Posts tagged acetylcholine
Articles and news from the latest research reports.
How female fruit flies know when to say ‘yes’
A fundamental question in neurobiology is how animals, including humans, make decisions. A new study publishing in the open access journal PLOS Biology on October 7 reveals how fruit fly females make a very important decision: to either accept or reject male courtship. This decision appears to be generated by a very small number of excitatory neurons that use acetylcholine as their neurotransmitter located in three brain regions. This study provides the framework to understand how decisions are generated and suggests that a decision is reached because that option is literally the most exciting.
Child neurologist finds potential route to better treatments for Fragile X, autism
When you experience something, neurons in the brain send chemical signals called neurotransmitters across synapses to receptors on other neurons. How well that process unfolds determines how you comprehend the experience and what behaviors might follow. In people with Fragile X syndrome, a third of whom are eventually diagnosed with Autism Spectrum Disorder, that process is severely hindered, leading to intellectual impairments and abnormal behaviors.
In a study published in the online journal PLoS One, a team of UNC School of Medicine researchers led by pharmacologist C.J. Malanga, MD, PhD, describes a major reason why current medications only moderately alleviate Fragile X symptoms. Using mouse models, Malanga discovered that three specific drugs affect three different kinds of neurotransmitter receptors that all seem to play roles in Fragile X. As a result, current Fragile X drugs have limited benefit because most of them only affect one receptor.
Nearly one million people in the United States have Fragile X Syndrome, which is the result of a single mutated gene called FMR1. In people without Fragile X, the gene produces a protein that helps maintain the proper strength of synaptic communication between neurons. In people with Fragile X, FMR1 doesn’t produce the protein, the synaptic connection weakens, and there’s a decrease in synaptic input, leading to mild to severe learning disabilities and behavioral issues, such as hyperactivity, anxiety, and sensitivity to sensory stimulation, especially touch and noise.
More than two decades ago, researchers discovered that – in people with mental and behavior problems – a receptor called mGluR5 could not properly regulate the effect of the neurotransmitter, glutamate. Since then, pharmaceutical companies have been trying to develop drugs that target glutamate receptors. “It’s been a challenging goal,” Malanga said. “No one so far has made it work very well, and kids with Fragile X have been illustrative of this.”
But there are other receptors that regulate other neurotransmitters in similar ways to mGluR5. And there are drugs already available for human use that act on those receptors. So Malanga’s team checked how those drugs might affect mice in which the Fragile X gene has been knocked out.
By electrically stimulating specific brain circuits, Malanga’s team first learned how the mice perceived reward. The mice learned very quickly that if they press a lever, they get rewarded via a mild electrical stimulation. Then his team provided a drug molecule that acts on the same reward circuitry to see how the drugs affect the response patterns and other behaviors in the mice.
His team studied one drug that blocked dopamine receptors, another drug that blocked mGluR5 receptors, and another drug that blocked mAChR1, or M1, receptors. Three different types of neurotransmitters – dopamine, glutamate, and acetylcholine – act on those receptors. And there were big differences in how sensitive the mice were to each drug.
“Turns out, based on our study and a previous study we did with my UNC colleague Ben Philpot, that Fragile X mice and Angelman Syndrome mice are very different,” Malanga said. “And how the same pharmaceuticals act in these mouse models of Autism Spectrum Disorder is very different.”
Malanga’s finding suggests that not all people with Fragile X share the same biological hurdles. The same is likely true, he said, for people with other autism-related disorders, such as Rett syndrome and Angelman syndrome.
“Fragile X kids likely have very different sensitivities to prescribed drugs than do other kids with different biological causes of autism,” Malanga said.
(Source: news.unchealthcare.org)
New Strategy to Treat Multiple Sclerosis Shows Promise in Mice
Scientists at The Scripps Research Institute (TSRI) have identified a set of compounds that may be used to treat multiple sclerosis (MS) in a new way. Unlike existing MS therapies that suppress the immune system, the compounds boost a population of progenitor cells that can in turn repair MS-damaged nerve fibers.
One of the newly identified compounds, a Parkinson’s disease drug called benztropine, was highly effective in treating a standard model of MS in mice, both alone and in combination with existing MS therapies.
“We’re excited about these results, and are now considering how to design an initial clinical trial,” said Luke L. Lairson, an assistant professor of chemistry at TSRI and a senior author of the study, which is reported online in Nature on October 9, 2013.
Lairson cautioned that benztropine is a drug with dose-related adverse side effects, and has yet to be proven effective at a safe dose in human MS patients. “People shouldn’t start using it off-label for MS,” he said.
A New Approach
An autoimmune disease of the brain and spinal cord, MS currently affects more than half a million people in North America and Europe, and more than two million worldwide. Its precise triggers are unknown, but certain infections and a lack of vitamin D are thought to be risk factors. The disease is much more common among those of Northern European heritage, and occurs about twice as often in women as in men.
In MS, immune cells known as T cells infiltrate the upper spinal cord and brain, causing inflammation and ultimately the loss of an insulating coating called myelin on some nerve fibers. As nerve fibers lose this myelin coating, they lose their ability to transmit signals efficiently, and in time may begin to degenerate. The resulting symptoms, which commonly occur in a stop-start, “relapsing-remitting” pattern, may include limb weakness, numbness and tingling, fatigue, vision problems, slurred speech, memory difficulties and depression, among other problems.
Current therapies, such as interferon beta, aim to suppress the immune attack that de-myelinates nerve fibers. But they are only partially effective and are apt to have significant adverse side effects.
In the new study, Lairson and his colleagues decided to try a complementary approach, aimed at restoring a population of progenitor cells called oligodendrocytes. These cells normally keep the myelin sheaths of nerve fibers in good repair and in principle could fix these coatings after MS damages them. But oligodendrocyte numbers decline sharply in MS, due to a still-mysterious problem with the stem-like precursor cells that produce them. “Oligodendrocyte precursor cells (OPCs) are present during progressive phases of MS, but for unknown reasons don’t mature into functional oligodendrocytes,” Lairson said.
A 100,000-Molecule Screen
Using a sophisticated small-molecule screening laboratory that TSRI manages in conjunction with the California Institute of Regenerative Medicine and in collaboration with the California Institute for Biomedical Research (Calibr), Lairson and his team screened a library of about 100,000 diverse compounds for any that could potently induce OPCs to mature or “differentiate.”
Several compounds scored well as OPC differentiation-inducers. Most were compounds of unknown activity —but one, benztropine, had been well characterized and indeed was already FDA-approved for treating Parkinson’s disease. “That was a surprise, and it meant that we could move forward relatively quickly in testing it,” said graduate student Vishal A. Deshmukh, first author of the paper who performed most of these experiments.
With the help of Brian R. Lawson, a senior author of the paper and assistant professor of immunology at TSRI, and his colleague Research Associate Virginie Tardif, Deshmukh set up tests of benztropine in mice with an induced MS-like autoimmune disease—a model commonly used for testing prospective MS drugs.
In these tests, benztropine showed a powerful ability to prevent autoimmune disease and also was effective in treating it after symptoms had arisen—virtually eliminating the disease’s ability to relapse. Although benztropine on its own worked about as well as existing treatments, it also showed a remarkable ability to complement these existing treatments, in particular two first-line immune-suppressant therapies, interferon-beta and fingolimod.
“Adding even a suboptimal level of benztropine effectively allowed us, for example, to cut the dose of fingolimod by 90%—and achieve the same disease-modifying effect as a normal dose of fingolimod,” said Lawson. “In a clinical setting that dose-lowering could translate into a big reduction in fingolimod’s potentially serious side effects.”
In further analyses, the researchers confirmed that benztropine works against disease in this mouse model by boosting the population of mature oligodendrocytes, which in turn restore the myelin sheaths of damaged nerves—even as the immune attack continues. “The benztropine-treated mice showed no change in the usual signs of inflammation, yet their myelin was mostly intact, suggesting that it was probably being repaired as rapidly as it was being destroyed,” said Lawson.
Benztropine is known to have multiple specific effects on brain cells, including the blocking of activity at acetylcholine and histamine receptors and a boosting of activity at dopamine receptors. But Lairson and his colleagues found evidence that the drug stimulates OPCs to differentiate mainly by blocking M1 or M3 acetylcholine receptors on these cells.
In addition to setting up initial clinical trials, Lairson and his team hope to learn more about how benztropine induces OPC maturation, and how its molecular structure might be optimized for this purpose. “We’re also looking at some of the other, relatively unknown molecules that we identified in our initial screen, to see if any of those has better clinical potential than benztropine,” he said.
“This work, like our previous studies with hematopoietic and mesenchymal stem cells, illustrates the power of small molecules to control stem and precursor cells in ways that may ultimately lead to a new generation of drugs for regenerative medicine,” said Peter G. Schultz, the Scripps Family Chair Professor in the Department of Chemistry at TSRI and one of the study’s senior authors.
Researchers Find Early Success in New Treatment for Stroke Recovery
Researchers at The University of Texas at Dallas have taken a step toward developing a new treatment to aid the recovery of limb function after strokes.
In a study published online in the journal Neurobiology of Disease, researchers report the full recovery of forelimb strength in animals receiving vagus nerve stimulation.
“Stroke is a leading cause of disability worldwide,” said Dr. Navid Khodaparast, a postdoctoral researcher in the School of Behavioral and Brain Sciences and lead author of the study. “Every 40 seconds, someone in the U.S. has a stroke. Our results mark a major step in the development of a possible treatment.”
Vagus nerve stimulation (VNS) is an FDA-approved method for treating various illnesses, such as depression and epilepsy. It involves sending a mild electric pulse through the vagus nerve, which relays information about the state of the body to the brain.
Khodaparast and his colleagues used vagus nerve stimulation precisely timed to coincide with rehabilitative movements in rats. Each of the animals had previously experienced a stroke that impaired their ability to pull a handle.
Stimulation of the vagus nerve causes the release of chemicals in the brain known to enhance learning and memory called neurotransmitters, specifically acetylcholine and norepinephrine. Pairing this stimulation with rehabilitative training allowed Khodaparast and colleagues to improve recovery.
Many rehabilitative interventions try to enhance neuroplasticity (the brain’s ability to change) in conjunction with physical rehabilitation to drive the recovery of lost functions, according to Khodaparast. Unfortunately, up to 70 percent of stroke patients still display long-term impairment in arm function after traditional rehabilitation.
“For years, the majority of stroke patients have received treatment with various drugs and/or physical rehabilitation,” Khodaparast said. “Medications can have widespread effects in the brain and the effects can last for long periods of time. In some cases the side effects outweigh the benefits. Through the use of VNS, we are able to use the brain’s natural way of changing its neural circuitry and provide specific and long lasting effects.”
Khodaparast acknowledged the study has some limitations. For example, the animals were young and lacked some of the other illnesses that accompany an aged human population, such as diabetes or hypertension. But Khodaparast and his colleagues said they are optimistic about vagus nerve stimulation as a future tool. They will continue testing in chronically impaired animals with the hopes of translating the technique for stroke patients. Working with MicroTransponder Inc., a partner company in the current study, researchers at the University of Glasgow in Scotland have begun a small-scale trial in humans.
“There is strong evidence that VNS can be used safely in stroke patients because of its extensive use in the treatment of other neurological conditions,” said Dr. Michael Kilgard, professor in neuroscience at UT Dallas and senior author of the study.
Kilgard is also conducting clinical trials using vagus nerve stimulation to treat tinnitus, the medical condition of unexplained ringing in the ears. Kilgard’s lab first demonstrated the ability of vagus nerve stimulation to enhance brain adaptability in a 2011 Nature paper.
(Source: utdallas.edu)
Study creates new memories by directly changing the brain
Findings could prove helpful in understanding and resolving learning and memory disorders
By studying how memories are made, UC Irvine neurobiologists created new, specific memories by direct manipulation of the brain, which could prove key to understanding and potentially resolving learning and memory disorders.
Research led by senior author Norman M. Weinberger, a research professor of neurobiology & behavior at UC Irvine, and colleagues has shown that specific memories can be made by directly altering brain cells in the cerebral cortex, which produces the predicted specific memory. The researchers say this is the first evidence that memories can be created by direct cortical manipulation. Study results appeared in the August 29 issue of Neuroscience.
During the research, Weinberger and colleagues played a specific tone to test rodents then stimulated the nucleus basalis deep within their brains, releasing acetylcholine (ACh), a chemical involved in memory formation. This procedure increased the number of brain cells responding to the specific tone. The following day, the scientists played many sounds to the animals and found that their respiration spiked when they recognized the particular tone, showing that specific memory content was created by brain changes directly induced during the experiment. Created memories have the same features as natural memories including long-term retention.
"Disorders of learning and memory are a major issue facing many people and since we’ve found not only a way that the brain makes memories, but how to create new memories with specific content, our hope is that our research will pave the way to prevent or resolve this global issue," said Weinberger, who is also a fellow with the Center for the Neurobiology of Learning & Memory and the Center for Hearing Research at UC Irvine.
The creation of new memories by directly changing the cortex is the culmination of several years of research in Weinberger’s lab implicating the nucleus basalis and ACh in brain plasticity and specific memory formation. Previously, the authors had also shown that the strength of memory is controlled by the number of cells in the auditory cortex that process a sound.
Nicotinic receptor essential for cognition and mental health
The ability to maintain mental representations of ourselves and the world — the fundamental building block of human cognition — arises from the firing of highly evolved neuronal circuits, a process that is weakened in schizophrenia. In a new study, researchers at Yale University School of Medicine pinpoint key molecular actions of proteins that allow the creation of mental representations necessary for higher cognition that are genetically altered in schizophrenia. The study was released July 1 in the Proceedings of the National Academy of Sciences.
Working memory, the mind’s mental sketch pad, depends upon the proper functioning of a network of pyramid-shaped brain cells in the prefrontal cortex, the seat of higher order thinking in humans. To keep information in the conscious mind, these pyramidal cells must stimulate each other through a special group of receptors. The Yale team discovered this stimulation requires the neurotransmitter acetylcholine to activate a specific protein in the nicotinic family of receptors — the alpha7 nicotinic receptor.
Acetycholine is released when we are awake — but not in deep sleep. These receptors allow prefrontal circuits to come “online” when we awaken, allowing us to perform complex mental tasks. This process is enhanced by caffeine in coffee, which increases acetylcholine release. As their name suggests, nicotinic alpha-7 receptors are also activated by nicotine, which may may help to explain why smoking can focus attention and calm behavior, functions of the prefrontal cortex.
The results also intrigued researchers because alpha7 nicotinic receptors are genetically altered in schizophrenia, a disease marked by disorganized thinking. “Prefrontal networks allow us to form and hold coherent thoughts, a process that is impaired in schizophrenia,” said Amy Arnsten, professor of neurobiology, investigator for Kavli Institute, and one of the senior authors of the paper. “A great majority of schizophrenics smoke, which makes sense because stimulation of the nicotinic alpha7 receptors would strengthen mental representations and lessen thought disorder.”
Arnsten said that new medications that stimulate alpha-7 nicotinic receptors may hold promise for treating cognitive disorders.
Publication of the PNAS paper comes on the eve of the 10th anniversary of the death of Yale neurobiologist Patricia Goldman-Rakic, who was hit by a car in Hamden Ct. on July 31, 2003. Goldman-Rakic first identified the central role of prefrontal cortical circuits in working memory.
“Patricia’s work has provided the neural foundation for current studies of molecular influences on cognition and their disruption in cognitive disorders,” said Arnsten. “Our ability to apply a scientific approach to perplexing disorders such as schizophrenia is due to her groundbreaking research.”
“Forrest Gump” mice show too much of a good thing, can be bad
A line of genetically modified mice that Western University scientists call “Forrest Gump” because, like the movie character, they can run far but they aren’t smart, is furthering the understanding of a key neurotransmitter called acetylcholine (ACh). Marco Prado, PhD, and his team at Robarts Research Institute say the mice show what happens when too much of this neurotransmitter becomes available in the brain. Boosting ACh is a therapeutic target for Alzheimer’s disease because it’s found in reduced amounts when there’s cognitive failure. Prado’s research is published in the Journal of Neuroscience.
“We wanted to know what happens if you have more of the gene which controls how much acetylcholine is secreted by neurons,” says Prado, a Robarts scientist and professor in the Departments of Physiology and Pharmacology and Anatomy and Cell Biology at Western’s Schulich School of Medicine & Dentistry. “The response was the complete opposite of what we expected. It’s not a good thing. Acetylcholine release was increased threefold in these mice, which seemed to disturb cognitive function. But put them on a treadmill and they can run twice as far as normal mice before tiring. They’re super-athletes.” In addition to its function in modulating cognitive abilities, ACh drives muscle contraction which allowed for the marked improvement in motor endurance.
One of the tests the scientists, including first author Benjamin Kolisnyk, used is called the touch screen test for mice which uses technology similar to a tablet. After initiating the test, the mice have to scan five different spots on the touch screen to see a light flash, and then run and touch that area. If they get it right they get a reward. Compared to the control mice, the “Forrest Gump” mice failed miserably at the task. The researchers found the mice, which have the scientific name ChAT-ChR2-EYFP, had terrible attention spans, as well as dysfunction in working memory and spatial memory.
Prado interprets the research as showing ACh is very important for differentiating cues. So if your brain is presented with a lot of simultaneous information, it helps to pick what’s important. But when you flood the brain with ACh, your brain loses the ability to discern what’s relevant. This study was funded mainly by the Canadian Institutes of Health Research.
(Source: communications.uwo.ca)
Pay attention: How we focus and concentrate
Scientists at Newcastle University have shed new light on how the brain tunes in to relevant information.
Publishing in Neuron, the team reveal the interplay of brain chemicals which help us pay attention in work funded by the Wellcome Trust and BBSRC.
By changing the way neurons respond to external stimuli we improve our perceptual abilities. While these changes can affect the strength of a neuronal response, they can also affect the fidelity of that response.
Lead author Alex Thiele, Professor of Visual Neuroscience explains: “When you communicate with others, you can make yourself better heard by speaking louder or by speaking more clearly. Neurons appear to do similar things when we’re paying attention. They send their message more intensely to their partners, which compares to speaking louder. But more importantly, they also increase the fidelity of their message, which compares to speaking more clearly.
“Our earlier work has shown that attention is able to affect the intensity of responses – in effect the loudness - by means of the brain chemical acetylcholine. Now we have shown that the fidelity of the response is altered by a different brain chemical system.”
In the paper, the team reveal that the quality of the response is altered by means of glutamate coupling to NMDA receptors (a molecular device that mediates communication between neurons). Carried out in a primate model, these studies for the first time isolate different attention mechanisms at the receptor level.
The research builds on the team’s previous studies and has potentially significant implications not only for our understanding of how our brains work but also give an insight into conditions such as schizophrenia, Alzheimer’s disease and attention deficit disorder, and may aid in the development of treatments for them.
Waiting for a sign? Researchers find potential brain ‘switch’ for new behavior
You’re standing near an airport luggage carousel and your bag emerges on the conveyor belt, prompting you to spring into action. How does your brain make the shift from passively waiting to taking action when your bag appears?
A new study from investigators at the University of Michigan and Eli Lilly may reveal the brain’s “switch” for new behavior. They measured levels of a neurotransmitter called acetylcholine, which is involved in attention and memory, while rats monitored a screen for a signal. At the end of each trial, the rat had to indicate if a signal had occurred.
Researchers noticed that if a signal occurred after a long period of monitoring or “non-signal” processing, there was a spike in acetylcholine in the rat’s right prefrontal cortex. No such spike occurred for another signal occurring shortly afterwards.
"In other words, the increase in acetylcholine seemed to activate or ‘switch on’ the response to the signal, and to be unnecessary if that response was already activated," said Cindy Lustig, one of the study’s senior authors and an associate professor in the U-M Department of Psychology.
The researchers repeated the study in humans using functional magnetic resonance imaging (fMRI), which measures brain activity, and also found a short increase in right prefrontal cortex activity for the first signal in a series.
To connect the findings between rats and humans, they measured changes in oxygen levels, similar to the changes that produce the fMRI signal, in the brains of rats performing the task.
They again found a response in the right prefrontal cortex that only occurred for the first signal in a series. A follow-up experiment showed that direct stimulation of brain tissue using drugs that target acetylcholine receptors could likewise produce these changes in brain oxygen.
Together, the studies’ results provide some of the most direct evidence, so far, linking a specific neurotransmitter response to changes in brain activity in humans. The findings could guide the development of better treatments for disorders in which people have difficulty switching out of current behaviors and activating new ones. Repetitive behaviors associated with obsessive-compulsive disorder and autism are the most obvious examples, and related mechanisms may underlie problems with preservative behavior in schizophrenia, dementia and aging.
The findings appear in the current issue of Journal of Neuroscience.
Turning Alzheimer’s Fuzzy Signals Into High Definition
Scientists at the Virginia Tech Carilion Research Institute have discovered how the predominant class of Alzheimer’s pharmaceuticals might sharpen the brain’s performance.
One factor even more important than the size of a television screen is the quality of the signal it displays. Having a life-sized projection of Harry Potter dodging a Bludger in a Quidditch match is of little use if the details are lost to pixilation.
The importance of transmitting clear signals, however, is not relegated to the airwaves. The same creed applies to the electrical impulses navigating a human brain. Now, new research has shown that one of the few drugs approved for the treatment of Alzheimer’s disease helps patients by clearing up the signals coming in from the outside world.
The discovery was made by a team of researchers led by Rosalyn Moran, an assistant professor at the Virginia Tech Carilion Research Institute. Her study indicates that cholinesterase inhibitors — a class of drugs that stop the breakdown of the neurotransmitter acetylcholine — allow signals to enter the brain with more precision and less background noise.
“Increasing the levels of acetylcholine appears to turn your fuzzy, old analog TV signal into a shiny, new, high-definition one,” said Moran, who holds an appointment as an assistant professor in the Virginia Tech College of Engineering. “And the drug does this in the sensory cortices. These are the workhorses of the brain, the gatekeepers, not the more sophisticated processing regions — such as the prefrontal cortex — where one may have expected the drugs to have their most prominent effect.”
Alzheimer’s disease affects more than 35 million people worldwide — a number expected to double every 20 years, leading to more than 115 million cases by 2050. Of the five pharmaceuticals approved to treat the disease by the U.S. Food and Drug Administration, four are cholinesterase inhibitors. Although it is clear that the drugs increase the amount of acetylcholine in the brain, why this improves Alzheimer’s symptoms has been unknown. If scientists understood the mechanisms and pathways responsible for improvement, they might be able to tailor better drugs to combat the disease, which costs more than $200 billion annually in the United States alone.
In the new study, Moran recruited 13 healthy young adults and gave them doses of galantamine, one of the cholinesterase inhibitors commonly prescribed to Alzheimer’s patients. Two electroencephalographs were taken — one with the drugs and one without — as the participants listened to a series of modulating tones while focusing on a simple concentration task.
The researchers were looking for differences in neural activity between the two drug states in response to surprising changes in the sound patterns that the participants were hearing.
The scientists compared the results with computer models built on a Bayesian brain theory, known as the Free Energy Principle, which is a leading theory that describes the basic rules of neuronal communication and explains the creation of complex networks.
The theory hypothesizes that neurons seek to reduce uncertainty, which can be modeled and calculated using free energy molecular dynamics. Connecting tens of thousands of neurons behaving in this manner produces the probability machine that we call a brain.
Moran and her colleagues compiled 10 computer simulations based on the different effects that the drugs could have on the brain. The model that best fit the results revealed that the low-level wheels of the brain early on in the neural networking process were the ones benefitting from the drugs and creating clearer, more precise signals.
“When people take these drugs you can imagine the brain bathed in them,” Moran said. “But what we found is that the drugs don’t have broad-stroke impacts on brain activity. Instead, they are working very specifically at the cortex’s entry points, gating the signals coming into the network in the first place.”
The study appears in Wednesday’s (May 8) issue of The Journal of Neuroscience in the article, “Free Energy, Precision and Learning: The Role of Cholinergic Neuromodulation.”
(Source: newswise.com)