Behavioral animal models of depression

Depression is a chronic, recurring and potentially life-threatening illness that affects up to 20% of the population across the world. Despite its prevalence and considerable impact on human, little is known about its pathogenesis. One of the major reasons is the restricted availability of validated animal models due to the absence of consensus on the pathology and etiology of depression. Besides, some core symptoms such as depressed mood, feeling of worthlessness, and recurring thoughts of death or suicide, are impossible to be modeled on laboratory animals. Currently, the criteria for identifying animal models of depression rely on either of the 2 principles: actions of known antidepressants and responses to stress. This review mainly focuses on the most widely used animal models of depression, including learned helplessness, chronic mild stress, and social defeat paradigms. Also, the behavioral tests for screening antidepressants, such as forced swimming test and tail suspension test, are also discussed. The advantages and major drawbacks of each model are evaluated. In prospective, new techniques that will be beneficial for developing novel animal models or detecting depression are discussed.     

Importance of animal models in schizophrenia research

OBJECTIVE: This review aims to summarize the importance of animal models for research on psychiatric illnesses, particularly schizophrenia. METHOD AND RESULTS: Several aspects of animal models are addressed, including animal experimentation ethics and theoretical considerations of different aspects of validity of animal models. A more specific discussion is included on two of the most widely used behavioural models, psychotropic drug-induced locomotor hyperactivity and prepulse inhibition, followed by comments on the difficulty of modelling negative symptoms of schizophrenia. Furthermore, we emphasize the impact of new developments in molecular biology and the generation of genetically modified mice, which have generated the concept of behavioural phenotyping. CONCLUSIONS: Complex psychiatric illnesses, such as schizophrenia, cannot be exactly reproduced in species such as rats and mice. Nevertheless, by providing new information on the role of neurotransmitter systems and genes in behavioural function, animal 'models' can be an important tool in unravelling mechanisms involved in the symptoms and development of such illnesses, alongside approaches such as post-mortem studies, cognitive and psychophysiological studies, imaging and epidemiology.     

Stress, depression, and anhedonia: caveats concerning animal models

Numerous animal models of depression have been advanced, each having multiple attributes and some limitations. This review provides caveats concerning etiologically valid animal models of depression, focusing on characteristics of the depressive subtype being examined (e.g. typical vs atypical major depression, dysthymia, melancholia), and factors that contribute to the interindividual behavioral variability frequently evident in stressor-related behavioral paradigms. These include the stressor type (processive vs systemic stressors), and characteristics of the stressor (controllability, predictability, ambiguity, chronicity, intermittence), as well as organismic variables (genetic, age, sex), experiential variables (stressor history, early life events) and psychosocial and personality factors that moderate stressor reactivity. Finally, a model of depression is reviewed that evaluates the effects of stressors on hedonic processes, reflected by responding for rewarding brain stimulation. Anhedonia is a fundamental feature of depression, and assessment of stressor-related reductions in the rewarding value of brain stimulation, especially when coupled with other potential symptoms of depression, provides considerable face, construct and predictive validity. Stressful events markedly impact rewarding brain stimulation, and this effect varies across strains of mice differentially reactive to stressors, is modifiable by antidepressant treatments, and allows for analyses of the contribution of different brain regions to anhedonic processes. The paradigm is sensitive to several factors known to acts as moderators of stress responses, but analyses remain to be conducted with regard to several such variables.     

Learned helplessness and animal models of depression

The degree to which organisms can exert control over events to which they are exposed has a strong impact on behavior and physiological functioning. Effects caused by the uncontrollability of events that are beyond the organism's control rather than by the events per se have been called learned helplessness effects. The present paper reviews such learned helplessness effects. At a behavioral level, uncontrollable aversive events result in associative, motivational, and emotional deficits. At a neurochemical level, uncontrollable but not controllable aversive events have been reported to lead to disturbances in cholinergic, noradrenergic, dopaminergic, serotonergic, and GABAergic systems. However, there are interpretive difficulties in this literature, and these are discussed. The controllability/uncontrollability of aversive events has a role in producing stress-induced analgesia and the activation of endogenous opiate systems. These relationships are reviewed. It is proposed that the learning that aversive events cannot be controlled activates an opiate system. The research reviewed is related to depression, and the general issue of animal models of depression is discussed. It is concluded that no experimental paradigm can be a model of depression in some general sense, but can only model a particular aspect. Learned helplessness may model "stress and coping".     

精神分裂症动物模型研究进展

精神分裂症是一种常见而严重的精神疾病,给家庭和社会带来沉重的负担。虽然目前对精神分裂症的病因及发病机制尚不完全清楚,但随着对疾病认识的逐步深入,已经可以利用动物模型模拟精神分裂症的不同临床症状。制备可靠的、可预测的动物模型,对理解复杂精神疾病的神经生物学基础和开发新型抗精神病药物都是非常必要的。现针对目前研究较多的精神分裂症动物模型的研究进展进行综述,包括药物诱导动物模型、基因相关动物模型、神经发育动物模型、脑损伤动物模型、基因环境交互作用动物模型,可为今后精神分裂症的相关研究提供一定的参考。     

Genetic animal models: focus on schizophrenia

The neurobiology of schizophrenia remains poorly understood. Symptoms of schizophrenia are classically thought to be associated with an imbalance of the dopaminergic system. However, the contribution of other neurotransmitters, in particular glutamate, has been increasingly appreciated. The role of individual components of neurotransmitter systems in aberrant behaviors can be experimentally tested in transgenic animals. Dopamine transporter knockout mice display persistently elevated dopaminergic tone and therefore might be appropriate substrates to evaluate the dopamine hypothesis. Similarly, NMDA receptor-deficient mice can be used to evaluate the glutamate hypothesis of schizophrenia. In this review we discuss how such animal models might be relevant for understanding the neurochemical underpinnings of certain manifestations of schizophrenia.     

Biological markers of serotonin receptors in depression and animal models of depression

Summary

The mechanism of action of antidepressant drugs is postulated to be linked in part to alterations which these drugs cause in the availability of serotonin, and in the sensitivity of serotonin receptors. Studying biological markers of serotonin receptors in animal models of depression as well as in patients with depression can expand our understanding of how antidepressants work. This article reviews the actions of various known antidepressants on serotonin systems in animal models of depression, and how these actions are linked to the therapeutic mechanism of antidepressants in patients with major depressive disorder.     

抑郁症动物模型与肠道菌群研究进展

抑郁症发病率逐年增加,其产生机制主要有单胺类神经递质假说、单胺受体假说、神经内分泌假说和脑源性神经营养因子假说.目前,多数的抑郁症模型既能模拟临床中抑郁症患者的行为特征,还能模拟患者脑内神经递质的相关变化.近年来的研究发现,肠道菌群对机体的影响跨越神经、内分泌、免疫等系统并与抑郁症的发病具有相关性,抑郁症与肠道菌群关系...     

Epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression

Major depressive disorder (MDD), one of the most common mental disorders, is a significant risk factor for suicide and causes a low quality of life for many people. However, the causes and underlying mechanism of depression remain elusive. In the current work, we investigated epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression. Mice were exposed to inescapable stress and divided into learned helplessness (LH) and resilient (LH-R) groups depending on the number they failed to escape. We found that the LH group had longer immobility duration in the forced swimming test (FST) and tail suspension tests (TST), which is consistent with a depression-related phenotype. Western blotting analysis and enzyme-linked immunosorbent assay (ELISA) revealed that the LH group had lower BDNF expression than that of the LH-R group. The LH group consistently had lower BDNF mRNA levels, as detected by qPCR assay. In addition, we found BDNF exon IV was down-regulated in the LH group. Intraperitoneal injection of imipramine or histone deacetylase inhibitors (HDACi) to the LH mice for 14 consecutive days ameliorated depression-like behaviors and reversed the decrease in BDNF. The expression of HDAC5 was up-regulated in the LH mice, and a ChIP assay revealed that the level of HDAC5 binding to the promoter region of BDNF exon IV was higher than that seen in other groups. Knockdown of HDAC5 reduced depression-like behaviors in the LH mice. Taken together, these results suggest that epigenetic regulation of BDNF by HDAC5 plays an important role in the learned helplessness model of depression.     

Startle habituation and sensorimotor gating in schizophrenia and related animal models

Studies of the habituation and sensorimotor gating of startle responses to strong exteroceptive stimuli provide some unique opportunities for cross-species explorations into information processing and attentional deficits in schizophrenia. The behavioral plasticity of startle paradigms greatly facilitates the development of animal models of specifiable behavioral abnormalities in schizophrenic patients. This article reviews the promising findings of studies in which measures of startle have been used to clarify the importance of habituation and central inhibition deficits in schizophrenia. In addition, the development of closely related animal models of habituation and sensory gating of startle is discussed. Such animal model studies allow us to make strong inferences about the neurobiological substrate of schizophrenia. Recent evidence from animal studies of prepulse inhibition provides strong support for a schizophrenia-like loss of sensory gating with nucleus accumbens dopamine overactivity. These data are consistent with hypotheses regarding the significance of mesolimbic dopamine overactivity in schizophrenia. New results are also presented from animal model studies of the effects of serotonergic drugs on startle habituation, extending earlier findings of LSD-induced habituation deficits which are similar to those exhibited by schizophrenic patients. These new data indicate that the serotonergic system, working through serotonin-2 receptors, may play a pivotal role in the modulation of startle habituation. The relationship of serotonergic and catecholaminergic mechanisms is also discussed. Collectively, these studies demonstrate the utility of operationally defined measures of preattentive processes in the study of the neurobiological basis of the group of schizophrenias.     

Perinatal depression: Heterogeneity of disease and in animal models

Perinatal depression (PND) can have either an antepartum or postpartum onset. Although the greatest risk factor for PND is previous depression history, de novo PND occurs with the majority of cases occurring in the postpartum. Timing of depression can impact etiology, prognosis, and response to treatment. Thus, it is crucial to study the impact of the heterogeneity of PND for better health outcomes. In this review, we outline the differences between antepartum and postpartum depression onset of PND. We discuss maternal physiological changes that differ between pregnancy and postpartum and how these may differentially impact depression susceptibility. We highlight changes in the maternal steroid and peptide hormone levels, immune signalling, serotonergic tone, metabolic factors, brain morphology, and the gut microbiome. Finally, we argue that studying the heterogeneity of PND in clinical and preclinical models can lead to improved knowledge of disease etiopathology and treatment outcomes.     

Animal models for schizophrenia: the hippocampally lesioned animal

Animals with hippocampal lesions are evaluated as models for schizophrenia according to the criteria of McKinney and Bunney (1969). They seem to comply adequately with the following requirements: similarity of inducing conditions; similarity of behavioral states; similarity of underlying neurobiological mechanisms; and reversibility by usual pharmacological treatment. The model seems adequate to reproduce several symptoms of the disorder, offering a good experimental tool for the analysis of its inducing conditions, affected neurobiological mechanisms, and clinical treatment.     

Cytokines mediated inflammation and decreased neurogenesis in animal models of depression

In patients with major depression or in animal models of depression, significantly increases in the concentrations of pro-inflammatory cytokines have been consistently reported. Proinflammatory cytokines can stimulate the hypothalamic-pituitary-adrenal (HPA) axis to release stress hormone, glucocorticoids. As a consequence of excessive inflammatory response triggered by pro-inflammatory cytokines in the periphery, free radicals, oxidants and glucocorticoids are over-produced, which can affect glial cell functions and damage neurons in the brain. Indeed, decreased neurogenesis and the dysfunction of neurotrophic system (up- or down-regulations of neurotrophins and their receptors) have been recently found. Effective treatments for depressive symptoms, such as antidepressants and omega-3 fatty acids can increase or modulate neurotrophic system and enhance neurogenesis. However, the relationship between glial cells; microglia (mostly involved in neuroinflammation) and astrocytes (producing neurotrophins), and the contribution of inflammation to decreased neurogenesis and dysfunction of neurotrophic system are almost unknown. This review first introduces changes in behavior, neurotransmitter, cytokine and neurogenesis aspects in depressed patients and several animal models of depression, secondly explores the possible relationship between pro- and anti-inflammatory cytokines and neurogenesis in these models, then discusses the effects of current treatments on inflammation, neurotrophic system and neurogenesis, and finally pointes out the limitations and future research directions.     

Deep brain stimulation in clinical trials and animal models of depression

Deep brain stimulation (DBS) is currently being investigated as a therapy for the treatment of depression. Despite promising results of recent clinical trials, neural and chemical mechanisms responsible for the effects of stimulation are still unclear. In this article, we review clinical and laboratory findings on DBS for depression. Particular emphasis will be given to aspects involved in the translation of data from animal models to humans and in our findings on the potential substrates involved in the antidepressant effects of DBS in rats.     

Stress hormones and emotion-regulation in two genetic animal models of depression

Children of depressed parents often exhibit emotion-regulation deficits, characterized by either excessive withdrawal or approach strategies toward the mother. The current study examined behavioral and physiological emotion-regulation in preweanling pups (postnatal day 17-19) belonging to two different genetic animal models of depression, Wistar-Kyoto (WKY) and Flinders Sensitive-Line (FSL) rats. The study also examined the effects of stress on the two animal models, hypothesizing an interactive effect of hereditary vulnerability and exposure to stress. Chronic-stress was simulated by providing limited bedding to the dam and litter for a week, in the early postnatal period. Acute-stress was generated by exposure to an adult male rat, an ethologically valid stressor. Emotion-regulation of the pups was examined using a Y-maze preference test and radioimmunoassay of Hypothalamic-Pituitary-Adrenal (HPA) axis hormones (corticosterone & adreno-corticotropin/ACTH). WKY and FSL pups exhibited reduced approach-behavior toward the dam, an emotion-regulation profile reminiscent of avoidant attachment evident in many children of depressed parents. In contrast, the two animal models did not show similar HPA axis activity. FSL pups exhibited markedly lower ACTH levels compared to controls, while WKY pups did not differ from controls. With regard to the stress manipulations, the limited-bedding condition had no effect, while the acute-stressor induced overall effects on all groups, with more pronounced reactivity evident in the WKY and FSL pups. Taken together, the experiments indicate a similar behavioral profile of the two strains at the preweanling period, while suggesting HPA dysfunction in only one of the strains.     

Drug withdrawal-induced depression: serotonergic and plasticity changes in animal models

This review discusses recent research of mood disorders associated with the cessation of psychoactive substances, with an emphasis on preclinical studies that have been published in the last decade. Animal models exhibiting anhedonic and depressive-like behaviours associated with drug withdrawal have been used to study the neurobiology of mood disorders and have culminated in the identification of novel targets for the treatment of depressive-like symptoms. This review will introduce the behavioural as well as the neurochemical and plasticity changes in depressed patients and several animal models of depression. Following, we provide a more in-depth discussion of the role of serotonergic neurotransmission and Hypothalamic-Pituitary-Adrenal (HPA) axis regulation as well as the neurogenic changes occurring after chronic drug intake focusing on the withdrawal associated depression. Although we mainly focus on animal data, some relevant human studies are also discussed. Establishing the commonalities of depression and drug-seeking behaviour will allow us to elucidate the factors driving the high co-morbidity between mood disorders and drug dependence.     

Experimental animal models for the simulation of depression and anxiety

An impressive number of animal models to assess depression and anxiety are available today. However, the relationship between these models and the clinical syndromes of depression and anxiety is not always clear. Since human anxiety disorders represent a multifactorial phenomenon frequently comorbid with major depression and/or other psychiatric problems, the chance of creating animal models which consistently reflect the human situation is quite poor. When using experimental models to understand homologies between animal and human behavior, we have to consider the context in which an animal is investigated, and both the functional significance and relevance of the behavioral parameters that are quantified. Moreover, gender and interindividual and interspecies variabilities in behavioral responses to the test situation and in the sensitivity to pharmacological treatments are potential sources for confounding results. In the past, these aspects have been often neglected in preclinical approaches to behavioral pharmacology and psychopharmacology. A pragmatic approach of combined preclinical and clinical efforts is necessary to imitate one or more aspects relevant to pathological anxiety disorders and depression. The resulting models may identify central nervous processes regulating defined behavioral output, with the potential to develop more effective treatments.     

Contribution of nonprimate animal models in understanding the etiology of schizophrenia

Schizophrenia is a severe psychiatric disorder that is characterized by positive and negative symptoms and cognitive impairments. The etiology of the disorder is complex, and it is thought to follow a multifactorial threshold model of inheritance with genetic and neurodevelop mental contributions to risk. Human studies are particularly useful in capturing the richness of the phenotype, but they are often limited to the use of correlational approaches. By assessing behavioural abnormalities in both humans and rodents, nonprimate animal models of schizophrenia provide unique insight into the etiology and mechanisms of the disorder. This review discusses the phenomenology and etiology of schizophrenia and the contribution of current nonprimate animal models with an emphasis on how research with models of neuro transmitter dysregulation, environmental risk factors, neurodevelopmental disruption and genetic risk factors can complement the literature on schizophrenia in humans.