YSM Issue 86.3

NEUROSCIENCE
Uncovering The Biochemical Basis For Depression
BY SMITA SHUKLA
A staggering 40 percent of individuals afflicted with depression do not
react to popular antidepressants, which are usually selective serotonin
reuptake inhibitors (SSRIs). Although depressive episodes have often
been attributed to serotonin deficiencies, researchers at the Yale School
of Medicine recently discovered that other systems are likely at work.
“The acetylcholine system could also play a role in depression,” said
Marina Picciotto, the Charles B. G. Murphy Professor of Psychiatry and
Professor of Neurobiology and of Pharmacology, and senior author
of a new study, published in the Proceedings of the National Academy of
Sciences in February. First author Yann Mineur is an Associate Research
Scientist in Psychiatry at the Yale School of Medicine.
The Picciotto Laboratory had examined the acetylcholine system
before, particularly in connection with smoking. Their work focused
on the nicotinic acetylcholine receptors, which are the primary sensors
for the neurotransmitter acetylcholine. These receptors can be found
at the neuromuscular junction, where they mediate communication
between nerves and muscles. However, in the brain, the acetylcholine
system is much broader and more complex — for instance, acetylcholine
may either activate or inhibit cognitive processes based on its location
within the brain.
Nicotinic acetylcholine receptors activate during smoking, and there
is a known connection between smoking and depression. Picciotto
explained, “human smokers who have had a previous episode of depression
find it much harder to quit smoking, while those with no previous
history of depression may encounter their first episode after quitting.”
Withdrawal from smoking can account for a change in mood, since
changes in the activation of nicotinic receptors can generate a brain
imbalance that can contribute to depressive episodes.
In order to further understand how nicotinic acetylcholine receptors
affect mood in humans, the researchers developed a model for depression
with genetically altered mice. They found that regardless of nicotine
exposure, mice were less depressed when a blocker for acetylcholine was
present. Researchers thus inferred that the presence of this neurotransmitter
may play an integral role for depression in mice.
Research in the 1970s showed an analogous result in human subjects,
uncovering a relationship between acetylcholine and depression.
This existing knowledge about tobacco, acetylcholine, and depression
provided the motivation for the researchers to directly investigate the
connection between acetylcholine and depression.
To explore this theory, the researchers used a test for antidepressent
effects, where mice with varying levels of acetylcholine were placed in
a pool of water from which they could not escape. Normally, in similar
situations, mice have a positive reaction to stress and continuously search
for an exit. However, with higher levels of acetylcholine and greater
depression-like symptoms, mice displayed just enough motivation to
keep their noses out of the water.
As a follow-up experiment, researchers then used a top-down
approach by observing the effect of common SSRI antidepressants on
mice with depressive symptoms. These mice were less stress-sensitive
and reacted more normally — that is, they actively sought to escape the
stressful environment.
Additionally, the researchers determined that the major region of
IMAGE COURTESY OF THE MAYO FOUNDATION
These scans depict significant reduction in neurotransmitter
activity in brains of patients with depression.
the brain undergoing acetycholine changes resulting in symptoms of
depression was the hippocampus, which is associated with motivation
and emotions in both mice and humans. By increasing the amount of
acetylcholine in just the hippocampus, scientists could observe effects
throughout the body. This finding in particular gives researchers a
potential area of the brain in which to manipulate the genes involved
in depression.
Mineur and Picciotto also collaborated with colleagues in the Yale
Department of Psychiatry on a study where human subjects with varying
degrees of depression were given a tracer that competed with acetylcholine
for the nicotinic acetylcholine receptors. As expected, people with
chronic depression showed fewer sites for the tracer to bind, meaning
that either there was more competition for the receptors due to higher
concentrations of acetylcholine, or that these individuals had a decreased
number of acetylcholine receptors to begin with. The researchers
disproved the latter notion by examining post-mortem cortical tissue
from the Canadian brain bank. Brains from depressed individuals had
the same numbers of receptors compared to brains from people with
no history of depression, implying that the decreased tracer binding in
the imaging study was due to competition with acetylcholine for binding,
and that depressed individuals tend to have higher concentrations
of acetylcholine.
The implications of this research are vast, though the pathways
involved in motivation and mood regulation are just starting to become
understood. But by pinpointing the exact biochemical system involved
during the development of depression, researchers might eventually
be able to provide more effective cures than the currently used SSRIs.
“We’re interested in how stress regulates activity of neurons and whether
we can understand that using genetic techniques or other manipulations
in the mouse,” Picciotto said. In the near future, researchers hope to test
new antidepressants targeting acetylcholine receptors in the human brain.
8 Yale Scientific Magazine | April 2013 www.yalescientific.org