and ing a differential role of these two populations in mediating noradrenergic systems have provided obvious targets for such resilience to depressive-like behavior. Moreover, overexpressing modifications. Interestingly, genetic deletions of the norepin- of the signaling molecule β-catenin in D -expressing neurons 2- ephrine transporter are protective against depression induced only specifically increases resilience to the social defeat proto- by restrained stress or social defeat (Haenisch and Bönisch, col (Dias et al., 2014). Finally, stimulating the central nucleus of 2011), whereas deleting the serotonin transporter leads to a the amygdala reduces anxiety-like behavior (Tye et  al., 2011), phenotype that resembles the acute effect of selective sero- whereas specific molecular manipulations have revealed that tonin reuptake inhibitor treatment, including increased anxiety the habenula regulates reinforcement and aversion (Hsu and or even serotonergic syndrome (Lira et al., 2003). Genetic down- Wang, 2014) that can explain part of the depressive-like behav- regulation of tryptophan hydroxylase, the rate-limiting enzyme ior (Hsu et al., 2016). in serotonin synthesis, increases depressive-like behavior These experiments using specific genetic manipulations (Savelieva et al., 2008). have been extremely fruitful in terms of elucidating the neuro- A single nucleotide polymorphism in the human BDNF biological mechanisms that underlie various dimensions of gene increases vulnerability to stress-induced depression depressive-like behavior. Together with refined imaging in (Kaufman et  al., 2006), making this gene a target for depres- animals as well as humans, we will get an increased under- sion models. However, when BDNF function is reduced standing of how a specific neuronal population or network can through genetic modification of BDNF or its receptor TrkB, be involved in the pathophysiology of depression (Chen et  al., no unequivocal link to depression is found. Instead, reduced 2017), and they provide valuable information that can be used BDNF function leads to cognitive impairment and obesity to predict the clinical response to pharmacotherapy (Haenisch (Lindholm and Castrén, 2014). and Bönisch, 2011). However, it is striking to note how differ - Recent work describes depression as a misregulated glu- ent manipulations in different areas of the brain can induce a tamate transmission or an unbalance in excitation and similar phenotype. This may be interpreted either as overlap- inhibition, leading to studies targeting genes involved in the ping systems or that brain circuits interact: disrupting any one regulation of glutamate. For example, reduced levels of the of them trigger similar pathology. Thus, in addition to identify- vesicular glutamate transporter lead to increased depressive- ing the pieces of the puzzle, we must also assemble these pieces like behavior and increased vulnerability to stressors (Garcia- correctly to form a coherent picture. Garcia et al., 2009). In contrast to selectively bred animals, a model that has been Neuroinflammation modified with targeted genetic manipulation could allow to There is a well-established link between inflammation and establish a causative link between a biological function and the depression (Krishnadas and Cavanagh, 2012), and injection of depressive-like behavior. However, it is important to note that the inflammation-inducing agent lipopolysaccharide (LPS) is a the specificity of a genetic mutation can be deceiving. A  gen- popular model for inducing depression (Yirmiya, 1996). Specific etic change will affect many compensatory and downstream pathways in the inflammatory response have also been targeted pathways, and the most relevant mechanism may be hard to to study the mechanisms of inflammation-induced depression, pinpoint. In addition, many pathways converge on the same including IL-6, IL-1, and kynurenine. The injection of proinflam- behavior; for example, the 4 distinct genetic models targeting matory cytokines activates the hypothalamic–pituitary–adrenal serotonin, glucocorticoid, glutamate, and cannabinoid signal- axis as seen through increased cortisol levels, depletion of hypo- ing were all recently reported to share the behavioral changes thalamic noradrenaline, and increased extracellular levels of nor - (Hoyle et al., 2011). For an extensive review of targeted genetic adrenaline (Fleshner et al., 1995; Smagin et al., 1996). Activation of modifications that lead to depressive-like behavior, see (Renoir inflammatory pathways is, however, not enough, since cytokine- et al., 2013). induced depressive-like behavior was abolished in the serotonin transporter knock-out mice; this implies the involvement of the Animal Models with Specific Network Alterations serotonin modulatory system (van Heesch et  al., 2013). In add- The development of targeted genetic manipulations and ition to soluble signaling molecules, the vagus nerve plays a major optogenetics, where a light-activated ion-channel can be select- role in the communication between the peripheral inflammatory ively inserted and activated in a population of neurons, has response and the brain, and vagotomy protects from IL-1 and LPS- made it possible to study specific circuits and/or signaling path- induced depressive behavior (Konsman et al., 2000). ways in behavioral dimensions relevant to depression (Berton In humans, depression has been associated with increased et  al., 2012; Deisseroth, 2014). For example, stimulation of the serum levels of the proinflammatory cytokines IL-1β, IL-6, and raphe nucleus through direct activation of projection neurons TNFα (Howren et  al., 2009; Dowlati et  al., 2010). Furthermore, in the prefrontal cortex reduces immobility in the forced swim during severe infections and inflammatory diseases, patients test (Warden et al., 2012) as does inhibition of NMDA receptors often show a typical sickness behavior defined by lack of energy, in prefrontal projections to the thalamus (Miller et  al., 2017). apathy, lack of interest, reduced intake of food, etc., thus closely In addition, activating or inhibiting the dopaminergic neurons resembling major depression (Dantzer et  al., 2008). Recent Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 6 | International Journal of Neuropsychopharmacology, 2018 work reveals tryptophan catabolism as a converging point for immediately useful clinical tool.” However, as discouraging as immunological factors and neurotransmission. The conversion this may sound to any clinical psychiatrist, we argue that such of L-tryptophan to N-formyl-kynurenine is governed by the rate- a common context can be achieved without dramatic paradig- limiting IDO/TDO enzyme (Rafice et al., 2009). IDO is modulated matic shifts in the clinic. during immune responses (Babcock and Carlin, 2000), and major The current diagnostic criteria for major depression do not depression has been associated with increased levels of the emphasize how core symptoms of depression like anhedonia, tryptophan metabolite quinolinic acid in the cerebrospinal fluid motor retardation, and despair have developed. However, it is (Bay-Richter et al., 2015). only when the reported symptoms are combined with a thor - Overall, there is ample evidence from both animals and ough analysis of exposures to risk factors and vulnerability humans that inflammatory pathways are involved in depres- factors that the clinical picture emerges. Identification of the sion. Evaluation of their cross-talk is an important field of future relevant constructs of RDoC overlaps with the taking of such work (Feder et al., 2009). a clinical history (Table  2) and will be directly relevant for the diagnosis. From a clinical point of view, RDoC could be used to improve Discussion the diagnostic specificity and specificity of treatment by increas- ing the theoretical ground on which the clinical decisions are We have reviewed animal models used in depression research, based on how the depressive-like behavior is based. RDoC may thus guide the clinician to more information from the relevant animal models. For example, if the clinical induced. We argue that it is impossible to find one valid ani- mal model of depression that reflects all the aspects of the picture is dominated by the construct “response to threat” of the negative valence domain, the clinician may find more infor - disease; rather, different animal models should be used to study different aspects of depression. Experimental models mation from the corresponding animal models of social defeat and learned helplessness, and if the clinical picture involves offer the opportunity to expose the animals to one factor at a time, thus allowing us to study vulnerability factors and the construct “disrupted attachment” of the social processes domain, the clinician may gather more information from the objectively measure and quantify proposed mechanisms involved in depression. A  critical step to develop better corresponding animal model of maternal separation rather than without further notice giving the patient a major depressive dis- treatment and prevention of depression is now to improve the understanding between clinical practitioners and basic order diagnosis. From a neuroscience perspective, a common context of researchers through the development of a common context for depression. In our point of view, such a context must depression, where clinicians put more emphasis on risk fac- tors and vulnerability factors specified as constructs of RDoC, involve symptoms (regardless of whether these fulfill all the necessary criteria for major depressive disorder according to would lead to a stronger validation of the animal models, gen- erate more specific hypothesis, and enhance development of the DSM or not) as well as etiologic factors, exposure, and vulnerabilities. more specific drugs and better tools to uncover the neurobiology behind symptoms (Figure 2). To enhance the interaction between clinic and neuro- biology, the NIMH has proposed to use Research Domain In summary, the gap between the clinical practice and neuroscience may be smaller than initially thought, and the Criteria (RDoC) as a novel approach to categorizing psychiatric conditions (see http://www.nimh.nih.gov/research-priorities/ use of RDoC may indeed be a way to bridge this gap. Clinical experience is necessary to develop fruitful animal models, but rdoc/constructs/rdoc-matrix.shtml). The intention is to cre- ate a system based on well-defined constructs (e.g., response the animal models are also needed to delineate the complex patterns of different exposures and vulnerability factors char - to threat, responsiveness to reward, long-term memory within the larger domains: negative valence system, positive acterizing the clinical situation, indicating the potential mutual benefit between research and clinic (Figure 2). RDoC may facili- valence system, cognition, social response, and arousal) that will facilitate communication between research and clinic. At tate these iterations. If constructs are studied in patients and in animal models, this will shorten the length of the iteration cycle their homepage, the NIHM describes RDoC as “a framework to guide classification of patients for research studies, not as an and facilitate early identification of potential breakthroughs or Table 2. Research Domain Criteria as Risk Factors for Depression, Their Clinical Manifestations, and the Coresponding Animal Behavior Domain Constructs Clinical Manifestations Experimental Animal Tests Negative valence Acute threat Powerlessness Lack of social interaction Porsolt swim test Sustained threat Exhaustion, powerlessness Porsolt swim test Lack of social interaction Frustrative non-reward Exhaustion Lack social interaction Responses to potential harm Anxiety Elevated plus maze, Open field, Novelty suppressed feeding Positive valence Reward valuation Anhedonia Sucrose preference, self stimulation Arousal Arousal, interaction with Appetite, sleep, sex, locomotors Sleep-pattern, social interaction, modified valence activity serial-5 choice Social processes Disrupted attachment Disorganized attachment Aggressive behavior Disrupted affiliation Victimization Subordination, Social withdrawal Social withdrawal Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 Söderlund and Lindskog | 7 Besèr A, Sorjonen K, Wahlberg K, Peterson U, Nygren A, Asberg M (2014) Construction and evaluation of a self rating scale for stress-induced exhaustion disorder, the Karolinska exhaus- tion disorder scale. 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Am J Physiol Regul Yirmiya R (1996) Endotoxin produces a depressive-like episode Integr Comp Physiol 281:R786–R794. in rats. Brain Res 711:163–174. Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Neuropsychopharmacology Oxford University Press

Relevance of Rodent Models of Depression in Clinical Practice: Can We Overcome the Obstacles in Translational Neuropsychiatry?

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Abstract

The diagnosis of a mental disorder generally depends on clinical observations and phenomenological symptoms reported by the patient. The definition of a given diagnosis is criteria based and relies on the ability to accurately interpret subjective symptoms and complex behavior. This type of diagnosis comprises a challenge to translate to reliable animal models, and these translational uncertainties hamper the development of new treatments. In this review, we will discuss how depressive- like behavior can be induced in rodents, and the relationship between these models and depression in humans. Specifically, we suggest similarities between triggers of depressive-like behavior in animal models and human conditions known to increase the risk of depression, for example exhaustion and bullying. Although we acknowledge the potential problems in comparing animal findings to human conditions, such comparisons are useful for understanding the complexity of depression, and we highlight the need to develop clinical diagnoses and animal models in parallel to overcome translational uncertainties. Keywords: RDoC, stress, resilience, vulnerability Introduction One of the greatest challenges of our society is to prevent and research is hampered by the fact that the psychiatric diagnos- treat mental disorders. Despite major breakthroughs in neuro- tic procedure is open for subjective interpretation of reported science, only limited progress in the treatment of mental disor- symptoms and that it lacks objective measures of behavior or ders has been made in the last 30 years. This can be explained biomarkers. Regarding depression, the collection of disparate partly by a lack of compatibility between neuroscience and clin- symptoms is particularly troublesome (Spitzer et al., 1978). The ical practice. wide variability of symptoms and clinical presentations among The diagnosis major depression was introduced in the mid- subtypes of depression clearly indicates that depression is not a 1970s and incorporated in the third edition of the American homogenous disorder but is actually a spectrum of related dis- Psychiatric Association’s Diagnostic and Statistical Manual orders (Lux and Kendler, 2010). of Mental Disorders (DSM) (Spitzer et  al., 1978). Since then, We argue that animal models are necessary for understand- the diagnostic system has been improved and advances have ing the neurobiology of the disease. However, it is futile to seek been made, including increased awareness of mental health one single animal model for the diagnosis depression. Instead, issues and the development of specific forms of psychother - we should use various animal models, where depressive-like apy. However, the translation between clinical work and animal behavior has been induced in different ways, to learn more about Received: May 31, 2017; Revised: February 22, 2018; Accepted: 13 April 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 1 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 2 | International Journal of Neuropsychopharmacology, 2018 the mechanisms underlying the psychiatric conditions they What do we talk about when we talk about model (Table 1). When we compare animal models with clinical depression in rodents? conditions, we need to use less well-established clinical descrip- The translational uncertainties described above, including the tions. These conditions are often associated with an increased lack of functional biomarkers for major depression, compli- risk of developing major depression (Figure 1), but are not major cate the definition of an animal model of depression. Thus, the depression per se. It becomes clear that the animal models are evaluation of the model needs to be based on clinically relevant not diagnostic models, but rather models of risk and vulnerabil- symptoms, and these symptoms must be detectable and quan- ity factors of depression. Importantly, this is not a drawback of tifiable in the animals’ behavior. In this text we refer to “tests” the animal models, but again illustrates that the current diag- as behaviors that can be evaluated, whereas an “animal model” nostic system is neither compatible with neuroscience nor is it is an animal that has been manipulated as to score higher in sufficient to describe the underlying mechanisms of depression. these tests. We will also discuss how these weaknesses can be overcome. Table 1. Animal Models of Depression Based on their Mode of Induction as well as Functional Characteristics Animal Model References Induction Possible Disease Relevance Stress-Induced Chronic mild stress Katz, 1982; Willner et al., 1987 Unpredictable repeated stress Studying of risk-factors for burn-out Unescapable stress Maier, 1984; Telner and Acute, intense stress Possible overlapping mechanisms between Singhal, 1984 PTSD and depression Social defeat Golden et al., 2011; Forced to subordination Bullying as riskfactor for depression Krishnan and Nestler, 2011 Social isolation Grippo et al., 2007; Djordjevic Individual housing et al., 2012 Maternal separation Matthews and Robbins, 2003; Maternal separation Early separation/insecure attachment as Vetulani, 2013 riskfactor for depression Selectivly Bred FSL Gómez-Galán et al., 2013; Sensitivity to cholinergic agents Tests for antidepressant treatments Overstreet and Vulnerability for stress Wegener, 2013 Wistar-Kyoto Paré, 1989; Sensitivity to hypertension Vulnerability for stress Solberg et al., 2001; β-blockers effect on behavior Nam et al., 2014 Other selectively bred Sensitivity to stress, anxiety, Vulnerability factors and risk-behavior models subordination… associated with depression Genetic Manipulations SERT-KO Lira et al., 2003 Total knock-out of serotonin Increased anxiety, serotonergic syndrome, transporter NET-KO Haenisch and Bönisch, 2011 Total knock-out of noradrenaline Protective against depression transporter BDNF modification Kaufman et al., 2006 Knock-out of BDNF or TrkB Study of antidepressant effects vGlut1-KO Garcia-Garcia et al., 2009 Total knock-out of vesicular Depressive-like behavior glutamate transporter Vulnerability to depression DISC1 KO Shen et al., 2008 Total knock-out of DISC1 Overlapping symptoms between schizophrenia and depression Other transgenic Renoir et al., 2013 Specific genetic deletions in Systemic studies on vulnerability to animals targeted organs depression Network Alterations Stimulation of raphe Warden et al., 2012 Optogenetic activation of PFC The role of serotonin in depression nucleus projections to Raphe Nucleus Inhibition of VTA Tye et al., 2013 Optogenetic inhibition of VTA The role of dopamine in depression projections to Nucleus Neuronal activity pattern as vulnerability to Accumbens depression D2 receptors in basal Francis et al., 2014  Targeted modification of Dopamine pharmacology to treat ganglia Dias et al., 2014 D2-containing neurons in the depression striatum Striatal microcircuit involvement in depression Stimulaion of central Tye et al., 2011 Optgenetic activation of central Protective against development of amygdala nucleus of amygdala depression Stimulation of Hsu and Wang, 2014 Optogenetic activation of habenula Reinforcement and aversion in depression Hanbenula Neuroinflammation LPS injection Yirmiya, 1996 Stimulation of inflammation Relationship inflammation - depression Injections of IL6, IL1 or Fleshner et al., 1995; Stimulation of specific inflammatory Relationship inflammation – depression kynurenine Smagin et al., 1996 pathways Systemic signals involved in depression Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 Söderlund and Lindskog | 3 an animal model or the response to a drug; in particular, tests for memory and anxiety are commonly used (Lapiz-Bluhm et al., 2008). Stress-Induced Models of Depression In humans, depression can occur in the absence of any not- able life stressor, while conversely many individuals who are exposed to chronic life stressors never develop clinical depression (Feder et  al., 2009). Nevertheless, many patients with depression often describe stress-inducing life events as contributing factors, and stress is commonly used to induce depressive-like behavior in animals (Slattery and Cryan, 2017). Studies using these stress-induced models of depression have generally reported an increase of plasma corticosterone, and the depressive-like behavior is not elicited when the stress response is reduced (such as in adrenalectomized or genetic- ally modified animals; Keeney et al., 2006; Goshen et al., 2008) . Likewise, major depressive disorder has been associated with increased production of corticotropin-releasing hormone and cortisol as well as increased size of the pituitary and the Figure  1. Scheme of exposures (arrows) and vulnerabilities (circles) that adrenals, indicating a general increased activity of the hypo- increase risk of depression. By combining risk factors for depression identified thalamic–pituitary–adrenal axis (Dinan, 1994) together with in the clinic with specific neurobiological manipulations in animal models, we will achieve a better understanding of the pathophysiology of depression. possible glucocorticoid receptor resistance and defective nega- tive feedback (Pariante, 2004). The best established and most commonly used tests for depressive-like behavior in animals have been developed for Chronic Stress predictive value; that is, an animal’s response to a given treat- ment can predict if the treatment will have an antidepressant The most common model, and one of the best-validated, is effect in humans. The Porsolt swim test (Porsolt et  al., 1977) the chronic mild stress model (Katz, 1982; Willner et  al., 1987) and the tail suspension test (Cryan et  al., 2005) measure an in which animals are subjected to stressors several times a animal’s struggle to escape an unpleasant situation (i.e., being day at unpredictable time points. This protocol minimizes the in water or hanging upside-down, respectively), and these impact of acute stress, as each intervention (loud noise, tilting tests are commonly used by the pharmaceutical industry to of the cage, wet bedding, etc.) causes only moderate stress. One predict how patients will respond to a given antidepressant major advantage of the chronic mild stress model is long-last- drug. It can be argued that these tests also have face value, as ing effects allowing investigation of long-term administration of a decreased struggle can be interpreted as a lack of motivation antidepressant drugs. Although this model has a reputation of or despair—behaviors that are common among patients with being unreliable, a recent survey suggested that the unreliability depression. may not be worse in this model compared with other depression Another commonly used test for depression is to measure models (Willner, 2017). anhedonia (a loss of the ability to derive pleasure from an activ- By design, the chronic mild stress model could be viewed as ity that usually produces pleasure) by comparing how much an resembling exhaustion disorder, in humans caused by difficul- animal prefers sweetened water to unsweetened water. A  lost ties in coping with life and occupational stress. Exhaustion dis- preference for sweet water is interpreted as anhedonia, a depres- order is characterized by a long prodromal phase that can include sive symptom (Willner et  al., 1987). To avoid any possible bias reduced energy and increased emotional instability, eventually due to metabolic factors, anhedonia can be tested more directly progressing to an acute phase that includes exhaustion, hope- using a self-stimulating paradigm where a stimulating electrode lessness, and apathy. Recent studies suggest that exhaustion is implanted in a brain area mediating reward. The animal can disorder is separate from anxiety and major depression (Besèr then self-stimulate by pressing a lever or poking its nose into a et  al., 2014), whereas others report considerable comorbidity hole; a decreased propensity to self-stimulate is considered to between exhaustion disorder and major depression (Glise et al., reflect anhedonia (Vogel et al., 1986). 2012). This may indicate either that exhaustion corresponds to A newly developed test is aiming for another core symp- one aspect of depression or that exhaustion increases the risk tom in depression: negative bias. In this test the propensity of depression. Regardless of the interpretation, the chronic mild for a rat to choose a reward rather than to avoid something stress animal model is an important tool for understanding the unpleasant is measured (Hales et  al., 2014). Other tests that relationship between depressive-like behavior and sustained, are gaining in popularity are based on natural behaviors, such unpredictable stress. as social interaction and/or the motivation to explore, rather than examining the response to a given stimulus or stressful Acute Stress situation. For example, our group and others have shown that Another well-characterized model of depression displaying a decreased exploratory behavior is associated with a depres- sion-like phenotype (Kasahara et  al., 2007; Li et  al., 2010; wide variety of depressive-like behavior is the learned help- lessness model. This model is based on repeated exposure to Gómez-Galán et  al., 2013; Magara et  al., 2015). Several auxil- iary tests can be used to obtain a more complete evaluation of an inescapable acute threat, such as a foot-shock or a pinch to Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 4 | International Journal of Neuropsychopharmacology, 2018 the tail in a box where the animal learns that it has nowhere Neurobiological Models of Depression to escape (Maier, 1984; Telner and Singhal, 1984). Social defeat can be considered a variant of the learned helplessness model, Selectively Bred Animal Models where the stressor is chosen to be innate to the rodent, namely Selectively bred animal models are used to study depression, subordination to a dominant peer (Golden et al., 2011; Krishnan with the 2 most commonly used being the Flinders sensitive line and Nestler, 2011). Typically, animals are put as intruders in (FSL) and the Wistar-Kyoto line. The FSL rat was selectively bred the home cage of a large dominant male and thus forced to for sensitivity to acetylcholinesterase inhibitors (Overstreet subordination. et  al., 1986) and displays several depressive-like behaviors, In addition to being well characterized models for depres- including increased immobility time in the Porsolt’s swim test, sion, the learned helplessness model, as well as the social decreased cognition, and increased anxiety (Gómez-Galán et al., defeat model, produce physiologic and behavioral symptoms 2013; Overstreet and Wegener, 2013). Thus, one could hypothe- that models aspects of PTSD (Pulliam, 2010; Schöner, 2017). size that an increased sensitivity in the acetylcholine system The exposure to an inescapable acute threat, as in the learned is associated with depressive-like symptoms, although FSL helplessness model, corresponds to the first DSM criterion for rats also have deficiencies in many other systems, including posttraumatic stress disorder (PTSD). Interestingly, situations of dopaminergic and glutamatergic transmission (Overstreet and power imbalance such as workplace bullying, often including Wegener, 2013). sexual harassment, are also associated with an increased risk The Wistar-Kyoto line was developed as a control group of development of PTSD (Spence Laschinger and Nosko, 2015) for hypertensive rats and was subsequently found to have as well as depression (Lund et  al., 2009). Moreover, patients increased stress responses, altered sleep patterns, and depres- exposed to trauma or stressful events often exhibit anhedonia sive-like behavior in the Porsolt’s swim test (Paré, 1989; Solberg and dysphoric symptoms (among others) rather than anxiety- et al., 2001; Nam et al., 2014). These rats have a mixed response or fear-based symptoms. The learned helplessness and social to antidepressants and have been selectively bred further to defeat models may thus be useful tools to study how differ- establish lines of “more immobility” and “less immobility,” ent types of acute, severe stress affects the risk of acquiring which respond differently to antidepressants (Will et al., 2003; depressive-like behavior. Andrus et al., 2012). Although we still do not understand the underlying mecha- Social Stress nisms of depressive-like behavior in the FSL and Wistar-Kyoto lines, the transmitter systems used for selection in the devel- Another way to use social stress in animal models is social iso- opment of these two lines are paralleled with observations in lation. Individual housing for 4 weeks has been shown to induce human depression. Cholinergic signaling, which was the tar - depressive-like behavior (Grippo et  al., 2007; Djordjevic et  al., get system in the development of the FSL rat, regulates social 2012). A specific form of social isolation is maternal separation, stress, anxiety, and depressive-like behavior (Mineur et  al., another commonly used model of depression (Matthews and 2013). The adrenergic system, which regulates blood pres- Robbins, 2003; Vetulani, 2013). In this model, the lactating dam sure and was targeted in the development of the Wistar-Kyoto is taken out of the cage for about 3 hours every day from the sec- rats, has not been primarily associated with depression, and ond to the twelfth day postpartum. This treatment is complex results obtained from clinical trials using antihypertensive and goes beyond pure isolation (Lehmann and Feldon, 2000), drugs vary. Although ß-blockers, and propranolol in particular, and it leads to depressive-like behavior that persists into adult- have been found to be associated with depression, it has been hood. This agrees with the fact that childhood separation and argued that the behavioral changes associated with propran- parental neglect can lead to long-lasting attachment insecurity olol do not resemble classic depressive syndrome (Patten and in humans (Waters et al., 2000). Both attachment insecurity and Barbui, 2004). early separation have been associated with depression (Roberts In addition to the well-characterized FSL and Wistar-Kyoto et al., 1996; Otowa et al., 2014), and emotional dysregulation has lines, several groups have bred animals selecting for a specific been proposed as the link between these triggering events and depression-like behavior. In addition to the behaviors that they depression (Malik et al., 2015). were selected on, these animals show disturbed sleep pattern, increased plasma corticosterone, and reduced levels of base- Vulnerability to Stress line serotonin and brain-derived neurotrophic factor (BDNF) (El Yacoubi et al., 2003; Will et al., 2003; Gersner et al., 2014). In addition to these commonly used models of stress-induced Selectively bred models can focus on one particular behav- depression, many other paradigms of stress have been used. ior among the depressive-like symptoms, thus allowing study Nevertheless, we still lack a comprehensive picture of how of the neurobiology or potential treatment of that particular different depression-triggering mechanisms are induced by construct. In contrast to models where selection is based on a different modalities of stress, or differences in when, and for known mechanism, models based on a specific behavior allow how long, stress is applied. Comparing different stress-induced us to discover unexpected mechanisms of relevance to depres- models will help us to get a clearer picture of the differential sion. The drawback of the unknown etiology is that it does not effect of different types of stress and its timing. Experimental allow us to draw causative conclusions. animal models can also be studied to identify factors of vulner- ability and resilience to different types of stressors (Dias et al., 2014). Vulnerability factors and environment may interact to Genetic Models produce depression, as has been shown for a specific serotonin transporter allele that renders an individual more sensitive or Twin studies suggest that the genetic contribution to depression less sensitive to stressful life events (Caspi et  al., 2010; Wang ranges from 10% to 50% (Silberg et  al., 1990; Edvardsen et  al., et al., 2011). 2009), and several genes have been associated with depression; Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 Söderlund and Lindskog | 5 however, no gene has emerged as the main gene underlying the in the ventral tegmental area‒nucleus accumbens connection disorder (Flint and Kendler, 2014). The lack of conclusive genetics can reduce or increase depressive-like behavior, respectivly (Tye data in animal models and human patients can have two pos- et al., 2013), and phasic firing of these projections increases sus- sible explanations: either depression is a highly complex trait, or ceptibility to social stress (Chaudhury et al., 2013). Stimulating depression is not actually one disease but rather a disease spec- the dopamine D -receptor expressing neurons in the basal trum that can be induced by a wide variety of biological causes ganglia increases the resilience to developing depressive-like (Andrus et al., 2012; Gómez-Galán et al., 2016). behavior, whereas activating the D -receptor expressing neu- Nevertheless, attempts have been made to use genetic mod- rons increases the vulnerability (Francis et  al., 2015), suggest- ifications in mice to study depression, and the serotonergic and ing a differential role of these two populations in mediating noradrenergic systems have provided obvious targets for such resilience to depressive-like behavior. Moreover, overexpressing modifications. Interestingly, genetic deletions of the norepin- of the signaling molecule β-catenin in D -expressing neurons 2- ephrine transporter are protective against depression induced only specifically increases resilience to the social defeat proto- by restrained stress or social defeat (Haenisch and Bönisch, col (Dias et al., 2014). Finally, stimulating the central nucleus of 2011), whereas deleting the serotonin transporter leads to a the amygdala reduces anxiety-like behavior (Tye et  al., 2011), phenotype that resembles the acute effect of selective sero- whereas specific molecular manipulations have revealed that tonin reuptake inhibitor treatment, including increased anxiety the habenula regulates reinforcement and aversion (Hsu and or even serotonergic syndrome (Lira et al., 2003). Genetic down- Wang, 2014) that can explain part of the depressive-like behav- regulation of tryptophan hydroxylase, the rate-limiting enzyme ior (Hsu et al., 2016). in serotonin synthesis, increases depressive-like behavior These experiments using specific genetic manipulations (Savelieva et al., 2008). have been extremely fruitful in terms of elucidating the neuro- A single nucleotide polymorphism in the human BDNF biological mechanisms that underlie various dimensions of gene increases vulnerability to stress-induced depression depressive-like behavior. Together with refined imaging in (Kaufman et  al., 2006), making this gene a target for depres- animals as well as humans, we will get an increased under- sion models. However, when BDNF function is reduced standing of how a specific neuronal population or network can through genetic modification of BDNF or its receptor TrkB, be involved in the pathophysiology of depression (Chen et  al., no unequivocal link to depression is found. Instead, reduced 2017), and they provide valuable information that can be used BDNF function leads to cognitive impairment and obesity to predict the clinical response to pharmacotherapy (Haenisch (Lindholm and Castrén, 2014). and Bönisch, 2011). However, it is striking to note how differ - Recent work describes depression as a misregulated glu- ent manipulations in different areas of the brain can induce a tamate transmission or an unbalance in excitation and similar phenotype. This may be interpreted either as overlap- inhibition, leading to studies targeting genes involved in the ping systems or that brain circuits interact: disrupting any one regulation of glutamate. For example, reduced levels of the of them trigger similar pathology. Thus, in addition to identify- vesicular glutamate transporter lead to increased depressive- ing the pieces of the puzzle, we must also assemble these pieces like behavior and increased vulnerability to stressors (Garcia- correctly to form a coherent picture. Garcia et al., 2009). In contrast to selectively bred animals, a model that has been Neuroinflammation modified with targeted genetic manipulation could allow to There is a well-established link between inflammation and establish a causative link between a biological function and the depression (Krishnadas and Cavanagh, 2012), and injection of depressive-like behavior. However, it is important to note that the inflammation-inducing agent lipopolysaccharide (LPS) is a the specificity of a genetic mutation can be deceiving. A  gen- popular model for inducing depression (Yirmiya, 1996). Specific etic change will affect many compensatory and downstream pathways in the inflammatory response have also been targeted pathways, and the most relevant mechanism may be hard to to study the mechanisms of inflammation-induced depression, pinpoint. In addition, many pathways converge on the same including IL-6, IL-1, and kynurenine. The injection of proinflam- behavior; for example, the 4 distinct genetic models targeting matory cytokines activates the hypothalamic–pituitary–adrenal serotonin, glucocorticoid, glutamate, and cannabinoid signal- axis as seen through increased cortisol levels, depletion of hypo- ing were all recently reported to share the behavioral changes thalamic noradrenaline, and increased extracellular levels of nor - (Hoyle et al., 2011). For an extensive review of targeted genetic adrenaline (Fleshner et al., 1995; Smagin et al., 1996). Activation of modifications that lead to depressive-like behavior, see (Renoir inflammatory pathways is, however, not enough, since cytokine- et al., 2013). induced depressive-like behavior was abolished in the serotonin transporter knock-out mice; this implies the involvement of the Animal Models with Specific Network Alterations serotonin modulatory system (van Heesch et  al., 2013). In add- The development of targeted genetic manipulations and ition to soluble signaling molecules, the vagus nerve plays a major optogenetics, where a light-activated ion-channel can be select- role in the communication between the peripheral inflammatory ively inserted and activated in a population of neurons, has response and the brain, and vagotomy protects from IL-1 and LPS- made it possible to study specific circuits and/or signaling path- induced depressive behavior (Konsman et al., 2000). ways in behavioral dimensions relevant to depression (Berton In humans, depression has been associated with increased et  al., 2012; Deisseroth, 2014). For example, stimulation of the serum levels of the proinflammatory cytokines IL-1β, IL-6, and raphe nucleus through direct activation of projection neurons TNFα (Howren et  al., 2009; Dowlati et  al., 2010). Furthermore, in the prefrontal cortex reduces immobility in the forced swim during severe infections and inflammatory diseases, patients test (Warden et al., 2012) as does inhibition of NMDA receptors often show a typical sickness behavior defined by lack of energy, in prefrontal projections to the thalamus (Miller et  al., 2017). apathy, lack of interest, reduced intake of food, etc., thus closely In addition, activating or inhibiting the dopaminergic neurons resembling major depression (Dantzer et  al., 2008). Recent Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 6 | International Journal of Neuropsychopharmacology, 2018 work reveals tryptophan catabolism as a converging point for immediately useful clinical tool.” However, as discouraging as immunological factors and neurotransmission. The conversion this may sound to any clinical psychiatrist, we argue that such of L-tryptophan to N-formyl-kynurenine is governed by the rate- a common context can be achieved without dramatic paradig- limiting IDO/TDO enzyme (Rafice et al., 2009). IDO is modulated matic shifts in the clinic. during immune responses (Babcock and Carlin, 2000), and major The current diagnostic criteria for major depression do not depression has been associated with increased levels of the emphasize how core symptoms of depression like anhedonia, tryptophan metabolite quinolinic acid in the cerebrospinal fluid motor retardation, and despair have developed. However, it is (Bay-Richter et al., 2015). only when the reported symptoms are combined with a thor - Overall, there is ample evidence from both animals and ough analysis of exposures to risk factors and vulnerability humans that inflammatory pathways are involved in depres- factors that the clinical picture emerges. Identification of the sion. Evaluation of their cross-talk is an important field of future relevant constructs of RDoC overlaps with the taking of such work (Feder et al., 2009). a clinical history (Table  2) and will be directly relevant for the diagnosis. From a clinical point of view, RDoC could be used to improve Discussion the diagnostic specificity and specificity of treatment by increas- ing the theoretical ground on which the clinical decisions are We have reviewed animal models used in depression research, based on how the depressive-like behavior is based. RDoC may thus guide the clinician to more information from the relevant animal models. For example, if the clinical induced. We argue that it is impossible to find one valid ani- mal model of depression that reflects all the aspects of the picture is dominated by the construct “response to threat” of the negative valence domain, the clinician may find more infor - disease; rather, different animal models should be used to study different aspects of depression. Experimental models mation from the corresponding animal models of social defeat and learned helplessness, and if the clinical picture involves offer the opportunity to expose the animals to one factor at a time, thus allowing us to study vulnerability factors and the construct “disrupted attachment” of the social processes domain, the clinician may gather more information from the objectively measure and quantify proposed mechanisms involved in depression. A  critical step to develop better corresponding animal model of maternal separation rather than without further notice giving the patient a major depressive dis- treatment and prevention of depression is now to improve the understanding between clinical practitioners and basic order diagnosis. From a neuroscience perspective, a common context of researchers through the development of a common context for depression. In our point of view, such a context must depression, where clinicians put more emphasis on risk fac- tors and vulnerability factors specified as constructs of RDoC, involve symptoms (regardless of whether these fulfill all the necessary criteria for major depressive disorder according to would lead to a stronger validation of the animal models, gen- erate more specific hypothesis, and enhance development of the DSM or not) as well as etiologic factors, exposure, and vulnerabilities. more specific drugs and better tools to uncover the neurobiology behind symptoms (Figure 2). To enhance the interaction between clinic and neuro- biology, the NIMH has proposed to use Research Domain In summary, the gap between the clinical practice and neuroscience may be smaller than initially thought, and the Criteria (RDoC) as a novel approach to categorizing psychiatric conditions (see http://www.nimh.nih.gov/research-priorities/ use of RDoC may indeed be a way to bridge this gap. Clinical experience is necessary to develop fruitful animal models, but rdoc/constructs/rdoc-matrix.shtml). The intention is to cre- ate a system based on well-defined constructs (e.g., response the animal models are also needed to delineate the complex patterns of different exposures and vulnerability factors char - to threat, responsiveness to reward, long-term memory within the larger domains: negative valence system, positive acterizing the clinical situation, indicating the potential mutual benefit between research and clinic (Figure 2). RDoC may facili- valence system, cognition, social response, and arousal) that will facilitate communication between research and clinic. At tate these iterations. If constructs are studied in patients and in animal models, this will shorten the length of the iteration cycle their homepage, the NIHM describes RDoC as “a framework to guide classification of patients for research studies, not as an and facilitate early identification of potential breakthroughs or Table 2. Research Domain Criteria as Risk Factors for Depression, Their Clinical Manifestations, and the Coresponding Animal Behavior Domain Constructs Clinical Manifestations Experimental Animal Tests Negative valence Acute threat Powerlessness Lack of social interaction Porsolt swim test Sustained threat Exhaustion, powerlessness Porsolt swim test Lack of social interaction Frustrative non-reward Exhaustion Lack social interaction Responses to potential harm Anxiety Elevated plus maze, Open field, Novelty suppressed feeding Positive valence Reward valuation Anhedonia Sucrose preference, self stimulation Arousal Arousal, interaction with Appetite, sleep, sex, locomotors Sleep-pattern, social interaction, modified valence activity serial-5 choice Social processes Disrupted attachment Disorganized attachment Aggressive behavior Disrupted affiliation Victimization Subordination, Social withdrawal Social withdrawal Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy037/4982723 by Ed 'DeepDyve' Gillespie user on 08 June 2018 Söderlund and Lindskog | 7 Besèr A, Sorjonen K, Wahlberg K, Peterson U, Nygren A, Asberg M (2014) Construction and evaluation of a self rating scale for stress-induced exhaustion disorder, the Karolinska exhaus- tion disorder scale. 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International Journal of NeuropsychopharmacologyOxford University Press

Published: Apr 23, 2018

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