May 5, 2014

Self-Tuning Neurons Promote Resilience to Stress, Depression

Nerves firing.

Enhancing brain mechanisms triggered by stress raised the resilience of mice to stress and relieved depression-like behaviors. The surprising results suggest novel approaches to promoting mental health.

Some mice exposed to repeated encounters with a dominant animal develop depression-like behaviors, while others don’t. Sensitive mice avoid other animals and lose their preference for sugar. In past work, a group of researchers led by Dr. Ming-Hu Han of the Icahn School of Medicine at Mount Sinai found that neurons in the ventral tegmental area (VTA)—one of the “reward” areas deep in the brain—fire at higher rates in mice that are more susceptible to social stress. These neurons are known to secrete the chemical messenger dopamine.

The scientists later found that mouse susceptibility to social stress could be turned on and off by manipulating the firing rates of these neurons. To explore how this mechanism works at the cellular level, the researchers focused on electrical events within the neurons. The study, funded in part by NIH’s National Institute of Mental Health (NIMH), appeared on April 18, 2014, in Science.

The researchers found that while stress-resilient mice had VTA dopamine neurons with stable firing rates and normal dopamine activity, these neurons had higher levels of an excitatory electrical current than those of stressed mice. The higher activation currents were accompanied by higher inhibitory potassium channel currents. The researchers hypothesized that, in resilient animals, runaway excitatory currents trigger a boost in inhibitory currents, resulting in normal mood-related behaviors.

The team thus tested whether boosting excitatory currents could activate compensatory currents in susceptible mice. Over 5 days, the scientists repeatedly infused the VTA of susceptible mice with a drug called lamotrigine, which is known to increase excitatory currents. The treated mice socialized more and their characteristic rodent sweet tooth came back. At the cellular level, these mice showed a marked increase in both excitatory and inhibitory currents, resulting in normal neuron activity. This self-tuning balance of activity, common in other body systems, is called homeostasis.

The scientists achieved similar results using a technique called optogenetics to activate neuronal activity. Further experiments showed that the homeostatic mechanism worked specifically in the reward circuit running from the VTA to cells in a brain area called the nucleus accumbens.

“To our surprise, neurons in this circuit harbor their own self-tuning, homeostatic mechanism of natural resilience,” Han says. When an excitatory current develops in response to social stress—and is driven high enough for a sustained period—it triggers its own compensatory adaptation. Inhibitory currents correct out-of-balance electrical activity and thus produce resilience.

As counterintuitive as it seems, in this case, exaggerating an abnormality can be beneficial. Future strategies might harness this homeostatic mechanism to promote resilience to stress and combat depression.

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Reference: Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J, Li X, Dietz DM, Pan N, Vialou VF, Neve RL, Yue Z, Han MH. Science. 2014 Apr 18;344(6181):313-9. doi: 10.1126/science.1249240. PMID: 24744379.

Funding: NIH’s National Institute of Mental Health (NIMH) and Johnson & Johnson International Mental Health Research Organization.