Behavioral Models of Depression and Antidepressant Action

To understand the relationship between a particular stress-induced molecular change and depression, we study animals, in which the molecular change is mimicked or blocked, in behavioral models of this disorder. Accordingly, our Center maintains a broad battery of assays that test natural reward (including sexual and feeding behavior), depression- and anxiety-like behavior, and cognitive function. Examples of standard tests for depression- and antidepressant-like activity are the forced swim test and learned helplessness test. A more advanced test that measures the affective (emotional) state of a rodent is intra-cranial self-stimulation. We also maintain several chronic stress models in mice that recreate at least some of the symptoms seen in depressed humans. Importantly, all of these chronic stress models are available in both female and male mice. Chronic social defeat stress is one of our most heavily used paradigms. In this model, mice of one strain (which tend to be small) are placed in the cage of a larger (and naturally aggressive) mouse. After a brief (few minute) period during which the larger mouse attacks the smaller one, the two are separated by a divider that prevents physical contact but allows sensory contact for the 24 hours. This process is repeated daily for 10 days after which the smaller mice exhibit a behavioral syndrome classified as social defeat. We have found that chronic social defeat induces a very long-lasting social aversion, which is reversed by chronic (but not acute) antidepressant treatment. This is important, because this assay is one of just a very small number that shows such unique responsiveness to chronic antidepressants, which mimics the clinical situation. In addition, social defeat induces a profound anhedonia and a range of other behavioral abnormalities still under investigation. Other often used chronic stress models include chronic variable stress, prolonged social isolation during adolescence or adulthood, as well as early life stress (where pups are separated from their mothers). Each of these chronic stress paradigms has its own unique strengths and weaknesses. We believe that the combined use of several models provides Center investigators with an unparalleled ability to study depression-related phenomena in the laboratory, with a major focus on sex differences.