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.

Research advances understanding of the human brain

Advanced neuroimaging techniques are giving researchers new insight into how the human brain plans and controls limb movements. This advance could one day lead to new understanding of disease and dysfunction in the brain and has important implications for movement-impaired patient populations, like those who suffer from spinal cord injuries.

Randy Flanagan (Psychology and Centre for Neuroscience Studies), working with colleagues at Western University, used functional magnetic resonance imaging (fMRI) to uncover what regions of the human brain are used to plan hand actions with the left and right arm. This study, spearheaded by Jason Gallivan, a Banting postdoctoral fellow at Queen’s found that by using the fMRI signals from several different brain regions, they could predict the limb to be used (left vs. right) and hand action to be performed (grasping vs. touching an object), moments before that movement is actually executed.

“We are trying to understand how the brain plans actions,” says Dr. Gallivan. “By using highly sensitive analysis techniques that enable the detection of subtle changes in brain activity patterns, we can reveal which of a series of actions a volunteer is merely intending to do, seconds later. Mapping and characterizing these predictive signals across the human brain allows us to pinpoint the key brain structures involved in generating normal, everyday behaviours.”

In another study, Dr. Flanagan and doctoral student Jonathan Diamond examined how the brain learns object mechanical properties, knowledge that is essential for skilled manipulation. They found that, through experience, humans use mismatches between predicted and actual fingertip forces and between predicted and actual object motions to build internal representations, or models, of the mechanical properties of the objects.

“The goal of this work is to understand the representations underlying skilled manipulation,” explains Dr. Flanagan. “This is important because it will enable us to better characterize deficits in manipulation tasks that often result from stroke and neurological diseases.”

Dr. Flanagan, Dr. Gallivan, and Ingrid Johnsrude (Psychology and Centre for Neuroscience Studies) have recently been awarded a CIHR operating grant to support ongoing neuroimaging work.

Both research papers were published in the Journal of Neuroscience. Read Dr. Flanagan’s paper here and read the joint paper here.

(Image: Getty Images)

A proposed link between aging, autism, and oxidation

Like any fac­tory, the body burns oxygen to get energy for its var­ious needs. As a result, detri­mental byprod­ucts are released and our cells try to clean up shop with antiox­i­dants. But as we age, this process becomes a losing battle.

“Oxi­da­tion inex­orably moves us along toward an oxi­dized state,” said phar­ma­ceu­tical sci­ences pro­fessor Richard Deth. “You have to deal with it progressively.”

One option is to slow down the syn­thesis of new pro­teins, a process that requires energy. Indeed, as we age, we pro­duce fewer new pro­teins, which explains why our capacity for learning and healing suffer as we grow old.

Since every pro­tein orig­i­nates from instruc­tions in the DNA, pro­tein syn­thesis can be slowed down by turning off par­tic­ular genes. A process called epi­ge­netic reg­u­la­tion accom­plishes the task by adding mol­e­c­ular tags on top of the genome. The pro­tein methio­nine syn­thase reg­u­lates this process. But what reg­u­lates methio­nine syn­thase? Oxidation.

“This enzyme is the most easily oxi­dized mol­e­cule in the body,” said Deth, whose research on the sub­ject was recently pub­lished in the journal PLOS ONE. The senior author for the study, Christina Mura­tore, received her doc­torate in phar­ma­ceu­tical sci­ences from North­eastern in 2010.

When­ever the body is under oxida­tive stress, Deth explained, methio­nine syn­thase, or MS, stops working. He and his team hypoth­e­sized that MS plays an impor­tant reg­u­la­tory role in aging and that it might be impaired in autism, which Deth has con­nected to unchecked oxida­tive stress in pre­vious research.

To examine their hypoth­esis, the researchers looked at post­mortem human brain sam­ples across the lifespan, with sub­jects as young as 28 weeks of fetal devel­op­ment to as old as 84 years. They mea­sured the levels of a mol­e­cule called MS mRNA, which tran­scribes the genetic code for methio­nine syn­thase into actual protein.

As the sub­jects aged, their brain tissue showed lower levels of MS mRNA. But, sur­pris­ingly, the levels of the pro­tein itself remained con­stant across the lifespan.

Deth and his col­leagues sus­pect that this observed decrease in MS mRNA over our lives may act as a check in the system to save energy that we no longer have in plen­tiful supply and to slow down oxida­tive stress. “One way that the system can guard against too much pro­tein syn­thesis is to restrict the amount of mRNA,” Deth said.

The team also com­pared MS pro­tein and mRNA levels between brain tissue sam­ples from autistic and nor­mally devel­oping sub­jects. Autistic brains had markedly less MS mRNA than the con­trol sam­ples but sim­ilar pro­tein levels. Addi­tion­ally, the age-​​dependent trend seen in nor­mally devel­oping brains was not mim­icked among the autistic sample.

If decreased MS mRNA does mean decreased pro­tein pro­duc­tion, it’s no big deal for adults who don’t need to make new pro­teins as often. But for the devel­oping brain, new pro­teins are crit­ical. “Your capacity for learning might be pre­ma­turely reduced because meta­bol­i­cally you can’t afford it,” Deth suggested.

While the results are pre­lim­i­nary and will ben­efit from repeated studies and more inves­ti­ga­tion, Deth’s find­ings add to a growing body of evi­dence linking both aging and autism to oxida­tive stress.

Adding to the list of disease-causing proteins in brain disorders

A multi-institution group of researchers has found new candidate disease proteins for neurodegenerative disorders. James Shorter, Ph.D., assistant professor of Biochemistry and Biophysics at the Perelman School of Medicine, University of Pennsylvania, Paul Taylor, M.D., PhD, St. Jude Children’s Research Hospital, and colleagues describe in an advanced online publication of Nature that mutations in prion-like segments of two RNA-binding proteins are associated with a rare inherited degeneration disorder affecting muscle, brain, motor neurons and bone (called multisystem proteinopathy) and one case of the familial form of amyotrophic lateral sclerosis (ALS).

"This study uses a variety of scientific approaches to provide powerful evidence that unregulated polymerization of proteins involved in RNA metabolism may contribute to ALS and related diseases," said Amelie Gubitz, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS).

ALS, or Lou Gehrig’s disease, is a universally fatal neurodegenerative disease. Previous studies found that mutations in two related RNA-binding proteins, TDP-43 and FUS, cause some forms of ALS, but more proteins were suspected of causing other forms of the disease. TDP-43 and FUS regulate how the genetic code is translated for the assembly of proteins.

There are over 200 human RNA-binding proteins, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathology. Computer algorithms, based on protein sequences, designed to identify yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbor a distinctive prion-like segment. These segments are essential for the assembly of certain protein complexes. But, the interplay between human prion-like segments and disease is not well understood.

Using yeast as a model organism, co-author Aaron Gitler, while at Penn in 2011, surveyed 133 of 200-plus candidate human RNA-binding proteins to predict new ALS disease genes, other than TDP-43 and FUS. They further winnowed the candidates to about 10 proteins with prion-like segments, and selected two candidates, TAF15 and EWSR1, for further study. Both TAF15 and EWSR1 aggregated in the test tube and were toxic in yeast.

Remarkably, they also uncovered TAF15 and EWSR1 mutations in ALS patients that were not found in healthy individuals. Based on these findings, they proposed that RNA-binding proteins with prion-like segments might contribute very broadly to the pathology of ALS and related brain disorders.

Characterizing the Top-Ten

Taylor, Gitler, Shorter, and others continued to characterize the top-ten human RNA-binding proteins with prion-like segments. The Nature study describes that two more of the top-ten candidates, called hnRNPA1 and hnRNPA2B1, are mutated and cause familial cases of brain disease. The mutations in hnRNPA1 and hnRNPA2B1 were present in two families with an extremely rare inherited degeneration affecting muscle, brain, motor neuron, and bone and another from a person with familial ALS.

Mutations in these two proteins fell in the prion-like segments and coincided with “sticky” regions in the proteins, making these regions more prone to assemble into self-organizing fibrils. The normal form of the proteins shows a natural tendency to assemble into fibrils, which is exacerbated by the disease mutations.

"The mutations accelerate the formation of the fibrils that recruit normal protein to form more fibrils," noted co-first author Emily Scarborough, from Penn. This dysregulated assembly likely contributes to disease. Indeed, the disease mutations also promote excess incorporation of the proteins into stress granules within a cell and the formation of clumps in the cells of animal models of human neurodegenerative disease.

"Neurodegenerative disease could ensue from unregulated fibril formation initiated spontaneously by environmental stress or another factor that regulates a protein’s assembly," says Scarborough.

"This paper reflects an amazing collaborative effort and provides a great example of how understanding the underlying pure protein biochemistry can help explain how genetic mutations might cause pathology and disease," says Shorter.

"The findings confirm a strong prediction that the disease-causing mutations make the prion-like segment ‘stickier’ and more prone to clump," added co-first author Zamia Diaz, also from Penn.

Diseases associated with fibrils forming from prion-like domains in proteins frequently show “spreading” pathology, in which cellular degeneration via inclusions starts in one center of the brain and “spreads” to neighboring tissue. Although not directly addressed in the Nature study, the findings suggest that cell-to-cell transmission of a self-templating protein could contribute to the spreading pathology that is characteristic of these diseases.

"Related proteins with prion-like domains must be considered candidates for initiating and perhaps propagating similar pathologies in muscle, brain, motor neurons, and bone," concluded Shorter.

Scientists Identify ‘Clean-Up’ Snafu That Kills Brain Cells in Parkinson’s Disease

Researchers at Albert Einstein College of Medicine of Yeshiva University have discovered how the most common genetic mutations in familial Parkinson’s disease damage brain cells. The study, which published online in the journal Nature Neuroscience, could also open up treatment possibilities for both familial Parkinson’s and the more common form of Parkinson’s that is not inherited.

"Our study found that abnormal forms of LRRK2 protein disrupt an important garbage-disposal process in cells that normally digests and recycles unwanted proteins including one called alpha-synuclein - the main component of those protein aggregates that gunk up nerve cells in Parkinson’s patients," said study leader Ana Maria Cuervo, M.D., Ph.D., professor of  developmental and molecular biology, of anatomy and structural biology, and of medicine and the Robert and Renee Belfer Chair for the Study of Neurodegenerative Diseases at Einstein.

The name for the disrupted disposal process is chaperone-mediated autophagy (the word “autophagy” literally means “self-eating”). It involves specialized molecules that “guide” old and damaged proteins to enzyme-filled structures called lysosomes; there the proteins are digested into amino acids, which are then recycled within the cell.

"We showed that when LRRK2 inhibits chaperone-mediated autophagy,
alpha-synuclein doesn’t get broken down and instead accumulates to toxic levels in nerve cells,” said Dr. Cuervo.

The study involved mouse neurons in tissue culture from four different animal models, neurons from the brains of patients with Parkinson’s with  LRRK2 mutations, and neurons derived from the skin cells of Parkinson’s patients via induced pluripotent stem (iPS) cell technology. All the lines of research confirmed the researchers’ discovery.

"We’re now looking at ways to enhance the activity of this recycling system to see if we can prevent or delay neuronal death and disease," said Dr. Cuervo. "We’ve started to analyze some chemical compounds that look very promising."

Dr. Cuervo hopes that such treatments could help patients with familial as well as nonfamilial Parkinson’s - the predominant form of the disease that also involves the buildup of alpha-synuclein.

Dr. Cuervo is credited with discovering chaperone-mediated autophagy. She has published extensively on autophagy and its role in numerous diseases, such as cancer and Huntington’s disease, and its role in age-related conditions, including organ decline and weakened immunity. Dr. Cuervo is co-director of Einstein’s  Institute of Aging Research.

(Image: Shutterstock)

Clever Battery Completes Stretchable Electronics Package

Northwestern University’s Yonggang Huang and the University of Illinois’ John A. Rogers are the first to demonstrate a stretchable lithium-ion battery — a flexible device capable of powering their innovative stretchable electronics.

No longer needing to be connected by a cord to an electrical outlet, the stretchable electronic devices now could be used anywhere, including inside the human body. The implantable electronics could monitor anything from brain waves to heart activity, succeeding where flat, rigid batteries would fail.

Huang and Rogers have demonstrated a battery that continues to work — powering a commercial light-emitting diode (LED) — even when stretched, folded, twisted and mounted on a human elbow. The battery can work for eight to nine hours before it needs recharging, which can be done wirelessly.

The new battery enables true integration of electronics and power into a small, stretchable package. Details are published by the online journal Nature Communications.

“We start with a lot of battery components side by side in a very small space, and we connect them with tightly packed, long wavy lines,” said Huang, a corresponding author of the paper. “These wires provide the flexibility. When we stretch the battery, the wavy interconnecting lines unfurl, much like yarn unspooling. And we can stretch the device a great deal and still have a working battery.”

Huang led the portion of the research focused on theory, design and modeling. He is the Joseph Cummings Professor of Civil and Environmental Engineering and Mechanical Engineering at Northwestern’s McCormick School of Engineering and Applied Science.

The power and voltage of the stretchable battery are similar to a conventional lithium-ion battery of the same size, but the flexible battery can stretch up to 300 percent of its original size and still function.

“Seq-ing” Insights into the Epigenetics of Neuronal Gene Regulation

The epigenetic control of neuronal gene expression patterns has emerged as an underlying regulatory mechanism for neuronal function, identity, and plasticity, in which short- to long-lasting adaptation is required to dynamically respond and process external stimuli. To achieve a comprehensive understanding of the physiology and pathology of the brain, it becomes essential to understand the mechanisms that regulate the epigenome and transcriptome in neurons. Here, we review recent advances in the study of regulated neuronal gene expression, which are dramatically expanding as a result of the development of new and powerful contemporary methodologies, based on next-generation sequencing. This flood of new information has already transformed our understanding of many biological processes and is now driving discoveries elucidating the molecular mechanisms of brain function in cognition, behavior, and disease and may also inform the study of neuronal identity, diversity, and neuronal reprogramming.