7. Etiology of Depression and Animal Models
As with other neuropsychiatric disorders, depression has a multifaceted and varied etiology, including genetic, epigenetic, and environmental factors. The most prevalent of these factors is stress. Stress is cited as the leading cause of depression by depressed patients [59]. Unipolar depression is associated with abnormal hypothalamic-pituitary adrenal (HPA) axis function such as hypersecretion of cortisol, abnormal diurnal secretion of cortisol resulting in a flattened circadian rhythm and impaired negative feedback [59, 60]. Interestingly, normalization of HPA function is seen after chronic exposure to antidepressants, an effect coincident with, or slightly preceding, behavioural alleviation of depressive symptoms [61]. As such normalization of HPA function has become a major target of novel therapies [59, 62].
Many animal models of depression capitalize on the association of stress and depression; such models have a solid ethological basis. For instance, models using exposure to chronic variable stress (CVS) have shown good face, construct, and predictive validity, making it one of the most commonly used paradigms to model depression [63]. For example, CVS increases immobility in the forced swim test (FST, a putative measure of behavioural despair) [64], reduces sucrose preference (anhedonia) [65], increases novelty-induced hypophagia [21, 64], reduces hippocampal neurogenesis [21, 65], and reduces the expression of proteins associated with neuroplasticity such as PSA-NCAM [66]. Although it is not possible to model all symptoms of depression in rodents, a battery of key endophenotypes can be examined such as anhedonia, body weight changes, behavioural despair, HPA function, and brain alterations (such as reduced hippocampal volume, neurogenesis, and neural plasticity), as have been observed in human patients with depression [67].