Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience

Allyson K. Friedman, Jessica J. Walsh, Barbara Juarez, Stacy M. Ku, Dipesh Chaudhury, Jing Wang, Xianting Li, David M. Dietz, Nina Pan, Vincent F. Vialou, Rachael L. Neve, Zhenyu Yue, Ming Hu Han

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)313-319
Number of pages7
JournalScience
Volume344
Issue number6181
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • General

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    Friedman, A. K., Walsh, J. J., Juarez, B., Ku, S. M., Chaudhury, D., Wang, J., Li, X., Dietz, D. M., Pan, N., Vialou, V. F., Neve, R. L., Yue, Z., & Han, M. H. (2014). Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science, 344(6181), 313-319. https://doi.org/10.1126/science.1249240