No animal model is entirely comparable to the human disease, this is particularly true for psychiatric diseases which are mainly perceived subjectively and expressed verbally. However, it is possible to model many aspects of depression in rodents.
Screening paradigms like the Porsolt swim test or the tail suspension test are in a strict sense not animal models of depression because they do not induce long-lasting behavioral changes comparable to human depression in the animals and the pharmacologic effects are detectable without the time lag characteristic for antidepressant therapy. Nevertheless, screening tests are very suitable to predict the antidepressant effect of a pharmacological compound and they are routinely used to screen for potentially new compounds because they are much more easy to apply and much cheaper than the more complex animal models.
However, in order to understand the molecular changes underlying major depression true animal models are needed. The best animal model of depression simulates the etiology and replicates symptoms, course and treatment of human depression. In the case of depression stressful life events constitute a factor playing an etiological role. Acute and chronic uncontrollable stress has therefore been used to induce depressive-like behavior in rodents. All animal models have to define clear criteria which allow the validity of the model to be ascertained. This is somewhat difficult in psychiatric conditions, which are in part defined through subjective experience and cannot be assessed in animals. The face validity of a depressive model can be examined by looking at those vegetative symptoms that are altered clinically. These include concentration, appetite, sleep, and libido. One can look for physiological changes that are associated with the condition, in depression this involves altered HPA axis function. One central test is to determine if the behavioral changes induced are specifically reversible using clinically effective treatments. A clear and specific treatment response is central in developing a useful and valid animal model. Finally, one can utilize one symptom as a key marker and develop tests for this symptom. In stress models, anhedonia has been suggested by Willner as such a marker12,13. He has argued that anhedonia - as assessed as a decrease in the sensitivity to sweet palatable solutions - reflects the lack of pleasure and low mood essential for a diagnosis of depression.
Among the stress-induced depression models, learned helplessness - initially described by Seligman and Overmier - has excellent validity14. This model derives from a cognitive view of depression in which events are viewed negatively and interpreted as not controllable leading to feelings of anxiety and helplessness. In fact, animals exposed to uncontrollable and unpredictable stress such as inescapable shock develop helpless behavior when tested in an escape paradigm 24 h later. We established a reliable paradigm both for rats and mice, using shock of moderate intensity and carefully excluding possible artifacts15,16. When tested with this paradigm 20% of the rats and 30% of mice exposed to inescapable shocks show escape deficits that can be interpreted as persistent reduction in coping (helplessness, despair). Moreover, helpless animals demonstrate a variety of additional behavioral, vegetative, and endocrine symptoms analogous to human depression such as changes in body weight and food consumption, REM sleep disturbance, elevation of corticosterone, and nonsuppression in the dexamethasone (DEX) test, indicating a resistance to the feedback mechanisms of corticosteroids17. Finally, learned helpless rats have been found to be responsive to essentially every antidepressant treatment effective in human depression18-20.
The fact that only a proportion of the animals exposed to stress develop helplessness suggested that this model has a genetic component and is suitable for studying the interaction of stress and genetic vulnerability. In an attempt to select for the genes predisposing to helpless or not helpless behavior, helpless and not helpless rats were mated selectively for more than 50 generations yielding two strains: congenitally learned helpless (cLH) rats exhibiting a helpless phenotype without exposure to uncontrollable shock, and a congenitally not learned helpless (cNLH) rats being resistant to the effects of inescapable shock21. In a series of experiments we verified that cLH rats have anhedonia and anergia which are seen in analogy to the hallmarks of depression: loss of interest and pleasure. The sensitivity to the rewarding properties of sucrose is regarded as an index of hedonia in rodents. We were able to show that cLH rats show a lower preference for sucrose in their home cage22. However, for conventional measurements of sucrose preference food deprivation is required and introduces several confounding factors of consummatory behavior like stress of deprivation and reduced body weight. We therefore established a procedure comparing several sucrose solutions over a range of concentrations against each other and detected a reduced sensitivity to sucrose in cLH rats which had no food deprivation23. Furthermore, applying a progressive ratio schedule we have demonstrated that cLH rats have less capacity to sustain bar pressing for sucrose reward which can be interpreted as anergia24. Altered expression of genes with functions in synaptic transmission is summarized below in Section 6.
In the chronic stress models developed initially by Katz25 and further refined in several studies12,13,26 an anhedonic state is induced by the repeated application of mild-to-moderate stressors over a prolonged time period. Rats were exposed to stressors like soiled cages, restricted food access, alterations of the light dark cycle, cage tilt, change of cage mate, and introduction of novel objects into the cage for up to 3 months. The model mirrors most of the findings seen in depressive episodes that can be examined in animals. Hedonic measures are the primary focus of the model and the effects of stress are assessed with repeated tests for preference for a palatable weak sucrose solution or saccharin solution. Chronic mild stress decreases preference for sweet solutions which is interpreted as a sign of anhedonia. Higher brain stimulation thresholds as well as decreased place preference conditioning also suggest decreased response to rewarding stimuli after chronic mild stress. After chronic mild stress animals show a wide variety of symptoms that parallel extensive and comprehensive features of human depression: vegetative changes such as decreases in locomotor activity, weight loss, and a decrease of sexual behavior. The animals also show altered diurnal rhythms and sleep disturbances with decreased REM latency and increased number of REM episodes. The model is pharmacologically sensitive and a variety of antidepressant treatments, including electroconvulsive therapy (ECT), are effective in reversing anhedonia after chronic mild stress13.
There is an urgent need for mouse models of depression to study behavioral consequences of genetically altered mice. A recent study described a murine model of chronic stress, in which mice were exposed to a 4-week-long chronic stress procedure, which consisted of rat exposure, restrained stress, and tail suspension.
The mice showed reduced preference to sucrose solution versus drinking water, that was regarded as anhedonia. The following behavioral analyses of mice aimed to dissect the specific correlates of anhedonic status versus those related merely to the chronic stress. Since the employed chronic stress procedure resulted in hedonic deficit in the majority, but not in all animals, the individuals that did not develop anhedonic status were taken as an internal control of the effects of chronic stress alone. It was found that anhedonia, but not chronic stress per se correlates with key analogs of depressive symptoms, such as drastically increased floating behavior and decreased exploration of novelty. In contrast, increased anxiety and locomotor disturbances (hyperlocomotion triggered by light and hypolocomotion in stressfree situation) were found to be the consequences of chronic stress alone. In addition, individual vulnerability to the stress-induced anhedonia is related to passive coping in resident-intruder test27.
Another way to validate or reject hypotheses regarding the biochemical or molecular mechanisms underlying depression is to alter the expression of genes related to stress reactions, namely the monoamine- and the HPA system28. In looking at the HPA axis the glucocorticoid receptors (GRs) are central in the feedback loop29. Mice with a general genetic downregulation of GRs (GR-heterozygote) show significantly increased helplessness30. Furthermore, these animals have a pathological DEX/CRH test (nonsuppression), similar to severely depressed patients. In line with these findings, mice that overexpress GRs via a yeast artificial chromosome (YGR mice) resulting in a twofold gene dose elevation are stress-resistant with reduced helplessness, and are "oversuppressors" in the DEX/CRH test. An interesting phenotype is also observed in mice with a brain-specific knockout of the GRs. In terms of the endocrine system these animals show a disinhibition of the HPA system with hypercortisolemia very similar to depressed patients. Because these animals still express GRs outside the nervous system, they exhibit a Cushing-like phenotype with body fat redistribution, osteoporosis, etc. However, they do not have behavioral signs of depression, because they do not express any GR in the brain, so the hypercortisolism cannot be detected in the brain areas mediating depressive-like behavior. In fact, on the behavioral level, these mice seem to represent a stress-resistant strain. Interestingly, GR-heterozygous mice show a downregulation of BDNF in the hippocampus, while GR-overexpressing mice exhibit an upregulation, both in accordance with the neurotrophin hypothesis of depression. Thus, GR-heterozygous mice represent a transgenic model with depression-like features on the molecular, neuro-endocrinological, and behavioral level.
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