The recent progress in animal models of depression

https://doi.org/10.1016/j.pnpbp.2017.04.008Get rights and content

Highlights

  • Availability of current animal models of depression

  • Critical evaluation of behavioral paradigms being used to phenotype depression in animals.

  • Availability genetic models of depression and their usefulness

  • Discuss current challenges and future studies to focus on the underlying mechanism on depression and resilience

Abstract

Major depression disorder (MDD) is a debilitating mental illness with significant morbidity and mortality. Despite the growing number of studies that have emerged, the precise underlying mechanisms of MDD remain unknown. When studying MDD, tissue samples like peripheral blood or post-mortem brain samples are used to elucidate underlying mechanisms. Unfortunately, there are many uncontrollable factors with such samples such as medication history, age, time after death before post-mortem tissue was collected, age, sex, race, and living conditions. Although these factors are critical, they introduce confounding variables that can influence the outcome profoundly. In this regard, animal models provide a crucial approach to examine neural circuitry and molecular and cellular pathways in a controlled environment. Further, manipulations with pharmacological agents and gene editing are accepted methods of studying depression in animal models, which is impossible to employ in human patient studies. Here, we have reviewed the most widely used animal models of depression and delineated the salient features of each model in terms of behavioral and neurobiological outcomes. We have also illustrated the current challenges in using these models and have suggested strategies to delineate the underlying mechanism associated with vulnerability or resilience to developing depression.

Introduction

Major depressive disorder (MDD) is one of the most debilitating mental illnesses with a 12-month life-time prevalence of ~ 17% (Kessler et al., 2003). About 350 million people worldwide suffer from MDD (World Health Organization, 2003), whereas within the United States, about 15 million people are affected with this mental illness (Hedden et al., 2015). MDD is associated with significant morbidity and mortality (Carney et al., 2002). About 50% of depressed patients show suicidal ideation or thought and ~ 10% commit suicide (Kovacs and Garrison, 1985). The existing mechanisms for the development of therapeutic drugs are mostly based on “monoamine hypothesis” which suggests that decreased concentration of monoamine neurotransmitters plays a role in MDD (Tran et al., 2003). These drugs include selective serotonin reuptake inhibitors (SSRIs), tricyclics (TCAS) and inhibitors of degradation of neurotransmitters such as monoamine oxidase inhibitors (MAOIs) (Brunello et al., 2002). However, a significant population of depressed patients (20% to 30%) does not respond to these medications. This is partially due to our limited understanding of the precise neurobiological mechanisms associated with depression (Krishnan and Nestler, 2008). Recent evidence suggests that the incidence of depression is caused by alterations in the complex signaling networks. These networks cover monoamine neurotransmitter systems, neuroendocrine system, neurotrophic factors, neurogenesis, altered immune system, and epigenetic modifications (Abrous et al., 2005, Butler et al., 1989, Calvano et al., 2005, Castrén et al., 2007, Kim et al., 2006, Ponomarev et al., 2012). There is also a considerable contribution of genetic factors to the pathogenesis of depression (Shi et al., 2011). In addition, the interaction of susceptible genes and stress environment also plays a major role in the etiology of this disorder (Ohadi et al., 2012).

The major limitations in delineating the precise neurobiological mechanisms of depression lie in its complex nature, its heterogeneity, and its association with other comorbid psychiatric disorders (Krishnan and Nestler, 2008). The use of peripheral tissues from patients, such as blood, has limited value. Some of the limitations have been overcome by using post-mortem brain samples from human subjects; however, their availability is scarce and is often associated with confounding variables such as prior or current antidepressant treatment, post-mortem interval, agonal state, and pH of the brain (Bunney et al., 2003, Lewis, 2002). In a majority of the cases, post-mortem tissues are available from depressed patients who committed suicide, which may have its own or overlapping neurobiological mechanisms (Krishnan and Nestler, 2008). In this regard, animal models provide a crucial avenue to examine neural circuitry along with molecular and cellular pathways that may be critical in the pathogenesis of depression. There has been skepticism of the use of animal models because animal cognition is dissimilar to the higher cognitive and emotional prowess of humans. However, over the years, these models have been refined to cover several aspects of depression-like and cognitive behavior that closely resemble human depression (Nestler and Hyman, 2010, Wong and Licinio, 2001). Animal models are also helpful not only in avoiding obstacles in human studies of depression-related ethical concerns, but also in issues with obtaining adequate sample sizes (Pryce et al., 2005).

Animal models are established based on three basic constructs: face validity (phenotype similar to humans who have the illness), construct validity (processes that result in human pathology are recapitulated with the model), and predictive validity (sensitivity to pharmacological and non-pharmacological interventions that are effective for the disease or condition in humans) (Nestler and Hyman, 2010). However, some of the studies propose to include other features such as homological validity (species and strain validity), mechanistic validity (similar cognitive or biological mechanisms) and pathogenic validity (etiological and biomarker validity) (Belzung and Lemoine, 2011). Based on the etiology of depression, the animal models have been developed on the basis of acute or chronic stress exposure, gene-environmental interaction, exogenous administration of glucocorticoids, and genetic manipulations (Caspi and Moffitt, 2006, McGonagle and Kessler, 1990, Surís et al., 2010, Uher and McGuffin, 2010). Each model has its own set of advantages and disadvantages. We have reviewed the often used depression models in rodents and their usefulness in delineating the neurobiological and molecular mechanisms. It is difficult to cover every aspect of each model described here; however, our approach has been to provide an overview of the salient features that can be used to advance research designed to improve our understanding of neurobiology and treatment of depression. The salient features of each model is listed in Table 1, Table 2.

Section snippets

Cognition and emotion

When considering the use of animals for studying depression, one must take into account the assessment methods for evaluating behavioral changes. Several aspects of cognitive and emotional features can be assessed including fear conditioning which can be used to measure fear response, memory, and anxiety (Dibbets et al., 2015, LeDoux et al., 1990, Phillips and LeDoux, 1992). The general setup of fear conditioning is that the rat is placed in a fear conditioning chamber. It is then presented

Learned helplessness (learned helpless, LH)

Learned helplessness (LH) is a phenomenon discovered and explored initially by Seligman and his colleagues in the 1970s (Seligman, 1972). For the first experiments, dogs were placed in chambers where electric shocks were applied to their paws from which they were unable to escape. They were then tested in a chamber where they had a visible escape route; they needed to jump over a hurdle when the shock was applied to escape the shock. According to Seligman, 2/3 of the 150 (or 100 dogs) dogs

Discussion and conclusion

Depression is a heterogeneous and complex disorder. Several factors alone or in combination may predispose a person to the risk of depression. Animal models allow one to study the neurobiological basis of depression and provide a promising and much needed approach. Although there are some limitations in the existing depression rodent models, such that the feelings of sadness, guilt, suicidal thoughts cannot be fully captured, the existing models of depression to some extent provide the

Funding

The research was supported by grants from National Institute of Mental Health (R01MH082802; R21MH081099; 1R01MH101890; R01MH100616; 1R01MH107183), and American Foundation for Suicide Prevention (SRG-XXXX-001778-1209) to Dr. Dwivedi.

Declaration of interest

Authors declare no potential conflict of interest including financial or otherwise.

Author contribution and disclosure

Each author has contributed substantially in collecting the literature and writing the manuscript and has approved the final manuscript for submission.

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