Stress and Depression Mediated by Single Brain Protein
Medscape Psychiatry and Mental Health
November 20, 2014
A single brain protein appears to mediate resilience to stress and susceptibility to depression, US scientists have discovered in findings that may offer targets for novel and more effective antidepressants.
The researchers found that beta-catenin activity in D2-type dopamine receptor neurons in the nucleus accumbens plays a central role in the ability to deal with stress and be resilient to depression. Moreover, activity is reduced in the brains of depressed patients.
The research was published online November 12 in Nature.
"We got keyed in on this gene because earlier genome-wide data in animals and humans suggested that beta-catenin signaling might be altered in the nucleus accumbens," 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 in New York City, told Medscape Medical News.
"So we started out by verifying whether that was true."
In a mouse model, the team demonstrated that control animals that were exposed to an accelerated social defeat stress developed social avoidance, suggesting depression like behavior. Overexpression of beta-catenin prevented this phenotype.
Beta-catenin also mediated an antidepressant like response in a forced swim test and anxiolytic effects in an elevated maze puzzle. With mice showing no changes in preference for sucrose or cocaine, the team established that beta-catenin does not cause hedonic effects.
Further examination revealed that overexpression of beta-catenin in D2-type dopamine receptor medium spiny neurons in the nucleus accumbens induced a proresilient phenotype in the face of stress. This effect was not seen with D1-type medium spiny neurons.
The researchers also found that blocking beta-catenin signaling in the nucleus accumbens increased susceptibility to stress in mice undergoing a subthreshold defeat procedure. However, it had no impact on social interaction or locomotion in control animals, indicating a specific link to stress.
"Then we validated that in humans by showing that in depressed humans on autopsy, beta-catenin activity is lower in the nucleus accumbens of depressed patients," Dr Nestler said.
The researchers went on to show in animals that had undergone 10 days of chronic social defeat stress that beta-catenin signaling was upregulated in resilient mice and downregulated in susceptible animals, with the activity located in D2-type medium spiny neurons.
Dr Nestler commented: "The last part was us basically saying, Okay, beta catenin is a transcription factor that regulates a number of genes. What are those other genes that mediate this action?"
The team used a technique called chromatin immunoprecipitation followed by sequencing to conduct genome-wide mapping of beta-catenin after social defeat. They found a connection between beta- catenin and the Dicer1 gene, which encodes for a protein critical in microRNA biogenesis.
Knocking out Dicer1 in the mouse model resulted in animals that demonstrated social avoidance, thus mimicking the effects of blocking beta-catenin, whereas control mice had normal social interactions. Further experiments confirmed the role of Dicer1 and identified potential associations with specific microRNAs.
The current findings challenge the predominant view of depression and how it should be treated. "All of the current treatments that we have for depression are based on serendipitous discoveries made 6 decades ago," Dr Nestler said.
"All current antidepressants activate norepinephrine or serotonin in the brain. They are very nonspecific, so the drugs are useful for a wide range of disorders, not specifically depression."
He added: "We very much believe that serotonin and norepinephrine are more indirectly related to depression, and what we are discovering here are fundamentally different pathways that are truly involved in causing depression, and now provide a template that can be used to develop antidepressants with different mechanisms of action."
With a higher degree specificity, the outcomes with such novel antidepressants might be expected to be greater than with current drugs. However, their development will not necessarily be straightforward.
"The challenge is always that drug discovery is never easy," Dr Nestler stated. "It's going to be difficult, but the genes that are regulated by beta-catenin in our study, which presumably mediate this effect, represent multiple targets that now need to be characterized."
"The other thing to say is that most previous drug discovery efforts for depression have looked for ways to undo the bad effects of stress. What our study suggests is an additional way to do it."
"So, rather than looking for ways to undergo the bad effects of stress, we can actually look for ways to induce resilience, to make individuals who are inherently more susceptible more resilient. We are very excited about that possibility," he concluded.
This work was supported by grants from the National Institute of Mental Health and the Hope for Depression Research Foundation. Dr Nestler has disclosed no relevant financial relationships.
Nature. Published online November 12, 2014. Abstract
Medscape Psychiatry and Mental Health
November 20, 2014
A single brain protein appears to mediate resilience to stress and susceptibility to depression, US scientists have discovered in findings that may offer targets for novel and more effective antidepressants.
The researchers found that beta-catenin activity in D2-type dopamine receptor neurons in the nucleus accumbens plays a central role in the ability to deal with stress and be resilient to depression. Moreover, activity is reduced in the brains of depressed patients.
The research was published online November 12 in Nature.
"We got keyed in on this gene because earlier genome-wide data in animals and humans suggested that beta-catenin signaling might be altered in the nucleus accumbens," 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 in New York City, told Medscape Medical News.
"So we started out by verifying whether that was true."
In a mouse model, the team demonstrated that control animals that were exposed to an accelerated social defeat stress developed social avoidance, suggesting depression like behavior. Overexpression of beta-catenin prevented this phenotype.
Beta-catenin also mediated an antidepressant like response in a forced swim test and anxiolytic effects in an elevated maze puzzle. With mice showing no changes in preference for sucrose or cocaine, the team established that beta-catenin does not cause hedonic effects.
Further examination revealed that overexpression of beta-catenin in D2-type dopamine receptor medium spiny neurons in the nucleus accumbens induced a proresilient phenotype in the face of stress. This effect was not seen with D1-type medium spiny neurons.
The researchers also found that blocking beta-catenin signaling in the nucleus accumbens increased susceptibility to stress in mice undergoing a subthreshold defeat procedure. However, it had no impact on social interaction or locomotion in control animals, indicating a specific link to stress.
"Then we validated that in humans by showing that in depressed humans on autopsy, beta-catenin activity is lower in the nucleus accumbens of depressed patients," Dr Nestler said.
The researchers went on to show in animals that had undergone 10 days of chronic social defeat stress that beta-catenin signaling was upregulated in resilient mice and downregulated in susceptible animals, with the activity located in D2-type medium spiny neurons.
Dr Nestler commented: "The last part was us basically saying, Okay, beta catenin is a transcription factor that regulates a number of genes. What are those other genes that mediate this action?"
The team used a technique called chromatin immunoprecipitation followed by sequencing to conduct genome-wide mapping of beta-catenin after social defeat. They found a connection between beta- catenin and the Dicer1 gene, which encodes for a protein critical in microRNA biogenesis.
Knocking out Dicer1 in the mouse model resulted in animals that demonstrated social avoidance, thus mimicking the effects of blocking beta-catenin, whereas control mice had normal social interactions. Further experiments confirmed the role of Dicer1 and identified potential associations with specific microRNAs.
The current findings challenge the predominant view of depression and how it should be treated. "All of the current treatments that we have for depression are based on serendipitous discoveries made 6 decades ago," Dr Nestler said.
"All current antidepressants activate norepinephrine or serotonin in the brain. They are very nonspecific, so the drugs are useful for a wide range of disorders, not specifically depression."
He added: "We very much believe that serotonin and norepinephrine are more indirectly related to depression, and what we are discovering here are fundamentally different pathways that are truly involved in causing depression, and now provide a template that can be used to develop antidepressants with different mechanisms of action."
With a higher degree specificity, the outcomes with such novel antidepressants might be expected to be greater than with current drugs. However, their development will not necessarily be straightforward.
"The challenge is always that drug discovery is never easy," Dr Nestler stated. "It's going to be difficult, but the genes that are regulated by beta-catenin in our study, which presumably mediate this effect, represent multiple targets that now need to be characterized."
"The other thing to say is that most previous drug discovery efforts for depression have looked for ways to undo the bad effects of stress. What our study suggests is an additional way to do it."
"So, rather than looking for ways to undergo the bad effects of stress, we can actually look for ways to induce resilience, to make individuals who are inherently more susceptible more resilient. We are very excited about that possibility," he concluded.
This work was supported by grants from the National Institute of Mental Health and the Hope for Depression Research Foundation. Dr Nestler has disclosed no relevant financial relationships.
Nature. Published online November 12, 2014. Abstract
