Posts tagged science

About a dozen years ago, scientists discovered that a hormone called ghrelin enhances appetite. Dubbed the “hunger hormone,” ghrelin was quickly targeted by drug companies seeking treatments for obesity — none of which have yet panned out.

MIT neuroscientists have now discovered that ghrelin’s role goes far beyond controlling hunger. The researchers found that ghrelin released during chronic stress makes the brain more vulnerable to traumatic events, suggesting that it may predispose people to posttraumatic stress disorder (PTSD).

Drugs that reduce ghrelin levels, originally developed to try to combat obesity, could help protect people who are at high risk for PTSD, such as soldiers serving in war, says Ki Goosens, an assistant professor of brain and cognitive sciences at MIT, and senior author of a paper describing the findings in the Oct. 15 online edition of Molecular Psychiatry.

“Perhaps we could give people who are going to be deployed into an active combat zone a ghrelin vaccine before they go, so they will have a lower incidence of PTSD. That’s exciting because right now there’s nothing given to people to prevent PTSD,” says Goosens, who is also a member of MIT’s McGovern Institute for Brain Research.

Lead author of the paper is Retsina Meyer, a recent MIT PhD recipient. Other authors are McGovern postdoc Anthony Burgos-Robles, graduate student Elizabeth Liu, and McGovern research scientist Susana Correia.

Stress and fear

Stress is a useful response to dangerous situations because it provokes action to escape or fight back. However, when stress is chronic, it can produce anxiety, depression and other mental illnesses.

At MIT, Goosens discovered that one brain structure that is especially critical for generating fear, the amygdala, has a special response to chronic stress. The amygdala produces large amounts of growth hormone during stress, a change that seems not to occur in other brain regions.

In the new paper, Goosens and her colleagues found that the release of the growth hormone in the amygdala is controlled by ghrelin, which is produced primarily in the stomach and travels throughout the body, including the brain.

Ghrelin levels are elevated by chronic stress. In humans, this might be produced by factors such as unemployment, bullying, or loss of a family member. Ghrelin stimulates the secretion of growth hormone from the brain; the effects of growth hormone from the pituitary gland in organs such as the liver and bones have been extensively studied. However, the role of growth hormone in the brain, particularly the amygdala, is not well known.

The researchers found that when rats were given either a drug to stimulate the ghrelin receptor or gene therapy to overexpress growth hormone over a prolonged period, they became much more susceptible to fear than normal rats. Fear was measured by training all of the rats to fear an innocuous, novel tone. While all rats learned to fear the tone, the rats with prolonged increased activity of the ghrelin receptor or overexpression of growth hormone were the most fearful, assessed by how long they froze after hearing the tone. Blocking the cell receptors that interact with ghrelin or growth hormone reduced fear to normal levels in chronically stressed rats.

When rats were exposed to chronic stress over a prolonged period, their circulating ghrelin and amygdalar growth hormone levels also went up, and fearful memories were encoded more strongly. This is similar to what the researchers believe happens in people who suffer from PTSD.

“When you have people with a history of stress who encounter a traumatic event, they are more likely to develop PTSD because that history of stress has altered something about their biology. They have an excessively strong memory of the traumatic event, and that is one of the things that drives their PTSD symptoms,” Goosens says.

New drugs, new targets

Over the last century, scientists have described the hypothalamic-pituitary-adrenal (HPA) axis, which produces adrenaline, cortisol (corticosterone in rats), and other hormones that stimulate “fight or flight” behavior. Since then, stress research has focused almost exclusively on the HPA axis.

After discovering ghrelin’s role in stress, the MIT researchers suspected that ghrelin was also linked to the HPA axis. However, they were surprised to find that when the rats’ adrenal glands — the source of corticosterone, adrenaline, and noradrenaline — were removed, the animals still became overly fearful when chronically stressed. The authors also showed that repeated ghrelin-receptor stimulation did not trigger release of HPA hormones, and that blockade of the ghrelin receptor did not blunt release of HPA stress hormones. Therefore, the ghrelin-initiated stress pathway appears to act independently of the HPA axis. “That’s important because it gives us a whole new target for stress therapies,” Goosens says.

Pharmaceutical companies have developed at least a dozen possible drug compounds that interfere with ghrelin. Many of these drugs have been found safe for humans, but have not been shown to help people lose weight. The researchers believe these drugs could offer a way to vaccinate people entering stressful situations, or even to treat people who already suffer from PTSD, because ghrelin levels remain high long after the chronic stress ends.

PTSD affects about 7.7 million American adults, including soldiers and victims of crimes, accidents, or natural disasters. About 40 to 50 percent of patients recover within five years, Meyer says, but the rest never get better.

The researchers hypothesize that the persistent elevation of ghrelin following trauma exposure could be one of the factors that maintain PTSD. “So, could you immediately reverse PTSD? Maybe not, but maybe the ghrelin could get damped down and these people could go through cognitive behavioral therapy, and over time, maybe we can reverse it,” Meyer says.

Working with researchers at Massachusetts General Hospital, Goosens’ lab is now planning to study ghrelin levels in human patients suffering from anxiety and fear disorders. They are also planning a clinical trial of a drug that blocks ghrelin to see if it can prevent relapse of depression.

(Source: web.mit.edu)

Scientists at the University of Washington have used genetic engineering to identify a population of neurons that tell the brain to shut off appetite. Their study, “Genetic identification of a neural circuit that suppresses appetite,” was published Oct. 13 in Nature.

To identify these neurons, or cells that process and transmit information in the brain, researchers first considered what makes an animal lose its appetite. There are a number of natural reasons, including infection, nausea, pain or simply having eaten too much already.

Nerves within the gut that are distressed or insulted send information to the brain through the vagus nerve. Appetite is suppressed when these messages activate specific neurons – ones that contain CGRP, (calcitonin gene-related peptide) in a region of the brain called the parabrachial nucleus.

In mouse trials, researchers used genetic techniques and viruses to introduce light-activatable proteins into CGRP neurons. Activation of these proteins excites the cells to transmit chemical signals to other regions of the brain. When they activated the CGRP neurons with a laser, the hungry mice immediately lost their appetite and walked away from their liquid diet (Ensure); when the laser was turned off, the mice resumed drinking the liquid diet.

"These results demonstrate that activation of the CGRP-expressing neurons regulates appetite. This is a nice example of how the brain responds to unfavorable conditions in the body, such as nausea caused by food poisoning" said Richard Palmiter, UW professor of biochemistry and investigator of the Howard Hughes Medical Institute.

Using a similar approach, neurons in other brain regions have been identified that can stimulate the appetite of mice that are not hungry. Researchers hope to identify the complete neural circuit (wiring diagram) in the brain that regulates feeding behavior. By identifying these neural circuits, scientists may be able to design therapies that promote or decrease appetite.

(Source: eurekalert.org)

The brain is plastic - adapting to the hundreds of experiences in our daily lives by reorganizing pathways and making new connections between nerve cells. This plasticity requires that memories of new information and experiences are formed fast. So fast that the body has a special mechanism, unique to nerve cells, that enables memories to be made rapidly. In a new study from The Montreal Neurological Institute and Hospital, The Neuro, McGill University with colleagues at the Université de Montréal, researchers have discovered that nerve cells have a special ‘pre-assembly’ technique to expedite the manufacture of proteins at nerve cell connections (synapses), enabling the brain to rapidly form memories and be plastic.

Making a memory requires the production of proteins at synapses. These proteins then change the strength of the connection or pathway. In nerve cells the production process for memory proteins is already pre-assembled at the synapse but stalled just before completion, awaiting the proper signals to finish, thereby speeding up the entire process. When it comes time to making the memory, the process is switched on and the protein is made in a flash. The mechanism is analogous to a pre-fab home, or pre-made pancake batter that is assembled in advance and then quickly completed in the correct location at the correct time.

“It’s not only important to make proteins in the right place but, it’s also important not to make the protein when it’s the wrong time,” says Dr. Wayne Sossin, neuroscientist at The Neuro and senior investigator on the paper. “This is especially important with nerve cells in the brain, as you only want the brain to make precise connections. If this process is indiscriminate, it leads to neurological disease. This mechanism to control memory protein synthesis solves two problems: 1) how to make proteins only at the right time and 2) how to make proteins as quickly as possible in order to tightly associate the synaptic change with the experience/memory.

Making proteins from genetic material involves two major steps [a Nobel prize was awarded for the identification of the cell’s protein-making process]. In the first step, called transcription, the information in DNA that is stored and protected within the centre of the cell is copied to a messenger RNA (mRNA) – this copy is then moved to where it is needed in the cell. In the second step, called translation, the mRNA is used as a template of genetic information and ‘read’ by little machines called ribosomes, which decode the mRNA sequence and stitch together the correct amino acids to form the protein.

Dr. Sossin’s group at The Neuro has discovered that the mRNA travels to the synapse already attached to the ribosome, with the protein production process stopped just before completion of the product (at the elongation/termination step of translation, where amino acids are being assembled into protein). The ‘pre-assembly’ process then waits for synaptic signals before re-activating to produce a lot of proteins quickly in order to form a memory. “Our results reveal a new mechanism underlying translation-dependent synaptic plasticity, which is dysregulated in neurodevelopmental and psychiatric pathologies”, added Dr. Sossin. “Understanding the pathways involved may provide new therapeutic targets for neurodevelopmental disorders. “

(Source: mcgill.ca)

A brain region activated when people are asked to perform mathematical calculations in an experimental setting is similarly activated when they use numbers — or even imprecise quantitative terms, such as “more than”— in everyday conversation, according to a study by Stanford University School of Medicine scientists.

Using a novel method, the researchers collected the first solid evidence that the pattern of brain activity seen in someone performing a mathematical exercise under experimentally controlled conditions is very similar to that observed when the person engages in quantitative thought in the course of daily life.

“We’re now able to eavesdrop on the brain in real life,” said Josef Parvizi, MD, PhD, associate professor of neurology and neurological sciences and director of Stanford’s Human Intracranial Cognitive Electrophysiology Program. Parvizi is the senior author of the study, published Oct. 15 in Nature Communications. The study’s lead authors are postdoctoral scholar Mohammad Dastjerdi, MD, PhD, and graduate student Muge Ozker.

The finding could lead to “mind-reading” applications that, for example, would allow a patient who is rendered mute by a stroke to communicate via passive thinking. Conceivably, it could also lead to more dystopian outcomes: chip implants that spy on or even control people’s thoughts.

“This is exciting, and a little scary,” said Henry Greely, JD, the Deane F. and Kate Edelman Johnson Professor of Law and steering committee chair of the Stanford Center for Biomedical Ethics, who played no role in the study but is familiar with its contents and described himself as “very impressed” by the findings. “It demonstrates, first, that we can see when someone’s dealing with numbers and, second, that we may conceivably someday be able to manipulate the brain to affect how someone deals with numbers.”

The researchers monitored electrical activity in a region of the brain called the intraparietal sulcus, known to be important in attention and eye and hand motion. Previous studies have hinted that some nerve-cell clusters in this area are also involved in numerosity, the mathematical equivalent of literacy.

However, the techniques that previous studies have used, such as functional magnetic resonance imaging, are limited in their ability to study brain activity in real-life settings and to pinpoint the precise timing of nerve cells’ firing patterns. These studies have focused on testing just one specific function in one specific brain region, and have tried to eliminate or otherwise account for every possible confounding factor. In addition, the experimental subjects would have to lie more or less motionless inside a dark, tubular chamber whose silence would be punctuated by constant, loud, mechanical, banging noises while images flashed on a computer screen.

“This is not real life,” said Parvizi. “You’re not in your room, having a cup of tea and experiencing life’s events spontaneously.” A profoundly important question, he said, is: “How does a population of nerve cells that has been shown experimentally to be important in a particular function work in real life?”

His team’s method, called intracranial recording, provided exquisite anatomical and temporal precision and allowed the scientists to monitor brain activity when people were immersed in real-life situations. Parvizi and his associates tapped into the brains of three volunteers who were being evaluated for possible surgical treatment of their recurring, drug-resistant epileptic seizures.

The procedure involves temporarily removing a portion of a patient’s skull and positioning packets of electrodes against the exposed brain surface. For up to a week, patients remain hooked up to the monitoring apparatus while the electrodes pick up electrical activity within the brain. This monitoring continues uninterrupted for patients’ entire hospital stay, capturing their inevitable repeated seizures and enabling neurologists to determine the exact spot in each patient’s brain where the seizures are originating.

During this whole time, patients remain tethered to the monitoring apparatus and mostly confined to their beds. But otherwise, except for the typical intrusions of a hospital setting, they are comfortable, free of pain and free to eat, drink, think, talk to friends and family in person or on the phone, or watch videos.

The electrodes implanted in patients’ heads are like wiretaps, each eavesdropping on a population of several hundred thousand nerve cells and reporting back to a computer.

In the study, participants’ actions were also monitored by video cameras throughout their stay. This allowed the researchers later to correlate patients’ voluntary activities in a real-life setting with nerve-cell behavior in the monitored brain region.

As part of the study, volunteers answered true/false questions that popped up on a laptop screen, one after another. Some questions required calculation — for instance, is it true or false that 2+4=5? — while others demanded what scientists call episodic memory — true or false: I had coffee at breakfast this morning. In other instances, patients were simply asked to stare at the crosshairs at the center of an otherwise blank screen to capture the brain’s so-called “resting state.”

Consistent with other studies, Parvizi’s team found that electrical activity in a particular group of nerve cells in the intraparietal sulcus spiked when, and only when, volunteers were performing calculations.

Afterward, Parvizi and his colleagues analyzed each volunteer’s daily electrode record, identified many spikes in intraparietal-sulcus activity that occurred outside experimental settings, and turned to the recorded video footage to see exactly what the volunteer had been doing when such spikes occurred.

They found that when a patient mentioned a number — or even a quantitative reference, such as “some more,” “many” or “bigger than the other one” — there was a spike of electrical activity in the same nerve-cell population of the intraparietal sulcus that was activated when the patient was doing calculations under experimental conditions.

That was an unexpected finding. “We found that this region is activated not only when reading numbers or thinking about them, but also when patients were referring more obliquely to quantities,” said Parvizi.

“These nerve cells are not firing chaotically,” he said. “They’re very specialized, active only when the subject starts thinking about numbers. When the subject is reminiscing, laughing or talking, they’re not activated.” Thus, it was possible to know, simply by consulting the electronic record of participants’ brain activity, whether they were engaged in quantitative thought during nonexperimental conditions.

Any fears of impending mind control are, at a minimum, premature, said Greely. “Practically speaking, it’s not the simplest thing in the world to go around implanting electrodes in people’s brains. It will not be done tomorrow, or easily, or surreptitiously.”

Parvizi agreed. “We’re still in early days with this,” he said. “If this is a baseball game, we’re not even in the first inning. We just got a ticket to enter the stadium.”

(Source: med.stanford.edu)

Neurons that process sensory information such as touch and vision are arranged in precise, well-characterized maps that are crucial for translating perception into understanding. A study published by Cell Press on October 14 in the journal Developmental Cell reveals that the actual act of birth in mice causes a reduction in a brain chemical called serotonin in the newborn mice, triggering sensory maps to form. The findings shed light on the key role of a dramatic environmental event in the development of neural circuits and reveal that birth itself is one of the triggers that prepares the newborn for survival outside the womb.

"Our results clearly demonstrate that birth has active roles in brain formation and maturation," says senior study author Hiroshi Kawasaki of Kanazawa University in Japan. "We found that birth regulates neuronal circuit formation not only in the somatosensory system but also in the visual system. Therefore, it seems reasonable to speculate that birth actually plays a wider role in various brain regions."

Mammals ranging from mice to humans have brain maps that represent various types of sensory information. In a region of the rodent brain known as the barrel cortex, neurons that process tactile information from whiskers are arranged in a map corresponding to the spatial pattern of whiskers on the snout, with neighboring columns of neurons responding to stimulation of adjacent whiskers. Although previous studies have shown that the neurotransmitter serotonin influences the development of sensory maps, its specific role during normal development has not been clear until now.

In this new study, Kawasaki and his team find that the birth of mouse pups leads to a drop in serotonin levels in the newborn’s brain, triggering the formation of neural circuits in the barrel cortex and in the lateral geniculate nucleus (LGN), a brain region that processes visual information. When mice were treated with drugs that either induced preterm birth or decreased serotonin signaling, neural circuits in the barrel cortex as well as in the LGN formed more quickly. Conversely, neural circuits in the barrel cortex failed to form when the mice were treated with a drug that increased serotonin signaling, suggesting that a reduction in levels of this neurotransmitter is crucial for sensory map formation.

Because serotonin also plays a key role in mental disorders, it is possible that abnormalities in birth processes and the effects on subsequent serotonin signaling and brain development could increase the risk of psychiatric diseases. “Uncovering the entire picture of the downstream signaling pathways of birth may lead to the development of new therapeutic methods to control the risk of psychiatric diseases induced by abnormal birth,” Kawasaki says.

(Source: eurekalert.org)

Faced with news of suicides and brain damage in former professional football players, geneticist Barry Ganetzky bemoaned the lack of model systems for studying the insidious and often delayed consequences linked to head injuries.

Then he remembered an unexplored observation from nearly 40 years ago: a sharp strike to a vial of fruit flies left them temporarily stunned, only to recover a short time later. At the time he had marked it only as a curiosity.

Now a professor of genetics at UW–Madison, Ganetzky is turning his accidental discovery into a way to study traumatic brain injury (TBI). He and David Wassarman, a UW professor of cell and regenerative biology, report this week (Oct. 14) in the Proceedings of the National Academy of Sciences on the first glimpses of the genetic underpinnings of susceptibility to brain injuries and links to human TBI.

TBIs occur when a force on the body jostles the brain inside the head, causing it to strike the inside of the skull. More than 1.7 million TBIs occur each year in the United States, about one-third due to falls and the rest mainly caused by car crashes, workplace accidents, and sports injuries. TBIs are also a growing issue in combat veterans exposed to explosions.

In many cases, the immediate effects of TBI are temporary and may seem mild — confusion, dizziness or loss of coordination, headaches, vision problems. But over time, impacts may lead to neurodegeneration and related symptoms, including memory loss, cognitive problems, severe depression, or Alzheimer’s-like dementia. Together TBIs cost tens of billions of dollars annually in medical expenses and indirect costs such as lost productivity.

Though TBIs can be classified from “mild” to “severe” based on symptoms, there is a poor understanding of the underlying medical causes.

“Unlike many important medical problems — high blood pressure, cancer, diabetes, heart disease — where we know something about the biology, we know almost nothing about TBI,” Ganetzky says. “Why does a blow to the head cause epilepsy? Or how does it lead down the road to neurodegeneration? Nobody has answers to those questions — in part, because it’s really hard to study in humans.”

Enter the fruit fly. The fly brain is encased in a hard cuticle analogous to the skull, and the basic mechanisms affecting nervous system function are the same in flies and mammals. In the new study, Ganetzky and Wassarman describe a way to reproducibly inflict traumas that seem to mimic the injuries and symptoms of human TBI.

“Now we have a system where we can look at the variables that are the inputs into TBI and determine the relative contributions of each to the pathological outcomes. That’s the real power of the flies,” says Wassarman.

As with humans, few flies die from the immediate impact. Afterward, though, the treated flies show many of the same physical consequences as humans who sustain concussions or other TBIs, including temporary incapacitation, loss of coordination and activation of the innate immune response in the short term, followed by neurodegeneration and sometimes an early death.

The researchers, led by Rebeccah Katzenberger, senior research specialist in the UW Department of Cell and Regnerative Biology, also found that age seems to play an important role. Older flies are more susceptible than younger ones to the effects of the impact and, Wassarman says, many of the outcomes of TBI are very similar to normal aging processes.

With this model, the researchers say, they can now draw on the vast collection of genetic tools and techniques available for fruit flies to probe the underlying drivers of damage.

“What we really want is to understand the immediate and long term consequences in cellular and molecular terms,” says Ganetzky. “From that understanding we can proceed in a more directed way to diagnostics and therapeutics.”

One of the key things they have already identified is the crucial role genetics plays in determining the outcome of an injury, revealed by the high degree of variability seen among different strains of flies. This finding may explain why all potential TBI drugs to date have failed in clinical trials despite showing promise in individual rodent models.

As Wassarman explains, “The heart of the problem of solving traumatic brain injury is that we’re all different.”

They are continuing to develop the model through large-scale genetic analysis and have already found that different sets of genes correlate with susceptibility in flies of different ages. With their system, they can also examine the effects of repeated injuries.

Ganetzky sees tremendous potential for developing applications from the fly-based approach and the Wisconsin Alumni Research Foundation (WARF) has filed for patent protection on the discovery.

“These exciting findings that we can study traumatic brain injury — a disorder of growing concern for athletes, the military, and parents — in the elegantly simple model of fruit flies is sure to interest those researchers and companies looking to address this concern,” says Jennifer Gottwald, WARF licensing manager. “The use of this model can accelerate the work of the medical research community in finding treatments and therapies to help patients.”

(Source: news.wisc.edu)

Recent scientific findings have raised the fear that young athletes may fare worse after sustaining a sports-related concussion than older athletes.

Researchers in the Vanderbilt Sports Concussion Center compared symptoms associated with concussion in middle- and high-school aged athletes with those in college-age athletes and found no significant differences between the two age groups.

The study, “Does age affect symptom recovery after sports-related concussion? A study of high school and college athletes,” was published online Sept. 24 ahead of print in the Journal of Neurosurgery: Pediatrics.

Lead authors were Vanderbilt University School of Medicine students Young Lee and Mitchell Odom. Other researchers were Scott Zuckerman, M.D., Gary Solomon, Ph.D., and Allen Sills, M.D.

In this retrospective study, the researchers reviewed a database containing information on pre-concussion and post-concussion symptoms in two different age groups: younger (13-16 years old) and older (18-22 years old). Athletes (92 in each group) were evenly matched with respect to gender, number of previous concussions, and time to the first post-concussion test.

Each athlete completed individual pre- and post-concussion questionnaires that covered a variety of symptoms associated with concussion, some of which were headache, nausea, dizziness, fatigue, sleep problems, irritability and difficulties with concentration or memory. Each athlete’s post-concussion scores were compared to his or her own individual baseline scores.

The number or severity of symptoms cited at baseline and post-concussion showed no significant difference between the two age groups. Symptoms returned to baseline levels within 30 days after concussion in 95.7 percent of the younger athletes and in 96.7 percent of the older athletes.

“In the evaluation of sports-related concussion, it is imperative to parse out different ways of assessing outcomes: neurocognitive scores versus symptom endorsement versus balance issues, school performance, etc,” Zuckerman said.

“It appears that symptoms may not be a prominent driver when assessing outcomes of younger versus older athletes. We hope that our study can add insight into the evaluation of youth athletes after sports-related concussion.”

(Source: news.vanderbilt.edu)