Journal
SCIENCE
Volume 344, Issue 6181, Pages 313-319Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1249240
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Funding
- National Institute of Mental Health [R01 MH092306]
- National Research Service Award [F31 MH095425, T32 MH 087004, F32 MH096464]
- Johnson & Johnson-International Mental Health Research Organization (IMHRO) Rising Star Translational Research Award
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Typical therapies try to reverse pathogenic mechanisms. Here, we describe treatment effects achieved by enhancing depression-causing mechanisms in ventral tegmental area (VTA) dopamine (DA) neurons. In a social defeat stress model of depression, depressed (susceptible) mice display hyperactivity of VTA DA neurons, caused by an up-regulated hyperpolarization-activated current (I-h). Mice resilient to social defeat stress, however, exhibit stable normal firing of these neurons. Unexpectedly, resilient mice had an even larger Ih, which was observed in parallel with increased potassium (K+) channel currents. Experimentally further enhancing Ih or optogenetically increasing the hyperactivity of VTA DA neurons in susceptible mice completely reversed depression-related behaviors, an antidepressant effect achieved through resilience-like, projection-specific homeostatic plasticity. These results indicate a potential therapeutic path of promoting natural resilience for depression treatment.
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