A mouse that's uninterested in new foods and tasty drinks and easily despairs in a challenging situation has more than a case of the blues. This is a strain of mouse created by Jason Snyder and his colleagues at the National Institute of Mental Health to model human depression. To bring on the mouse's symptoms, all that was necessary was to stop one part of its brain from creating new cells.
The researchers wanted to investigate the link between depression and the brain's ability to grow new neurons, called neurogenesis. Most of your brain cells are born before you are, but new neurons also appear throughout adulthood. One of the main sites of their creation is in the hippocampus, an area of the brain associated with memory and navigation. The hippocampus is one of the first regions ravaged by Alzheimer's disease. It's also home to a high concentration of stress hormone receptors, making it especially sensitive to their effects.
Stress and stress hormones (glucocorticoids) are known to slow down the growth of new brain cells in the hippocampus. But the hippocampus is also involved in dialing down the body's stress response. Would an adult brain that can't grow new neurons--an impairment that would especially affect the hippocampus--have an out-of-whack stress reaction to stress? And would it become depressive?
To find out, Snyder and his colleagues manipulated mouse genes to create the strain that couldn't grow new neurons in adulthood. In their day-to-day life, the transgenic mice (and their stress hormones) behaved normally. But when the researchers stressed the mice out by keeping them restrained for 30 minutes, their stress hormones stayed elevated for much longer than in normal mice. It seemed that a nongrowing hippocampus was specifically impairing how the mice reacted to stress.
The researchers found the same result when they used radiation to target neurogenesis in the precise brain region they suspected to be at work, an area inside the hippocampus called the dentate gyrus. This suggested that the symptoms in their mice came from a lack of neurogenesis in this small region specifically.
Next, the neurogenesis-deficient mice underwent several tests for depressive-like behavior. In one test, the mice were placed in an open space with food at its center. The transgenic mice went to investigate the food just as quickly as ordinary mice did. But when researchers stressed the mice out immediately beforehand (by restraining them, again), the transgenic mice were much slower to go to the food, or didn't investigate it at all. The ordinary mice, though, weren't bothered.
Another test involved sugar water, which mice, like soda-susceptible humans, usually prefer to plain water. The neurogenesis-deficient mice didn't care much about sugar water, a symptom the researchers say is comparable to anhedonia, the depressed person's inability to take pleasure from usually enjoyable activities.
Finally, the mice were tested for "behavioral despair," rather upsettingly described here:
We next tested depressive-like behavior, using the forced swim test, in which rodents are placed in an inescapable cylinder of water and immobility is used as a measure of behavioral despair.*
In their inescapable water tank, the transgenic mice gave up and stopped swimming sooner than normal mice. They also stayed immobile for longer periods. (After the test, mice were dried off and placed in a heated cage to recover.)
It seems, then, that not being able to create new cells in the hippocampus exaggerates the stress response (as in the forced swim test, and the tests done after restraining the mice) and makes mice lose interest in pleasurable activities.
Neurogenesis is needed to buffer the stress response--but neurogenesis itself is impaired by stress. If their mouse model is a fair approximation of depression, the researchers speculate, maybe depressive symptoms are the result of a bad feedback loop: stress impairs neurogenesis, which in turn makes a person more reactive to stress. Future research may show that the ability to grow new brain cells is an important factor in human depression. A predisposition to overreact to stress hormones, or a sluggishness in generating new neurons, might be what leads a human adult to the feeling that they'll never swim out of the tank.
Snyder, J., Soumier, A., Brewer, M., Pickel, J., & Cameron, H. (2011). Adult hippocampal neurogenesis buffers stress responses and depressive behaviour Nature DOI: 10.1038/nature10287
*This sort of treatment is what might encourage a group of NIMH rodents to run away and create their own organized society under a rosebush somewhere.