Trailblazing Study Identifies a New Pathway to Treat Depression

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Robert Malenka, M.D., Ph.D.
Robert Malenka, M.D., Ph.D.

From The Quarterly, Summer 2012

In groundbreaking research published this July in the journal Nature, Brain & Behavior Research Foundation Scientific Council Member, Robert Malenka, M.D., Ph.D., led a team of researchers at the Stanford University School of Medicine in the discovery of a novel molecular mechanism linked to the inability to experience pleasure in depression. The importance of this work is not only in the identification of a mechanism never before linked to depression, but also in the inventive methodology used to track what causes the reward circuitry in the brain to shut down.

Anhedonia, the inability to experience pleasure, is a frequent and crippling symptom of depression. To understand what causes it, the Stanford team used animal models in which they altered the standard research methodology for ‘stress.’ In typical research models, mice are exposed to a single stressful event. Here, however, they were exposed to repeated stress. Once ‘stressed,’ the animals’ interest in pleasure-seeking was measured by their preference for sugar water over plain water. Chronically stressed mice lost the preference for sugar water, in a similar way that people who suffer depression induced by life’s chronic stresses lose the joy of good food, sex, physical comfort, etc.

Antidepressants developed from research using single-stress behavioral models, now considered to not accurately simulate depression, work via the same molecular mechanisms. Many of them block the reabsorption of neurotransmitters such as serotonin in the gaps, or synapses, between brain cells and are frequently ineffective. With the behavioral model of chronic stress, the team hoped to learn something new about the brain biology underlying key symptoms of depression.

“A few scattered studies suggested that chronic stress increased levels of melanocortin—a naturally occurring molecule known to affect appetite —in the brain,” said Dr. Malenka, the Pritzker Professor in Psychiatry and Behavioral Sciences. And it was known that stressed animals have a higher number of melanocortin receptors in the nucleus accumbens (NAc), part of an ancient brain circuit involved in reward-related behaviors. But, Dr. Malenka explained, it wasn’t yet known if melanocortin actually affected the NAc, and if it did, how.
 
Rather than simply noting the altered sugar-preference behaviors in the chronically-stressed mice, the investigators used electrophysiological, biochemical and gene-transferring techniques to manipulate and, ultimately, identify the precise brain circuitry involved right down to the molecular level. The scientists found that both chronic stress and the direct administration of melanocortin diminished the signaling strength of some of the synapses on a set of nerve cells in the NAc that contain the receptors for melanocortin. When these receptors were removed, the same stressful conditions no longer caused changes in those nerve cells’ synapses. Simultaneously, despite a week-long stressful experience, the mice’s sugar preference was returned to normal.

This is the first study to implicate the role of melanocortin in anhedonia, opening a new pathway for the treatment of depression. While the study was conducted in mice, the brain circuit involved is largely identical in humans.

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