Neuroscience

Scientists have known for some time that the human brain’s ability to stay calm and focused is limited and can be overwhelmed by the constant noise and hectic, jangling demands of city living, sometimes resulting in a condition informally known as brain fatigue.

With brain fatigue, you are easily distracted, forgetful and mentally flighty — or, in other words, me.

But an innovative new study from Scotland suggests that you can ease brain fatigue simply by strolling through a leafy park.

The idea that visiting green spaces like parks or tree-filled plazas lessens stress and improves concentration is not new. Researchers have long theorized that green spaces are calming, requiring less of our so-called directed mental attention than busy, urban streets do. Instead, natural settings invoke “soft fascination,” a beguiling term for quiet contemplation, during which directed attention is barely called upon and the brain can reset those overstretched resources and reduce mental fatigue.

But this theory, while agreeable, has been difficult to put to the test. Previous studies have found that people who live near trees and parks have lower levels of cortisol, a stress hormone, in their saliva than those who live primarily amid concrete, and that children with attention deficits tend to concentrate and perform better on cognitive tests after walking through parks or arboretums. More directly, scientists have brought volunteers into a lab, attached electrodes to their heads and shown them photographs of natural or urban scenes, and found that the brain wave readouts show that the volunteers are more calm and meditative when they view the natural scenes.

But it had not been possible to study the brains of people while they were actually outside, moving through the city and the parks. Or it wasn’t, until the recent development of a lightweight, portable version of the electroencephalogram, a technology that studies brain wave patterns.

For the new study, published this month in The British Journal of Sports Medicine, researchers at Heriot-Watt University in Edinburgh and the University of Edinburgh attached these new, portable EEGs to the scalps of 12 healthy young adults. The electrodes, hidden unobtrusively beneath an ordinary looking fabric cap, sent brain wave readings wirelessly to a laptop carried in a backpack by each volunteer.

The researchers, who had been studying the cognitive impacts of green spaces for some time, then sent each volunteer out on a short walk of about a mile and half that wound through three different sections of Edinburgh.

The first half mile or so took walkers through an older, historic shopping district, with fine, old buildings and plenty of pedestrians on the sidewalk, but only light vehicle traffic.

The walkers then moved onto a path that led through a park-like setting for another half mile.

Finally, they ended their walk strolling through a busy, commercial district, with heavy automobile traffic and concrete buildings.

The walkers had been told to move at their own speed, not to rush or dawdle. Most finished the walk in about 25 minutes.

Throughout that time, the portable EEGs on their heads continued to feed information about brain wave patterns to the laptops they carried.

Afterward, the researchers compared the read-outs, looking for wave patterns that they felt were related to measures of frustration, directed attention (which they called “engagement”), mental arousal and meditativeness or calm.

What they found confirmed the idea that green spaces lessen brain fatigue.

When the volunteers made their way through the urbanized, busy areas, particularly the heavily trafficked commercial district at the end of their walk, their brain wave patterns consistently showed that they were more aroused, attentive and frustrated than when they walked through the parkland, where brain-wave readings became more meditative.

While traveling through the park, the walkers were mentally quieter.

Which is not to say that they weren’t paying attention, said Jenny Roe, a professor in the School of the Built Environment at Heriot-Watt University, who oversaw the study. “Natural environments still engage” the brain, she said, but the attention demanded “is effortless. It’s called involuntary attention in psychology. It holds our attention while at the same time allowing scope for reflection,” and providing a palliative to the nonstop attentional demands of typical, city streets.

Of course, her study was small, more of a pilot study of the nifty new, portable EEG technology than a definitive examination of the cognitive effects of seeing green.

But even so, she said, the findings were consistent and strong and, from the viewpoint of those of us over-engaged in attention-hogging urban lives, valuable. The study suggests that, right about now, you should consider “taking a break from work,” Dr. Roe said, and “going for a walk in a green space or just sitting, or even viewing green spaces from your office window.” This is not unproductive lollygagging, Dr. Roe helpfully assured us. “It is likely to have a restorative effect and help with attention fatigue and stress recovery.”

-by Gretchen Reynolds, The New York Times

Focusing on the present rather than letting the mind drift may help to lower levels of the stress hormone cortisol, suggests new research from the Shamatha Project at the University of California, Davis.

The ability to focus mental resources on immediate experience is an aspect of mindfulness, which can be improved by meditation training.

"This is the first study to show a direct relation between resting cortisol and scores on any type of mindfulness scale," said Tonya Jacobs, a postdoctoral researcher at the UC Davis Center for Mind and Brain and first author of a paper describing the work, published this week in the journal Health Psychology.

High levels of cortisol, a hormone produced by the adrenal gland, are associated with physical or emotional stress. Prolonged release of the hormone contributes to wide-ranging, adverse effects on a number of physiological systems.

The new findings are the latest to come from the Shamatha Project, a comprehensive long-term, control-group study of the effects of meditation training on mind and body.

Led by Clifford Saron, associate research scientist at the UC Davis Center for Mind and Brain, the Shamatha Project has drawn the attention of both scientists and Buddhist scholars including the Dalai Lama, who has endorsed the project.

In the new study, Jacobs, Saron and their colleagues used a questionnaire to measure aspects of mindfulness among a group of volunteers before and after an intensive, three-month meditation retreat. They also measured cortisol levels in the volunteers’ saliva.

During the retreat, Buddhist scholar and teacher B. Alan Wallace of the Santa Barbara Institute for Consciousness Studies trained participants in such attentional skills as mindfulness of breathing, observing mental events, and observing the nature of consciousness. Participants also practiced cultivating benevolent mental states, including loving kindness, compassion, empathic joy and equanimity.

At an individual level, there was a correlation between a high score for mindfulness and a low score in cortisol both before and after the retreat. Individuals whose mindfulness score increased after the retreat showed a decrease in cortisol.

"The more a person reported directing their cognitive resources to immediate sensory experience and the task at hand, the lower their resting cortisol," Jacobs said.

The research did not show a direct cause and effect, Jacobs emphasized. Indeed, she noted that the effect could run either way — reduced levels of cortisol could lead to improved mindfulness, rather than the other way around. Scores on the mindfulness questionnaire increased from pre- to post-retreat, while levels of cortisol did not change overall.

According to Jacobs, training the mind to focus on immediate experience may reduce the propensity to ruminate about the past or worry about the future, thought processes that have been linked to cortisol release.

"The idea that we can train our minds in a way that fosters healthy mental habits and that these habits may be reflected in mind-body relations is not new; it’s been around for thousands of years across various cultures and ideologies," Jacobs said. "However, this idea is just beginning to be integrated into Western medicine as objective evidence accumulates. Hopefully, studies like this one will contribute to that effort."

Saron noted that in this study, the authors used the term “mindfulness” to refer to behaviors that are reflected in a particular mindfulness scale, which was the measure used in the study.

"The scale measured the participants’ propensity to let go of distressing thoughts and attend to different sensory domains, daily tasks, and the current contents of their minds. However, this scale may only reflect a subset of qualities that comprise the greater quality of mindfulness, as it is conceived across various contemplative traditions," he said.

Previous studies from the Shamatha Project have shown that the meditation retreat had positive effects on visual perception, sustained attention, socio-emotional well-being, resting brain activity and on the activity of telomerase, an enzyme important for the long-term health of body cells.

Johns Hopkins scientists say they have evidence from animal studies that a type of central nervous system cell other than motor neurons plays a fundamental role in the development of amyotrophic lateral sclerosis (ALS), a fatal degenerative disease. The discovery holds promise, they say, for identifying new targets for interrupting the disease’s progress.

In a study described online in Nature Neuroscience, the researchers found that, in mice bred with a gene mutation that causes human ALS, dramatic changes occurred in oligodendrocytes — cells that create insulation for the nerves of the central nervous system — long before the first physical symptoms of the disease appeared. Oligodendrocytes located near motor neurons — cells that govern movement — died off at very high rates, and new ones regenerated in their place were inferior and unhealthy.

The researchers also found, to their surprise, that suppressing an ALS-causing gene in oligodendrocytes of mice bred with the disease — while still allowing the gene to remain in the motor neurons — profoundly delayed the onset of ALS. It also prolonged survival of these mice by more than three months, a long time in the life span of a mouse. These observations suggest that oligodendrocytes play a very significant role in the early stage of the disease.

“The abnormalities in oligodendrocytes appear to be having a negative impact on the survival of motor neurons,” says Dwight E. Bergles, Ph.D., a co-author and a professor of neuroscience at the Johns Hopkins University School of Medicine. “The motor neurons seem to be dependent on healthy oligodendrocytes for survival, something we didn’t appreciate before.”

“These findings teach us that cells we never thought had a role in ALS not only are involved but also clearly contribute to the onset of the disease,” says co-author Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology at Johns Hopkins and director of the Johns Hopkins Medicine Brain Science Institute.

Scientists have long believed that oligodendrocytes functioned only as structural elements of the central nervous system. They wrap around nerves, making up the myelin sheath that provides the “insulation” that allows nerve signals to be transmitted rapidly and efficiently. However, Rothstein and others recently discovered that oligodendrocytes also deliver essential nutrients to neurons, and that most neurons need this support to survive.

The Johns Hopkins team of Bergles and Rothstein published a paper in 2010 that described in mice with ALS an unexpected massive proliferation of oligodendrocyte progenitor cells in the spinal cord’s motor neurons, and that these progenitors were being mobilized to make new oligodendrocytes. The researchers believed that these cells were multiplying because of an injury to oligodendrocytes, but they weren’t sure what was happening. Using a genetic method of tracking the fate of oligodendrocytes, in the new study, the researchers found that cells present in young mice with ALS were dying off at an increasing rate in concert with advancing disease. Moreover, the development of the newly formed oligodendrocytes was stalled and they were not able to provide motor neurons with a needed source of cell nutrients.

To determine whether the changes to the oligodendrocytes were just a side effect of the death of motor neurons, the scientists used a poison to kill motor neurons in the ALS mice and found no response from the progenitors, suggesting, says Rothstein, that it is the mutant ALS gene that is damaging oligodendrocytes directly.

Meanwhile, in separate experiments, the researchers found similar changes in samples of tissues from the brains of 35 people who died of ALS. Rothstein says it may be possible to see those changes early on in the disease and use MRI technology to follow progression.

“If our research is confirmed, perhaps we can start looking at ALS patients in a different way, looking for damage to oligodendrocytes as a marker for disease progression,” Rothstein says. “This could not only lead to new treatment targets but also help us to monitor whether the treatments we offer are actually working.”

ALS, also known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, affects nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary.

There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival.

Even though myelin loss has not previously been thought to occur in the gray matter, a region in the brain where neurons process information, the researchers in the new study found in ALS patients a significant loss of myelin in one of every three samples of human tissue taken from the brain’s gray matter, suggesting that the oligodendrocytes were abnormal. It isn’t clear if the oligodendrocytes that form this myelin in the gray matter play a different role than in white matter — the region in the brain where signals are relayed.

The findings further suggest that clues to the treatment of other diseases long believed to be focused in the brain’s gray matter — such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease — may be informed by studies of diseases of the white matter, such as multiple sclerosis (MS). Bergles says ALS and MS researchers never really thought their diseases had much in common before.

Oligodendrocytes have been under intense scrutiny in MS, Bergles says. In MS, the disease over time can transform from a remitting-relapsing form — in which myelin is attacked but then is regenerated when existing progenitors create new oligodendrocytes to re-form myelin — to a more chronic stage in which oligodendrocytes are no longer regenerated. MS researchers are working to identify new ways to induce the creation of new oligodendrocytes and improve their survival. “It’s possible that we may be able to dovetail with some of the same therapeutics to slow the progression of ALS,” Bergles says.

Replicative aging (also known as replicative senescence) causes mammalian cells to undergo a process of growth arrest dependent on telomeres (the shortening of repeated sequences at the ends of chromosomes). Neurons, on the other hand, are exempt from aging, and so the question of their actual lifespan has remained unanswered. Recently, however, scientists at the University of Pavia and the University of Turin demonstrated that neuronal lifespan is not limited by the organism’s maximum lifespan but, remarkably, continues when transplanted in a longer-living host. The researchers accomplished this by transplanting embryonic mouse cerebellar precursors into the developing brain of longer-living rats, in which the grafted mouse neurons survived for up to three years – twice the average lifespan of the donor mice.

Dr. Lorenzo Magrassi discussed the challenges he and his colleagues, Dr. Ketty Leto and Dr. Ferdinando Rossi, encountered in their research. “Cell transplantation into the developing rat brain is a technique that was originally developed by us and other research groups in the early nineties of the last century,” Magrassi tells Medical Xpress. “In recent years, we improved the protocol that, now standardized, allows reliable implantation rates with good survival rates.” While not all implanted embryos develop into adult animals carrying a viable transplant, Magrassi adds, the percentage of those that do is sufficient to plan a long-term survival experiment involving roughly 100 such successfully-born animals.

In addressing these challenges, Magrassi says that together with the intrinsic bonus of studying cells inside the nervous system, which is immunoprivileged, they transplanted cells before development of the thymus (a specialized organ of the immune system) was complete. The latter can help induce immunological tolerance in the host to the engrafted cells.

One remaining question is if their research can potentially be extended to determine whether or not a maximum lifespan exists for any postmitotic mammalian cells – Including neurons. “Similar techniques can, in principle, be extended to other organs containing perennial cells,” Magrassi notes, “but we don’t have direct experience with injecting cells into organs outside of the central nervous system.” Since the central nervous system is privileged compared to other organs that are more prone to immunological surveillance and attack, a major problem when transferring their experimental paradigm to other organs, he explains, could be an increase in immunological problems.

The scientists say their results suggest that neuronal survival and aging are coincidental but separable processes, thus increasing the hope that extending organismal lifespan by dietary, behavioral, and pharmacologic interventions will not necessarily result in a neuronally depleted brain. “Even after taking into account the obvious species differences, our results in rodents can be extrapolated by analogy to humans and other longer-living species where this sort of experiment is impossible,” Magrassi explains. “Our findings suggest that extending life by extending average organismal lifespan – a hallmark of all technologically advanced societies – will not necessarily result in neuron-impoverished brains well before the longer-living individual dies.” This bodes well for those studying life extension: Their efforts are not intrinsically futile, Magrassi notes, because in the absence of pathology, prolonging life span does not necessarily mean dementia due to widespread loss of neurons, as many people still think. “Roughly speaking,” Magrassi illustrates, “if the average lifespan of humans is now 80 years, our results suggest that at ages up to 160 years our neurons can survive if not hit by specific insults.

That said, however, Magrassi acknowledges that neuronal death is not the only effect of normal aging in the brain. “For example,” he illustrates, “cerebellar neurons – which in term of synaptic loss behave like the majority of neurons in the brain – show a substantial loss of dendritic branches, spines and synapses in normal aging. In our research, we studied transplanted mouse Purkinje cells to determine if their spine density decreased with time at the same rate of Purkinje cells in the mouse or in the rat.” Purkinje cells are large GABAergic (that is, gamma-Aminobutyric acid-producing) neurons, with many branching extensions, found in the cortex of the cerebellum. “The results of our experiments indicate that age-related progressive spine loss of grafted mouse Purkinje cells follows a slower pace, typical of the longer living rat, thus reaching absolute levels of spine loss comparable to those observed in aged mice at much longer survival times that are typical of the rat.”

Moreover, Magrassi adds that their experiments clearly show that by escaping immunological rejection, transplanted neurons can survive undisturbed for the entire life of the host. “This has implications for the ongoing discussion of the detrimental effects of immune attacks on transplanted neural cells for therapeutic purposes,”

Moving forward, in order to screen for intra- and extracellular changes that could be responsible for the long term survival of the mouse cells transplanted into rat brains – as well as the slowdown of dendritic spine loss – the team is planning to perform host and transplanted cell microdissection followed by a proteomic approach. “If we discover what factor or factors cause those changes,” Magrassi points out, “we could hopefully then develop more efficient drugs for treating all pathological neurodegenerative conditions in which neurons start to lose synaptic contacts and die well before organismal death – for example, dementia, memory loss and cognitive impairment. Of course,” he adds, “this work is still in progress and the results are preliminary.”

In addition, the scientists are currently testing xenotransplantation using different transgenic mouse strains with altered aging pathways as donors to characterize the pathways that led to their results.

Magrassi sees other areas of research that might benefit from their study. “Knowing that neuronal aging in rodents is not a cell-autonomous process is important not only for neuroscience,” he concludes. “It also has implications for evolutionary biology and epidemiology.”

The smooth operation of the brain requires a certain robustness to fluctuations in its home within the body. At the same time, its extraordinary power derives from an activity structure poised at criticality. In other words, it is highly responsive to many low-threshold events. When forced beyond its comfort zone in parameter space—its operating temperature, electrolytes, sugars, blood gas or even sensory input— the direct result is seizure, coma, or both. It would appear that anything rendered too hot or cold, too concentrated or scarce, precipitates seizure. In those genetically predisposed, or compromised by head trauma, the seizing tends toward full-blown epilepsy. A group in Hamburg, led by Michael Frotscher has been chipping away at the causes of common form a epilepsy, temporal lobe epilepsy (TLE). Their latest research published in the journal, Cerebral Cortex, takes a closer at differentiated neurons in the dentate gyrus of mouse hippocampus. Once thought to be completely immobilized by virtue of their broadly integrated dendritic trees, these neurons are now shown to become migratory once again in direct response to seizure activity.

Genetic predisposition to seizure can come in the form of ongoing chemical or metabolic imbalance due to defects in enzymes, ion channels or receptors. Alternatively it manifests through direct structural defect as a result of a developmental flaw. In slice preparations, Frotscher looked at a particular form of TLE, where the granule cell layer (GCL) in the dentate gyrus is disrupted. The cells there have either failed to migrate along glial scaffolds into a compact layer with clearly defined margins, or aberrant clumps of cells congregate in the wrong places. Seizures secondary to fever have been known to cause this aberrant migration of granule cells, as has a particular kind of mouse mutant known as the reeler mouse.

The catalog of mouse mutants is expansive; it is a veritable library of hopeless monsters. The reeler mutant, known since 1951, has a unique set of issues wherein cells fail to migrate to the right spots in the cerebellum, cortex, and hippocampus. The protein, reelin was later discovered as one of the causes of this particular phenotype. Reelin is an extracellular matrix protein which initially provides scaffolding for neuron migration, and later a fence to fix neurons in place. In mice with mutated reelin protein, cells in all parts of the hippocampus, not just the dentate gyrus are spread out into a broad and diffuse layer.

By injecting kainate (KA), an excitotoxin that predictably results in seizures, into the dentate gyrus, Frotscher biased the granule cells into entering a phase of bursting activity. With their glutamate receptors fully activated by KA, the granule cells fire rapid volleys of spikes followed by deep depolarization periods. Cells that had been fluorescently labeled with GFP and observed with real time video microscopy were also seen to become motile and dispersed. The normal band of granule cells doubled, or tripled, in thickness. Next, Frostcher looked for a link between this response to KA and the reelin protein. Both reelin mRNA and reelin immunoreactivity were found to be reduced in the dentate granule cells that had been dispersed by KA.

Against this tableau of complex responses to KA, is the fact that adult neurogenesis of dentate granule cells occurs within many mammalian species. A narrowly-defined rostral migratory stream normally delivers fresh cells to both the dentate gyrus and olfactory bulb. Application of BrdU, a marker of newly born cells, labeled microglial and astrocytes near the site of injection, but only a few of the granule cells. As an excitotoxin, KA may be expected to kill at least some cells outright, and cause significant dendritic degeneration in many more. An interesting question to ask, is how does KA induce granule cell dispersion despite the dense interconnections with their neighbors?

During KA induced motility, the nucleus was typically observed to translocate within the cell into one of the dendrites, pulling the soma along with it. This process is believed to involve a myosin-dependant forward flow of actin structural protein within the cell. Outside the cell, changes to the reelin matrix appear to be involved as well. One potential mechanism that has emerged is that reelin induces serine phosporylation of cofilin, an actin-associated protein involved in depolymerization. The authors conclude reelin-induced cofilin phosphorylation controls neuronal migration during development, and prevents abnormal motility in the mature brain.

Undoubtedly many mechanisms are involved in the KA-induced seizure and reelin story. Other cell types in the dentate gyrus need to be looked at in closer detail. For example, how reelin expression is regulated, and which cells manufacture it are current areas of study. It is important as well to differentiate between the causes of seizure, and its consequences. On paper they can be neatly packaged concepts but in the real tissue, and in intact animals, they can be anything but.

Clumps of α-synuclein protein in nerve cells are hallmarks of many degenerative brain diseases, most notably Parkinson’s disease.

“No one has been able to determine if Lewy bodies and Lewy neurites, hallmark pathologies in Parkinson’s disease can be degraded,” says Virginia Lee, PhD, director of the Center for Neurodegenerative Disease Research, at the Perelman School of Medicine, University of Pennsylvania.

“With the new neuron model system of Parkinson’s disease pathologies our lab has developed recently, we demonstrated that these aberrant clumps in cells resist degradation as well as impair the function of the macroautophagy  system, one of the major garbage disposal systems within the cell.”

Macroautophagy, literally self eating, is the degradation of unnecessary or dysfunctional cellular bits and pieces by a compartment in the cell called the lysosome.

Lee, also a professor of Pathology and Laboratory Medicine, and colleagues published their results in the early online edition of the Journal of Biological Chemistry this week.

Alpha-synuclein (α-syn ) diseases all have  clumps of the protein and include Parkinson’s disease (PD), and array of related disorders: PD with dementia , dementia with Lewy bodies, and multiple system atrophy. In most of these, α-syn forms insoluble aggregates of stringy fibrils that accumulate in the cell body and extensions of neurons.

These unwanted α-syn clumps are modified by abnormal attachments of many phosphate chemical groups as well as by the protein ubiquitin, a molecular tag for degradation. They are widely distributed in the central nervous system, where they are associated with neuron loss.

Using cell models in which intracellular α-syn clumps accumulate after taking up synthetic α-syn fibrils, the team showed that α-syn inclusions cannot be degraded, even though they are located near the  lysosome and the proteasome, another type of garbage disposal in the cell.

The α-syn aggregates persist even after soluble α-syn levels within the cell are substantially reduced, suggesting that once formed, the α-syn inclusions are resistant to being cleared. What’s more, they found that α-syn aggregates impair the overall autophagy degradative process by delaying the maturation of autophagy machines known as autophagosomes, which may contribute to the increased cell death seen in clump-filled nerve cells. Understanding the impact of α-syn aggregates on autophagy may help elucidate therapies for α-syn-related neurodegeneration.

Women who abruptly and prematurely lose estrogen from surgical menopause have a two-fold increase in cognitive decline and dementia.

"This is what the clinical studies indicate and our animal studies looking at the underlying mechanisms back this up," said Brann, corresponding author of the study in the journal Brain. “We wanted to find out why that is occurring. We suspect it’s due to the premature loss of estrogen.”

In an effort to mimic what occurs in women, Brann and his colleagues looked at rats 10 weeks after removal of their estrogen-producing ovaries that were either immediately started on low-dose estrogen therapy, started therapy 10 weeks later or never given estrogen.

When the researchers caused a stroke-like event in the brain’s hippocampus, a center of learning and memory, they found the rodents treated late or not at all experienced more brain damage, specifically to a region of the hippocampus called CA3 that is normally stroke-resistant.

To make matters worse, untreated or late-treated rats also began an abnormal, robust production of Alzheimer’s disease-related proteins in the CA3 region, even becoming hypersensitive to one of the most toxic of the beta amyloid proteins that are a hallmark of Alzheimer’s.

Both problems appear associated with the increased production of free radicals in the brain. In fact, when the researchers blocked the excessive production, heightened stroke sensitivity and brain cell death in the CA3 region were reduced.

Interestingly the brain’s increased sensitivity to stressors such as inadequate oxygen was gender specific, Brann said. Removing testes in male rats, didn’t affect stroke size or damage.

Although exactly how it works is unknown, estrogen appears to help protect younger females from problems such as stroke and heart attack. Their risks of the maladies increase after menopause to about the same as males. Follow up studies are needed to see if estrogen therapy also reduces sensitivity to the beta amyloid protein in the CA3 region, as they expect, Brann noted.

Brann earlier showed that prolonged estrogen deprivation in aging rats dramatically reduces the number of brain receptors for the hormone as well as its ability to prevent strokes. Damage was forestalled if estrogen replacement was started shortly after hormone levels drop, according to the 2011 study in the journal Proceedings of the National Academy of Sciences.

The surprising results of the much-publicized Women’s Health Initiative – a 12-year study of 161,808 women ages 50-79 – found hormone therapy generally increased rather than decreased stroke risk as well as other health problems. Critics said one problem with the study was that many of the women, like Brann’s aged rats, had gone years without hormone replacement, bolstering the case that timing is everything.

Scientists have identified a key molecule responsible for triggering the chemical processes in our brain linked to our formation of memories.  The findings, published in the journal Frontiers in Neural Circuits, reveal a new target for therapeutic interventions to reverse the devastating effects of memory loss.

The BBSRC-funded research, led by scientists at the University of Bristol, aimed to better understand the mechanisms that enable us to form memories by studying the molecular changes in the hippocampus — the part of the brain involved in learning.

Previous studies have shown that our ability to learn and form memories is due to an increase in synaptic communication called Long Term Potentiation [LTP].  This communication is initiated through a chemical process triggered by calcium entering brain cells and activating a key enzyme called ‘Ca2+ responsive kinase’ [CaMKII].  Once this protein is activated by calcium it triggers a switch in its own activity enabling it to remain active even after the calcium has gone. This special ability of CaMKII to maintain its own activity has been termed ‘the molecular memory switch’.

Until now, the question still remained as to what triggers this chemical process in our brain that allows us to learn and form long-term memories.  The research team, comprising scientists from the University’s School of Physiology and Pharmacology, conducted experiments using the common fruit fly [Drosophila] to analyse and identify the molecular mechanisms behind this switch. Using advanced molecular genetic techniques that allowed them to temporarily inhibit the flies’ memory the team were able to identify a gene called CASK as the synaptic molecule regulating this ‘memory switch’.

Dr James Hodge, the study’s lead author, said: “Fruit flies are remarkably compatible for this type of study as they possess similar neuronal function and neural responses to humans.  Although small they are very smart, for instance, they can land on the ceiling and detect that the fruit in your fruit bowl has gone off before you can.”

“In experiments whereby we tested the flies’ learning and memory ability, involving two odours presented to the flies with one associated with a mild shock, we found that around 90 per cent were able to learn the correct choice remembering to avoid the odour associated with the shock. Five lessons of the odour with punishment made the fly remember to avoid that odour for between 24 hours and a week, which is a long time for an insect that only lives a couple of months.“

By localising the function of the key molecules CASK and CaMKII to the flies’ equivalent brain area to the human hippocampus, the team found that the flies lacking these genes showed disrupted memory formation.  In repeat memory tests those lacking these key genes were shown to have no ability to remember at three hours (mid-term memory) and 24 hours (long-term memory) although their initial learning or short-term memory wasn’t affected.

Finally, the team introduced a copy of the human CASK gene — it is 80 per cent identical to the fly CASK gene — into the genome of a fly that completely lacked its own CASK gene and was therefore not usually able to remember.  The researchers found that flies which had a copy of the human CASK gene could remember like a normal wildtype fly.

Dr Hodge, from the University’s School of Physiology and Pharmacology, said: “Research into memory is particularly important as it gives us our sense of identity, and deficits in learning and memory occur in many diseases, injuries and during aging”.

“CASK’s control of CaMKII ‘molecular memory switch’ is clearly a critical step in how memories are written into neurons in the brain.  These findings not only pave the way for to developing new therapies which reverse the effects of memory loss but also prove the compatibility of Drosophila to model these diseases in the lab and screen for new drugs to treat these diseases. Furthermore, this work provides an important insight into how brains have evolved their huge capacity to acquire and store information.”

These findings clearly demonstrate that neuronal function of CASK is conserved between flies and human, validating the use of Drosophila to understand CASK function in both the healthy and diseased brain. Mutations in human CASK gene have been associated with neurological and cognitive defects including severe learning difficulties.

New research from the Massachusetts Eye and Ear, Harvard Medical School and Harvard Program in Speech and Hearing Bioscience and Technology may have discovered a key piece in the puzzle of how hearing works by identifying the role of the olivocochlear efferent system in protecting ears from hearing loss. The findings could eventually lead to screening tests to determine who is most susceptible to hearing loss. Their paper is published today in the Journal of Neuroscience.

Until recently, it was common knowledge that exposure to a noisy environment (concert, iPod, mechanical tools, firearm, etc.), could lead to permanent or temporary hearing loss. Most audiologists would assess the damage caused by this type of exposure by measuring hearing thresholds, the lowest level at which one starts to detect/sense a sound at a particular frequency (pitch). Drs. Sharon Kujawa and Charles Liberman, both researchers at Mass. Eye and Ear, showed in 2009 that noise exposures leading to a temporary hearing loss in mice (when hearing thresholds return to what they were before exposure) in fact can be associated with cochlear neuropathy, a situation in which, despite having a normal threshold, a portion of auditory nerve fibers is missing).

The inner ear, the organ that converts sounds into messages that will be conveyed to and decoded by the brain, receives in turn fibers from the central nervous system. Those fibers are known as the olivocochlear efferent system. Up to now, the involvement of this efferent system in the protection from acoustic injury – although clearly demonstrated – has been a matter of debate because all the previous experiments were probing its protective effects following noise exposures very unlikely to be found in nature.

Stephane Maison, Ph.D., investigator at the Eaton-Peabody Laboratory at Mass. Eye and Ear and lead author, explains. “Humans are currently exposed to the type of noise used in those experiments but it’s hard to conceive that some vertebrates, thousands of years ago, were submitted to stimuli similar to those delivered by speakers. So many researchers believed that the protective effects of the efferent system were an epiphenomenon – not its true function.”

Instead of using loud noise exposures evoking a change in hearing threshold, we used a moderate noise exposure at a level similar to those found in restaurants, conferences, malls, and also in nature (some frogs emit vocalizations at similar or higher levels) and instead of looking at thresholds, we looked for signs of cochlear neuropathy, Dr. Maison continued.

The researchers demonstrated that such moderate exposure lead to cochlear neuropathy (loss of auditory nerve fibers), which causes difficulty to hear in noisy environments.

"This is tremendously important because all of us are submitted to such acoustic environments and it takes a lot of auditory nerve fiber loss before it gets to be detected by simply measuring thresholds as it’s done when preforming an audiogram," Dr. Maison said. "The second important discovery is that, in mice where the efferent system has been surgically removed, cochlear neuropathy is tremendously exacerbated. That second piece proves that the efferent system does play a very important role in protecting the ear from cochlear neuropathy and we may have found its main function."

The researchers say they are excited about this discovery because the strength of the efferent system can be recorded non-invasively in humans and a non-invasive assay to record the efferent system strength has already been developed and shows that one is able to predict vulnerability to acoustic injury (Maison and Liberman, Predicting vulnerability to acoustic injury with a noninvasive assay of olivocochlear reflex strength, Journal of Neuroscience, 20:4701-4707, 2000).

"One could envision applying this assay or a modified version of it to human populations to screen for individuals most at risk in noise environments," Dr. Maison concluded.

Novel intercellular transportation system may have potential for delivering RNAi and other gene-based therapeutics

Important new research from UMass Medical School demonstrates how exosomes shuttle proteins from neurons to muscle cells where they take part in critical signaling mechanisms, an exciting discovery that means these tiny vehicles could one day be loaded with therapeutic agents, such as RNA interference (RNAi), and directly target disease-carrying cells. The study, published this month in the journal Neuron, is the first evidence that exosomes can transfer membrane proteins that play an important role in cell-to-cell signaling in the nervous system.

“There has been a long-held belief that certain cellular materials, such as integral membrane proteins, are unable to pass from one cell to another, essentially trapping them in the cell where they are made,” said Vivian Budnik, PhD, professor of neurobiology and lead author of the study. “What we’ve shown in this study is that these cellular materials can actually move between different cell types by riding in the membrane of exosomes.

“What is so exciting about this discovery is that these exosomes can deliver materials from one cell, over a distance, to a very specific and different cell,” said Dr. Budnik. “Once inside the recipient cell, the materials contained in the exosome can influence or perform processes in the new cell. This raises the enticing possibility that exosomes can be packed with gene therapies, such as RNAi, and delivered to diseased cells where they could have a therapeutic effect for people.”

Discovered in the mid-80s, exosomes have only recently attracted the attention of scientists at large, according to Budnik. Exosomes are small vesicles containing cellular materials such as microRNA, messenger RNAs (mRNAs) and proteins, packaged inside larger, membrane-bound bodies called multivesicular bodies (MVBs) inside cells. When MVBs containing exosomes fuse with the cell plasma membrane, they release these exosome vesicles into the extracellular space. Once outside the cell, exosomes can then travel to other cells, where they are taken up. The recipient cells can then use the materials contained within exosomes, influencing cellular function and allowing the recipient cell to carry out certain processes that it might not be able to complete otherwise.

Budnik and colleagues made this startling discovery while investigating how the synapses at the end of neurons and nearby muscle cells communicate in the developing Drosophila fruit fly to form the neuromuscular junction (NMJ). The NMJ is essential for transmitting electrical signals between neurons and muscles, allowing the organism to move and control important physiological processes. Alterations of the NMJ can lead to devastating diseases, such as muscular dystrophy and Amyotrophic lateral sclerosis (ALS). Understanding how the NMJ develops and is maintained is important for human health.

As organisms develop, the synapse and muscle cell need to grow in concert. If one or the other grows too quickly or not quickly enough, it could have dire consequences for the ability of the organism to move and survive. To coordinate development, signals are sent from the neuron to the muscle cell (anterograde signals) and from the muscle cell to the neuron (retrograde signals). However, the identity of these signals and how their release is coordinated is poorly understood.

Normally, the vesicle protein Synaptotagmin 4 (Syt4) is found in both the synapse and the muscle cells. Previous knockout experiments eliminating the Syt4 protein from Drosophila have resulted in stunted NMJs. Suspecting that Syt4 played an important role in retrograde signaling at the developing NMJ, Budnik and colleagues used knockdown experiments to decrease Syt4 protein levels in either the neurons or the muscle cells. Surprisingly, when RNAi was used to knockdown Syt4 in the neurons alone, Syt4 protein was eliminated in both neurons and muscles. The opposite was not the case. When Syt4 was knocked down in muscle cells only, there was no change in the levels of Syt4 in either muscles or neurons.

To confirm this, Budnik and colleagues inserted a Syt4 gene into the neurons of a Drosophila mutant completely lacking the normal protein. This restored Syt4 in both neurons and muscle cells. Further experiments suggested that the only source of Syt4 is the neuron. These observations were consistent with the model that Syt4 is actually transferred from neurons to muscle cells. As a transmembrane protein, however, Syt4 was thought to be unable to move from one cell to another through traditional avenues. How the Syt4 protein was moving from neuron to muscle cell was unclear.

Knowing that exosomes had been observed to carry transmembrane proteins in other systems and from their own work on the Drosophila NMJ, Budnik and colleagues began testing to see if exosomes could be the vehicle responsible for carrying Syt4 form neurons to muscles. “We had previously observed that it was possible to transfer transmembrane proteins across the NMJ through exosomes, a process also observed in the immune system,” said Budnik. “We suspect this was how Syt4 was making its way from the neuron to the muscle.”

When exosomes were purified from cultured cells containing Syt4, they found that exosomes indeed contained Syt4. In addition, when these purified exosomes were applied to cultured muscle cells from fly embryos, these cells were able to take up the purified Syt4 exosomes. Taken together, these findings indicate that Syt4 plays a critical role in the signaling process between synapse and muscle cell that allows for coordinated development of the NMJ. While Syt4 is required to release a retrograde signal from muscle to neuron, a component of this retrograde signal must be supplied from the neuron to the muscle. This establishes a positive feedback loop that ensures coordinated growth of the NMJ. Equally important is the finding that this feedback mechanism is enabled by the use of exosomes, which can shuttle transmembrane proteins across cells.

“While this discovery greatly enhances our understanding of how the neural muscular junction develops and works, it also has tremendous promise as a potential vector for targeted genetic therapies,” said Budnik. “More work needs to be done, but this study significantly supports the possibility that exosomes could be loaded with therapeutic agents and delivered to specific cells in patients.”

Neurobiologists at the Friedrich Miescher Institute have been able to dissect a mechanism in the retina that facilitates our ability to see both in the dark and in the light. They identified a cellular switch that activates distinct neuronal circuits at a defined light level. The switch cells of the retina act quickly and reliably to turn on and off computations suited specifically for vision in low and high light levels thus facilitating the transition from night to day vision. The scientists have published their results online in Neuron.

"It was fascinating to see how modern neurobiological methods allowed us to answer a question about vision that has been controversially discussed for the last 50 years", said Karl Farrow, postdoctoral fellow in Botond Roska’s group at the Friedrich Miescher Institute for Biomedical Research. Since the late 1950 scientists debated how the retina handles the different visual processes at low and high light intensities, at starlight and at daylight. Farrow and his colleagues have now identified a cellular switch in the retina that controls perception during these two settings.

At first glance, everything seems clear. The interplay of two photoreceptor types in the retina, the rods and the cones, allow us to see across a wide range of light intensities. The rods are highly sensitive and spring into action in the dark; the cones are activated during the day and in humans come in three diversities allowing us to see color. The rods help us detect objects during the night; while the cones allow us to discriminate the fine details of those objects during the day. The plethora of initial signals originating from the photoreceptors is computed in a system of only approximately 20 neuronal channels that transport information to the brain. The relay stations are the roughly 20 types of ganglion cells in the retina. How they manage the transition from light to dark and enable vision at the different light regimes has remained unclear.

In the retina several cell layers are stacked on top of each other. The photoreceptors are the first to be activated by light; they relay the information to bipolar cells, which in turn activate ganglion cells. The different types of ganglion cells take on distinct tasks during vision. These ganglion cells are embedded in a mesh of amacrine cells that modulate their activity. “Here is where our new genetic tools proofed very helpful,” said Farrow, “because they allowed us to look at individual ganglion cell types and to specifically measure their activities at different light intensities.” Farrow and colleagues could thus show that the activity of one particular type of ganglion cells, called PV1, is modulated like a switch by amacrine cells. The amacrine cells inhibit the ganglion cell strongly at high light intensities and weakly at low ambient light levels. This switch is abrupt and reversible and it occurs at the light intensities where cones are starting to be activated. “We were surprised to see how fast this switch occurs and how reliable we were able to switch between the two states at defined light intensities”, comments Farrow.

While the above experiments were done in a mouse model, the FMI neurobiologists could show that a similar switch operates in human vision. Their volunteers had to look at narrow and broader stripes at different light levels. They could show that there again a switch operates. While the general ability to see all striped patterns improved with increasing light intensity, suddenly, at a certain light level, the volunteers were much better able to detect thinner patterns as compared to the broader ones. Interestingly enough this switch happened at precisely the light level where the volunteers were also able to discriminate between red and blue, hence where the cones spring into action. “We think we have found a regulatory principle that could apply to several processes in the brain”, said Roska, “This principle could explain some situations when gradual changes in the sensory environment leads to abrupt changes in brain computations and perception”

A new study published in the March issue of Autism Research from the University of Tennessee Health Science Center and Le Bonheur researchers is making the genetic connections between autism and Chromosome 15q Duplication Syndrome (Dup15q).

The Memphis researchers determined that the maternally derived or inherited duplication of the region inclusive of the UBE3A gene (also known as the Angelman/Prader-Willi syndrome locus) are sufficient to produce a phenotype on the autism spectrum in all ten maternal duplication subjects. The number of subjects was too small to determine if parental duplications do not cause autism. The team assembled the largest single cohort of interstitial 15q duplication subjects for phenotype/genotype analysis of the autism component of the syndrome.

Chromosome 15q Duplication Syndrome (Dup15q) results from duplications of chromosome 15q11-q13. Duplications that are maternal in origin often result in developmental problems. The larger 15q duplication syndrome, which includes individuals with idic15, manifests itself in a wide range of developmental disabilities including autism spectrum disorders; motor, cognitive and speech/language delays; and seizure disorders among others. While there is no specific treatment plan, therapies are available to address or manage symptoms.

Previous research suggests that as many as 1,000 genes may contribute to autism phenotypes, but as much as 1-3 percent of all autism spectrum disorder cases may be a result of 15q11-q13 duplication alone.

The researchers also found through EEG evaluations a pattern that looks like the type of signal you see when individuals take GABA promoting drugs (benzodiazepines). The lead researcher on this study, Lawrence T. Reiter, PhD, says this signal gives clinicians a clue about what types of anti-seizure medication may be most useful in children with 15q duplications.

Reiter says genetic testing can help families connect to resources, like the Dup15q Alliance. Reiter is an associate professor in Department of Neurology with an adjunct appointment in Pediatrics at UTHSC.

“If a pediatrician suspects autism due to hypotonia and developmental delay, I highly recommend they order an arrayCGH test. Duplication 15q is the second most common duplication in autism. The test will help families in future treatments specific to this sub-type of autism,” he said.

A new study suggests that migraines are related to brain abnormalities present at birth and others that develop over time. The research is published online in the journal Radiology.

Migraines are intense, throbbing headaches, sometimes accompanied by nausea, vomiting and sensitivity to light. Some patients experience auras, a change in visual or sensory function that precedes or occurs during the migraine. More than 300 million people suffer from migraines worldwide, according to the World Health Organization.

Previous research on migraine patients has shown atrophy of cortical regions in the brain related to pain processing, possibly due to chronic stimulation of those areas. Cortical refers to the cortex, or outer layer of the brain.

Much of that research has relied on voxel-based morphometry, which provides estimates of the brain’s cortical volume. In the new study, Italian researchers used a different approach: a surface-based MRI method to measure cortical thickness.

"For the first time, we assessed cortical thickness and surface area abnormalities in patients with migraine, which are two components of cortical volume that provide different and complementary pieces of information," said Massimo Filippi, M.D., director of the Neuroimaging Research Unit at the University Ospedale San Raffaele and professor of neurology at the University Vita-Salute’s San Raffaele Scientific Institute in Milan. "Indeed, cortical surface area increases dramatically during late fetal development as a consequence of cortical folding, while cortical thickness changes dynamically throughout the entire life span as a consequence of development and disease."

Dr. Filippi and colleagues used magnetic resonance imaging (MRI) to acquire T2-weighted and 3-D T1-weighted brain images from 63 migraine patients and 18 healthy controls. Using special software and statistical analysis, they estimated cortical thickness and surface area and correlated it with the patients’ clinical and radiologic characteristics.

Compared to controls, migraine patients showed reduced cortical thickness and surface area in regions related to pain processing. There was only minimal anatomical overlap of cortical thickness and cortical surface area abnormalities, with cortical surface area abnormalities being more pronounced and distributed than cortical thickness abnormalities. The presence of aura and white matter hyperintensities—areas of high intensity on MRI that appear to be more common in people with migraine—was related to the regional distribution of cortical thickness and surface area abnormalities, but not to disease duration and attack frequency.

"The most important finding of our study was that cortical abnormalities that occur in patients with migraine are a result of the balance between an intrinsic predisposition, as suggested by cortical surface area modification, and disease-related processes, as indicated by cortical thickness abnormalities," Dr. Filippi said. "Accurate measurements of cortical abnormalities could help characterize migraine patients better and improve understanding of the pathophysiological processes underlying the condition."

Additional research is needed to fully understand the meaning of cortical abnormalities in the pain processing areas of migraine patients, according to Dr. Filippi.

"Whether the abnormalities are a consequence of the repetition of migraine attacks or represent an anatomical signature that predisposes to the development of the disease is still debated," he said. "In my opinion, they might contribute to make migraine patients more susceptible to pain and to an abnormal processing of painful conditions and stimuli."

The researchers are conducting a longitudinal study of the patient group to see if their cortical abnormalities are stable or tend to worsen over the course of the disease. They are also studying the effects of treatments on the observed modifications of cortical folding and looking at pediatric patients with migraine to assess whether the abnormalities represent a biomarker of the disease.

The field of cell therapy, which aims to form new cells in the body in order to cure disease, has taken another important step in the development towards new treatments. A new report from researchers at Lund University in Sweden shows that it is possible to re-programme other cells to become nerve cells, directly in the brain.

Two years ago, researchers in Lund were the first in the world to re-programme human skin cells, known as fibroblasts, to dopamine-producing nerve cells – without taking a detour via the stem cell stage. The research group has now gone a step further and shown that it is possible to re-programme both skin cells and support cells directly to nerve cells, in place in the brain.

“The findings are the first important evidence that it is possible to re-programme other cells to become nerve cells inside the brain”, said Malin Parmar, research group leader and Reader in Neurobiology.

The researchers used genes designed to be activated or de-activated using a drug. The genes were inserted into two types of human cells: fibroblasts and glia cells – support cells that are naturally present in the brain. Once the researchers had transplanted the cells into the brains of rats, the genes were activated using a drug in the animals’ drinking water. The cells then began their transformation into nerve cells.

In a separate experiment on mice, where similar genes were injected into the mice’s brains, the research group also succeeded in re-programming the mice’s own glia cells to become nerve cells.

“The research findings have the potential to open the way for alternatives to cell transplants in the future, which would remove previous obstacles to research, such as the difficulty of getting the brain to accept foreign cells, and the risk of tumour development”, said Malin Parmar.

All in all, the new technique of direct re-programming in the brain could open up new possibilities to more effectively replace dying brain cells in conditions such as Parkinson’s disease.

“We are now developing the technique so that it can be used to create new nerve cells that replace the function of damaged cells. Being able to carry out the re-programming in vivo makes it possible to imagine a future in which we form new cells directly in the human brain, without taking a detour via cell cultures and transplants”, concluded Malin Parmar.

The research article is entitled ‘Generation of induced neurons via direct conversion in vivo’ and has been published in the Proceedings of the National Academy of Science (PNAS)

The virus that causes cold sores, along with other viral or bacterial infections, may be associated with cognitive problems, according to a new study published in the March 26, 2013, print issue of Neurology®, the medical journal of the American Academy of Neurology.

The study found that people who have had higher levels of infection in their blood (measured by antibody levels), meaning they had been exposed over the years to various pathogens such as the herpes simplex type 1 virus that causes cold sores, were more likely to have cognitive problems than people with lower levels of infection in the blood. “We found the link was greater among women, those with lower levels of education and Medicaid or no health insurance, and most prominently, in people who do not exercise,” said author Mira Katan, MD, with the Northern Manhattan Study at Columbia University Medical Center in New York and a member of the American Academy of Neurology. The study was performed in collaboration with the Miller School of Medicine at the University of Miami in Miami, FL.

For the study, researchers tested thinking and memory in 1,625 people with an average age of 69 from northern Manhattan in New York. Participants gave blood samples that were tested for five common low grade infections: three viruses (herpes simplex type 1 (oral) and type 2 (genital), and cytomegalovirus), chlamydia pneumoniae (a common respiratory infection) and Helicobacter pylori (a bacteria found in the stomach).

The results showed that the people who had higher levels of infection had a 25 percent increase in the risk of a low score on a common test of cognition called the Mini-Mental State Examination.

The memory and thinking skills were tested every year for an average of eight years. But infection was not associated with changes in memory and thinking abilities over time.

“While this association needs to be further studied, the results could lead to ways to identify people at risk of cognitive impairment and eventually lower that risk,” said Katan. “For example, exercise and childhood vaccinations against viruses could decrease the risk for memory problems later in life.” The study was supported by the National Institutes of Neurological Disorders and Stroke (NINDS), the Swiss National Science Foundation and the Leducq Foundation.