Posts tagged science

National Institutes of Health researchers used the popular anti-wrinkle agent Botox to discover a new and important role for a group of molecules that nerve cells use to quickly send messages. This novel role for the molecules, called SNARES, may be a missing piece that scientists have been searching for to fully understand how brain cells communicate under normal and disease conditions.

"The results were very surprising," said Ling-Gang Wu, Ph.D., a scientist at NIH’s National Institute of Neurological Disorders and Stroke. "Like many scientists we thought SNAREs were only involved in fusion."

Every day almost 100 billion nerve cells throughout the body send thousands of messages through nearly 100 trillion communication points called synapses. Cell-to-cell communication at synapses controls thoughts, movements, and senses and could provide therapeutic targets for a number of neurological disorders, including epilepsy.

Nerve cells use chemicals, called neurotransmitters, to rapidly send messages at synapses. Like pellets inside shotgun shells, neurotransmitters are stored inside spherical membranes, called synaptic vesicles. Messages are sent when a carrier shell fuses with the nerve cell’s own shell, called the plasma membrane, and releases the neurotransmitter “pellets” into the synapse.

SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) are three proteins known to be critical for fusion between carrier shells and nerve cell membranes during neurotransmitter release.

"Without SNAREs there is no synaptic transmission," said Dr. Wu.

Botulinum toxin, or Botox, disrupts SNAREs. In a study published in Cell Reports, Dr. Wu and his colleagues describe how they used Botox and similar toxins as tools to show that SNAREs may also be involved in retrieving message carrier shells from nerve cell membranes immediately after release.

To study this, the researchers used advanced electrical recording techniques to directly monitor in real time carrier shells being fused with and retrieved from nerve cell membranes while the cells sent messages at synapses. The experiments were performed on a unique synapse involved with hearing called the calyx of Held. As expected, treating the synapses with toxins reduced fusion. However Dr. Wu and his colleagues also noticed that the toxins reduced retrieval.

"The results were very surprising," said Dr. Wu. "Like many scientists we thought SNAREs were only involved in fusion."

For at least a decade scientists have known that carrier shells have to be retrieved before more messages can be sent. Retrieval occurs in two modes: fast and slow. A different group of molecules are known to control the slow mode.

"Until now most scientists thought fusion and retrieval were two separate processes controlled by different sets of molecules", said Dr. Wu.

Nevertheless several studies suggested that one of the SNARE molecules could be involved with both modes.

In this study, Dr. Wu and his colleagues systematically tested this idea to fully understand retrieval. The results showed that all three SNARE proteins may be involved in both fast and slow retrieval.

"Our results suggest that SNAREs link fusion and retrieval," said Dr. Wu.

The results may have broad implications. SNAREs are commonly used by other cells throughout the body to release chemicals. For example, SNAREs help control the release of insulin from pancreas cells, making them a potential target for diabetes treatments. Recent studies suggest that SNAREs may be involved in neurological and psychiatric disorders, such as schizophrenia and spastic ataxia.

"We think SNARES work like this in most nerve cell synapses. This new role could change the way scientists think about how SNAREs are involved in neuronal communication and diseases," said Dr. Wu.

(Source: ninds.nih.gov)

A new study led by University of North Carolina School of Medicine researchers is the first to identify a genetic risk factor for persistent pain after traumatic events such as motor vehicle collision and sexual assault.

In addition, the study contributes further evidence that persistent pain after stressful events has a specific biological basis. A manuscript of the study was published online ahead of print by the journal Pain on April 29.

“Our study findings indicate that mechanisms influencing chronic pain development may be related to the stress response, rather than any specific injury caused by the traumatic event,” said Samuel McLean, MD, MPH, senior author of the study and assistant professor of anesthesiology. “In other words, our results suggest that in some individuals something goes wrong with the body’s ‘fight or flight’ response or the body’s recovery from this response, and persistent pain results.”

The study assessed the role of the hypothalamic-pituitary adrenal (HPA) axis, a physiologic system of central importance to the body’s response to stressful events. The study evaluated whether the HPA axis influences musculoskeletal pain severity six weeks after motor vehicle collision (MVC) and sexual assault. Its findings revealed that variation in the gene encoding for the protein FKBP5, which plays an important role in regulating the HPA axis response to stress, was associated with a 20 percent higher risk of moderate to severe neck pain six weeks after a motor vehicle collision, as well as a greater extent of body pain. The same variant also predicted increased pain six weeks after sexual assault.

"Right now, if an someone comes to the emergency department after a car accident, we don’t have any interventions to prevent chronic pain from developing," McLean said. Similarly, if a woman comes to the emergency department after sexual assault, we have medications to prevent pregnancy or sexually transmitted disease, but no treatments to prevent chronic pain. This is because we understand what causes pregnancy or infection, but we have no idea what the biologic mechanisms are that cause chronic pain. Chronic pain after these events is common and can cause great suffering, and there is an urgent need to understand what causes chronic pain so that we can start to develop interventions. This study is an important first step in developing this understanding."

"In addition, because we don’t understand what causes these outcomes, individuals with chronic pain after traumatic events are often viewed with suspicion, as if they are making up their symptoms for financial gain or having a psychological reaction," McLean said. "An improved understanding of the biology helps with this stigma," McLean said. 

(Source: news.unchealthcare.org)

A team of researchers at the University of Calgary’s Hotchkiss Brain Institute (HBI) have discovered that adult brain cell production might be determined, in part, by the early parental environment. The study suggests that dual parenting may be more beneficial than single parenting.

Scientists studied mouse pups that were raised by either dual or single parents and found that adult cell production in the brain might be triggered by early life experiences. The scientists also found that the increased adult brain cell production varied based on gender. Specifically, female pups raised by two parents had enhanced white matter production as adults, increasing motor coordination and sociability. Male pups raised by dual parents displayed more grey matter production as an adult, which improves learning and memory.

“Our new work adds to a growing body of knowledge, which indicates that early, supportive experiences have long lasting, positive impact on adult brain function,” says Samuel Weiss, PhD, senior author of the study and director of the HBI.

Surprisingly, the advantages of dual parenting were also passed along when these two groups reproduced, even if their offspring were raised by one female. The advantages of dual parenting were thus passed along to the next generation.

To conduct the study, scientists divided mice into three groups i) pups raised to adulthood by one female ii) pups raised to adulthood by one female and one male and iii) pups raised to adulthood by two females. Researchers then waited for the offspring to reach adulthood to find out if there was any impact on brain cell production.

Scientists say that this research provides evidence that, in the mouse model, parenting and the environment directly impact adult brain cell production. While it’s not known at this point, it is possible that similar effects could be seen in other mammals, such as humans. The study is published in the May 1 edition of PLOS ONE.

(Source: ucalgary.ca)

Abuse during childhood is different.

A study of adult civilians with PTSD (post-traumatic stress disorder) has shown that individuals with a history of childhood abuse have distinct, profound changes in gene activity patterns, compared to adults with PTSD but without a history of child abuse.

A team of researchers from Atlanta and Munich probed blood samples from 169 participants in the Grady Trauma Project, a study of more than 5000 Atlanta residents with high levels of exposure to violence, physical and sexual abuse and with high risk for civilian PTSD.

The results were published Monday, April 29 in Proceedings of the National Academy of Sciences, Early Edition.

“These are some of the most robust findings to date showing that different biological pathways may describe different subtypes of a psychiatric disorder, which appear similar at the level of symptoms but may be very different at the level of underlying biology,” says Kerry Ressler, MD, PhD, professor of psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center.

“As these pathways become better understood, we expect that distinctly different biological treatments would be implicated for therapy and recovery from PTSD based on the presence or absence of past child abuse.”

Ressler, a Howard Hughes Medical Institute Investigator, is co-director of the Grady Trauma Project, along with co-author Bekh Bradley, PhD, assistant professor of psychiatry and behavioral sciences at Emory and director of the Trauma Recovery Program at the Atlanta Veterans Affairs Medical Center.

The first author of the paper is Divya Mehta, PhD, a postdoctoral fellow in Munich. The senior author is Elisabeth Binder, MD, PhD, associate professor of psychiatry and behavioral sciences at Emory and group leader at the Max-Planck Institute of Psychiatry in Munich, Germany.

Mehta and her colleagues examined changes in the patterns of which genes were turned on and off in blood cells from patients. They also looked at patterns of methylation, a DNA modification on top of the four letters of the genetic code that causes genes to be ‘silenced’ or made inactive.

Study participants were divided into three groups: people who experienced trauma without developing PTSD, people with PTSD who were exposed to child abuse, and people with PTSD who were not exposed to child abuse.

The researchers were surprised to find that although hundreds of genes had significant changes in activity in the PTSD with and without child abuse groups, there was very little overlap in patterns between these groups. The two groups shared similar symptoms of PTSD, which include intrusive thoughts such as nightmares and flashbacks, avoidance of trauma reminders, and symptoms of hyperarousal and hypervigilance.

The PTSD with child abuse group displayed more changes in genes linked with development of the nervous system and regulation of the immune system, while the PTSD minus child abuse group displayed more changes in genes linked with apoptosis (cell death) and growth rate regulation. In addition, changes in methylation were more frequent in the PTSD with child abuse group. The authors believe that these biological pathways may lead to different mechanisms of PTSD symptom formation within the brain.

The Max Planck/Emory scientists were probing gene activity in blood cells, rather than brain tissue. Similar results have been obtained by researchers studying the influence of child abuse on the brains of people who had committed suicide.

“Traumatic events that happen in childhood are embedded in the cells for a long time,” Binder says. “Not only the disease itself, but the individual’s life experience is important in the biology of PTSD, and this should be to be reflected in the way we treat these disorders.”

(Source: news.emory.edu)

When a pedestrian hears the screech of a car’s brakes, she has to decide whether, and if so, how, to move in response. Is the action taking place blocks away, or 20 feet to the left?

One of the truly primal mechanisms that we depend on every day of our lives — acting on the basis of information gathered by our sense of hearing — is yielding its secrets to modern neuroscience. A team of researchers from Cold Spring Harbor Laboratory (CSHL) today publishes experimental results in the journal Nature which they describe as surprising. The results fill in a key piece of the puzzle about how mammals act on the basis of sound cues.

It’s well known that sounds detected by the ears wind up in a part of the brain called the auditory cortex, where they are translated – transduced – into information that scientists call representations. These representations, in turn, form the informational basis upon which other parts of the brain can make decisions and issue commands for specific actions. What scientists have not understood is what happens between the auditory cortex and portions of the brain that ultimately issue commands, say, for muscles to move in response to the sound of that car’s screeching brakes.

To find out, CSHL Professor Anthony Zador and Dr. Petr Znamenskiy trained rats to listen to sounds and to make decisions based on those sounds. When a high-frequency sound is played, the animals are rewarded if they move to the left. When the sound is low-pitched, the reward is given if the animal moves right.

To the striatum

On the simplest level, says Zador, “we know that sound is coming into the ear; and we know what’s coming out in the end – a decision,” in the form of a muscle movement. The surprise, he says, is the destination of the information used by the animal to perform this task of discriminating between sounds of high and low frequency, as revealed in his team’s experiments.

“It turns out the information passes through a particular subset of neurons in the auditory cortex whose axons wind up in another part of the brain, called the striatum,” says Zador. The classic series of experiments that provided inspiration and a model for this work, performed at Stanford University by William Newsome and colleagues, involved the visual system of primates, and had led Zador to expect by analogy that representations formed in the auditory cortex would lead to other locations within the cortex.

These experiments in rats have implications for how neural circuits make decisions, according to Zador. Even though many neurons in auditory cortex are “tuned” to low or high frequencies, most do not transmit their information directly to the striatum. Rather, their information is transmitted by a much smaller number of neurons in their vicinity, which convey their “votes” directly to the striatum.

“This is like the difference between a direct democracy and a representative democracy, of the type we have in the United States,” Zador explains. “In a direct democracy model of how the auditory cortex conveys information to the rest of the brain, every neuron activated by a low- or high-pitched sound would have a ‘vote.’ Since there is noise in every perception, some minority of neurons will indicate ‘low’ when the sound is in fact ‘high,’ and vice-versa. In the direct democracy model, the information sent to the striatum for further action would be the equivalent of a simple sum of all these votes.

“In contrast – and this is what we found to be the case – the neurons registering ‘high’ and ‘low’ are represented by a specialized subset of neurons in their local area, which we might liken to members of Congress or the Electoral College: these in turn transmit the votes of the larger population to the place — in this case the auditory striatum — in which decisions are made and actions are taken.”

(Source: cshl.edu)

While the search continues for the Fountain of Youth, researchers may have found the body’s “fountain of aging”: the brain region known as the hypothalamus. For the first time, scientists at Albert Einstein College of Medicine of Yeshiva University report that the hypothalamus of mice controls aging throughout the body. Their discovery of a specific age-related signaling pathway opens up new strategies for combating diseases of old age and extending lifespan. The paper was published today in the online edition of Nature.

“Scientists have long wondered whether aging occurs independently in the body’s various tissues or if it could be actively regulated by an organ in the body,” said senior author Dongsheng Cai, M.D., Ph.D., professor of molecular pharmacology at Einstein. “It’s clear from our study that many aspects of aging are controlled by the hypothalamus. What’s exciting is that it’s possible — at least in mice — to alter signaling within the hypothalamus to slow down the aging process and increase longevity.”

The hypothalamus, an almond-sized structure located deep within the brain, is known to have fundamental roles in growth, development, reproduction, and metabolism. Dr. Cai suspected that the hypothalamus might also play a key role in aging through the influence it exerts throughout the body.

“As people age,” he said, “you can detect inflammatory changes in various tissues. Inflammation is also involved in various age-related diseases, such as metabolic syndrome, cardiovascular disease, neurological disease and many types of cancer.” Over the past several years, Dr. Cai and his research colleagues showed that inflammatory changes in the hypothalamus can give rise to various components of metabolic syndrome (a combination of health problems that can lead to heart disease and diabetes).    

To find out how the hypothalamus might affect aging, Dr. Cai decided to study hypothalamic inflammation by focusing on a protein complex called NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). “Inflammation involves hundreds of molecules, and NF-κB sits right at the center of that regulatory map,” he said.

In the current study, Dr. Cai and his team demonstrated that activating the NF-κB pathway in the hypothalamus of mice significantly accelerated the development of aging, as shown by various physiological, cognitive, and behavioral tests. “The mice showed a decrease in muscle strength and size, in skin thickness, and in their ability to learn — all indicators of aging. Activating this pathway promoted systemic aging that shortened the lifespan,” he said.

Conversely, Dr. Cai and his group found that blocking the NF-κB pathway in the hypothalamus of mouse brains slowed aging and increased median longevity by about 20 percent, compared to controls.

The researchers also found that activating the NF-κB pathway in the hypothalamus caused declines in levels of gonadotropin-releasing hormone (GnRH), which is synthesized in the hypothalamus. Release of GnRH into the blood is usually associated with reproduction. Suspecting that reduced release of GnRH from the brain might contribute to whole-body aging, the researchers injected the hormone into a hypothalamic ventricle (chamber) of aged mice and made the striking observation that the hormone injections protected them from the impaired neurogenesis (the creation of new neurons in the brain) associated with aging. When aged mice received daily GnRH injections for a prolonged period, this therapy exerted benefits that included the slowing of age-related cognitive decline, probably the result of neurogenesis.  

According to Dr. Cai, preventing the hypothalamus from causing inflammation and increasing neurogenesis via GnRH therapy are two potential strategies for increasing lifespan and treating age-related diseases. This technology is available for licensing.

(Source: einstein.yu.edu)

A small group of elusive neurons in the brain’s cortex play a big role in ALS (amyotrophic lateral sclerosis), a swift and fatal neurodegenerative disease that paralyzes its victims. But the neurons have always been difficult to study because there are so few of them and they look so similar to other neurons in the cortex.

In a new preclinical study, a Northwestern Medicine® scientist has isolated the motor neurons in the brain that die in ALS and, for the first time, dressed them in a green fluorescent jacket. Now they’re impossible to miss and easy to study.

The cells slide on neon jackets when they are born and continue to wear them as they age and become sick. As a result, scientists will now be able to track what goes wrong in these cells to cause their deaths and be able to search for effective treatments.

"We have developed the tool to investigate what makes these cells become vulnerable and sick," said Hande Ozdinler, senior author of the study and assistant professor of neurology at Northwestern University Feinberg School of Medicine. "This was not possible before."

Ozdinler and colleagues also identified the motor neurons that don’t die, enabling scientists to study what protects them.

The study will be published in the Journal of Neuroscience on May 1.

ALS, also known as Lou Gehrig’s disease, causes the death of muscle-controlling nerve cells in the brain and spinal cord (motor neurons). It results in rapidly progressing paralysis and death usually within three to five years of the onset of symptoms.

There are about 75,000 upper motor neurons affected in ALS out of some 2 billion cells in the brain. Previously, the only way to study the upper motor neurons was to extract them through surgery, a difficult process that was beyond the scope of most scientists and still didn’t allow examination of the ailing neurons at various stages of the disease.

"You couldn’t study them at the cellular level, so the research field ignored them," Ozdinler said. She is one of the few scientists in the country who studies cortical motor neurons. Most of ALS research has focused on the death of motor neurons in the spinal cord.

Key puzzle piece: Why ALS moves so swiftly

But the brain’s motor neurons are a key piece of the ALS puzzle. Their disintegration explains why the disease advances more swiftly than other neurodegenerative diseases. It had previously been thought that the spinal motor neurons died first and their demise led to the secondary death of the brain’s motor neurons. But Ozdinler’s recent research showed that the motor neurons in the brain and spinal cord die simultaneously.

"The whole system collapses at once," Ozdinler said. "It’s degeneration from both ends which is why the disease moves so swiftly."

Every voluntary movement is initiated and modulated by upper motor neurons — answering a cell phone, typing an email, walking to the store. The upper motor neurons tell the spinal motor neurons what to do. In ALS, both the directing neurons and the neurons that create the movement disintegrate at the same time.

Finding the light that never goes out

Ozdinler spent the last four years figuring out how to permanently sheath cortical motor neurons in fluorescence.

Although scientists can flag spinal cord motor neurons in fluorescence, it wears off as the neuron ages because the process uses an embryonic gene. Ozdinler wanted a longer lasting effect so scientists could study the neuron as it ages and develops ALS. She sorted through 6,000 upper motor neuron genes that are vulnerable to ALS before she found one — UCHL1 — that is expressed through adulthood.

She used that gene — which had been cloned with the fluorescence molecule — and created a mouse model whose upper motor neurons shimmer in green. Then she mated that mouse with an ALS transgenic mouse model. The result is a mouse with fluorescent diseased motor neurons in the brain.

"Now we have a model of one motor neuron population that dies and one that is resistant," Ozdinler said. "That’s the perfect experiment. You can ask what does this neuron have that makes it resistant and what does the other one have that makes it vulnerable? That’s what we will find out."

Marina Yasvoina, a graduate student, and Baris Genc, a postdoctoral fellow, both in Ozdinler’s lab, are the lead authors of the paper. Ozdinler collaborated with Gordon Shepherd, associate professor of physiology, and C.J. Heckman, professor in physiology, both at Feinberg.

"This work was possible thanks to the collaborative nature of Northwestern," Ozdinler said.

(Source: eurekalert.org)