Novel storage mechanism allows command, control of memory

Introductions at a party seemingly go in one ear and out the other. However, if you meet someone two or three times during the party, you are more likely to remember his or her name. Your brain has taken a short-term memory - the introduction - and converted it into a long-term one. The molecular key to this activity is mTORC2 (mammalian target of rapamycin complex 2), according to researchers at Baylor College of Medicine in an article that appeared online in the journal Nature Neuroscience.

"Memory consolidation is a fundamental process," said Dr. Mauro Costa-Mattioli, assistant professor of neuroscience at BCM and corresponding author of the report. "Memories are at the center of our identity. They allow us to remember people, places and events for a long time, even a lifetime. Understanding the precise mechanism by which memories are stored in the brain will lead to the development of new treatments for conditions associated with memory loss".

Actin fibers

For the last five decades, neuroscientists have known that making long-lasting memories is dependent on the ability of brain cells (neurons) to synthesize new proteins. In their studies, Costa-Mattioli and his colleagues found a new mechanism by which memories are stored in the brain. The newly discovered mTORC2 regulates memory formation by modulating actin fibers, an important component of the architectural structure of the neuron.

"These actin fibers allow long-lasting changes in synaptic strength and ultimately long-term memories," said Wei Huang, a BCM graduate student and first author in the study.

Using genetically-engineered mice, the researchers found that turning off mTORC2 in the hippocampus (a crucial region required for memory formation) and surrounding areas allowed the animals to have a normal short-term memory, but prevented them from forming long-term memories. Similar to human patients with injury in the hippocampus, these mutant mice were no longer able to form new long-lasting memories.

According to Costa-Mattioli’s findings, mTORC2’s role is evolutionarily conserved and likely relevant to humans. Like mTORC2-deficient mice, fruit flies lacking TORC2 show defective long-term memory storage.

"Given that flies and mice last shared a common ancestor 500 million years ago, it is quite remarkable and telling that the function of mTORC2 in the regulation of memory is indeed maintained," said Dr. Gregg Roman, director of the Biology of Behavior Institute at the University of Houston, who contributed to the fly experiments.

Form long-term memories

The Holy Grail of memory neuroscience and to a certain extent, of industry efforts to produce a “smart drug,” has been the identification of molecules that promote the formation of long-term memory, said Costa-Mattioli. “We therefore wondered whether by turning on mTORC2 or even actin polymerization itself, we could form long-term memories more easily,” said Dr. Ping Jun Zhu, assistant professor of neuroscience at BCM, co-first author and senior scientist in Costa-Mattioli’s lab.

The team has identified a small molecule (a drug) that by activating mTORC2 and consequently actin polymerization enhances not only the synaptic strength between nerve cells but also long-term memory formation. In addition, the authors found that by directly promoting actin polymerization, with a second drug, long-term memory is generated more easily.

Costa-Mattioli’s team has identified two memory-enhancing drugs, but can they enhance memory in people? It is perhaps too early to say.

Huang said, “mTORC2, as far as we know, is really a new potential target for therapeutic treatments of human disorders. In the next few years, I predict we will see a lot of studies focusing on mTORC2 as a target.”

Memory cocktail

Costa-Mattioli’s short-term goals are to identify human cognitive disorders in which mTORC2 activity is dysfunctional and to see whether its restoration can return to normal impaired memory function in aging or even Alzheimer’s disease. But a small molecule alone might not do the job. Similar to the treatments for HIV or cancer, he believes that a combination of small molecules improving different aspects of memory formation will be required to efficiently treat cognitive disorders.

"We should start thinking about an efficient ‘memory cocktail’ rather than a single ‘memory pill.’ One molecule alone might not be enough. We may be years away from a decisive treatment, but I believe we are definitely on the right path," he said.

Others who took part in this work include Hongyi Zhou, Loredana Stoica and Mauricio Galiano, all of BCM, Krešimir Krnjević of McGill University in Montreal, Canada; and Shixing Zhang of the University of Houston.

(Image: Shutterstock)

Mental picture of others can be seen using fMRI

It is possible to tell who a person is thinking about by analyzing images of his or her brain. Our mental models of people produce unique patterns of brain activation, which can be detected using advanced imaging techniques according to a study by Cornell University neuroscientist Nathan Spreng and his colleagues.

"When we looked at our data, we were shocked that we could successfully decode who our participants were thinking about based on their brain activity," said Spreng, assistant professor of human development in Cornell’s College of Human Ecology.

Understanding and predicting the behavior of others is a key to successfully navigating the social world, yet little is known about how the brain actually models the enduring personality traits that may drive others’ behavior, the authors say. Such ability allows us to anticipate how someone will act in a situation that may not have happened before.

To learn more, the researchers asked 19 young adults to learn about the personalities of four people who differed on key personality traits. Participants were given different scenarios (i.e. sitting on a bus when an elderly person gets on and there are no seats) and asked to imagine how a specified person would respond. During the task, their brains were scanned using functional magnetic resonance imaging (fMRI), which measures brain activity by detecting changes in blood flow.

They found that different patterns of brain activity in the medial prefrontal cortex (mPFC) were associated with each of the four different personalities. In other words, which person was being imagined could be accurately identified based solely on the brain activation pattern.

The results suggest that the brain codes the personality traits of others in distinct brain regions and this information is integrated in the medial prefrontal cortex (mPFC) to produce an overall personality model used to plan social interactions, the authors say.

"Prior research has implicated the anterior mPFC in social cognition disorders such as autism and our results suggest people with such disorders may have an inability to build accurate personality models," said Spreng. "If further research bears this out, we may ultimately be able to identify specific brain activation biomarkers not only for diagnosing such diseases, but for monitoring the effects of interventions."

Human Connectome Project releases major data set on brain connectivity

The Human Connectome Project, a five-year endeavor to link brain connectivity to human behavior, has released a set of high-quality imaging and behavioral data to the scientific community. The project has two major goals: to collect vast amounts of data using advanced brain imaging methods on a large population of healthy adults, and to make the data freely available so that scientists worldwide can make further discoveries about brain circuitry.

The initial data release includes brain imaging scans plus behavioral information — individual differences in personality, cognitive capabilities, emotional characteristics and perceptual function — obtained from 68 healthy adult volunteers. Over the next several years, the number of subjects studied will increase steadily to a final target of 1,200. The initial release is an important milestone because the new data have much higher resolution in space and time than data obtained by conventional brain scans.

The Human Connectome Project (HCP) consortium is led by David C. Van Essen, PhD, Alumni Endowed Professor at Washington University School of Medicine in St. Louis, and Kamil Ugurbil, PhD, Director of the Center for Magnetic Resonance Research and the McKnight Presidential Endowed Chair Professor at the University of Minnesota.

“By making this unique data set available now, and continuing with regular data releases every quarter, the Human Connectome Project is enabling the scientific community to immediately begin exploring relationships between brain circuits and individual behavior,” says Van Essen. “The HCP will have a major impact on our understanding of the healthy adult human brain, and it will set the stage for future projects that examine changes in brain circuits underlying the wide variety of brain disorders afflicting humankind.”

The consortium includes more than 100 investigators and technical staff at 10 institutions in the United States and Europe (www.humanconnectome.org). It is funded by 16 components of the National Institutes of Health via the Blueprint for Neuroscience Research (www.neuroscienceblueprint.nih.gov).

“The high quality of the data being made available in this release reflects an intensive, multiyear effort to improve the data acquisition and analysis methods by this dedicated international team of investigators,” says Ugurbil.

The data set includes information about brain connectivity in each individual, using two distinct magnetic resonance imaging (MRI) approaches. One, called resting-state functional connectivity, is based on spontaneous fluctuations in functional MRI signals that occur in a complex pattern in space and time throughout the gray matter of the brain. Another, called diffusion imaging, provides information about the long-distance “wiring” – the anatomical pathways traversing the brain’s white matter. Each method has its own limitations, and analyses of both functional connectivity and structural connectivity in each subject should allow deeper insight than by either method alone.

Each subject is also scanned while performing a variety of tasks within the scanner, thereby providing extensive information about “Task-fMRI” brain activation patterns. Behavioral data using a variety of tests performed outside the scanner are being released along with the scan data for each subject. The subjects are drawn from families that include siblings, some of whom are twins. This will enable studies of the heritability of brain circuits.

The imaging data set released by the HCP takes up about two terabytes (2 trillion bytes) of computer memory — the equivalent of more than 400 DVDs — and is stored in a customized database called “ConnectomeDB.”

“ConnectomeDB is the next-generation neuroinformatics software for data sharing and data mining. It’s a convenient and user-friendly way for scientists to explore the available HCP data and to download data of interest for their research,” says Daniel S. Marcus, PhD, assistant professor of radiology and director of the Neuroinformatics Research Group at Washington University School of Medicine. “The Human Connectome Project represents a major advance in sharing brain imaging data in ways that will accelerate the pace of discovery about the human brain in health and disease.”

Mom’s Placenta Reflects Her Exposure to Stress

The mammalian placenta is more than just a filter through which nutrition and oxygen are passed from a mother to her unborn child. According to a new study by a research group from the University of Pennsylvania School of Veterinary Medicine, if a mother is exposed to stress during pregnancy, her placenta translates that experience to her fetus by altering levels of a protein that affects the developing brains of male and female offspring differently.

These findings suggest one way in which maternal-stress exposure may be linked to neurodevelopmental diseases such as autism and schizophrenia, which affect males more frequently or more severely than females.

“Most everything experienced by a woman during a pregnancy has to interact with the placenta in order to transmit to the fetus,” said Tracy L. Bale, senior author on the paper and an associate professor in the Department of Animal Biology at Penn Vet. “Now we have a marker that appears to signal to the fetus that its mother has experienced stress.”

Bale also holds an appointment in the Department of Psychiatry in Penn’s Perelman School of Medicine. Her coauthors include lead author and postdoctoral researcher Christopher L. Howerton, graduate student Christopher Morgan and former technician David B. Fischer, all of Penn Vet.

Published in the Proceedings of the National Academy of Sciences, the study builds on previous work by Bale and her colleagues which found that female mice exposed to stress during pregnancy gave birth to males who had heightened reactions to stress. Further research showed that the effect extended to the second generation: The sons of those male mice also had abnormal stress reactions.

Meanwhile, human studies conducted by other researchers have shown that males born to women who experience stress in the first trimester of pregnancy are at an increased risk of developing schizophrenia.

The Penn team hoped to find a biomarker that could account for these changes and risk factors. To be an effective signal of maternal stress, the researchers reasoned, a biomarker would need to show differences in expression between male and female offspring and would need to be different between stressed and unstressed mothers. They also wanted to find a marker that behaved similarly in humans.

Why your brain tires when exercising

A marathon runner approaches the finishing line, but suddenly the sweaty athlete collapses to the ground. Everyone probably assumes that this is because he has expended all energy in his muscles. What few people know is that it might also be a braking mechanism in the brain which swings into effect and makes us too tired to continue. What may be occurring is what is referred to as ‘central fatigue’.

"Our discovery is helping to shed light on the paradox which has long been the subject of discussion by researchers. We have always known that the neurotransmitter serotonin is released when you exercise, and indeed, it helps us to keep going. However, the answer to what role the substance plays in relation to the fact that we also feel so exhausted we have to stop has been eluding us for years. We can now see it is actually a surplus of serotonin that triggers a braking mechanism in the brain. In other words, serotonin functions as an accelerator but also as a brake when the strain becomes excessive," says Associate Professor Jean-François Perrier from the Department of Neuroscience and Pharmacology, who has spearheaded the new research.

Help in the battle against doping

Jean-François Perrier hopes that mapping the mechanism that prompts central fatigue will be useful in several ways. Central fatigue is a phenomenon which has been known for about 80 years; it is a sort of tiredness which, instead of affecting the muscles, hits the brain and nervous system. By conducting scientific experiments, it is possible to observe and measure that the brain sends insufficient signals to the muscles to keep going, which in turn means that we are unable to keep performing. This makes the mechanism behind central fatigue an interesting area in the battle against doping, and it is for this reason that Anti Doping Danmark has also helped fund the group’s research.

"In combating the use of doping, it is crucial to identify which methods athletes can use to prevent central fatigue and thereby continue to perform beyond what is naturally possible. And the best way of doing so is to understand the underlying mechanism," says Jean-François Perrier.

Developing better drugs

The brain communicates with our muscles using so-called motoneurons. In several diseases, motoneurons are hyperactive. This is true, for example, of people suffering from spasticity and cerebral palsy, who are unable to control their movements. Jean-François Perrier therefore hopes that, in the long term, this new knowledge can also be used to help develop drugs against these symptoms and to find out more about the effects of antidepressants.

"This new discovery brings us a step closer to finding ways of controlling serotonin. In other words, whether it will have an activating effect or trigger central fatigue. It is all about selectively activating the receptors which serotonin attaches to," explains Jean-François Perrier.

"For selective serotonin re-uptake inhibitor (SSRI) drugs which are used as antidepressants, we can possibly help explain why those who take the drugs often feel more tired and also become slightly clumsier than other people. What we now know can help us develop better drugs," concludes Jean-François Perrier.

(Image credit)

Brain adds cells in puberty to navigate adult world

The brain adds new cells during puberty to help navigate the complex social world of adulthood, two Michigan State University neuroscientists report in the current issue of the Proceedings of the National Academy of Sciences.

Scientists used to think the brain cells you’re born with are all you get. After studies revealed the birth of new brain cells in adults, conventional wisdom held that such growth was limited to two brain regions associated with memory and smell.

But in the past few years, researchers in MSU’s neuroscience program have shown that mammalian brains also add cells during puberty in the amygdala and interconnected regions where it was thought no new growth occurred. The amygdala plays an important role in helping the brain make sense of social cues. For hamsters, it picks up signals transmitted by smell through pheromones; in humans, the amygdala evaluates facial expressions and body language.

“These regions are important for social behaviors, particularly mating behavior,” said lead author Maggie Mohr, a doctoral student in neuroscience. “So, we thought maybe cells that are added to those parts of the brain during puberty could be important for adult reproductive function.”

To test that idea, Mohr and Cheryl Sisk, MSU professor of psychology, injected male hamsters with a chemical marker to show cell birth during puberty. When the hamsters matured into adults, the researchers allowed them to interact and mate with females.

Examining the brains immediately after that rendezvous, the researchers found new cells born during puberty had been added to the amygdala and associated regions. Some of the new cells contained a protein that indicates cell activation, which told Mohr and Sisk those cells had become part of the neural networks involved in social and sexual behavior.

“Before this study it was unclear if cells born during puberty even survived into adulthood,” Mohr said. “We’ve shown that they can mature to become part of the brain circuitry that underlies adult behavior.”

Their results also showed that more of the new brain cells survived and became functional in males raised in an enriched environment – a larger cage with a running wheel, nesting materials and other features – than in those with a plain cage.

While people act in more complicated ways than rodents, the researchers said they hope their work ultimately sheds light on human behavior.

“We don’t know if cells are added to the human amygdala during puberty,” Sisk said, “but we know the amygdala plays a similar role in people as in hamsters. We hope to learn whether similar mechanisms are at play as people’s brains undergo the metamorphosis that occurs during puberty.”

How the brain loses and regains consciousness

Study reveals brain patterns produced by a general anesthesia drug; work could help doctors better monitor patients.

Since the mid-1800s, doctors have used drugs to induce general anesthesia in patients undergoing surgery. Despite their widespread use, little is known about how these drugs create such a profound loss of consciousness.

In a new study that tracked brain activity in human volunteers over a two-hour period as they lost and regained consciousness, researchers from MIT and Massachusetts General Hospital (MGH) have identified distinctive brain patterns associated with different stages of general anesthesia. The findings shed light on how one commonly used anesthesia drug exerts its effects, and could help doctors better monitor patients during surgery and prevent rare cases of patients waking up during operations.

Anesthesiologists now rely on a monitoring system that takes electroencephalogram (EEG) information and combines it into a single number between zero and 100. However, that index actually obscures the information that would be most useful, according to the authors of the new study, which appears in the Proceedings of the National Academy of Sciences the week of March 4.

“When anesthesiologists are taking care of someone in the operating room, they can use the information in this article to make sure that someone is unconscious, and they can have a specific idea of when the person may be regaining consciousness,” says senior author Emery Brown, an MIT professor of brain and cognitive sciences and health sciences and technology and an anesthesiologist at MGH.

Parkinson’s Disease Brain Rhythms Detected

A team of scientists and clinicians at UC San Francisco has discovered how to detect abnormal brain rhythms associated with Parkinson’s by implanting electrodes within the brains of people with the disease.

The work may lead to developing the next generation of brain stimulation devices to alleviate symptoms for people with the disease.

Described this week in the journal Proceedings of the National Academy of Sciences (PNAS), the work sheds light on how Parkinson’s disease affects the brain, and is the first time anyone has been able to measure a quantitative signal from the disease within the cerebral cortex – the outermost layers of the brain that helps govern memory, physical movement and consciousness.

“Normally the individual cells of the brain are functioning independently much of the time, working together only for specific tasks,” said neurosurgeon Philip Starr, MD, PhD, a professor of neurological surgery at UCSF and senior author of the paper. But in Parkinson’s disease, he said, many brain cells display “excessive synchronization,” firing together inappropriately most of the time.

“They are locked into playing the same note as everyone else without exploring their own music,” Starr explained. This excessive synchronization leads to movement problems and other symptoms characteristic of the disease.

The new work also shows how deep brain stimulation (DBS), which electrifies regions deeper in the brain, below the cortex, can affect the cortex, itself. This discovery may change how DBS is used to treat Parkinson’s and other neurologically based movement disorders, and it may help refine the technique for other types of treatment.

What Predicts Distress After Episodes of Sleep Paralysis?

Ever find yourself briefly paralyzed as you’re falling asleep or just waking up? It’s a phenomenon is called sleep paralysis, and it’s often accompanied by vivid sensory or perceptual experiences, which can include complex and disturbing hallucinations and intense fear.

For some people, sleep paralysis is a once-in-a-lifetime experience; for others, it can be a frequent, even nightly, phenomenon.

Researchers James Allan Cheyne and Gordon Pennycook of the University of Waterloo in Canada explore the factors associated with distress after sleep paralysis episodes in a new article published in Clinical Psychological Science, a journal of the Association for Psychological Science.

The researchers used an online survey and follow-up emails to survey 293 people. They measured post-episode distress using a range of items, from post-episode rumination to interference with next-day functioning.

The level of distress following sleep paralysis episodes was associated with features of the sleep paralysis episode itself. For example, the results showed that the more fear people felt during sleep paralysis episodes, the more distress they felt afterward.

The researchers also found that sensory experiences during episodes of sleep paralysis predicted later distress. Feelings of threat and assault — such as sensing a presence in the room, feeling pressure on the chest, having difficulty breathing, or having a feeling of imminent death — were all associated with distress following sleep paralysis episodes. So, too, were vestibular-motor experiences, including feelings of floating or falling and out-of-body experiences.

Cheyne and Pennycook speculate that the sensory experiences that come with episodes of sleep paralysis could exacerbate people’s fear, creating a feedback loop that enhances memories of experiences later on.

Post-episode distress was also associated with a number of individual-level factors, including cognitive style, distress sensitivity, and supernatural beliefs about sleep paralysis.

People who held supernatural beliefs about sleep paralysis experiences also experienced greater post-episode distress. Those who had more analytic cognitive styles, on the other hand, experienced comparatively less distress after sleep paralysis episodes.

Taken together, these findings show that both situational factors and individual factors contribute to these common, and often stressful, personal experiences.

These findings are important, the researchers say, because they provide insight into a common experience of distress that is not well understood. Some participants lamented that their experiences of terror following episodes of sleep paralysis were often dismissed by clinicians.

Given that a large percentage of people report some carryover effects on their functioning the next day, sleep paralysis could “make a significant contribution to the billions of dollars, worldwide, in costs associated with accidents, illnesses, and lost productivity associated with sleep disturbances,” the researchers note.