Posts tagged norepinephrine
Articles and news from the latest research reports.
Researcher shows how stress hormones promote brain’s building of negative memories
When a person experiences a devastating loss or tragic event, why does every detail seem burned into memory whereas a host of positive experiences simply fade away?
It’s a bit more complicated than scientists originally thought, according to a study recently published in the journal Neuroscience by ASU researcher Sabrina Segal.
When people experience a traumatic event, the body releases two major stress hormones: norepinephrine and cortisol. Norepinephrine boosts heart rate and controls the fight-or-flight response, commonly rising when individuals feel threatened or experience highly emotional reactions. It is chemically similar to the hormone epinephrine – better known as adrenaline.
In the brain, norepinephrine in turn functions as a powerful neurotransmitter or chemical messenger that can enhance memory.
Research on cortisol has demonstrated that this hormone can also have a powerful effect on strengthening memories. However, studies in humans up until now have been inconclusive – with cortisol sometimes enhancing memory, while at other times having no effect.
A key factor in whether cortisol has an effect on strengthening certain memories may rely on activation of norepinephrine during learning, a finding previously reported in studies with rats.
In her study, Segal, an assistant research professor at the Institute for Interdisciplinary Salivary Bioscience Research at ASU, and her colleagues at the University of California-Irvine showed that human memory enhancement functions in a similar way.
Conducted in the laboratory of Larry Cahill at U.C. Irvine, Segal’s study included 39 women who viewed 144 images from the International Affective Picture Set. This set is a standardized picture set used by researchers to elicit a range of responses, from neutral to strong emotional reactions, upon view.
Segal and her colleagues gave each of the study’s subjects either a dose of hydrocortisone – to simulate stress – or a placebo just prior to viewing the picture set. Each woman then rated her feelings at the time she was viewing the image, in addition to giving saliva samples before and after. One week later, a surprise recall test was administered.
What Segal’s team found was that “negative experiences are more readily remembered when an event is traumatic enough to release cortisol after the event, and only if norepinephrine is released during or shortly after the event.”
“This study provides a key component to better understanding how traumatic memories may be strengthened in women,” Segal added, “because it suggests that if we can lower norepinephrine levels immediately following a traumatic event, we may be able to prevent this memory enhancing mechanism from occurring, regardless of how much cortisol is released following a traumatic event.”
Further studies are needed to explore to what extent the relationship between these two stress hormones differ depending on whether you are male or female, particularly because women are twice as likely to develop disorders from stress and trauma that affect memory, such as in Posttraumatic Stress Disorder (PTSD). In the meantime, the team’s findings are a first step toward a better understanding of neurobiological mechanisms that underlie traumatic disorders, such as PTSD.
(Image: Wikimedia Commons)
(Image caption: Astrocyte activity is shown in green in this slice of tissue from the brain region that controls movement in mice. Internal, structural elements of the astrocytes are shown in magenta; cell bodies are in red. Credit: Amit Agarwal and Dwight Bergles, courtesy of Cell Press)
Fight-Or-Flight Chemical Prepares Cells to Shift the Brain From Subdued to Alert State
A new study from The Johns Hopkins University shows that the brain cells surrounding a mouse’s neurons do much more than fill space. According to the researchers, the cells, called astrocytes because of their star-shaped appearance, can monitor and respond to nearby neural activity, but only after being activated by the fight-or-flight chemical norepinephrine. Because astrocytes can alter the activity of neurons, the findings suggest that astrocytes may help control the brain’s ability to focus.
The study involved observing the cells in the brains of living, active mice over long periods of time. A combination of genetically engineered mice and advanced microscopy allowed the researchers to visualize the activity of astrocyte networks in different regions of the brain to learn how these abundant supporting cells are controlled.
The scientists monitored astrocytes in the area of the brain responsible for controlling movement and saw that the cells often increased their activity as the mice walked on treadmills — but not always, and sometimes astrocytes became active when the animals were not moving. This lack of consistency suggested to the researchers that the astrocytes were not responding to nearby neurons, as had been thought.
Similarly, astrocytes in the vision processing area of the brain did not necessarily become active when the mice were stimulated with light, but they were sometimes active, even in the dark. The team solved both mysteries when they tested the idea that the astrocytes needed a signal to “wake them up” before they could respond to nearby neurons. That is how they found that norepinephrine, the brain’s broadly distributed fight-or-flight signal, primes the astrocytes in both locations to “listen in” on nearby neuronal activity.
“Astrocytes are among the most abundant cells in the brain, but we know very little about how they are controlled and how they contribute to brain function,” says Dwight Bergles, Ph.D., professor of neuroscience, who led the study. “Since memory formation and other important functions of the brain require a state of attention, we’re interested in learning more about how astrocytes help create that state.”
For example, Bergles says, “We know that astrocytes can regulate local blood flow, provide energy to neurons and release signaling molecules that alter neuronal activity. They could be doing any or all of those things in response to being activated. It is also possible that they act as a sort of megaphone to broadcast local norepinephrine signals to every neuron in the brain.” Whatever the case may be, researchers now know that astrocytes are not idle loiterers. This ability to study astrocyte network activity in animals as they do different things will help to reveal how these cells contribute to brain function.
This research was published in the journal Neuron on June 18.
New research sheds light on how the body regulates fundamental neuro-hormone
Researchers at the University of Bristol and University College London found that lactate – essentially lactic acid – causes cells in the brain to release more noradrenaline (norepinephrine in US English), a hormone and neurotransmitter which is fundamental for brain function. Without it people can hardly wake up or focus on anything.
Production of lactate can be triggered by muscle use, which reinforces the connection between exercise and positive mental wellbeing.
Lactate was first discovered in sour milk by Swedish chemist, Carl Wilhelm Scheele in 1780. It is produced naturally by the body, for example when muscles are at work. In the brain, it has always been regarded as an energy source which can be delivered to neurones as fuel to keep them working when brain activity increases.
This research, published today [11 February] in Nature Communications, identifies a secondary function for lactate as a signal between brain cells. It implies that there is an as yet unknown receptor for lactate in the brain which must be present on noradrenaline cells to make them sensitive to lactate.
Professor Sergey Kasparov, from Bristol University’s School of Physiology and Pharmacology, said: “Our findings suggest that lactate has more than one incarnation - in addition to its role as an energy source, it is also a signal to neurones to release more noradrenaline.”
Dr Anja Teschemacher, also from the University of Bristol, added: “The next big task is to identify the receptor which mediates this effect because this will help to design drugs to block or stimulate this response. If we can regulate the release of noradrenaline – which is absolutely fundamental for brain function - then this could have important implications for the treatment of major health problems such as stress, blood pressure, pain and depression.”
Astrocytes, small non-neuronal star-shaped cells in the brain and spinal cord, are the principle source of brain lactate. The discovery that astrocytes communicate directly with neurones opens up a whole new area of pharmacology which has been little explored.
(Source: bristol.ac.uk)
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)
Researchers Pinpoint Molecular Path that Makes Antidepressants Act Quicker in Mouse Model
Understanding alternate pathways for how mental meds work could lead to faster-acting drug targets
The reasons behind why it often takes people several weeks to feel the effect of newly prescribed antidepressants remains somewhat of a mystery – and likely, a frustration to both patients and physicians.
(Image: Mouse hippocampus expressing the Cre- virus. Credit: Julie Blendy, PhD; Brigitta Gunderson, PhD; Perelman School of Medicine, University of Pennsylvania)
Julie Blendy, PhD, professor of Pharmacology, at the Perelman School of Medicine, University of Pennsylvania; Brigitta Gunderson, PhD, a former postdoctoral fellow in the Blendy lab, and colleagues, have been working to find out why and if there is anything that can be done to shorten the time in which antidepressants kick in.
“Our goal is to find ways for antidepressants to work faster,” says Blendy.
The proteins CREB and CREM are both transcription factors, which bind to specific DNA sequences to control the “reading” of genetic information from DNA to messenger RNA (mRNA). Both CREB and CREM bind to the same 8-base-pair DNA sequence in the cell nucleus. But, the comparative influence of CREM versus CREB on the action of antidepressants is a “big unknown,” says Blendy.
CREB, and CREM to some degree, has been implicated in the pathophysiology of depression, as well as in the efficacy of antidepressants. However, whenever CREB is deleted, CREM is upregulated, further complicating the story.
Therefore, how an antidepressant works on the biochemistry and behavior in a mouse in which the CREB protein is deleted only in the hippocampus versus a wild type mouse in which CREM is overexpressed let the researchers tease out the relative influence of CREB and CREM on the pharmacology of an antidepressant. They saw the same results in each type of mouse line – increased nerve-cell generation in the hippocampus and a quicker response to the antidepressant. Their findings appear in the Journal of Neuroscience.
“This is the first demonstration of CREM within the brain playing a role in behavior, and specifically in behavioral outcomes, following antidepressant treatment,” says Blendy.
A Flood of Neurotransmitters
Antidepressants like SSRIs, NRIs, and older tricyclic drugs work by causing an immediate flood of neurotransmitters like serotonin, norepinephrine, and in some cases dopamine, into the synaptic space. However, it can take three to four weeks for patients to feel changes in mental state. Long-term behavioral effects of the drugs may take longer to manifest themselves, because of the need to activate CREB downstream targets such as BDNF and trkB, or as of yet unidentified targets, which could also be developed as new antidepressant drug targets.
The Penn team compared the behavior of the control, wild-type mice to the CREB mutant mice using a test in which the mouse is trained to eat a treat – Reese’s Pieces, to be exact – in the comfort of their home cage. The treat-loving mice are then placed in a new cage to make them anxious. They are given the treat again, and the time it takes for the mouse to approach the treat is recorded.
Animals that receive no drug treatment take a long time to venture out into the anxious environment to retrieve the treat, however, if given an antidepressant drug for at least three weeks, the time it takes a mouse to get the treat decreases significantly, from about 400 seconds to 100 seconds. In mice in which CREB is deleted or in mice in which CREM is upregulated, this reduction happens in one to two days versus the three weeks seen in wild-type mice.
The accelerated time to approach the treat in mice on the medication was accompanied by an increase in new nerve growth in the hippocampus.
“Our results suggest that activation of CREM may provide a means to accelerate the therapeutic efficacy of current antidepressant treatment,” says Blendy. Upregulation of CREM observed after CREB deletion, appears to functionally compensate for CREB loss at a behavioral level and leads to maintained or increased expression of some CREB target genes. The researchers’ next step is to identify any unique CREM target genes in brain areas such as the hippocampus, which may lead to the development of faster-acting antidepressants.
(Source: uphs.upenn.edu)
Sympathetic Neurons Engage in “Cross Talk” With Cells in the Pancreas During Early Development
The human body is a complicated system of blood vessels, nerves, organs, tissue and cells each with a specific job to do. When all are working together, it’s a symphony of form and function as each instrument plays its intended roles.
Biologist Rejji Kuruvilla and her fellow researchers uncovered what happens when one instrument is not playing its part.
Kuruvilla along with graduate students Philip Borden and Jessica Houtz, both from the Biology Department at Johns Hopkins University’s Krieger School of Arts and Sciences, and Dr. Steven Leach from the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins School of Medicine, recently published a paper in the journal Cell Reports exploring whether “cross-talk” or reciprocal signaling, takes place between the neurons in the sympathetic nervous system and the tissues that the nerves connect to. In this case the targeted tissue called islets, were in the pancreas.
“We knew that sympathetic neurons need molecular signals from the tissues that they connect with, to grow and survive,” said Kuruvilla. “What we did not know was whether the neurons would reciprocally signal to the target tissues to instruct them to grow and mature. It made sense to focus on the pancreas because of previous studies done in diabetic animal models where sympathetic nerves within the pancreas were found to retract early on in the disease, suggesting that dysfunction of the nerves could be an early trigger for pancreatic defects.”
The researchers spent approximately three years working with lab mice to test the various scenarios in which signaling between sympathetic neurons and islet cells might take place. The experiments focused on what effects removing the sympathetic nerves would have on pancreas development in newborn mice.
Previous studies had shown that pancreatic cells release a signal of their own, a nerve growth protein, that directs the sympathetic nerves toward the pancreas and provides necessary nutrition to sustain the nerves.
In turn, Kuruvilla’s team found that in mutant mice, the removal of the sympathetic neurons resulted in deformities in the architecture of the pancreatic islet cells and defects in insulin secretion and glucose metabolism.
Pancreatic islets are highly organized functional micro-organs with a defined size, shape and distinctive arrangement of endocrine cells. It’s this marriage of form and function that result in cells clustered close together, that creates greater, more efficient islet cell function.
However, the mutant mice, with their sympathetic neurons removed, had islet formations that were misshapen, sported lesions and developed in a patchy, uneven manner. Because of their dysfunctional islet cell development, postnatal mice did not secrete enough insulin when confronted with high glucose, and had high blood glucose levels as a result. Increased levels of blood glucose in humans is a hallmark of diabetes.
It’s known in neuroscience that the neurons in question from the sympathetic nervous system control the body’s “flight or fight” response and communicate with connected tissues by releasing a chemical messenger called norepinephrine. The release of norepinephrine also plays an important role in the development and maturation of islets, said Kuruvilla.
Using sympathetic neurons and islet cells grown together in a culture dish, the researchers observed that islet cells move toward the nerves and identified norepinephrine as the nerve signal that causes the movement of the islet cells.
“Seeing how these islet cells were responding to sympathetic neurons both in a dish and the effects of removing the nerves in a whole animal on islet shape and functions were pretty remarkable,” said Borden, lead author of the paper. “It was clear to us that sympathetic neurons were key to how islets were developing, something no one else had shown.”
Kuruvilla said these studies, identifying sympathetic nerves as a critical player in organizing pancreatic cells during development and influencing their later function, could add to a better understanding of treating diabetes in the future. The research also lends support to the value in considering the importance of external factors such as nerves and blood vessels when transplanting islet cells for the treatment of diabetes in patients.
“This study reveals interactions between two co-developing systems, sympathetic neurons and pancreatic islet cells, that has important implications for peripheral organ development, and for regeneration of these tissues following injury or disease,” said Kuruvilla.
(Source: releases.jhu.edu)
Drug improves cognitive function in mouse model of Down syndrome
An existing FDA-approved drug improves cognitive function in a mouse model of Down syndrome, according to a new study by researchers at the Stanford University School of Medicine.
The drug, an asthma medication called formoterol, strengthened nerve connections in the hippocampus, a brain center used for spatial navigation, paying attention and forming new memories, the study said. It also improved contextual learning, in which the brain integrates spatial and sensory information.
Both hippocampal function and contextual learning, which are impaired in Down syndrome, depend on the brain having a good supply of the neurotransmitter norepinephrine. This neurotransmitter sends its signal via several types of receptors on the neurons, including a group called beta-2 adrenergic receptors.
“This study provides the initial proof-of-concept that targeting beta-2 adrenergic receptors for treatment of cognitive dysfunction in Down syndrome could be an effective strategy,” said Ahmad Salehi, MD, PhD, the study’s senior author and a clinical associate professor of psychiatry and behavioral sciences. The study was published online July 2 in Biological Psychiatry.
Down syndrome, which is caused by an extra copy of chromosome 21, results in both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function. As a result, children with Down syndrome fall behind their peers’ cognitive development. In addition, adults with Down syndrome develop Alzheimer’s-type pathology in their brains by age 40. Down syndrome affects about 400,000 people in the United States and 6 million worldwide.
In prior Down syndrome research, scientists have seen deterioration of the brain center that manufactures norepinephrine in both people with Down syndrome and its mouse model. Earlier work by Salehi’s team found that giving a norepinephrine precursor could improve cognitive function in a mouse model genetically engineered to mimic Down syndrome.
(Source: med.stanford.edu)
Brief exercise immediately enhances memory
A short burst of moderate exercise enhances the consolidation of memories in both healthy older adults and those with mild cognitive impairment, scientists with UC Irvine’s Center for the Neurobiology of Learning & Memory have discovered.
Most research has focused on the benefits of a long-term exercise program on overall health and cognitive function with age. But the UCI work is the first to examine the immediate effects of a brief bout of exercise on memory.
In their study, post-doctoral researcher Sabrina Segal and neurobiologists Carl Cotman and Lawrence Cahill had people 50 to 85 years old with and without memory deficits view pleasant images – such as photos of nature and animals – and then exercise on a stationary bicycle for six minutes at 70 percent of their maximum capacity immediately afterward.
One hour later, the participants were given a surprise recall test on the previously viewed images. Results showed a striking enhancement of memory by exercise in both the healthy and cognitively impaired adults, compared with subjects who did not ride the bike.
“We found that a single, short instance of moderately intense exercise particularly improved memory in individuals with memory deficits,” Segal said. “Because of its implications and the need to better understand the mechanism by which exercise may enhance memory, we’re following up this study with an investigation of potential underlying biological factors.”
She believes the improved memory may be related to the exercise-induced release of norepinephrine, a chemical messenger in the brain known to play a strong role in memory modulation. This hypothesis is based on previous work demonstrating that increasing norepinephrine through pharmacological manipulation sharpens memory and that blocking norepinephrine impairs memory.
In the more recent research, Segal and her colleagues discovered that levels of salivary alpha amylase, a biomarker that reflects norepinephrine activity in the brain, significantly increased in participants after exercise. This correlation was especially strong in people with memory impairment.
“The current findings offer a natural and relatively safe alternative to pharmacological interventions for memory enhancement in healthy older individuals as well as those who suffer from cognitive deficits,” Segal noted. “With a growing population of the aged, the need for improvement of quality of life and prevention of mental decline is more important than ever before.”
Study results appear in the November issue (Volume 32, Number 4) of the Journal of Alzheimer’s Disease.
(Source: news.uci.edu)