A technique that might be expected to increase depression actually lessens it in mice a team at the Icahn School of Medicine at Mount Sinai, New York, have announced in Science, explaining why a clinically used drug works and opening up new paths to treating humans with the same condition.
The concept of depressed mice can lead to a fair amount of mocking outside the circles of those who study them. Are these not naturally cow'rin tim'rous beasties? Cute as the image of a mouse on suitably sized psychiatrist's couch might be, it is not as though they can tell us when they're feeling down. However, some mice do indeed show what are labeled “depressive-like behaviors” and these can serve as a model for the causes and treatments of human conditions.
So when Dr Ming-Hu Han found an association between these behaviors and hyperactive neuronal activity in the reward circuits of the brain, he sought a way to treat this activity. However, Han found that, far from reaping rewards from suppressing it the best thing he could do was promote it further.
"To our surprise, neurons in this circuit harbor their own self-tuning, homeostatic mechanism of natural resilience," said Han.
One of the causes of mouse depression is repeated encounters with a dominating fellow rodent. However, just as some humans are able to deal with bullying bosses or noxious neighbors, some mice cope with such situations much better than others. Several years ago Han's colleagues revealed that mice could be made more resilient to such circumstances through “optogenetics”, the use of light to control neurons that have been sensitized to be affected by it.
Mice that lack this resilience were found to have hyperactive dopamine secreting neurons in their reward center, which in turn were triggered by an electrical current, Ih. Oddly however, Ih turned out to be even higher in the resilient mice, but without the extra dopamine release.
Han wondered if this was because Ih also boosted an inhibitory potassium channel current, which had been found to also be higher in the resilient mice. When depression-susceptible mice were given a drug that boosted Ih it also increased the current inhibiting the potassium channel and leveled out the dopamine release. The mice showed signs of becoming more cheerful, regaining their love of sweet foods and becoming more sociable with other mice.
The same drug, lamotrigine, is used as a mood stabilizer for people with the depression symptoms of bipolar disorder, but until now the reasons why it works have been a mystery. Optogenetic techniques to stimulate neuronal activity in the reward circuit had the same effect on the mice behavior.
In other words, whether by drugs or the application of light, further stimulating an already abnormally high current produced a compensatory response on a different path, with the overall effect that mice become more able to cope with stressful situations. Understanding how this works greatly improves our prospects of developing more effective versions of lamotrigine or other mechanisms for tackling depression in humans.
Han discusses the potential implications of this work in the video below.