Editors' ChoiceDepression

An “Exciting” Way to Heal

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Science Translational Medicine  30 Apr 2014:
Vol. 6, Issue 234, pp. 234ec76
DOI: 10.1126/scitranslmed.3009259

Depression commonly evokes an image of a troubled mind that has succumbed to the pressure of stress. Therefore, the immediate reaction to a patient with depression is to take the stressors away and to calm down the troubled neuronal circuits that got activated by the stress. Paradoxically, new research from Friedman et al. suggests that one way to treat depression may lie not in pacifying the hyperexcitable dopamine neurons but rather in driving them into activity-fueled exhaustion.

Mice that are defeated socially over several days by a dominant aggressive cage mate naturally separate into two groups: mice that are susceptible to this stress and develop long-lasting depressive-like behavior such as avoiding social contact and losing motivation, and resilient mice that are unaffected by the stress. Depressive-like behavior in susceptible mice is associated with increased activity of dopamine-producing neurons in a brain region called the ventral tegmental area (VTA). If these neurons remain overactive, the mice are more likely to show signs of depression.

In a surprising twist, new data from Friedman et al. suggest that the best treatment for depression is not to attenuate the activity of these VTA neurons but rather to put them into overdrive. The researchers found that resilient mice displayed an even stronger activation of VTA neurons than did the “depressed” mice. The neuronal hyperactivity triggered a strong inhibitory current that counterbalanced the hyperexcitabiliy and normalized neuronal firing. Experimental overactivation of the VTA neurons by using optogenetics or lamotrigine, a drug used to treat bipolar disorder, induced a compensatory adaptation that corrected the out-of-balance electrical activity in susceptible mice and reversed symptoms, such as social withdrawal and anxiety. Importantly, whereas several days of repeated VTA neuronal hyperactivation was needed to induce the resilient state, once the new balance was established it rendered dopamine neurons resistant to perturbations, and the mice became resilient to future stress.

This elegant study suggests a new strategy to treat depression that relies on promoting or triggering natural resilience mechanisms in the brain.

A. K. Friedman et al., Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science 344, 313–319 (2014). [Abstract]

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