Figure 1: Mice lacking the Rines gene display increased anxiety and an abnormal stress response. Credit: iStockphoto/Thinkstock
Mood and emotion are extremely complex aspects of behavior that are known to involve the neurotransmitters serotonin and norepinephrine. Both neurotransmitters are broken down by an enzyme called monoamine oxidase A (MAO-A), and drugs that interfere with this system, such as the anti-depressant fluoxetine (Prozac), have long been used to treat mood disorders. Jun Aruga and colleagues from the RIKEN Brain Science Institute in Wako have now shown that a ligase enzyme called Rines regulates MAO-A activity and could prove to be a promising therapeutic target for the treatment of such disorders.
The metabolism of MAO-A, like that of many other proteins in the cell, is regulated by what is known as the ubiquitin–proteasome pathway, which tags old, misfolded or otherwise unwanted molecules and dispatches them to a cellular trash can. Aruga and his colleagues hypothesized that this pathway would be critical for regulating MAO-A levels in the brain.
To investigate the role of this pathway, the researchers used genetic engineering to create mice lacking the gene encoding the Rines E3 ubiquitin ligase—an enzyme that determines which proteins will be tagged for destruction.
Deletion of the Rines gene had a dramatic effect on the emotional behavior of the mice. For example, mice lacking the gene were far more reluctant to explore a new environment and spent less time in open spaces compared to healthy mice, indicating that the mutant mice were more anxious and had an abnormal stress response.
The researchers then examined the brains of these mice and found that the altered emotional behaviors were associated with significantly reduced levels of serotonin and norepinephrine in the locus ceruleus, prefrontal cortex and amygdala—regions of the brain that regulate emotion and stress responses. This was accompanied by enhanced activity of MAO-A in the locus ceruleus, the main source of norepinephrine in the brain. The researchers also found that some of the abnormal emotional behaviors were abolished by MAO inhibitors.
"The next step is to clarify the change in emotional response abnormalities using the animals' personal history," says Aruga. "Studies in humans indicate that the prevalence of aggressive and antisocial behavior in adults with the low-level MAO-A variant is affected by their history of stress during childhood, so personal history and gene–environment interaction studies with the mutant mice would contribute to a more comprehensive understanding of the pathophysiology of aggression and antisocial behavior."
Explore further: Researchers uncover brain molecule regulating human emotion, mood
More information: Kabayama, M., Sakoori, K., Yamada, K., Ornthanalai, V. G., Ota, M., Morimura, N., Katayama, K., Murphy, N. P. & Aruga, J. Rines E3 ubiquitin ligase regulates MAO-A levels and emotional responses, The Journal of Neuroscience 33, 12940–12953 (2013). dx.doi.org/10.1523/JNEUROSCI.5717-12.2013
Medical Xpress on facebook
Related Stories
Researchers uncover brain molecule regulating human emotion, mood
Aug 06, 2013
A RIKEN research team has discovered an enzyme called Rines that regulates MAO-A, a major brain protein controlling emotion and mood. The enzyme is a potentially promising drug target for treating diseases ...
Fear factor: Missing brain enzyme leads to abnormal levels of fear in mice
Jul 15, 2013
A little bit of learned fear is a good thing, keeping us from making risky, stupid decisions or falling over and over again into the same trap. But new research from neuroscientists and molecular biologists at USC shows that ...
Hulk smash? Maybe not anymore: scientists block excess aggression in mice
Jun 19, 2012
Pathological rage can be blocked in mice, researchers have found, suggesting potential new treatments for severe aggression, a widespread trait characterized by sudden violence, explosive outbursts and hostile overreactions ...
High levels of a specific enzyme in fetuses linked to anxiety
Jul 24, 2013
Mouse embryos with the human enzyme CYP2C19 in the brain develop a smaller hippocampus and anxiety-like behaviour as adults. The results of this new study, which is published in the journal Molecular Psychiatry, agree in pri ...
Proteins linked to longevity may be involved in mood control
Dec 09, 2011
(Medical Xpress) -- Over the past decade, MIT biologist Leonard Guarente and others have shown that very-low-calorie diets provoke a comprehensive physiological response that promotes survival, all orchestrated by a set of ...
Recommended for you
New hope for premature babies at risk of brain damage
1 hour ago
(Medical Xpress)—Babies who suffer a bleed on their brain could be saved from debilitating brain damage after researchers at the University of Birmingham found that a new drug can prevent the swelling of the organ which ...
New exercise guidelines developed for people with MS
2 hours ago
According to new research out of Queen's University, an active lifestyle has many benefits for adults living with multiple sclerosis. Based on that research, Amy Latimer-Cheung (School of Kinesiology and Health Studies) has ...
New theory of synapse formation in the brain
16 hours ago
The human brain keeps changing throughout a person's lifetime. New connections are continually created while synapses that are no longer in use degenerate. To date, little is known about the mechanisms behind ...
Nobel Prize winner reports new model for neurotransmitter release
21 hours ago
In a Neuron article published online October 10th, recent Nobel Laureate Thomas C. Südhof challenges long-standing ideas on how neurotransmitter gets released at neuronal synapses. On October 7th, Südho ...
We may make mistakes interpreting the emotions of others, but our brain can corrects us
23 hours ago
When we are sad the world seemingly cries with us. On the contrary, when we are happy everything shines and all around people's faces seem to rejoyce with us. These projection mechanisms of one's emotions onto others are ...
Maintenance mechanism that prevents stem cells aging discovered
Oct 10, 2013
A team of researchers at the Molecular Neurobiology Unit of the University of Valencia, led by Professor of Cell Biology Isabel Fariñas, just published in the journal Nature Neuroscience, the results of a research that m ...
User comments
© Medical Xpress 2011-2013, Phys.org network
Figure 1: Mice lacking the Rines gene display increased anxiety and an abnormal stress response. Credit: iStockphoto/Thinkstock
Mood and emotion are extremely complex aspects of behavior that are known to involve the neurotransmitters serotonin and norepinephrine. Both neurotransmitters are broken down by an enzyme called monoamine oxidase A (MAO-A), and drugs that interfere with this system, such as the anti-depressant fluoxetine (Prozac), have long been used to treat mood disorders. Jun Aruga and colleagues from the RIKEN Brain Science Institute in Wako have now shown that a ligase enzyme called Rines regulates MAO-A activity and could prove to be a promising therapeutic target for the treatment of such disorders.
The metabolism of MAO-A, like that of many other proteins in the cell, is regulated by what is known as the ubiquitin–proteasome pathway, which tags old, misfolded or otherwise unwanted molecules and dispatches them to a cellular trash can. Aruga and his colleagues hypothesized that this pathway would be critical for regulating MAO-A levels in the brain.
To investigate the role of this pathway, the researchers used genetic engineering to create mice lacking the gene encoding the Rines E3 ubiquitin ligase—an enzyme that determines which proteins will be tagged for destruction.
Deletion of the Rines gene had a dramatic effect on the emotional behavior of the mice. For example, mice lacking the gene were far more reluctant to explore a new environment and spent less time in open spaces compared to healthy mice, indicating that the mutant mice were more anxious and had an abnormal stress response.
The researchers then examined the brains of these mice and found that the altered emotional behaviors were associated with significantly reduced levels of serotonin and norepinephrine in the locus ceruleus, prefrontal cortex and amygdala—regions of the brain that regulate emotion and stress responses. This was accompanied by enhanced activity of MAO-A in the locus ceruleus, the main source of norepinephrine in the brain. The researchers also found that some of the abnormal emotional behaviors were abolished by MAO inhibitors.
"The next step is to clarify the change in emotional response abnormalities using the animals' personal history," says Aruga. "Studies in humans indicate that the prevalence of aggressive and antisocial behavior in adults with the low-level MAO-A variant is affected by their history of stress during childhood, so personal history and gene–environment interaction studies with the mutant mice would contribute to a more comprehensive understanding of the pathophysiology of aggression and antisocial behavior."
Explore further: Researchers uncover brain molecule regulating human emotion, mood
More information: Kabayama, M., Sakoori, K., Yamada, K., Ornthanalai, V. G., Ota, M., Morimura, N., Katayama, K., Murphy, N. P. & Aruga, J. Rines E3 ubiquitin ligase regulates MAO-A levels and emotional responses, The Journal of Neuroscience 33, 12940–12953 (2013). dx.doi.org/10.1523/JNEUROSCI.5717-12.2013
Medical Xpress on facebook
Related Stories
Researchers uncover brain molecule regulating human emotion, mood
Aug 06, 2013
A RIKEN research team has discovered an enzyme called Rines that regulates MAO-A, a major brain protein controlling emotion and mood. The enzyme is a potentially promising drug target for treating diseases ...
Fear factor: Missing brain enzyme leads to abnormal levels of fear in mice
Jul 15, 2013
A little bit of learned fear is a good thing, keeping us from making risky, stupid decisions or falling over and over again into the same trap. But new research from neuroscientists and molecular biologists at USC shows that ...
Hulk smash? Maybe not anymore: scientists block excess aggression in mice
Jun 19, 2012
Pathological rage can be blocked in mice, researchers have found, suggesting potential new treatments for severe aggression, a widespread trait characterized by sudden violence, explosive outbursts and hostile overreactions ...
High levels of a specific enzyme in fetuses linked to anxiety
Jul 24, 2013
Mouse embryos with the human enzyme CYP2C19 in the brain develop a smaller hippocampus and anxiety-like behaviour as adults. The results of this new study, which is published in the journal Molecular Psychiatry, agree in pri ...
Proteins linked to longevity may be involved in mood control
Dec 09, 2011
(Medical Xpress) -- Over the past decade, MIT biologist Leonard Guarente and others have shown that very-low-calorie diets provoke a comprehensive physiological response that promotes survival, all orchestrated by a set of ...
Recommended for you
New hope for premature babies at risk of brain damage
1 hour ago
(Medical Xpress)—Babies who suffer a bleed on their brain could be saved from debilitating brain damage after researchers at the University of Birmingham found that a new drug can prevent the swelling of the organ which ...
New exercise guidelines developed for people with MS
2 hours ago
According to new research out of Queen's University, an active lifestyle has many benefits for adults living with multiple sclerosis. Based on that research, Amy Latimer-Cheung (School of Kinesiology and Health Studies) has ...
New theory of synapse formation in the brain
16 hours ago
The human brain keeps changing throughout a person's lifetime. New connections are continually created while synapses that are no longer in use degenerate. To date, little is known about the mechanisms behind ...
Nobel Prize winner reports new model for neurotransmitter release
21 hours ago
In a Neuron article published online October 10th, recent Nobel Laureate Thomas C. Südhof challenges long-standing ideas on how neurotransmitter gets released at neuronal synapses. On October 7th, Südho ...
We may make mistakes interpreting the emotions of others, but our brain can corrects us
23 hours ago
When we are sad the world seemingly cries with us. On the contrary, when we are happy everything shines and all around people's faces seem to rejoyce with us. These projection mechanisms of one's emotions onto others are ...
Maintenance mechanism that prevents stem cells aging discovered
Oct 10, 2013
A team of researchers at the Molecular Neurobiology Unit of the University of Valencia, led by Professor of Cell Biology Isabel Fariñas, just published in the journal Nature Neuroscience, the results of a research that m ...
User comments
© Medical Xpress 2011-2013, Phys.org network
0 comments:
Post a Comment