2006/6/10

    Genetic analysis of psychiatric disorders has been hindered by a number of factors, including highly variable behavioral symptoms, disease heterogeneity, gene environment interactions, and most importantly, a lack of hereditary animal models. In order to find mice with hereditary traits of depression-like behavior, I have devoted my time to a study entitled ‘Screening mice with inheritable behaviors that are similar to psychiatric disorders’. Hearing about the topic at first time, most of my colleagues and friends would ask, ‘How do you know a mouse has psychiatric disorders?’ So, the first thing I have to say for this study is: I am looking for mice with behavior that is thought similar to behavior in humans with psychiatric disorders. For example, if a mouse travels a shorter distance than normal mice within specific space and time, we speculate that it may have a depressive mood and doesn’t want to move around. The excessively simplified rationale is: psychomotor retardation is a common and important symptom in people with depression. Surely we have to prove that the mouse has had adequate sleep, food, water, and isn’t suffering from a neurological deficiency or physical illness. A mouse in a test is tracked by a digital camera with powerful software. The total distances, speeds, and locations of the tested mouse are automatically recorded and analyzed in a computer. In addition to these records, the length of time the tested mouse stays in a specific area of the testing arena is also reported. Mice are afraid of staying in open area. If a mouse stays in the central area of the testing arena for a longer period of time than 99% of other mice do, we say it has got guts. On the other hand, normal mice will spend a small part of time to go to the central open area of the testing arena because they have an exploratory nature after all. If a mouse dares not spend even a few seconds to explore the central area, we say the mouse is abnormally fearful or timid. It may have an anxiety disorder or agoraphobia.

    Another example of depression-like traits in mice is a character of tending to give up. Behavioral scientists use a transparent cyclinder, a half of which is filled with water, to test a mouse’s volition or ability of fight. The cylinder is 30 cm in height, 10 cm in diameter. When a mouse is put in to the cylinder with water it will swim and struggle to get out. It’s impossible for a mouse to get out of the cylinder. So it will become less agitated gradually. Within 2-3 minutes, most mice will stop struggling and maintain a freezing posture to float on the water. The total test time is 6 minutes. It is speculated that a mouse under this situation is in a kind of despair. A mouse with a stronger will, fight or volition will swim or struggle in the cylinder for longer periods of time. A mouse with depression tends to give up struggling in a dangerous or uncomfortable situation. During a 6-minute test, a mouse with depression will have a shorter period of struggling or a longer period of freezing posture in the water.

    If I can identify a mouse with depression-like behavior, I’ll check its siblings. If there is one or more of its siblings that have the same behavioral trait, I will let the ‘abnormal’ mice breed. If I can prove a part of their offspring has the same trait, I have confidence to say, ‘I have got a mouse line with inheritable depression.’ Then I can use the genetically depressed mice to test and develop new antidepressants.

Hong CJ