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Revealed: the brain’s molecular mechanism behind why we get the blues

 Revealed: the brain's molecular mechanism behind why we get the blues

Whether it’s food, sex, comfort or, for that matter, any of life’s various kicks, a hallmark of of the neuropsychiatric syndrome known as depression – some people call it the blues – is the inability to experience pleasure. (It’s not the only symptom, others being feelings of guilt, sorrow and despair, as well as eating and sleeping irregularities.)

In a just-published Nature study, Stanford neuroscientist Rob Malenka, MD, PhD, has teased apart the particular circuit in the brain responsible for that intense inability to experience joy (the technical term is anhedonia) that marks depression. Malenka was able to show, in a series of experiments with mice, that it was possible to uncouple this aspect of the disorder from other criteria that have typically been used in rodent studies drug developers use for assessing new compounds’ utility in combating depression.

One such routine involves tossing normal, happy mice in a pool of water (which they hate), seeing how long they paddle around before they give up on trying to get out, then give them Compound X and see if they hang in there longer. This, say drug developers, is a measure of “behavioral despair.”

But, as Mount Sinai School of Medicine neuroscientist Eric Nestler, MD, PhD, told me in an interview for my news story on Malenka’s findings, “Tossing a person in a swimming pool and telling him to swim doesn’t induce despair.”

Broad Institute neurologicst and former Harvard provost Steve Hyman, MD, put it this way, as I wrote in my story (which, by the way, covers Malenka’s study in much more detail): “Who interviewed the mouse? Maybe it stopped swimming to conserve energy.”

Malenka acquired his findings by testing the degree to which mice - who were seriously down because they’d been repeatedly subjected to periods of confinement – preferred sugar water (a pleasurable experience for them) to plain water in comparison with normal, happy mice. Using the most sophisticated lab techniques available, Malenka was able to highlight the nerve circuitry and the molecular signals behind the bummed-out mice’s loss of interest in the thrill of sucrose, which he and his teammates were able to block or restore at will. In a like manner, they showed that manipulating the same circuitry diminished or enhanced the rodents’ ability to get a kick out of – yes - cocaine. (The little critters usually love it.)

The circuitry Malenka elucidated is part of an ancient brain network called, appropriately, the reward center, which is functionally almost identical in mammals from mice to humans. So, if an experimental compound given to those bummed-out animals can restore their joie de vivre, maybe it will work in people, too.

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