Neuroscience

Articles and news from the latest research reports.

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Depressed? Researchers identify new anti-depressant mechanisms, therapeutic approaches
Researchers at UT Southwestern Medical Center are making breakthroughs that could benefit people suffering from depression.
A team of physician-scientists at UT Southwestern has identified a major mechanism by which ghrelin (a hormone with natural anti-depressant properties) works inside the brain. Simultaneously, the researchers identified a potentially powerful new treatment for depression in the form of a neuroprotective drug known as P7C3.
The study, published online in April’s issue of Molecular Psychiatry, is notable because although a number of anti-depressant drugs and other treatments are available, an estimated one in 10 adults in the U.S. still report depression, according to the Centers for Disease Control and Prevention.
"By investigating the way the so-called ‘hunger hormone’ ghrelin works to limit the extent of depression following long-term exposure to stress, we discovered what could become a brand new class of anti-depressant drugs," said Dr. Jeffrey Zigman, Associate Professor of Internal Medicine and Psychiatry at UT Southwestern, and co-senior author of the study.
Ghrelin, a hormone produced in the stomach and intestines, has several widely known functions, including the ability to stimulate appetite. The latest research builds on a 2008 study led by Dr. Zigman, in which the team discovered that ghrelin exhibited natural anti-depressant effects that manifest when its levels rise as a result of caloric restriction or prolonged psychological stress.
The current findings identify ghrelin’s ability to stimulate adult hippocampal neurogenesis, the formation of new neurons, in animal models. In addition, Dr. Zigman and his colleagues also found that the regenerative process inside the hippocampus – a region of the brain that regulates mood, memory, and complex eating behaviors – is crucial in limiting the severity of depression following prolonged exposure to stress.
"After identifying the mechanism of ghrelin’s anti-depressant actions, we investigated whether increasing this ghrelin effect by directly enhancing hippocampal neurogenesis with the recently reported P7C3 class of neuroprotective compounds would result in even greater anti-depressant behavioral effects," Dr. Zigman said.
The P7C3 compounds were discovered in 2010 by a team of UT Southwestern researchers led by Dr. Steven McKnight, Chair of Biochemistry, Dr. Joseph Ready, Professor of Biochemistry, and Dr. Andrew Pieper, a former UT Southwestern faculty member and co-senior author of the current study. Previous research demonstrated P7C3’s promising neuroprotective abilities in instances of Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and traumatic brain injury. Today, researchers hope that it can have a transformative impact on depression treatment too.
"We found that P7C3 exerted a potent anti-depressant effect via its neurogenesis-promoting properties," said Dr. Pieper, who is now Associate Professor of Neurology and Psychiatry at the University of Iowa Carver College of Medicine. "Also exciting, a highly active P7C3 analog was able to quickly enhance neurogenesis to a much greater level than a wide spectrum of currently marketed anti-depressant drugs."
Based on the study’s behavioral findings, researchers believe that individuals with depression associated with chronic stress or with altered ghrelin levels or ghrelin resistance, as has been described or theorized for conditions such as obesity and anorexia nervosa, might be particularly responsive to treatment with highly neuroprotective drugs, such as the P7C3 compounds.
Future studies will examine the ability to apply these findings to other forms of depression, including the possibility of developing clinical trials aimed at identifying whether or not P7C3 compounds have anti-depressant effects in people with major depression, as predicted. The three main types of depressive disorders include major depression, dysthymia, and bipolar disorder.

Depressed? Researchers identify new anti-depressant mechanisms, therapeutic approaches

Researchers at UT Southwestern Medical Center are making breakthroughs that could benefit people suffering from depression.

A team of physician-scientists at UT Southwestern has identified a major mechanism by which ghrelin (a hormone with natural anti-depressant properties) works inside the brain. Simultaneously, the researchers identified a potentially powerful new treatment for depression in the form of a neuroprotective drug known as P7C3.

The study, published online in April’s issue of Molecular Psychiatry, is notable because although a number of anti-depressant drugs and other treatments are available, an estimated one in 10 adults in the U.S. still report depression, according to the Centers for Disease Control and Prevention.

"By investigating the way the so-called ‘hunger hormone’ ghrelin works to limit the extent of depression following long-term exposure to stress, we discovered what could become a brand new class of anti-depressant drugs," said Dr. Jeffrey Zigman, Associate Professor of Internal Medicine and Psychiatry at UT Southwestern, and co-senior author of the study.

Ghrelin, a hormone produced in the stomach and intestines, has several widely known functions, including the ability to stimulate appetite. The latest research builds on a 2008 study led by Dr. Zigman, in which the team discovered that ghrelin exhibited natural anti-depressant effects that manifest when its levels rise as a result of caloric restriction or prolonged psychological stress.

The current findings identify ghrelin’s ability to stimulate adult hippocampal neurogenesis, the formation of new neurons, in animal models. In addition, Dr. Zigman and his colleagues also found that the regenerative process inside the hippocampus – a region of the brain that regulates mood, memory, and complex eating behaviors – is crucial in limiting the severity of depression following prolonged exposure to stress.

"After identifying the mechanism of ghrelin’s anti-depressant actions, we investigated whether increasing this ghrelin effect by directly enhancing hippocampal neurogenesis with the recently reported P7C3 class of neuroprotective compounds would result in even greater anti-depressant behavioral effects," Dr. Zigman said.

The P7C3 compounds were discovered in 2010 by a team of UT Southwestern researchers led by Dr. Steven McKnight, Chair of Biochemistry, Dr. Joseph Ready, Professor of Biochemistry, and Dr. Andrew Pieper, a former UT Southwestern faculty member and co-senior author of the current study. Previous research demonstrated P7C3’s promising neuroprotective abilities in instances of Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and traumatic brain injury. Today, researchers hope that it can have a transformative impact on depression treatment too.

"We found that P7C3 exerted a potent anti-depressant effect via its neurogenesis-promoting properties," said Dr. Pieper, who is now Associate Professor of Neurology and Psychiatry at the University of Iowa Carver College of Medicine. "Also exciting, a highly active P7C3 analog was able to quickly enhance neurogenesis to a much greater level than a wide spectrum of currently marketed anti-depressant drugs."

Based on the study’s behavioral findings, researchers believe that individuals with depression associated with chronic stress or with altered ghrelin levels or ghrelin resistance, as has been described or theorized for conditions such as obesity and anorexia nervosa, might be particularly responsive to treatment with highly neuroprotective drugs, such as the P7C3 compounds.

Future studies will examine the ability to apply these findings to other forms of depression, including the possibility of developing clinical trials aimed at identifying whether or not P7C3 compounds have anti-depressant effects in people with major depression, as predicted. The three main types of depressive disorders include major depression, dysthymia, and bipolar disorder.

Filed under depression ghrelin P7C3 neurogenesis antidepressants neuroscience science

108 notes

Sleep disorder linked to brain disease

Researchers at the University of Toronto say a sleep disorder that causes people to act out their dreams is the best current predictor of brain diseases like Parkinson’s and many other forms of dementia.

image

"Rapid-eye-movement sleep behaviour disorder (RBD) is not just a precursor but also a critical warning sign of neurodegeneration that can lead to brain disease," says associate professor and lead author Dr. John Peever. In fact, as many as 80 to 90 per cent of people with RBD will develop a brain disease."

As the name suggests, the disturbance occurs during the rapid-eye-movement (REM) stage of sleep and causes people to act out their dreams, often resulting in injury to themselves and/or bed partner. In healthy brains, muscles are temporarily paralyzed during sleep to prevent this from happening.

"It’s important for clinicians to recognize RBD as a potential indication of brain disease in order to diagnose patients at an earlier stage," says Peever. "This is important because drugs that reduce neurodegeneration could be used in RBD patients to prevent (or protect) them from developing more severe degenerative disorders."

His research examines the idea that neurodegeneration might first affect areas of the brain that control sleep before attacking brain areas that cause more common brain diseases like Alzheimer’s.

Peever says he hopes the results of his study lead to earlier and more effective treatment of neurodegenerative diseases.

(Source: eurekalert.org)

Filed under sleep disorders REM sleep behavior disorder neurodegeneration neuroscience science

99 notes

(Image caption: Adult neurons are seen without (top) and following (below) treatment to inactivate Rb. Following treatment, the neurons show an increase in growth (branching) of axons. Credit: Bhagat Singh)
Scientists discover a new way to enhance nerve growth following injury
New research published today by researchers at the University of Calgary’s Hotchkiss Brain Institute uncovers a mechanism to promote growth in damaged nerve cells.
Dr. Doug Zochodne, a professor in the Department of Clinical Neurosciences, and his team have discovered a key molecule that directly regulates nerve cell growth in the damaged nervous system. This surprising discovery was published in the prestigious journal Nature Communications, with lead authors Kim Christie and Anand Krishnan.
“We have discovered that a protein called Retinoblastoma (Rb) is present in adult neurons,” explains Zochodne. “This protein appears to normally act as a brake – preventing nerve growth. What we have shown is that by inactivating Rb, we can release the brake and coax nerves to grow much faster.”
Clues from cancer
Zochodne and his team decided to look for Rb in nerve cells because of its known role in regulating cell growth elsewhere in the body.
“We know that cancer is characterized by excessive cell growth and we also know that Rb is often functioning abnormally in cancer,” says Zochodne. “So if cancer is able to release this brake and increase cell growth, we thought we’d try to mimic this same action in nerve cells and encourage growth where we want it.”
The key to this methodology, as Zochodne explains, is shutting down the brake for a very short, controlled period of time in order to avoid adverse effects such as excessive cell growth that could lead to cancer.
“In our tests, we were able to do this for a short amount of time,” says Zochodne. “We didn’t see any negative results, which leaves us optimistic that this could one day be used as a safe treatment for patients suffering from nerve damage.”
Peripheral nerve injuries and illnesses  
So far, Zochodne is only investigating this technique in the peripheral nervous system. Peripheral nerves connect the brain and spinal cord to the body and without them, there is no movement or sensation. Peripheral nerve damage can be incredibly debilitating, with patients experiencing symptoms like pain, tingling, numbness or difficulty co-ordinating hands, feet, arms or legs.
As Zochodne explains, “peripheral nerve damage is surprisingly common. We see patients with cut or crushed nerves from motor vehicle accidents and we also see patients that suffer from conditions called neuropathies – a range of disorders that damage peripheral nerves.”
For example, diabetic neuropathy is more common than multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) combined. More than half of all diabetics have some form of nerve pain and currently there is no treatment to stop damage or reverse it.
Facility a one-stop shop for translating discoveries from the lab into the clinic
Developing safe and effective therapies for conditions such as peripheral nerve disorders requires the ability to take investigations from cells in a petri dish to patients in a clinic. Zochodne and his team have been able to do that thanks in part to a preclinical facility that opened at the Hotchkiss Brain Institute (HBI) in 2010. The Regeneration Unit in Neurobiology (RUN) was created through a partnership between the HBI, the University of Calgary and the Canada-Alberta Western Economic Partnership Agreement. “The RUN facility has been critical for this research,” says Zochodne. “It provides the resources and cutting-edge equipment that we need all in one facility. RUN has allowed us to take this idea from nerve cells, to animal models and eventually will help us investigate whether it could be a feasible treatment in humans. It’s an incredible asset.”

(Image caption: Adult neurons are seen without (top) and following (below) treatment to inactivate Rb. Following treatment, the neurons show an increase in growth (branching) of axons. Credit: Bhagat Singh)

Scientists discover a new way to enhance nerve growth following injury

New research published today by researchers at the University of Calgary’s Hotchkiss Brain Institute uncovers a mechanism to promote growth in damaged nerve cells.

Dr. Doug Zochodne, a professor in the Department of Clinical Neurosciences, and his team have discovered a key molecule that directly regulates nerve cell growth in the damaged nervous system. This surprising discovery was published in the prestigious journal Nature Communications, with lead authors Kim Christie and Anand Krishnan.

“We have discovered that a protein called Retinoblastoma (Rb) is present in adult neurons,” explains Zochodne. “This protein appears to normally act as a brake – preventing nerve growth. What we have shown is that by inactivating Rb, we can release the brake and coax nerves to grow much faster.”

Clues from cancer

Zochodne and his team decided to look for Rb in nerve cells because of its known role in regulating cell growth elsewhere in the body.

“We know that cancer is characterized by excessive cell growth and we also know that Rb is often functioning abnormally in cancer,” says Zochodne. “So if cancer is able to release this brake and increase cell growth, we thought we’d try to mimic this same action in nerve cells and encourage growth where we want it.”

The key to this methodology, as Zochodne explains, is shutting down the brake for a very short, controlled period of time in order to avoid adverse effects such as excessive cell growth that could lead to cancer.

“In our tests, we were able to do this for a short amount of time,” says Zochodne. “We didn’t see any negative results, which leaves us optimistic that this could one day be used as a safe treatment for patients suffering from nerve damage.”

Peripheral nerve injuries and illnesses  

So far, Zochodne is only investigating this technique in the peripheral nervous system. Peripheral nerves connect the brain and spinal cord to the body and without them, there is no movement or sensation. Peripheral nerve damage can be incredibly debilitating, with patients experiencing symptoms like pain, tingling, numbness or difficulty co-ordinating hands, feet, arms or legs.

As Zochodne explains, “peripheral nerve damage is surprisingly common. We see patients with cut or crushed nerves from motor vehicle accidents and we also see patients that suffer from conditions called neuropathies – a range of disorders that damage peripheral nerves.”

For example, diabetic neuropathy is more common than multiple sclerosis, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) combined. More than half of all diabetics have some form of nerve pain and currently there is no treatment to stop damage or reverse it.

Facility a one-stop shop for translating discoveries from the lab into the clinic

Developing safe and effective therapies for conditions such as peripheral nerve disorders requires the ability to take investigations from cells in a petri dish to patients in a clinic. Zochodne and his team have been able to do that thanks in part to a preclinical facility that opened at the Hotchkiss Brain Institute (HBI) in 2010. The Regeneration Unit in Neurobiology (RUN) was created through a partnership between the HBI, the University of Calgary and the Canada-Alberta Western Economic Partnership Agreement.
 
“The RUN facility has been critical for this research,” says Zochodne. “It provides the resources and cutting-edge equipment that we need all in one facility. RUN has allowed us to take this idea from nerve cells, to animal models and eventually will help us investigate whether it could be a feasible treatment in humans. It’s an incredible asset.”

Filed under retinoblastoma neurons nerve regeneration nerve cells neuroscience science

116 notes

Researchers report first findings of virtual reality exposure therapy for veterans with PTSD
A randomized controlled clinical trial of Iraq and Afghanistan veterans with post-traumatic stress disorder (PTSD) found that shorter doses of virtual reality exposure therapy (VRE) reduces PTSD diagnoses and symptoms. The study was published in the April 18, 2014 online edition of the American Journal of Psychiatry.
Researchers at Emory University conducted the study with 156 veterans with combat-related PTSD. After an introductory session, each veteran was randomly assigned to receive d-cycloserine (DCS) (53 subjects), alprazolam (50 subjects), or a placebo (53 subjects) before each of five sessions of VRE.
The study found PTSD symptoms significantly improved from pre- to post-treatment with the VRE therapy and the DCS may enhance the VRE results for those veterans who demonstrated better emotional learning in sessions. In addition to self-reported symptoms, researchers used objective measures of cortisol, a stress hormone, and the startle response, and found reductions in reactivity after treatment. Alprazolam, known more commonly as Xanax, impaired recovery from symptoms.
"D-cycloserine, combined with only five sessions of the virtual reality exposure therapy, was associated with significant improvements in objective measures of startle and cortisol and overall PTSD symptoms for those who showed emotional learning in sessions," says lead researcher Barbara Rothbaum, PhD, professor of psychiatry and behavioral sciences at Emory University School of Medicine and director of the Trauma and Anxiety Recovery Program.
The double-blind, placebo-controlled study consisted of an initial screening assessment, six treatment visits, and follow-up assessments at three, six and 12 months post-treatment. The virtual reality exposure therapy involved 30-45 minutes of exposure to virtual environments on a head mounted video display that attempt to match stimuli described by the veteran. Scenes depict a variety of Iraq and Afghanistan environments, including street scenes and neighborhoods, as well as from different points of view, i.e. as a driver, passenger, or walking on foot. Thirty minutes before each session, participants took a single pill.
"We were very excited to see the substantial gains in self-reported and objective indices of PTSD with only five sessions of the virtual reality exposure therapy combined," says Rothbaum.

Researchers report first findings of virtual reality exposure therapy for veterans with PTSD

A randomized controlled clinical trial of Iraq and Afghanistan veterans with post-traumatic stress disorder (PTSD) found that shorter doses of virtual reality exposure therapy (VRE) reduces PTSD diagnoses and symptoms. The study was published in the April 18, 2014 online edition of the American Journal of Psychiatry.

Researchers at Emory University conducted the study with 156 veterans with combat-related PTSD. After an introductory session, each veteran was randomly assigned to receive d-cycloserine (DCS) (53 subjects), alprazolam (50 subjects), or a placebo (53 subjects) before each of five sessions of VRE.

The study found PTSD symptoms significantly improved from pre- to post-treatment with the VRE therapy and the DCS may enhance the VRE results for those veterans who demonstrated better emotional learning in sessions. In addition to self-reported symptoms, researchers used objective measures of cortisol, a stress hormone, and the startle response, and found reductions in reactivity after treatment. Alprazolam, known more commonly as Xanax, impaired recovery from symptoms.

"D-cycloserine, combined with only five sessions of the virtual reality exposure therapy, was associated with significant improvements in objective measures of startle and cortisol and overall PTSD symptoms for those who showed emotional learning in sessions," says lead researcher Barbara Rothbaum, PhD, professor of psychiatry and behavioral sciences at Emory University School of Medicine and director of the Trauma and Anxiety Recovery Program.

The double-blind, placebo-controlled study consisted of an initial screening assessment, six treatment visits, and follow-up assessments at three, six and 12 months post-treatment. The virtual reality exposure therapy involved 30-45 minutes of exposure to virtual environments on a head mounted video display that attempt to match stimuli described by the veteran. Scenes depict a variety of Iraq and Afghanistan environments, including street scenes and neighborhoods, as well as from different points of view, i.e. as a driver, passenger, or walking on foot. Thirty minutes before each session, participants took a single pill.

"We were very excited to see the substantial gains in self-reported and objective indices of PTSD with only five sessions of the virtual reality exposure therapy combined," says Rothbaum.

Filed under PTSD virtual reality virtual reality exposure therapy d-cycloserine alprazolam neuroscience science

144 notes

Life Stressors Trigger Neurological Disorders
When mothers are exposed to trauma, illness, alcohol or other drug abuse, these stressors may activate a single molecular trigger in brain cells that can go awry and activate conditions such as schizophrenia, post-traumatic stress disorder and some forms of autism.
Until now, it has been unclear how much these stressors have impacted the cells of a developing brain. Past studies have shown that when an expectant mother exposes herself to alcohol or drug abuse or she experiences some trauma or illness, her baby may later develop a psychiatric disorder, including some forms of autism or post-traumatic stress disorder, later in life. But the new findings, published online in Neuron, identifies a molecular mechanism in the prenatal brain that may help explain how cells go awry when exposed to certain environmental conditions.
Kazue Hasimoto-Torii, PhD, Principal Investigator of the Center for Neuroscience, Children’s National Health System, and a Scott-Gentle Foundation investigator, is lead author of the paper. Torii was previously at Yale, whose researchers were co-authors in the report. The research was funded primarily through National Institutes of Health grants.
Researchers found that mouse embryos exposed to alcohol, methyl-mercury, or maternal seizures activate a single gene, HSF1, also known as heat shock factor, in cerebral cortex. The HSF1 “plays a crucial role in the response of brain cells to prenatal environmental insults,” the researchers reported. “The gene protects and enables brain cells to survive prenatal assaults. Mice lacking the HSF1 gene showed structural brain abnormalities and were prone to seizures after birth following exposures to very low levels of toxins.”
Even in mice where the HSF1 gene was properly activated to combat environmental insults, the molecular mechanism alone may permanently change how brain cells respond, and may be a reason why someone may be more susceptible to neuropsychiatric disorders later in life.
Innovative work with stem cells also provided findings that supported the theory that stress induces vulnerable cells to malfunction, the researchers reported. For the study, researchers created stem cells from biopsies of people diagnosed with schizophrenia. Stem cells are capable of becoming many different tissue types, including neurons. In the study, genes from the stem cells of those with schizophrenia responded more dramatically when exposed to environmental insults than stem cells from non-schizophrenic individuals.
While it has been generally accepted that exposure to harmful environmental factors increase the susceptibility of the brain to neurological and psychiatric disorders, new types of environmental agents are continuingly added to the mix, requiring evolving studies, Hasimoto-Torii says.
Hashimoto-Torii notes that autism rates have increased substantially and “more people are having these exposures to environmental stressors,” she says. While there have been many studies that have identified singular stressors, such as alcohol, there have not been enough studies to focus on many different environmental factors and their impacts, such as heavy metals as well as alcohol and other toxic exposure, she adds.
Identifying many risk factors helped Hashimoto-Torii and other researchers identify the gene that may be linked to neurological problems. “Different stressors may have different stress responses,” she says. She examined risk factors specifically involving epilepsy, ADHD, autism and schizophrenia. Eventually, it may open the door “to provide therapy in the future to reduce the risk” and protect vulnerable cells.

Life Stressors Trigger Neurological Disorders

When mothers are exposed to trauma, illness, alcohol or other drug abuse, these stressors may activate a single molecular trigger in brain cells that can go awry and activate conditions such as schizophrenia, post-traumatic stress disorder and some forms of autism.

Until now, it has been unclear how much these stressors have impacted the cells of a developing brain. Past studies have shown that when an expectant mother exposes herself to alcohol or drug abuse or she experiences some trauma or illness, her baby may later develop a psychiatric disorder, including some forms of autism or post-traumatic stress disorder, later in life. But the new findings, published online in Neuron, identifies a molecular mechanism in the prenatal brain that may help explain how cells go awry when exposed to certain environmental conditions.

Kazue Hasimoto-Torii, PhD, Principal Investigator of the Center for Neuroscience, Children’s National Health System, and a Scott-Gentle Foundation investigator, is lead author of the paper. Torii was previously at Yale, whose researchers were co-authors in the report. The research was funded primarily through National Institutes of Health grants.

Researchers found that mouse embryos exposed to alcohol, methyl-mercury, or maternal seizures activate a single gene, HSF1, also known as heat shock factor, in cerebral cortex. The HSF1 “plays a crucial role in the response of brain cells to prenatal environmental insults,” the researchers reported. “The gene protects and enables brain cells to survive prenatal assaults. Mice lacking the HSF1 gene showed structural brain abnormalities and were prone to seizures after birth following exposures to very low levels of toxins.”

Even in mice where the HSF1 gene was properly activated to combat environmental insults, the molecular mechanism alone may permanently change how brain cells respond, and may be a reason why someone may be more susceptible to neuropsychiatric disorders later in life.

Innovative work with stem cells also provided findings that supported the theory that stress induces vulnerable cells to malfunction, the researchers reported. For the study, researchers created stem cells from biopsies of people diagnosed with schizophrenia. Stem cells are capable of becoming many different tissue types, including neurons. In the study, genes from the stem cells of those with schizophrenia responded more dramatically when exposed to environmental insults than stem cells from non-schizophrenic individuals.

While it has been generally accepted that exposure to harmful environmental factors increase the susceptibility of the brain to neurological and psychiatric disorders, new types of environmental agents are continuingly added to the mix, requiring evolving studies, Hasimoto-Torii says.

Hashimoto-Torii notes that autism rates have increased substantially and “more people are having these exposures to environmental stressors,” she says. While there have been many studies that have identified singular stressors, such as alcohol, there have not been enough studies to focus on many different environmental factors and their impacts, such as heavy metals as well as alcohol and other toxic exposure, she adds.

Identifying many risk factors helped Hashimoto-Torii and other researchers identify the gene that may be linked to neurological problems. “Different stressors may have different stress responses,” she says. She examined risk factors specifically involving epilepsy, ADHD, autism and schizophrenia. Eventually, it may open the door “to provide therapy in the future to reduce the risk” and protect vulnerable cells.

Filed under neurological disorders psychiatric disorders cerebral cortex HSF1 environmental stressors brain development neuroscience science

62 notes

Neuroimaging: Live from inside the cell
A novel imaging technique provides insights into the role of redox signaling and reactive oxygen species in living neurons, in real time. Scientists of the Technische Universität München (TUM) and the Ludwig-Maximilians-Universität München (LMU) have developed a new optical microscopy technique to unravel the role of “oxidative stress” in healthy as well as injured nervous systems. The work is reported in the latest issue of Nature Medicine.
Reactive oxygen species are important intracellular signaling molecules, but their mode of action is complex: In low concentrations they regulate key aspects of cellular function and behavior, while at high concentrations they can cause “oxidative stress”, which damages organelles, membranes and DNA. To analyze how redox signaling unfolds in single cells and organelles in real-time, an innovative optical microscopy technique has been developed jointly by the teams of LMU Professor Martin Kerschensteiner and TUM Professor Thomas Misgeld, both investigators of the Munich Cluster for Systems Neurology (SyNergy).
“Our new optical approach allows us to visualize the redox state of important cellular organelles, mitochondria, in real time in living tissue” Kerschensteiner says. Mitochondria are the cell’s power plants, which convert nutrients into usable energy. In earlier studies, Kerschensteiner and Misgeld had obtained evidence that oxidative damage of mitochondria might contribute to the destruction of axons in inflammatory diseases such as multiple sclerosis.
The new method allows them to record the oxidation states of individual mitochondria with high spatial and temporal resolution. Kerschensteiner explains the motivation behind the development of the technique: “Redox signals have important physiological functions, but can also cause damage, for example when present in high concentrations around immune cells.”
First surprisesKerschensteiner and Misgeld used redox-sensitive variants of the Green Fluorescent Protein (GFP) as visualization tools. “By combining these with other biosensors and vital dyes, we were able to establish an approach that permits us to simultaneously monitor redox signals together with mitochondrial calcium currents, as well as changes in the electrical potential and the proton (pH) gradient across the mitochondrial membrane,” says Thomas Misgeld.
The researchers have applied the technique to two experimental models, and have arrived at some unexpected insights. On the one hand, they have been able, for the first time, to study redox signal induction in response to neural damage – in this case, spinal cord injury –  in the mammalian nervous system. The observations revealed that severance of an axon results in a wave of oxidation of the mitochondria, which begins at the site of damage and is propagated along the fiber. Furthermore, an influx of calcium at the site of axonal resection was shown to be essential for the ensuing functional damage to mitochondria.
Perhaps the most surprising outcome of the new study was that the study’s first author, graduate student Michael Breckwoldt, was able to image, also for the first time, spontaneous contractions of mitochondria that are accompanied by a rapid shift in the redox state of the organelle. As Misgeld explains, “This appears to be a fail-safe system that is activated in response to stress and temporarily attenuates mitochondrial activity. Under pathological conditions, the contractions are more prolonged and may become irreversible, and this can ultimately result in irreparable damage to the nerve process.”

Neuroimaging: Live from inside the cell

A novel imaging technique provides insights into the role of redox signaling and reactive oxygen species in living neurons, in real time. Scientists of the Technische Universität München (TUM) and the Ludwig-Maximilians-Universität München (LMU) have developed a new optical microscopy technique to unravel the role of “oxidative stress” in healthy as well as injured nervous systems. The work is reported in the latest issue of Nature Medicine.

Reactive oxygen species are important intracellular signaling molecules, but their mode of action is complex: In low concentrations they regulate key aspects of cellular function and behavior, while at high concentrations they can cause “oxidative stress”, which damages organelles, membranes and DNA. To analyze how redox signaling unfolds in single cells and organelles in real-time, an innovative optical microscopy technique has been developed jointly by the teams of LMU Professor Martin Kerschensteiner and TUM Professor Thomas Misgeld, both investigators of the Munich Cluster for Systems Neurology (SyNergy).

“Our new optical approach allows us to visualize the redox state of important cellular organelles, mitochondria, in real time in living tissue” Kerschensteiner says. Mitochondria are the cell’s power plants, which convert nutrients into usable energy. In earlier studies, Kerschensteiner and Misgeld had obtained evidence that oxidative damage of mitochondria might contribute to the destruction of axons in inflammatory diseases such as multiple sclerosis.

The new method allows them to record the oxidation states of individual mitochondria with high spatial and temporal resolution. Kerschensteiner explains the motivation behind the development of the technique: “Redox signals have important physiological functions, but can also cause damage, for example when present in high concentrations around immune cells.”

First surprises
Kerschensteiner and Misgeld used redox-sensitive variants of the Green Fluorescent Protein (GFP) as visualization tools. “By combining these with other biosensors and vital dyes, we were able to establish an approach that permits us to simultaneously monitor redox signals together with mitochondrial calcium currents, as well as changes in the electrical potential and the proton (pH) gradient across the mitochondrial membrane,” says Thomas Misgeld.

The researchers have applied the technique to two experimental models, and have arrived at some unexpected insights. On the one hand, they have been able, for the first time, to study redox signal induction in response to neural damage – in this case, spinal cord injury – in the mammalian nervous system. The observations revealed that severance of an axon results in a wave of oxidation of the mitochondria, which begins at the site of damage and is propagated along the fiber. Furthermore, an influx of calcium at the site of axonal resection was shown to be essential for the ensuing functional damage to mitochondria.

Perhaps the most surprising outcome of the new study was that the study’s first author, graduate student Michael Breckwoldt, was able to image, also for the first time, spontaneous contractions of mitochondria that are accompanied by a rapid shift in the redox state of the organelle. As Misgeld explains, “This appears to be a fail-safe system that is activated in response to stress and temporarily attenuates mitochondrial activity. Under pathological conditions, the contractions are more prolonged and may become irreversible, and this can ultimately result in irreparable damage to the nerve process.”

Filed under oxidative stress microscopy neuroimaging mitochondria cells neuroscience science

76 notes

First brain images of African infants enable research into cognitive effects of nutrition
Brain activity of babies in developing countries could be monitored from birth to reveal the first signs of cognitive dysfunction, using a new technique piloted by a London-based university collaboration.
The cognitive function of infants can be visualised and tracked more quickly, more accurately and more cheaply using the method, called functional near infra-red spectroscopy (fNIRS), compared to the behavioural assessments Western regions have relied upon for decades.
Professor Clare Elwell, Professor of Medical Physics at University College London (UCL), said: “Brain activity soon after birth has barely been studied in low-income countries, because of the lack of transportable brain imaging facilities needed to do this at any reasonable scale. We have high hopes of building on these promising findings to develop functional near infra-red spectroscopy into an assessment tool for investigating cognitive function of infants who may be at risk of malnutrition or childhood diseases associated with low income settings.”
The pioneering study, published this week in Nature Scientific Reports, was performed by a collaboration of researchers from UCL; the London School of Hygiene and Tropical Medicine; the Babylab at Birkbeck, University of London; and the Medical Research Council unit in Gambia. It aimed to investigate the impact of nutrition in resource-poor regions on infant brain development, and was funded by the Bill and Melinda Gates Foundation.
Professor Clare Elwell (UCL Medical Physics & Bioengineering), said: “This is the first use of brain imaging methods to investigate localised brain activity in African infants.
"Until now, much of our understanding of brain development in low income countries has relied upon behavioural assessments which need careful cultural and linguistic translations to ensure they are accurate. Our technology, functional near infrared spectroscopy, can provide a more objective marker of brain activity."
For the studies in the Gambia, babies aged 4–8 months old were played sounds and shown videos of adults performing specific movements, such as playing ‘peek-a-boo’. The fNIRS system monitored changes in blood flow to the baby’s brain and showed that distinct brain regions responded to visual–social prompts, while others responded to auditory-social stimuli. Comparison of the results with those obtained from babies in the UK showed that the responses were similar in both groups.
fNIRS has previously been used to study brain development in UK infants and most recently to investigate early markers of autism during the first few months of life.
Professor Andrew Prentice (Medical Research Council International Nutrition Group, London School of Hygiene and Tropical Medicine) said: “Humans have evolved to survive and succeed on the basis of their large brain and intelligence, but nutritional deficits in early life can limit this success. In order to plan the best interventions to maximise brain function we need tools that can give us an early read out. fNIRS is showing great promise in this respect.”

First brain images of African infants enable research into cognitive effects of nutrition

Brain activity of babies in developing countries could be monitored from birth to reveal the first signs of cognitive dysfunction, using a new technique piloted by a London-based university collaboration.

The cognitive function of infants can be visualised and tracked more quickly, more accurately and more cheaply using the method, called functional near infra-red spectroscopy (fNIRS), compared to the behavioural assessments Western regions have relied upon for decades.

Professor Clare Elwell, Professor of Medical Physics at University College London (UCL), said: “Brain activity soon after birth has barely been studied in low-income countries, because of the lack of transportable brain imaging facilities needed to do this at any reasonable scale. We have high hopes of building on these promising findings to develop functional near infra-red spectroscopy into an assessment tool for investigating cognitive function of infants who may be at risk of malnutrition or childhood diseases associated with low income settings.”

The pioneering study, published this week in Nature Scientific Reports, was performed by a collaboration of researchers from UCL; the London School of Hygiene and Tropical Medicine; the Babylab at Birkbeck, University of London; and the Medical Research Council unit in Gambia. It aimed to investigate the impact of nutrition in resource-poor regions on infant brain development, and was funded by the Bill and Melinda Gates Foundation.

Professor Clare Elwell (UCL Medical Physics & Bioengineering), said: “This is the first use of brain imaging methods to investigate localised brain activity in African infants.

"Until now, much of our understanding of brain development in low income countries has relied upon behavioural assessments which need careful cultural and linguistic translations to ensure they are accurate. Our technology, functional near infrared spectroscopy, can provide a more objective marker of brain activity."

For the studies in the Gambia, babies aged 4–8 months old were played sounds and shown videos of adults performing specific movements, such as playing ‘peek-a-boo’. The fNIRS system monitored changes in blood flow to the baby’s brain and showed that distinct brain regions responded to visual–social prompts, while others responded to auditory-social stimuli. Comparison of the results with those obtained from babies in the UK showed that the responses were similar in both groups.

fNIRS has previously been used to study brain development in UK infants and most recently to investigate early markers of autism during the first few months of life.

Professor Andrew Prentice (Medical Research Council International Nutrition Group, London School of Hygiene and Tropical Medicine) said: “Humans have evolved to survive and succeed on the basis of their large brain and intelligence, but nutritional deficits in early life can limit this success. In order to plan the best interventions to maximise brain function we need tools that can give us an early read out. fNIRS is showing great promise in this respect.”

Filed under brain activity infants nutrition cognitive function cognition fNIRS neuroscience science

144 notes

Scientists Identify Critical New Protein Complex Involved in Learning and Memory
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a protein complex that plays a critical but previously unknown role in learning and memory formation.
The study, which showed a novel role for a protein known as RGS7, was published April 22, 2014 in the journal eLife, a publisher supported by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.
“This is a critical building block that regulates a fundamental process—memory,” said Kirill Martemyanov, a TSRI associate professor who led the study. “Now that we know about this important new player, it offers a unique therapeutic window if we can find a way to enhance its function.”
The team looked at RGS7 in the hippocampus, a small part of the brain that helps turn short-term memory in long-term memory.
The scientists found the RGS7 protein works in concert with another protein, R7BP, to regulate a key signaling cascade that is increasingly seen as a critical to cognitive development. The cascade involves the neurotransmitter GABA, which binds to the GABAb receptor and opens inhibitory channels known as GIRKs in the cell membrane. This process ultimately makes it more difficult for a nerve cell to fire.
This process turned out to be critical to normal functioning, as the research showed mice lacking RGS7 exhibited deficits in learning and memory.
Martemyanov believes the findings could ultimately have broad therapeutic application. “GIRK channels are implicated in a range of neuropsychiatric conditions, including drug addiction and Down’s syndrome, that result from a disproportionate increase in neuronal inhibition as a result of greater mobilization of these channels,” he said. “Now that we know the identity of the critical modulator of GIRK channels we can try to find a way to increase its power with the hopes of reducing the inhibitory overdrive, and that might potentially alleviate some of the  disruptions seen in Down’s syndrome. It is possible that similar strategies might apply for dealing with addiction, where adaptations in the GABAb-GIRK pathway play a significant role.”
Targeting the RGS7 protein could allow for better therapeutic outcomes with fewer side effects because it allows for fine tuning of the signaling, according to Olga Ostrovskaya, the first author of the study and a member of Martemyanov’s lab, who sees many ways to follow up on the findings.
“We’re looking into how RGS7 is involved in neural circuitry and functions tied to the striatum, another part of the brain responsible for procedural memory, mood disorders, motivation and addiction,” Ostrovskaya said. “We may uncover the RGS7 regulation of other signaling complexes that may be very different from those in hippocampus.”

Scientists Identify Critical New Protein Complex Involved in Learning and Memory

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a protein complex that plays a critical but previously unknown role in learning and memory formation.

The study, which showed a novel role for a protein known as RGS7, was published April 22, 2014 in the journal eLife, a publisher supported by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.

“This is a critical building block that regulates a fundamental process—memory,” said Kirill Martemyanov, a TSRI associate professor who led the study. “Now that we know about this important new player, it offers a unique therapeutic window if we can find a way to enhance its function.”

The team looked at RGS7 in the hippocampus, a small part of the brain that helps turn short-term memory in long-term memory.

The scientists found the RGS7 protein works in concert with another protein, R7BP, to regulate a key signaling cascade that is increasingly seen as a critical to cognitive development. The cascade involves the neurotransmitter GABA, which binds to the GABAb receptor and opens inhibitory channels known as GIRKs in the cell membrane. This process ultimately makes it more difficult for a nerve cell to fire.

This process turned out to be critical to normal functioning, as the research showed mice lacking RGS7 exhibited deficits in learning and memory.

Martemyanov believes the findings could ultimately have broad therapeutic application. “GIRK channels are implicated in a range of neuropsychiatric conditions, including drug addiction and Down’s syndrome, that result from a disproportionate increase in neuronal inhibition as a result of greater mobilization of these channels,” he said. Now that we know the identity of the critical modulator of GIRK channels we can try to find a way to increase its power with the hopes of reducing the inhibitory overdrive, and that might potentially alleviate some of the  disruptions seen in Down’s syndrome. It is possible that similar strategies might apply for dealing with addiction, where adaptations in the GABAb-GIRK pathway play a significant role.”

Targeting the RGS7 protein could allow for better therapeutic outcomes with fewer side effects because it allows for fine tuning of the signaling, according to Olga Ostrovskaya, the first author of the study and a member of Martemyanov’s lab, who sees many ways to follow up on the findings.

“We’re looking into how RGS7 is involved in neural circuitry and functions tied to the striatum, another part of the brain responsible for procedural memory, mood disorders, motivation and addiction,” Ostrovskaya said. “We may uncover the RGS7 regulation of other signaling complexes that may be very different from those in hippocampus.”

Filed under memory formation learning hippocampus RGS7 memory striatum neuroscience science

160 notes

Commonly available blood-pressure drug prevents epilepsy after brain injury
Between 10 and 20 percent of all cases of epilepsy result from severe head injury, but a new drug promises to prevent post-traumatic seizures and may forestall further brain damage caused by seizures in those who already have epilepsy.
A team of researchers from UC Berkeley, Ben-Gurion University in Israel and Charité-University Medicine in Germany reports in the current issue of the journal Annals of Neurology that a commonly used hypertension drug prevents a majority of cases of post-traumatic epilepsy in a rodent model of the disease. If independent experiments now underway in rats confirm this finding, human clinical trials could start within a few years.
“This is the first-ever approach in which epilepsy development is stopped, as opposed to common drugs that try to prevent seizures once epilepsy develops,” said coauthor Daniela Kaufer, UC Berkeley associate professor of integrative biology and a member of the Helen Wills Neuroscience Institute. “Those drugs have a very limited success and many side effects, so we are excited about the new approach.”
The team, led by Kaufer; neurosurgeon Alon Friedman, associate professor of physiology and neurobiology at the Ben-Gurion University of the Negev; and Uwe Heinemann of the Charite, provides the first explanation for how brain injury caused by a blow to the head, stroke or infection leads to epilepsy. Based on 10 years of collaborative research, their findings point a finger at the blood-brain barrier – the tight wall of cells lining the veins and arteries in the brain that is breached after trauma.
“This study for the first time offers a new mechanism and an existing, FDA-approved drug to potentially prevent epilepsy in patients after brain injuries or after they develop an abnormal blood-brain barrier,” Friedman said.
The drug, losartan (Cozaar®), prevented seizures in 60 percent of the rats tested, when normally 100 percent of the rats develop seizures after injury. In the 40 percent of rats that did develop seizures, they averaged about one quarter the number of seizures typical for untreated rats. Another experiment showed that administration of losartan for three weeks at the time of injury was enough to prevent most cases of epilepsy in normal lab rats in the following months.
“This is a very exciting result, telling us that the drug worked to prevent the development of epilepsy and not by suppressing the symptoms,” Kaufer said.
Breakdown of the blood-brain barrier
Kaufer and Friedman have been collaboratively investigating the effects of trauma on the brain since Kaufer was a graduate student in Israel 20 years ago. Throughout a postdoctoral position at Stanford University and after joining the UC Berkeley faculty in 2005, she maintained her interest in the blood-brain barrier, which normally protects the brain from potentially damaging chemicals or bacteria in the blood and prevents brain chemicals from leaking into the blood stream.
She and Friedman showed earlier that breaking down the barrier causes inflammation and leads to the development of epilepsy. They pinned the effect to a single protein called albumin, the most common protein in blood serum.
In 2009, they showed that albumin affects astrocytes, the brain’s support cells, by binding to the TGF-β (transforming growth factor-beta) receptor. This initiates a cascade of steps that lead to localized inflammation, which appears to permanently damage the brain’s wiring, leading to the electrical misfiring characteristic of epilepsy. The current paper conclusively demonstrates that blocking the TGF-beta receptor with losartan stops that cascade and prevents the disorder.
Drug’s side effect proves crucial
Coauthor Guy Bar-Klein, a doctoral student at Ben-Gurion University, searched a long list of drugs before discovering losartan, which is approved to treat high blood pressure because it blocks the angiotensin receptor 1, but which incidentally also blocks TGF-β. It worked in the rats when delivered in their drinking water, which means that it somehow gets into the brain through the blood-brain barrier. The experiments suggest that the drug is unable to cross an intact blood-brain barrier, but reaches the brain through a breached barrier when it is most needed, Kaufer said.
Friedman developed a protocol to use MRI to check whether the blood brain barrier has been breached, allowing doctors to give losartan as a preventive treatment, if necessary, after trauma. Kaufer said that the barrier may remain open for only a few weeks after injury, so the drug would not have to be given very long to prevent damage.
“Right now, if someone comes to the emergency room with traumatic brain injury, they have a 10 to 50 percent chance of developing epilepsy, and epilepsy from brain injuries tends to be unresponsive to drugs in many patients.” she said. “I’m very hopeful that our research can spare these patients the added trauma of epilepsy.”

Commonly available blood-pressure drug prevents epilepsy after brain injury

Between 10 and 20 percent of all cases of epilepsy result from severe head injury, but a new drug promises to prevent post-traumatic seizures and may forestall further brain damage caused by seizures in those who already have epilepsy.

A team of researchers from UC Berkeley, Ben-Gurion University in Israel and Charité-University Medicine in Germany reports in the current issue of the journal Annals of Neurology that a commonly used hypertension drug prevents a majority of cases of post-traumatic epilepsy in a rodent model of the disease. If independent experiments now underway in rats confirm this finding, human clinical trials could start within a few years.

“This is the first-ever approach in which epilepsy development is stopped, as opposed to common drugs that try to prevent seizures once epilepsy develops,” said coauthor Daniela Kaufer, UC Berkeley associate professor of integrative biology and a member of the Helen Wills Neuroscience Institute. “Those drugs have a very limited success and many side effects, so we are excited about the new approach.”

The team, led by Kaufer; neurosurgeon Alon Friedman, associate professor of physiology and neurobiology at the Ben-Gurion University of the Negev; and Uwe Heinemann of the Charite, provides the first explanation for how brain injury caused by a blow to the head, stroke or infection leads to epilepsy. Based on 10 years of collaborative research, their findings point a finger at the blood-brain barrier – the tight wall of cells lining the veins and arteries in the brain that is breached after trauma.

“This study for the first time offers a new mechanism and an existing, FDA-approved drug to potentially prevent epilepsy in patients after brain injuries or after they develop an abnormal blood-brain barrier,” Friedman said.

The drug, losartan (Cozaar®), prevented seizures in 60 percent of the rats tested, when normally 100 percent of the rats develop seizures after injury. In the 40 percent of rats that did develop seizures, they averaged about one quarter the number of seizures typical for untreated rats. Another experiment showed that administration of losartan for three weeks at the time of injury was enough to prevent most cases of epilepsy in normal lab rats in the following months.

“This is a very exciting result, telling us that the drug worked to prevent the development of epilepsy and not by suppressing the symptoms,” Kaufer said.

Breakdown of the blood-brain barrier

Kaufer and Friedman have been collaboratively investigating the effects of trauma on the brain since Kaufer was a graduate student in Israel 20 years ago. Throughout a postdoctoral position at Stanford University and after joining the UC Berkeley faculty in 2005, she maintained her interest in the blood-brain barrier, which normally protects the brain from potentially damaging chemicals or bacteria in the blood and prevents brain chemicals from leaking into the blood stream.

She and Friedman showed earlier that breaking down the barrier causes inflammation and leads to the development of epilepsy. They pinned the effect to a single protein called albumin, the most common protein in blood serum.

In 2009, they showed that albumin affects astrocytes, the brain’s support cells, by binding to the TGF-β (transforming growth factor-beta) receptor. This initiates a cascade of steps that lead to localized inflammation, which appears to permanently damage the brain’s wiring, leading to the electrical misfiring characteristic of epilepsy. The current paper conclusively demonstrates that blocking the TGF-beta receptor with losartan stops that cascade and prevents the disorder.

Drug’s side effect proves crucial

Coauthor Guy Bar-Klein, a doctoral student at Ben-Gurion University, searched a long list of drugs before discovering losartan, which is approved to treat high blood pressure because it blocks the angiotensin receptor 1, but which incidentally also blocks TGF-β. It worked in the rats when delivered in their drinking water, which means that it somehow gets into the brain through the blood-brain barrier. The experiments suggest that the drug is unable to cross an intact blood-brain barrier, but reaches the brain through a breached barrier when it is most needed, Kaufer said.

Friedman developed a protocol to use MRI to check whether the blood brain barrier has been breached, allowing doctors to give losartan as a preventive treatment, if necessary, after trauma. Kaufer said that the barrier may remain open for only a few weeks after injury, so the drug would not have to be given very long to prevent damage.

“Right now, if someone comes to the emergency room with traumatic brain injury, they have a 10 to 50 percent chance of developing epilepsy, and epilepsy from brain injuries tends to be unresponsive to drugs in many patients.” she said. “I’m very hopeful that our research can spare these patients the added trauma of epilepsy.”

Filed under blood-brain barrier albumin epilepsy epileptic seizures brain injury neuroscience science

103 notes

Researchers find link between sleep and immune function in fruit flies
When we get sick it feels natural to try to hasten our recovery by getting some extra shuteye. Researchers from the Perelman School of Medicine at the University of Pennsylvania found that this response has a definite purpose, in fruitflies: enhancing immune system response and recovery to infection. Their findings appear online in two related papers in the journal Sleep, in advance of print editions in May and June.
"It’s an intuitive response to want to sleep when you get sick," notes Center for Sleep and Circadian Neurobiology research associate Julie A. Williams, PhD. "Many studies have used sleep deprivation as a means to understand how sleep contributes to recovery, if it does at all, but there is surprisingly little experimental evidence that supports the notion that more sleep helps us to recover. We used a fruitfly model to answer these questions." Along with post-doctoral fellow, Tzu-Hsing Kuo, PhD, Williams conducted two related studies to directly examine the effects of sleep on recovery from and survival after an infection.
In the first paper, they took a conventional approach by subjecting fruit flies to sleep deprivation before infecting them with either Serratia marcescens or Pseudomonas aeruginosa bacteria. Both the sleep-deprived flies and a non-sleep-deprived control group displayed increased sleep after infection, what the experimenters call an “acute sleep response.”
Unexpectedly, the pre-infection, sleep-deprived flies had a better survival rate. “To our surprise they actually survived longer after the infection than the ones who were not sleep-deprived,” notes Williams. The Penn team found that prior sleep deprivation made the flies sleep for a longer period after infection as compared to the undisturbed controls. They slept longer and they lived longer during the infection. Inducing sleep deprivation after infection rather than before made little difference, as long as the infected flies then got adequate recovery sleep. “We deprived flies of sleep after infection with the idea that if we blocked this sleep, things would get worse in terms of survival,” Williams explains. “Instead they got better, but not until after they had experienced more sleep.”
Sleep deprivation increases activity of an NFkB transcription factor, Relish, which is also needed for fighting infection. Flies without the Relish gene do not experience an acute sleep response and very quickly succumb to infection. But, when these mutants are sleep-deprived before infection, they displayed increased sleep and survival rates after infection. The team then evaluated mutant flies that lacked two varieties of NFkB (Relish and Dif). When flies lacked both types of NFkB genes, sleep deprivation had no effect on the acute sleep response, and the effect on survival was abolished. Flies from both sleep-deprived and undisturbed groups succumbed to infection at equal rates within hours.
"Taken together, all of these data support the idea that post-infection sleep helps to improve survival," Williams says.
In the second study, the researchers manipulated sleep through a genetic approach. They used the drug RU486 to induce expression of ion channels to alter neuronal activity in the mushroom body of the fly brain, and thereby regulate sleep patterns. Compared to a control group, flies that were induced to sleep more, and for longer periods of time for up to two days before infection, showed substantially greater survival rates. The flies with more sleep also showed faster and more efficient rates of clearing the bacteria from their bodies. “Again, increased sleep somehow helps to facilitate the immune response by increasing resistance to infection and survival after infection,” notes Williams.
Because the genetic factors investigated by the Penn team, such as the NFkB pathway, are preserved in mammals, the relative simplicity of the Drosophila model provides an ideal avenue to explore basic functions like sleep. “Investigators have been working on questions about sleep and immunity for more than 40 years, but by narrowing down the questions in the fly we’re now in a good position to identify potentially novel genes and mechanisms that may be involved in this process that are difficult to see in higher animals,” explains Williams.
"These studies provide new evidence of the direct and functional effects of sleep on immune response and of the underlying mechanisms at work. The take-home message from these papers is that when you get sick, you should sleep as much as you can — we now have the data that supports this idea," she concludes.

Researchers find link between sleep and immune function in fruit flies

When we get sick it feels natural to try to hasten our recovery by getting some extra shuteye. Researchers from the Perelman School of Medicine at the University of Pennsylvania found that this response has a definite purpose, in fruitflies: enhancing immune system response and recovery to infection. Their findings appear online in two related papers in the journal Sleep, in advance of print editions in May and June.

"It’s an intuitive response to want to sleep when you get sick," notes Center for Sleep and Circadian Neurobiology research associate Julie A. Williams, PhD. "Many studies have used sleep deprivation as a means to understand how sleep contributes to recovery, if it does at all, but there is surprisingly little experimental evidence that supports the notion that more sleep helps us to recover. We used a fruitfly model to answer these questions." Along with post-doctoral fellow, Tzu-Hsing Kuo, PhD, Williams conducted two related studies to directly examine the effects of sleep on recovery from and survival after an infection.

In the first paper, they took a conventional approach by subjecting fruit flies to sleep deprivation before infecting them with either Serratia marcescens or Pseudomonas aeruginosa bacteria. Both the sleep-deprived flies and a non-sleep-deprived control group displayed increased sleep after infection, what the experimenters call an “acute sleep response.”

Unexpectedly, the pre-infection, sleep-deprived flies had a better survival rate. “To our surprise they actually survived longer after the infection than the ones who were not sleep-deprived,” notes Williams. The Penn team found that prior sleep deprivation made the flies sleep for a longer period after infection as compared to the undisturbed controls. They slept longer and they lived longer during the infection. Inducing sleep deprivation after infection rather than before made little difference, as long as the infected flies then got adequate recovery sleep. “We deprived flies of sleep after infection with the idea that if we blocked this sleep, things would get worse in terms of survival,” Williams explains. “Instead they got better, but not until after they had experienced more sleep.”

Sleep deprivation increases activity of an NFkB transcription factor, Relish, which is also needed for fighting infection. Flies without the Relish gene do not experience an acute sleep response and very quickly succumb to infection. But, when these mutants are sleep-deprived before infection, they displayed increased sleep and survival rates after infection. The team then evaluated mutant flies that lacked two varieties of NFkB (Relish and Dif). When flies lacked both types of NFkB genes, sleep deprivation had no effect on the acute sleep response, and the effect on survival was abolished. Flies from both sleep-deprived and undisturbed groups succumbed to infection at equal rates within hours.

"Taken together, all of these data support the idea that post-infection sleep helps to improve survival," Williams says.

In the second study, the researchers manipulated sleep through a genetic approach. They used the drug RU486 to induce expression of ion channels to alter neuronal activity in the mushroom body of the fly brain, and thereby regulate sleep patterns. Compared to a control group, flies that were induced to sleep more, and for longer periods of time for up to two days before infection, showed substantially greater survival rates. The flies with more sleep also showed faster and more efficient rates of clearing the bacteria from their bodies. “Again, increased sleep somehow helps to facilitate the immune response by increasing resistance to infection and survival after infection,” notes Williams.

Because the genetic factors investigated by the Penn team, such as the NFkB pathway, are preserved in mammals, the relative simplicity of the Drosophila model provides an ideal avenue to explore basic functions like sleep. “Investigators have been working on questions about sleep and immunity for more than 40 years, but by narrowing down the questions in the fly we’re now in a good position to identify potentially novel genes and mechanisms that may be involved in this process that are difficult to see in higher animals,” explains Williams.

"These studies provide new evidence of the direct and functional effects of sleep on immune response and of the underlying mechanisms at work. The take-home message from these papers is that when you get sick, you should sleep as much as you can — we now have the data that supports this idea," she concludes.

Filed under fruit flies immune system sleep genetics neuroscience science

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