Monday, February 23, 2015

Fighting Depression With Depression

Any college experience is not complete without the existence of social stressors. Although one can prove resilient and cope with these pressures while maintaining proper psychological functioning, there are those that cannot. These people are deemed “susceptible” to depressive symptoms and tend to be given antidepressants. 44% of college students in the United States report symptoms of depression, highlighting the increased use of depressive therapy and the importance of this study. Although the neurophysiological processes of the brain’s ability to cope with stress is not well understood, Friedman and her team of scientists investigate depression mechanisms in the midbrain to come to an unexpected conclusion that may offer a new take on therapy.

Friedman et al. used mice to characterize differences in the brain of a resilient versus susceptible mouse. What they found with the susceptible mouse was expected: hyperactivity in the ventral tegmental area (VTA) dopamine neurons caused by an up-regulated hyperpolarization-activated current. This means that there was increased firing of VTA dopamine neurons and an increased excitatory electrical current. Typical therapies such as antidepressants treat this by minimizing neuronal firing in the brain.

"Nucleus accumbens" by The Licensed under CC BY-SA 3.0 via Wikimedia Commons -

You would expect that because antidepressants work to lessen activity, that resilient mice would subsequently show a similar pattern in the brain. This however, is not the case. The resilient mice actually showed similar levels of firing to the control (normal) mice, with a significant increase in hyperpolarization and inhibitory potassium channel currents as compared to the susceptible group. Thus, the resilient mice had greater excitatory electrical currents. What was before seen as a stress-induced symptom, now appears to be the opposite.

Thus, Friedman and her team hypothesized that the increased excitatory electrical currents cause extremely high neuronal firing and prompt the inhibitory potassium channels to “self-tune”. This self-tuning controls the high, imbalanced firing (excitatory electrical activity) and normalizes depressive symptoms, causing a natural resilience. Other researchers call this the “tipping point”, wherein excitatory currents caused by stressors is sustained at a high level until a point of compensatory response which in turn builds resilience. Friedman et al. referred to this as “homeostatic plasticity” wherein homeostatic mechanisms regulate physiological processes, and plasticity refers to the brain modifying its structure and function. In this case, the depressive symptoms are regulated and the brain’s VTA dopamine neuron structure is altered and functions to become resilient towards depressive symptoms.

The researchers went on to test their hypothesis on the susceptible mice in two ways: pharmacologically and optogenetically. Their first experiment used a drug, lamotrigine, to increase the hyperpolarization-activated current. A single infusion into the VTA of susceptible mice increased their depressive symptoms. This was not surprising, as the susceptible mice were not maintaining high enough levels of excitatory currents to allow the potassium channels to self-tune. Instead, the single infusion merely mimicked their already depressed state. Thus, Friedman and her team went on to perform a repeated 5-day infusion of the lamotrigine into the VTA. The results showed a “profound reversal” of depressive symptoms as the hyperpolarization was maintained causing an increase in compensatory potassium channel currents that normalized their mental states and created a natural resilience. A phenomenon otherwise not observed in lower doses of lamotrigine.

Friedman et al.’s second experiment utilized optogenetic activation (the use of light to control neurons) to investigate the specific pathways of the homeostatic mechanism. Similar to lamotrigine, repeated optogenetic stimulation increases hyperpolarization and thus inhibitory electrical currents, allowing for self-tuning and a normalization of depressive symptoms. They found that the VTA dopamine neurons project onto two different pathways: to the nucleus accumbens and prefrontal cortex.

From Wikimedia Commons

These two areas of the brain demonstrate two different types of plasticity, wherein homeostatic plasticity works only in the projection onto the nucleus accumbens. The VTA dopamine neuron to prefrontal cortex pathway did not show an increase in excitatory currents and thus could not be involved in the regulation of depressive symptoms. The nucleus accumbens pathway, also known as the reward circuit, showed an increased level of hyperpolarization. As found in their previous experiment, this allowed for an increase in potassium channels and a regulation of depressive symptoms.

Friedman and her team of scientists made a discovery that could change the future of antidepressants. Although still in the research phase, the notion that your brain can build resilience to depression through homeostatic plasticity is novel and exciting. There still remains the question of how essentially increasing depressive symptoms to reach a "tipping point" would work in humans, and whether there would be any negative side effects. But with increased rates of depression among teenagers, building resilience can be used as a totally new type of therapy that could prove more effective than antidepressant pills.


Friedman, Allyson (04/18/2014). "Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience". Science (New York, N.Y.) (0036-8075), 344 (6181), p. 313.
Jump-starting natural resilience reverses stress susceptibility. (2014, April 17). Retrieved February 24, 2015, from
Kerr, M. (2012, March 29). Depression and College Students. Retrieved February 24, 2015, from
Self-Tuning Neurons Promote Resilience to Stress, Depression - NIH Research Matters - National Institutes of Health (NIH). (2014, May 5). Retrieved February 24, 2015, from


  1. This is very interesting research and I would like to know if there were any negative effects seen in the mice. Furthermore, can depression stem from other locations int he brain as well, for would this "treating depression with depression" be effective elsewhere as well? This could have implications in other neural diseases as well.

  2. This research is groundbreaking and if it proves effective in humans could revolutionize the treatment of depression, and mental disorders as a whole. Although antidepressants can be quite effective for many people, they are erratic and oftentimes people who aren't helped at all by drug treatment will have to resort to ECT (electroconvulsive therapy) for some relief. It seems that this treatment would be successful in most people, if not all. It certainly is exciting!

  3. This article does a great job of highlighting one of the biggest themes of our course, which is homeostasis. When we think about therapeutic treatments, I find that there's an inclination to counteract the up-regulation of excitatory signals through down-regulation without considering that fluctuations around a certain point are necessary for proper function. In this case, we see how fluctuations around the "tipping point" in excitatory signaling can determine resilience or susceptibility. I think this is HUGE for pharmaceuticals, because maybe this can eliminate many of the side effects that come with taking antidepressants if they can properly target the mechanisms associated with depression.