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Boosting depression-causing mechanisms in brain increases resilience, surprisingly

Date:
April 17, 2014
Source:
Mount Sinai Medical Center
Summary:
New research uncovers a conceptually novel approach to treating depression. Instead of dampening neuron firing found with stress-induced depression, researchers demonstrated for the first time that further activating these neurons opens a new avenue to mimic and promote natural resilience.

Researchers produced antidepressant-like behavioral effects by reversing out-of-balance electrical activity in reward circuit neurons of susceptible mice exposed to social stress. Further increasing an excitatory current (lh potentiation) triggered a compensatory increase in a potassium channel current (K' current) -- as did activating the potassium channel (K+ current) using pulses of light in mice with brain circuitry genetically engineered to respond to it (optogenetic excessive activation).
Credit: Ming-Hu Han, Ph.D., Icahn School of Medicine at Mount Sinai

A new study points to a conceptually novel therapeutic strategy for treating depression. Instead of dampening neuron firing found with stress-induced depression, researchers demonstrated for the first time that further activating these neurons opens a new avenue to mimic and promote natural resilience. The findings were so surprising that the research team thinks it may lead to novel targets for naturally acting antidepressants.

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Results from the study are published online April 18 in the journal Science.

Researchers from the Icahn School of Medicine at Mount Sinai point out that in mice resilient to social defeat stress (a source of constant stress brought about by losing a dispute or from a hostile interaction), their cation channel currents, which pass positive ions in dopamine neurons, are paradoxically elevated to a much greater extent than those of depressed mice and control mice. This led researchers to experimentally increase the current of cation channels with drugs in susceptible mice, those prone to depression, to see whether it would enhance coping and resilience. They found that such boosting of cation channels in dopamine neurons caused the mice to tolerate the increased stress without succumbing to depression-related symptoms, and unexpectedly the hyperactivity of the dopamine neurons was normalized.

Allyson K. Friedman, PhD, Postdoctoral Fellow in Pharmacology and Systems Therapeutics at the Icahn School of Medicine at Mount Sinai, and the study's lead author said: "To achieve resiliency when under social stress, the brain must perform a complex balancing act in which negative stress-related changes in the brain actively trigger positive changes. But that can only happen once the negative changes reach a tipping point."

The research team used optogenetics, a combination of laser optics and gene virus transfer, to control firing activity of the dopamine neurons. When light activation or the drug lamotrigine is given to these neurons, it drives the current and neuron firing higher. But at a certain point, it triggers compensatory mechanisms, normalizes neuron firing, and achieves a kind of homeostatic (or balanced) resilience.

"To our surprise, we found that resilient mice, instead of avoiding deleterious changes in the brain, experience further deleterious changes in response to stress, and use them beneficially," said Ming-Hu Han, PhD, at Icahn School of Medicine at Mount Sinai, who leads the study team as senior author.

Drs. Friedman and Han see this counterintuitive finding as stimulating research in a conceptually novel antidepressant strategy. If a drug could enhance coping and resilience by pushing depressed (or susceptible) individuals past the tipping point, it potentially might have fewer side effects, and work as a more naturally acting antidepressant.

Eric Nestler, MD, PhD, at the Icahn School of Medicine at Mount Sinai praised the study. "In this elegant study, Drs. Friedman and Han and their colleagues reveal a highly novel mechanism that controls an individual's susceptibility or resilience to chronic social stress. The discoveries have important implications for the development of new treatments for depression and other stress-related disorders."

The study, "Enhancing Depression Mechanisms in Midbrain Dopamine Neurons Achieves Homeostatic Resilience," was also coauthored by J.J. Walsh, B. Juarez, S.M. Ku, D. Chaudhury, J. Wang, X. Li, D.M. Dietz, N. Pan, V.F. Vialou, Z. Yue, from the Icahn School of Medicine at Mount Sinai in New York and R. L. Neve at Massachusetts Institute of Technology in Cambridge MA.

National Institute of Mental Health Grant R01 MH092306 and F32 MH096464 provided support for this research.


Story Source:

The above story is based on materials provided by Mount Sinai Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. A. K. Friedman, J. J. Walsh, B. Juarez, S. M. Ku, D. Chaudhury, J. Wang, X. Li, D. M. Dietz, N. Pan, V. F. Vialou, R. L. Neve, Z. Yue, M.-H. Han. Enhancing Depression Mechanisms in Midbrain Dopamine Neurons Achieves Homeostatic Resilience. Science, 2014; 344 (6181): 313 DOI: 10.1126/science.1249240

Cite This Page:

Mount Sinai Medical Center. "Boosting depression-causing mechanisms in brain increases resilience, surprisingly." ScienceDaily. ScienceDaily, 17 April 2014. <www.sciencedaily.com/releases/2014/04/140417141821.htm>.
Mount Sinai Medical Center. (2014, April 17). Boosting depression-causing mechanisms in brain increases resilience, surprisingly. ScienceDaily. Retrieved April 24, 2015 from www.sciencedaily.com/releases/2014/04/140417141821.htm
Mount Sinai Medical Center. "Boosting depression-causing mechanisms in brain increases resilience, surprisingly." ScienceDaily. www.sciencedaily.com/releases/2014/04/140417141821.htm (accessed April 24, 2015).

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