Post by Former NIMH Director Thomas Insel: Accentuate the Positive: Rhythm and Blues
Increasingly as I attend scientific meetings, I hear depression addressed as a kind of cortical arrhythmia. The idea is that the rhythms in brain networks are out of whack and that depression can be treated by changing those rhythms either through non-invasive interventions, like repetitive transcranial magnetic stimulation, or invasive approaches, like deep brain stimulation. With arrhythmias in the heart, we know the pacemaker and the pathways. In contrast, our understanding of rhythms in the brain and how they connect to depression remains primitive.
A paper from Ramirez and colleagues at MIT sheds new light, quite literally, on the brain circuits involved in depression and its treatment.1 This study in mice used clever genetic engineering to define a set of cells that are activated by a rewarding or positive experience, cells that the group calls “engram” or memory cells in the hippocampus. Positive engram cells (in this case activated by social experience) were distinct from cells activated by neutral or negative (stressful) experiences. Each of these groups of cells was engineered to be responsive to light. Mice then received ten days of stressful experience, resulting in enduring increases in behaviors like passivity and anhedonia. Anhedonia means low motivation to seek pleasure (which for mice is measured by less interest in drinking a sugar solution). Passivity and anhedonia have previously been used as evidence of a depression-like syndrome in mice.
Ramirez and his colleagues wanted to answer three very significant questions. First, would activating the positive engram cells mitigate the signs of depression? By using a laser focused on the positive engram cells, they found that reactivating the positive engram with light mitigated both the passivity and the anhedonia resulting from repeated stress. It was as if reactivating a positive memory (or more precisely, the cells associated with a positive memory) was enough to reverse the effects of ten stressful days. Reactivating the neutral cells or negative engram cells had no benefit. Curiously, activating the positive engram influenced only some of the effects of stress. In contrast to the benefits for depression-related behavior, activation of the positive engram had no impact on the stress-induced changes in behavior associated with anxiety, such as exploratory behaviors.
Second, knowing that acute stimulation of the positive engram could transiently reduce the symptoms, the team asked if chronic stimulation would have enduring effects. Activating the same cells with light daily for five days did, in fact, show sustained effects following treatment, just as one would expect with an antidepressant. Repeated stimulation of the engram even increased neurogenesis (growth of new neurons), a cardinal feature of antidepressants. What was surprising, however, was that five days of the positive experience was not effective. Apparently reactivating the brain cells associated with a positive experience was more effective than actually reliving the experience.
And third, what brain circuit was involved? A modern view of brain stimulation recognizes that any group of cells or any region is just a portal into the various networks involved in behavior. Ramirez and team looked at the impact of activating their positive engram on brain areas near and far from the hippocampus. By altering the various regions responding to the positive engram, they were able to reveal a critical circuit linking hippocampus, basolateral amygdala, and the nucleus accumbens. Each of these regions would have been among the usual suspects for behaviors associated with depression, but this may be the first demonstration of how they link together for behavioral change.
No question that studies in mice have a lot of shortcomings as a path to a deeper understanding of human mood disorders. Unfortunately we do not have the tools to monitor and manipulate circuits in humans with the precision now available for the mouse brain, so these behavioral approximations of mood in mice are the best we can do. But accepting these caveats, research like that reported by Ramirez and his colleagues is a powerful demonstration of the importance of experience, or more precisely, the neural representation of experience for recovery from a profound change in behavior. Understanding the circuits and the rhythms in those circuits may now be our best insight into the blues.
1 Ramirez S et al. Activating positive memory engrams suppresses depression-like behaviour . Nature. 2015 Jun 18;522(7556):335-9. doi: 10.1038/nature14514.