A Conversation with Eric Nestler

Dr. Nestler: Yes, exactly. Most of the depression field has utilized what are called despair tests, something like the forced swim test where a mouse or rat would be placed in a beaker of water. It would swim for a while, then stop. People say that when it stops it’s despairing although we really have no reason to think that. When you give the animal an acute dose of an antidepressant, it swims a little longer. It’s hard to imagine a test with so little validity being so widely used in depression research. Several years ago we set out to try to develop a test that is better validated and has more ethological relevance for a mouse. We figured that social stress was a domain of behavior that really hadn’t been studied very much in animal depression models. In this model, which we call social defeat, a normal inbred C57 mouse is placed in the cage of a retired male breeder CD1 mouse. The retired breeder is bigger and meaner and as soon as the test mouse is placed in that cage, the larger mouse attacks it. We only allow the physical interaction to occur for a couple of minutes before placing a screen between the mice. The test mouse continues to be subjected to all the aggressive cues of the larger mouse but has no more physical contact for the rest of the day. We repeat that process every day, typically for 10 days. Afterwards, we can show that we have induced, in that C57 mouse, a behavioral syndrome that’s characterized by anhedonia, which means a loss of interest in pleasurable activities. The mice are less interested in drinking sugar water, eating Reese’s Pieces, having sex, or running on a running wheel.