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 brain.mcgill.ca. Licensed under CC BY-SA 3.0 via
Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Nucleus_accumbens.jpg#mediaviewer/File:Nucleus_accumbens.jpg
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.
Ref:
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 http://www.nih.gov/news/health/apr2014/nimh-17.htm
Kerr, M. (2012, March 29). Depression
and College Students. Retrieved February 24, 2015, from
http://www.healthline.com/health/depression/college-students
Self-Tuning Neurons Promote
Resilience to Stress, Depression - NIH Research Matters - National Institutes
of Health (NIH). (2014, May 5). Retrieved February 24, 2015, from
http://www.nih.gov/researchmatters/may2014/05052014resilience.htm
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