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| Credit: Rice University |
The brain's ability to effectively deal with stress or to lack that
ability and be more susceptible to depression, depends on a single protein type
in each person's brain, according to a study conducted at the Icahn School of
Medicine at Mount Sinai and published November 12 in the journal Nature.
The Mount Sinai study findings challenge the current thinking about depression and the
drugs currently used to treat the disorder.
"Our findings are distinct from serotonin and other neurotransmitters
previously implicated in depression or resilience against it," says the
study's lead investigator, Eric J. Nestler, MD, PhD, Nash Family Professor,
Chair of the Department of Neuroscience and Director of the Friedman Brain
Institute at the Icahn School of Medicine at Mount Sinai. "These data
provide a new pathway to find novel and potentially more effective
antidepressants."
The protein involved in this new model of depression is beta-catenin
(B-catenin), which is expressed throughout the brain and is known to have many
biological roles. Using mouse models exposed to chronic social stress, Mount
Sinai investigators discovered that it is the activity of the protein in the D2
neurons, a specific set of nerve cells (neurons) in the nucleus accumbens
(NAc), the brain's reward and motivation center, which drives resiliency.
Specifically, the research team found that animals whose brains activated
B-catenin were protected against stress, while those with inactive B-catenin
developed signs of depression in their behavior. The study also showed
suppression of this protein in brain tissue of depressed patients examined post
mortem.
"Our human data are notable in that we show decreased activation of
B-catenin in depressed humans, regardless of whether these individuals were on
or off antidepressants at the time of death," says the study's co-lead
investigator, Caroline Dias, an MD-PhD student at the Icahn School of Medicine
at Mount Sinai. "This implies that the antidepressants were not adequately
targeting this brain system."
In the study, researchers blocked B-catenin in the D2 brain cells in mice
that had previously shown resilience to depression and found the animals became
susceptible to stress. Conversely, activating B-catenin in stress mice
bolstered their resilience to stress.
Nearly all nerve cells in the NAc brain region are called
medium spiny neurons. These cells are divided into two types based on how they
detect the neurotransmitter dopamine, which is important in regulating reward
and motivation. One type of neuron detects dopamine with D1 receptors and the
other with D2 receptors. The Mount Sinai data specifically implicate the D2
neurons in mediating deficits in reward and motivation that contribute to
depression or enhancements that mediate resilience.
Examining the genes regulated by B-catenin, the team then traced the
pathway that was engaged when B-catenin was activated in the D2 neurons and
discovered a novel connection between the protein and Dicer1, an enzyme
important in making microRNAs, small molecules which control gene expression.
"While we have identified some of the genes that are targeted, future
studies will be key to see how these genes affect depression. Presumably, they
are important in mediating the pro-resilient effects of the B-catenin-Dicer
cascade," says Dr. Dias.
While the molecular underpinnings of depression have remained elusive
despite decades of research, the new Mount Sinai study breaks new ground in
understanding depression in three important ways. It is the first report that
B-catenin is deficient in nucleus accumbens in
human depression and mouse depression models; it is the first study to show
that higher activity of B-catenin drives resilience and the first report
demonstrating a strong connection between B-catenin and control of microRNA
synthesis.
The findings also suggest that future therapy for depression could be
aimed at bolstering resilience against stress.
"While most prior efforts in antidepressant drug discovery have
focused on ways to undo the bad effects of stress, our findings provide a
pathway to generate novel antidepressants that instead activate mechanisms of
natural resilience," says Dr. Nestler.
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