Animal models of depression are research tools used to investigate depression and action of antidepressants as a simulation to investigate the symptomatology and pathophysiology of depressive illness or used to screen novel antidepressants.
Introduction
Depression Major depressive disorder is commonly called "clinical depression" or "depression." It is a common, long-lasting and diverse psychiatric syndrome that significantly affects a person's thoughts, behavior, feelings and sense of well-being. According to the DSM-5, someone diagnosed with depression should be showing at least five symptoms and they should last two weeks. Depression can include a variety of different symptoms and does not always look the same for everyone. Some of these symptoms may include sadness, anxiousness, emptiness, hopelessness, worry, helplessness, worthlessness, guilt, irritableness, hurt, or restlessness. People experiencing depression may also lose interest in activities that once were pleasurable, experience loss of appetite, overeat, have problems concentrating, remembering details, making decisions, and may contemplate or attempt suicide. Insomnia, excessive sleeping, fatigue, loss of energy, aches, pains, or digestive problems that are resistant to treatment may also be present.
Modeling depression in animals It is difficult to develop an animal model that perfectly reproduces the symptoms of depression in patients. It is generic that 3 standards may be used to evaluate the reliability of an animal version of depression: the phenomenological or morphological appearances (face validity), a comparable etiology (assemble validity), and healing similarities (predictive validity). Many animals lack self-consciousness, self-reflection, and consideration; moreover, hallmarks of the disorder such as depressed mood, low self-esteem or suicidality are hardly accessible in non-humans. However, depression, as other mental disorders, consists of endophenotypes that can be reproduced independently and evaluated in animals. An ideal animal model offers an opportunity to understand molecular, genetic, and epigenetic factors that may lead to depression. By using animal models, the underlying molecular alterations and the causal relationship between genetic, or environmental, alterations and depression can be examined. This would afford a better insight into pathology of depression because animal models are indispensable for identifying novel therapies for depression.Hao, Yuanzhen, Huixiang Ge, Mengyun Sun, and Yun Gao. 2019. "Selecting an Appropriate Animal Model of Depression" International Journal of Molecular Sciences 20, no. 19: 4827. https://doi.org/10.3390/ijms20194827 To improve the usefulness of studies using animal models of psychiatric disorders, including depression, the 'Improving Translational Relevance in Preclinical Psychopharmacology' (iTRIPP) guidelines for planning and reporting of such studies have been developed.
Endophenotypes in animal model of depression The following endophenotypes have been described: Anhedonia: The loss of interest is a core symptom of depression. Anhedonia in rodents can be assessed by sucrose preference or by intracranial self-stimulation. Behavioral despair: Behavioral despair might be assessed with tests such as the forced-swimming test or the tail suspension test. Changes in appetite or weight gain: Depression is often associated with changes in appetite or weight gain, which is easily measured in rodents. There was a study done where the experimental group of mice had a suppressed feeding schedule; this resulted in the mice showing depressive-like symptoms. Neuroanatomy: Depressed subjects display decreased hippocampal volume. Rodents exposed to chronic stress or excess glucocorticoids exhibit similar signs of hippocampal loss of neurons and dendritic atrophy. Neuroendocrine disturbances: Disturbances of the hypothalamic–pituitary–adrenal axis (HPA) are one of the most consistent symptoms in major depression. The functionality of the HPA can be assessed by dexamethasone suppression test . Alterations in sleep architecture: Disturbances in the circadian rhythm and especially in the sleep architecture are often observed in depression. In rodents, it is accessible via electroencephalography (EEG). Anxiety-related behavior: Anxiety is a symptom with high prevalence in depression. Animal models of depression often display altered anxiety-related behavior.
Criteria for valid animal models of depression An appropriate animal model of human depression should fulfill the following criteria as much as possible: strong phenomenological similarities and similar pathophysiology (face validity), comparable etiology (construct validity), and common treatment (predictive validity). Depression is a heterogeneous disorder and its many symptoms are hard to produce in laboratory animals. When studying depression used in animals originally, symptoms equivalent to odd social behavior and emotion were used to determine if the animal had depression. The question therefore remains whether we can know if the animal is "depressed". They are unable to have the emotions that are associated specifically with humans, like sadness. Few models of depression fully fit these validating criteria, and most models currently used rely on either actions of known antidepressants or responses to stress. It is not necessary for an "ideal" animal model of depression to exhibit all the abnormalities of depression-relevant behaviors, just as not all patients manifest every possible symptom of depression.
Creating models Research use a number of standardized ways to induce depression-like symptoms in lab animals. The most commonly used type of models are based on stress.
Stress models Certain types of human depression are precipitated by stressful life events, and vulnerable individuals experiencing these stressors. Consequently, the majority of animal models of depression are based on the exposure to various types of acute or chronic stressors.
Adult stress models Learned helplessness: The learned helplessness model (LH), one of the well validated animal models, is the best replicated one. The rationale is that exposure to uncontrollable and stressful life events makes people feel like they are losing control, and this sometimes leads to depressive like behaviors. The model is based on the observation that animals also develop deficits in escape, cognitive and rewarded behaviors when they have been subjected to repeated unavoidable and uncontrollable shocks. LH is induced in one day or over several days of repeated inescapable stress by the treating of tail shock or foot shock in shuttle boxes. Helpless behavior is evaluated by analyzing the performance in an active escape test, such as the latency to press a lever or cross a door. An advantage of LH is that the cognitive and other behavioral outcomes seem to be correlated, thus helping to understand the depressive symptomatology in humans. This model can also be generally used to measure the escape performance of mice with different mutations in which target genes of depression may affect the vulnerability to develop a depressive-like state. These excellent face and predictive validities make LH an interesting model to explore the pathophysiology of depression. The biggest disadvantage of LH is it requires very strong stressors to induce the behavioral phenotypes which does raise ethical problems. Also, most of the symptoms do not persist long enough following cessation of the uncontrollable shock. Chronic mild stress: The chronic mild stress (CMS) model is probably the most valid animal model of depression. It aims to model a chronic depressive-like state that develops gradually over time in response to stress, and they can provide more natural induction. CMS involves the exposure of animals to a series of mild and unpredictable stressors (periods of food and water deprivation, small temperature reductions, changes of cage mates, and other similar individually innocuous manipulations) during at least 2 weeks. The model has been reported to result in long lasting changes of behavioral, neurochemical, neuroimmune, and neuroendocrinological variables. This resembles reward functions, that include decreased intracranial self-stimulation, and reflects anhedonia that is reversed by chronic, but not acute, antidepressant treatment. This CMS model can be used to screen and test potential antidepressant compounds and to develop new treatment strategies.The advantages of this model are its good predictive validity (behavioral changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been reproduced), and construct validity (CMS causes a generalized decrease in responsiveness to rewards). However, there is a common practical difficulty in carrying out CMS experiments, which are labor-intensive, demanding of space, and of long duration. The procedure can be difficult to be established and data can be hardly replicated. Social defeat stress: Social defeat stress (SDS) is a chronic and recurring factor in the lives of virtually all higher animal species. Humans experiencing social defeat show increased symptoms of depression, loneliness, anxiety, social withdrawal and a loss of self-esteem. Since the majority of stress stimuli in humans that lead to psychopathological changes are of social nature, SDS model have gained increasing attention since they might render useful to study certain endophenotypes of depression. During the stress period, the male rodent will be introduced into a different territory of other males for each day as an intruder. This causes it to be investigated, attacked and defeated by the residents. The consequent behavior changes in the subject caused by SDS, like decreased social interaction or lack of interest, are similar to some parts of human depression. Behavioral treatment and antidepressants can reverse these changes in an SDS model.Like CMS, SDS has good predictive validity (behavioral changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (many symptoms of depression have been reproduced), and construct validity (causing a generalized decrease in responsiveness to rewards). SDS gives another validity that only chronic, but not acute, antidepressant administration can reverse the social aversion. One disadvantage of SDS model is the long duration. To apply an SDS model for studying human depression, the period of it should last at least 20 days or only anxiety symptoms could be induced. Only male rodents can be used for this model, since female rodents do not fight each other in a resident–intruder confrontation.
Early life stress models Early adverse experiences such as traumatic life events in childhood result in an increased sensitivity to the effects of stress later in life and influence the vulnerability to depression. Suitable animal models could provide a basis for understanding potential mechanisms of environmental and developmental factors of individual differences in stress reactivity and vulnerability to disorders. Models of early life stress involve prenatal stress, early postnatal handling and maternal separation. All these treatments have been demonstrated to produce significant effects that last until adulthood. Maternal deprivation: The maternal deprivation model is the most widely used early life stress model. This model manipulates the maternal separation of early life deprivation, in which pups are separated from the dam for 1–24 h per day during the first two postnatal weeks. Maternal separation results in increased anxiety- and depression-like behaviors and increased HPA response in adulthood.
Other models