Die Therapie mit SSRIs setzt ein einheitliches Serotonin-System voraus.
Neueste Forschungsergebnisse zeigen, warum schwere Nebenwirkungen bei dieser Medikamentengruppe auftreten.
Besonders bei geriatrischen Patienten muss die Indikation für eine Medikation mit SSRIs sehr streng gestellt werden.
AUGUST 23, 2018
Stanford scientists paint nuanced picture of brain system regulating moods, movements
New findings reveal that the brain’s serotonin system – which regulates everything from our moods to our movements – is made up of multiple parallel pathways that affect the brain in different, and sometimes opposing, ways.
BY KER THAN
As Liqun Luo was writing his introductory textbook on neuroscience in 2012, he found himself in a quandary. He needed to include a section about a vital system in the brain controlled by the chemical messenger serotonin, which has been implicated in everything from mood to movement regulation. But the research was still far from clear on what effect serotonin has on the mammalian brain.
A 3D rendering of the serotonin system in the left hemisphere of the mouse brain reveals two groups of serotonin neurons in the dorsal raphe that project to either cortical regions (blue) or subcortical regions (green) while rarely crossing into the other’s domain. (Image credit: Jing Ren)
“Scientists were reporting divergent findings,” said Luo, who is the Ann and Bill Swindells Professor in the School of Humanities and Sciences at Stanford University. “Some found that serotonin promotes pleasure. Another group said that it increases anxiety while suppressing locomotion, while others argued the opposite.”
Fast forward six years, and Luo’s team thinks it has reconciled those earlier confounding results. Using neuroanatomical methods that they invented, his group showed that the serotonin system is actually composed of at least two, and likely more, parallel subsystems that work in concert to affect the brain in different, and sometimes opposing, ways. For instance, one subsystem promotes anxiety, whereas the other promotes active coping in the face of challenges.
“The field’s understanding of the serotonin system was like the story of the blind men touching the elephant,” Luo said. “Scientists were discovering distinct functions of serotonin in the brain and attributing them to a monolithic serotonin system, which at least partly accounts for the controversy about what serotonin actually does. This study allows us to see different parts of the elephant at the same time.”
The findings, published online on August 23 in the journal Cell, could have implications for the treatment of depression and anxiety, which involves prescribing drugs such as Prozac that target the serotonin system – so-called SSRIs (selective serotonin reuptake inhibitors). However, these drugs often trigger a host of side effects, some of which are so intolerable that patients stop taking them.
“If we can target the relevant pathways of the serotonin system individually, then we may be able to eliminate the unwanted side effects and treat only the disorder,” said study first author Jing Ren, a postdoctoral fellow in Luo’s lab.
Organized projections of neurons
The Stanford scientists focused on a region of the brainstem known as the dorsal raphe, which contains the largest single concentration in the mammalian brain of neurons that all transmit signals by releasing serotonin (about 9,000).
The nerve fibers, or axons, of these dorsal raphe neurons send out a sprawling network of connections to many critical forebrain areas that carry out a host of functions, including thinking, memory, and the regulation of moods and bodily functions. By injecting viruses that infect serotonin axons in these regions, Ren and her colleagues were able to trace the connections back to their origin neurons in the dorsal raphe.
This allowed them to create a visual map of projections between the dense concentration of serotonin-releasing neurons in the brainstem to the various regions of the forebrain that they influence. The map revealed two distinct groups of serotonin-releasing neurons in the dorsal raphe, which connected to cortical and subcortical regions in the brain.
“Serotonin neurons in the dorsal raphe project to a bunch of places throughout the brain, but those bunches of places are organized,” Luo said. “That wasn’t known before.”
Two parts of the elephant
In a series of behavioral tests, the scientists also showed that serotonin neurons from the two groups can respond differently to stimuli. For example, neurons in both groups fired in response to mice receiving rewards like sips of sugar water but they showed opposite responses to punishments like mild foot shocks.
“We now understand why some scientists thought serotonin neurons are activated by punishment, while others thought it was inhibited by punishment. Both are correct – it just depends on which subtype you’re looking at,” Luo said.
What’s more, the group found that the serotonin neurons themselves were more complex than originally thought. Rather than just transmitting messages with serotonin, the cortical-projecting neurons also released a chemical messenger called glutamate – making them one of the few known examples of neurons in the brain that release two different chemicals.
“It raises the question of whether we should even be calling these serotonin neurons because neurons are named after the neurotransmitters they release,” Ren said.
Taken together, these findings indicate that the brain’s serotonin system is not made up of a homogenous population of neurons but rather many subpopulations acting in concert. Luo’s team has identified two groups, but there could be many others.
In fact, Robert Malenka, a professor and associate chair of psychiatry and behavioral sciences at Stanford’s School of Medicine, and his team recently discovered a group of serotonin neurons in the dorsal raphe that project to the nucleus accumbens, the part of the brain that promotes social behaviors.
“The two groups that we found don’t send axons to the nucleus accumbens, so this is clearly a third group,” Luo said. “We identified two parts of the elephant, but there are more parts to discover.”
Luo is also an investigator at the Howard Hughes Medical Institute in Maryland and a member of Stanford Bio-X, the Stanford Cancer Institute, and the Stanford Neurosciences Institute. Other Stanford coauthors on the study include Drew Friedmann, Jing Xiong, Cindy Liu, Brielle Ferguson, Tanya Weerakkody, Katherine DeLoach, Chen Ran, Albert Pun, Yanwen Sun, Brandon Weissbourd, John Huguenard, and Mark Horowitz.
The research was supported by BRAIN initiative grants from the National Institutes of Health and National Science Foundation.
Neurons in the brain that produce the pleasure-signaling neurotransmitter dopamine also directly control the brain’s circadian center, or „body clock“ – the area that regulates eating cycles, metabolism and waking/resting cycles – a key link that possibly affects the body’s ability to adapt to jet lag and rotating shift work, a new University of Virginia study has demonstrated.
The finding is reported in today’s online edition of the journal Current Biology.
„This discovery, which identifies a direct dopamine neuron connection to the circadian center, is possibly the first step toward the development of unique drugs, targeting specific neurons, to combat the unpleasant symptoms of jet-lag and shiftwork, as well as several dangerous pathologies,“ said Ali Deniz Güler, a UVA professor of biology and neuroscience who oversaw the study in his lab.
Modern society often places abnormal pressure on the human body—from shifting time schedules due to air travel, to work cycles that don’t conform to natural light, to odd eating times—and these external conditions create an imbalance in the body’s natural cycles, which are evolutionarily synchronized to day and night. These imbalances may contribute to depression, obesity, cardiovascular diseases and even cancer.
„Scientists have been working for decades to help the body’s circadian system readily re-synchronize to variable work and eating schedules and flights across multiple time zones,“ Güler said. „Finding this connection between dopamine-producing neurons and the circadian center allows us to target these neurons with therapies that could potentially provide relief of symptoms for travelers and shift workers particularly, and possibly people with insomnia.“
Sleep disorders and abnormal circadian rhythms affecting the brain and other organs can worsen many pathologies involving aberrant dopamine neurotransmission, Güler said, including Parkinson’s disease, depression, attention deficit/hyperactivity disorder, bipolar disorder, schizophrenia and drug addiction.
„New understanding of dopamine-producing neurons and the connection to the body’s biorhythms may go a long way toward treatments to alleviate the harmful effects of these serious pathologies,“ Güler said.
Güler’s laboratory specializes in identifying neural circuits that govern biological rhythms in the brain, providing unique therapeutic targets for a range of diseases. Ph.D. candidate Ryan Grippo, Güler’s graduate student, led the Current Biology study.
The researchers used two types of mice in their investigation: one normal, the other with dopamine signaling disrupted. By shifting the light schedules of the two groups by six hours, a jet-lag effect, they found that the dopamine-disrupted animals took much longer to resynchronize to the six-hour time shift, indicating feedback between the dopamine neurons and the circadian center.
„This shows that when we engage in rewarding activities like eating, we are inadvertently affecting our biological rhythms,“ Güler said. „We may have found the missing link to how pleasurable things and the circadian system influence one another.“
More information: Current Biology (2017). DOI: 10.1016/j.cub.2017.06.084
TORC1 ist ein Proteinkomplex, der mTOR und einige andere assoziierte Proteine mit einschließt. Dieser Komplex fungiert in der Zelle als Sensor für den Status von Nährstoffen, oxidativem Stress und Energie. Kontrolliert wird dieser Komplex durch Insulin, Wachstumshormone, oxidativem Stress und Aminosäuren, hier besonders durch Leucin.
Ein aktiviertes TORC1 aktiviert seinerseits die Proteinbiosynthese. Um eine Zelle wachsen zu lassen, müssen eine Reihe von Ressourcen für die Proteinbiosynthese vorhanden sein, wie genug zelluläre Energie in Form von ATP, Sauerstoff, Nährstoffe, die richtigen Wachstumsfaktoren und so weiter. mTOR ist ebenfalls ein Protein, das eine Reihe von Aktivitäten der Zelle reguliert, wie das Zellwachstum, Zellteilung, Zellmotilität, das Überleben der Zelle, Proteinbiosynthese und Transkription bei der Biosynthese.
Wenn also aufgrund der anspruchsvollen Anforderungen für die Aktivierung von TORC1 – ATP, Sauerstoff, Nährstoffe, die richtigen Wachstumsfaktoren und so weiter – ein Faktor fehlt, dann bleibt die Aktivierung von TORC1 aus. Und das genau geschieht beim Fehlen von Nährstoffen wie sie mit einer Kalorienrestriktion einhergehen.
Das Mikrobiom des Menschen ist essentiell für Gesundheit und Wohlbefinden. Störungen durch Konservierungsmittel in Kosmetika und Geräte, die die Hautbarriere schädigen, sind Ursache für chronische Hauterkrankungen.
‚Cutaneous microbiome composition in neonatal life is crucial in shaping adaptive immune responses to skin surface microbiome, and disrupting these interactions by frequent bathing might have enduring health implication.
As infants contact environmental microbiota and as different areas of the skin develop distinct moisture, temperature, and glandular characteristics, individual skin habitats arise with divergent, increasingly diverse microbiota.
These habitats then continue to transform with puberty, aging, and environmental exposures. The skin is a site of constant dialog between the immune system and skin surface flora (microbiome).‘ Florence Barrett-Hill!