Social stressors come in many forms: A flat tire on your way
to your long-awaited medical appointment. The rising cost of necessities like
food and gas. Family tension, work pressures, and on it goes.
These stressors can add up to an avalanche of worries and
even develop into chronic stress.
Most people cope with stress without developing major
psychopathologies. But for others, stress-induced disorders -- including
depression -- can lead to profound changes in mood, sleep, daily interests, and
a poor outlook on life.
Herb Covington, an assistant professor of psychology and
neuroscience, and Dr. Kafui Dzirasa, assistant professor of psychiatry and
behavioral sciences, want to find treatment for such stress-related maladies.
They are framing their research by asking how multiple
neurological circuits come together to make up complex mental disorders --
including depression.
"We're hoping to gain information on the neural
mechanisms that lead to vulnerability and stress-related diseases, and how can
we target these neural mechanisms to reverse, or how to better treat, these disorders,"
said Covington, who arrived at Duke in fall 2010 after finishing his
postdoctoral fellowship.
Covington notes that methods of treating depression have
remained largely unchanged since the 1950s, with about 30 percent of sufferers
receiving insufficient treatment.
It's a condition that affects about 121 million people
worldwide and is expected to be the second-largest contributor to the global
burden of disease by the year 2012. Depression is also linked to about 850,000
deaths around the world each year, according to the World Health Organization.
The duo plan to apply for several grants that will allow
them to expand on the work they were initially trained in. Covington started as
a graduate student in the laboratory of Klaus Miczek (Tufts University), and
subsequently extended his training as a postdoctoral fellow at the University
of Texas Southwestern Medical Center, followed by the Department of
Neuroscience at Mount Sinai School of Medicine in New York.
Dr. Dzirasa, who graduated from the Duke School of Medicine
in 2009, has transitioned from his training in the laboratory of Miguel
Nicolelis, a Duke professor of neuroscience, to establish his own lab. He now
focuses on the neurophysiology of psychiatric disorders such as attention
deficit disorder, schizophrenia, bipolar depression and addiction. He has hopes
of one day being able to diagnose psychiatric diseases using physical evidence
in the same way cardiovascular diseases are diagnosed today.
"We're hoping to garner the attention of the NIH,
National Institute of Mental Health and the National Institute on Drug
Abuse," Covington said.
Using Light and Animal Models
Unlike most animals, which deal with problems in
fight-or-flight mode, humans have the capacity to worry about trouble -- for
prolonged periods of time. Covington incorporates an animal model to try to
capture this aspect of our daily human experience, confining a mouse with a
larger, more aggressive and dominant mouse for many days on end.
Even though the mice are separated by a partition that only
allows for sensory contact, the subordinate mouse cannot really get out of the
presence of the aggressor. This creates a level of "chronic" stress
for the subordinate mouse.
Covington said mice that are subjected to chronic
subordination stress usually respond with depression-like behavior: social
avoidance, an inability to experience pleasure, impaired coping responses to
other environmental stressors and anxiety-like behavior.
Also, Covington's research uses optogenetics, which
introduces light-sensitive proteins into "excitable" cells. This
makes it possible to control specific activities within cells and remotely turn
a single cell on or off, something electrical and other forms of stimulation
could not do.
Using "in vivo neurophysiological recording
techniques," Dzirasa captures in great detail patterns of brain activity
from one area of the brain to another. The technique is similar to an fMRI, but
captures cellular events in more detail, even at the level of one cell’s
activity taking place in one brain area.
"When we combine the experimental control we have over
neural circuits, we not only get the relative contribution of activity within a
specific area during the expression of a behavior, but we can also probe the
specific effect that any given circuit has directly on behavior,"
Covington said.
He is building on some of his initial findings as a
post-doctoral scholar, which showed the prefrontal cortex is crucial for
producing depression-like behaviors following social stress.
"We revealed this using optogenetic approaches where
stimulation of the prefrontal cortex showed strong anti-depression-like
effects, and this approach lends itself to what was recently discovered using
deep-brain stimulations," he said.
"All of this work indicates that there are complex
circuits involved in the emergence of depression and the persistence of
depression, and all of these circuits need to be treated individually to treat
specific depression-like symptoms," he said. "Dzirasa's interests are
exactly that, to investigate circuits that are quite complex using highly
sophisticated and novel technology."
They also hope to identify the longstanding elusive changes
in neural circuits that occur during chronic antidepressant treatments such as
imipramine or fluoxetine (Prozac).
"The resulting insights will lay the groundwork for a
circuit-level understanding of behavioral pathologies observed in depression,
and shed light on those circuitry-level changes necessary for successful
treatment," Dzirasa said.
"What we are doing now is trying to manipulate neural
circuits to prevent the effects of continuous stress from ever occurring in the
first place," added Covington. "Herein, there are opportunities for
both effectively creating novel treatments for specific affective disorders,
and a unique opportunity to generate cognitive strategies that protect against
the occurrence of any devastating effects of stress from occurring in the first
place, which may be an inherent and unfortunate predisposition for many people."