Neuroscience

TAU researchers find chemicals in marijuana could help treat MS

Multiple sclerosis is an inflammatory disease in which the immune system attacks the nervous system. The result can be a wide range of debilitating motor, physical, and mental problems. No one knows why people get the disease or how to treat it.

In a new study published in the Journal of Neuroimmune Pharmacology, Drs. Ewa Kozela, Ana Juknat, Neta Rimmerman and Zvi Vogel of Tel Aviv University’s Dr. Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases and Sackler Faculty of Medicine demonstrate that some chemical compounds found in marijuana can help treat MS-like diseases in mice by preventing inflammation in the brain and spinal cord.

"Inflammation is part of the body’s natural immune response, but in cases like MS it gets out of hand," says Kozela. "Our study looks at how compounds isolated from marijuana can be used to regulate inflammation to protect the nervous system and its functions." Researchers from the Weizmann Institute of Science co-authored the study.

Mind-altering findings

Israel has a strong tradition of marijuana research. Israeli scientists Raphael Mechoulam and Yechiel Gaoni discovered THC, or tetrahydrocannabinol, in 1964, kick-starting the scientific study of the plant and its chemical constituents around the world. Since then, scientists have identified about 70 compounds — called cannabinoids — that are unique to cannabis and have interesting biological effects. In the 1990s, Prof. Vogel was among the first researchers to describe endocannabinoids, molecules that act like THC in the body.

Besides THC, the most plentiful and potent cannabinoid in marijuana is cannabidiol, or CBD. The TAU researchers are particularly interested in CBD, because it offers medicinal benefits without the controversial mind-altering effects of THC.

In a 2011 study, they showed that CBD helps treat MS-like symptoms in mice by preventing immune cells in their bodies from transforming and attacking the insulating covers of nerve cells in the spinal cord. After inducing an MS-like condition in mice — partially paralyzing their limbs — the researchers injected them with CBD. The mice responded by regaining movement, first twitching their tails and then beginning to walk without a limp. The researchers noted that the mice treated with CBD had much less inflammation in the spinal cord than their untreated counterparts.

High hopes for humans

In the latest study, the researchers set out to see if the known anti-inflammatory properties of CBD and THC could also be applied to the treatment of inflammation associated with MS — and if so, how. This time they turned to the immune system.

The researchers took immune cells isolated from paralyzed mice that specifically target and harm the brain and spinal cord, and treated them with either CBD or THC. In both cases, the immune cells produced fewer inflammatory molecules, particularly one called interleukin 17, or IL-17, which is strongly associated with MS and very harmful to nerve cells and their insulating covers. The researchers concluded that the presence of CBD or THC restrains the immune cells from triggering the production of inflammatory molecules and limits the molecules’ ability to reach and damage the brain and spinal cord.

Further research is needed to prove the effectiveness of cannabinoids in treating MS in humans, but there are reasons for hope, the researchers say. In many countries, CBD and THC are already prescribed for the treatment of MS symptoms, including pain and muscle stiffness.

"When used wisely, cannabis has huge potential," says Kozela, who previously studied opiates like morphine, derived from the poppy plant. "We’re just beginning to understand how it works."

Researchers discover that an important clue to diagnosing Parkinson’s disease may lie just beneath the skin

Although Parkinson’s disease is the second most prevalent neurodegenerative disorder in the U.S., there are no standard clinical tests available to identify this widespread condition. As a result, Parkinson’s disease often goes unrecognized until late in its progression, when the brain’s affected neurons have already been destroyed and telltale motor symptoms such as tremor and rigidity have already appeared.

Now researchers from Beth Israel Deaconess Medical Center (BIDMC) have discovered that an important clue to diagnosing Parkinson’s may lie just beneath the skin.

In a study scheduled to appear in the October 29 print issue of the journal Neurology and currently published on-line, the investigators report that elevated levels of a protein called alpha-synuclein can be detected in the skin of Parkinson’s patients, findings that offer a possible biomarker to enable clinicians to identify and diagnose PD before the disease has reached an advanced stage.

Parkinson’s disease affects more than 1 million individuals throughout the U.S. Diagnosis is currently made through neurological history and examination, often by a patient’s primary care physician.

“Even the experts are wrong in diagnosing Parkinson’s disease a large percentage of the time,” says senior author Roy Freeman, MD, Director of the Autonomic and Peripheral Nerve Laboratory at BIDMC and Professor of Neurology at Harvard Medical School. “A reliable biomarker could help doctors in more accurately diagnosing Parkinson’s disease at an earlier stage and thereby offer patients therapies before the disease has progressed.”

Alpha-synuclein is a protein found throughout the nervous system. Although its function is unknown, it is the primary component of protein clumps known as Lewy bodies, which are considered the hallmark of Parkinson’s disease. There is accumulating evidence that the protein plays a role in Parkinson’s disease development.

“Alpha-synuclein deposition occurs early in the course of Parkinson’s disease and precedes the onset of clinical symptoms,” explains Freeman, who with his coauthors suspected that the protein was elevated in the skin’s structures with autonomic innervation.

“Symptoms related to the autonomic nervous system, including changes in bowel function, temperature regulation, and blood pressure control may antedate motor symptoms in Parkinson’s patients,” he explains. “Skin-related autonomic manifestations, including excessive and diminished sweating and changes in skin color and temperature, occur in almost two-thirds of patients with Parkinson’s disease. The skin can provide an accessible window to the nervous system and based on these clinical observations, we decided to test whether examination of the nerves in a skin biopsy could be used to identify a PD biomarker.”

To test this hypothesis, the research team enrolled 20 patients with Parkinson’s disease and 14 control subjects of similar age and gender. The participants underwent examinations, autonomic testing and skin biopsies in three locations on the leg. Alpha-synuclein deposition and density of cutaneous sensory, sudomotor and pilomotor nerve fibers were measured.

As predicted, their results showed that alpha-synuclein was increased in the cutaneous nerves supplying the sweat glands and pilomotor muscles in the Parkinson’s patients. Higher alpha-synuclein deposition in the nerves supplying the skin’s autonomic structures was associated with more advanced Parkinson’s disease and worsening autonomic function.

“There is a strong and unmet need for a biomarker for Parkinson’s disease,” says Freeman. “Alpha-synuclein deposition within the skin has the potential to provide a safe, accessible and repeatable biomarker. Our next steps will be to test whether this protein is present in the cutaneous nerves of individuals at risk for Parkinson’s disease, and whether measurement of alpha-synuclein deposition in the skin can differentiate Parkinson’s disease from other neurodegenerative disorders.”

Babies learn how to anticipate touch while in the womb, according to new research.

Using 4-d scans psychologists at Durham and Lancaster universities found, for the first time, that fetuses were able to predict, rather than react to, their own hand movements towards their mouths as they entered the later stages of gestation compared to earlier in a pregnancy.

The Durham-led team of researchers said that the latest findings could improve understanding about babies, especially those born prematurely, their readiness to interact socially and their ability to calm themselves by sucking on their thumb or fingers.

They said the results could also be a potential indicator of how prepared babies are for feeding.

The researchers carried out a total of 60 scans of 15 healthy fetuses at monthly intervals between 24 weeks and 36 weeks gestation.

Fetuses in the earlier stage of gestation more frequently touched the upper part and sides of their heads.

As the fetuses matured they began to increasingly touch the lower, more sensitive, part of their faces including their mouths.

By 36 weeks a significantly higher proportion of fetuses were observed opening their mouths before touching them, suggesting that later in pregnancy they were able to anticipate that their hands were about to touch their mouths, rather than reacting to the touch of their hands, the researchers said.

Increased sensitivity around a fetus’ mouth at this later stage of pregnancy could mean that they have more “awareness” of mouth movement, they added.

Previous theories have suggested that movement in sequence could form the basis for the development of intention in fetuses.

The researchers said their findings could potentially be an indicator of healthy development, as arguably fetuses who are delayed in this development due to illness, such as growth restriction, might not show the same behaviour observed during the study.

The research, published in the journal Developmental Psychobiology, involved eight girls and seven boys and the researchers noticed no difference in behaviour between boys and girls.

Lead author Dr Nadja Reissland, in the Department of Psychology, at Durham University, said: “Increased touching of the lower part of the face and mouth in fetuses could be an indicator of brain development necessary for healthy development, including preparedness for social interaction, self-soothing and feeding.

“What we have observed are sequential events, which show maturation in the development of fetuses, which is the basis for life after birth.

“The findings could provide more information about when babies are ready to engage with their environment, especially if born prematurely.”

Brian Francis, Professor of Social Statistics at Lancaster, added: “This effect is likely to be evolutionally determined, preparing the child for life outside the womb. Building on these findings, future research could lead to more understanding about how the child is prepared prenatally for life, including their ability to engage with their social environment, regulate stimulation and being ready to take a breast or bottle.”

The study builds on previous research by Durham and Lancaster into fetal development. Earlier this year another of their studies showed that unborn babies practise facial expressions in the womb in what is thought to be preparation for communicating after birth.

And in 2012 Dr Reissland published research showing that unborn babies yawn in the womb, suggesting that yawning is a developmental process which could potentially give doctors another index of a fetus’ health.

It’s a question that has long fascinated and flummoxed those who study human behavior: From whence comes the impulse to dream? Are dreams generated from the brain’s “top” — the high-flying cortical structures that allow us to reason, perceive, act and remember? Or do they come from the brain’s “bottom” — the unheralded brainstem, which quietly oversees such basic bodily functions as respiration, heart rate, salivation and temperature control?

At stake is what to make of the funny, sexual, scary and just plain bizarre mental scenarios that play themselves out in our heads while we sleep. Are our subconsious fantasies coming up for a breath of air, as Sigmund Freud believed? Is our brain consolidating lessons learned and pitching out unneeded data, as neuroscientists suggest? Or are dreams no more meaningful than a spontaneous run of erratic heartbeats, a hot flash, or the frisson we feel at the sight of an attractive passer-by?

A study published this week in the journal Brain suggests that the impulse to dream may be little more than a tickle sent up from the brainstem to the brain’s sensory cortex.

The full dream experience — the complex scenarios, the feelings of fear, delight or longing — may require the further input of the brain’s higher-order cortical areas, the new research suggests. But even people with grievous injury to the brain’s prime motivational machinery are capable of dreams, the study found.

The latest research looked for sleep-time “mentation” — thoughts, essentially — in a small group of very unusual patients. These patients — 13 in all — had suffered damage within their brains’ limbic system, the seat of our basic desires and motivations — for sex, for food, for pleasurable sensations brought on by drugs and friendship and whatever else turns us on.

As a result of that damage, they had a neuropsychological syndrome called auto-activation deficit, or AAD: Even while fully conscious, they could sit completely idle and mute for hours if they were not prodded to action or speech by caregivers. In fact, they were more than unmotivated to do anything; when asked about their thoughts, they would frequently report that their mind was completely blank. When prompted, they could often do math, sing a song or conjure up memories. But left on their own, these patients might have no spontaneous thoughts at all.

Do these people dream? The answer might suggest the answer to the question of where dreams come from.

Indeed, they do dream — or at least some of them did, in an experiment that compared the nighttime mentations of normal, healthy subjects with subjects who suffered from AAD. When awakened from rapid eye movement (REM) sleep — the sleep stage at which dreams are thought to be most common and complex — four of the patients with AAD — 31% of them — reported mentations.

That was a lot less dreaming than was happening in the healthy subjects, 92% of whom reported dreams — and much more colorful and bizarre ones — when they were awakened from REM sleep.

In the AAD patients, the dreams were rarer, shorter and less complex: they said they dreamed of things like shaving, taking a walk or seeing a relative. But even these rudimentary dreams cast them in situations that, in a conscious state, they were unlikely to think of unprompted.

That these inert patients could generate dreams was a “most unexpected result,” said the study’s authors, a team of French neurologists, neuroscientists and sleep specialists based in several institutes in Paris. It supports the hypothesis that “dreams are generated through bottom-up processes,” they concluded.

The “top-down theory” — that dreams originate from the brain’s higher-order cortex, the place from which imagination springs — “is not supported here,” the authors said, “as patients with AAD who have a mental emptiness and no imagination during wakefulness do report some dream mentations upon emerging from sleep.”

Of course, the dreams of healthy subjects may be enbellished by input from the cortical areas that are the seats of perception, memory, emotion and reason, the authors said: That is demonstrated by the vastly richer dreams described by normal subjects.

A lot of dream research in humans has been based on subjects with bizarre damage to the brain. People who have had frontal lobotomies, for instance, report an abrupt cessation of dream activity — an observation that had rallied the top-down view of the dream impulse.

It’s an imperfect method of research, since such subjects are rare and no two have exactly the same injuries. So, while the rest of us dream away unbothered, this intriguing debate is likely to remain open for some time to come.

An inhibitory neuron type is found to specifically suppress the activation of other inhibitory neurons in cerebral cortex.

The cerebral cortex contains two major types of neurons: principal neurons that are excitatory and interneurons that are inhibitory, all interconnected within the same network. New research now reveals that one class of inhibitory neurons – called VIP interneurons — specializes in inhibiting other inhibitory neurons in multiple regions of cortex, and does so under specific behavioral conditions.

The new research finds that VIP interneurons, when activated, release principal cells from inhibition, thus boosting their responses. This provides an additional layer of control over cortical processing, much like a dimmer switch can fine-tune light levels.

The discovery was made by a team of neuroscientists at Cold Spring Harbor Laboratory (CSHL) led by Associate Professor Adam Kepecs, Ph.D. Their research, published online today in Nature, shows that neurons expressing vasoactive intestinal polypeptide, or VIP, provide disinhibition in the auditory cortex and the medial prefrontal cortex. 

The researchers used molecular tagging techniques developed by team member Z. Josh Huang, a CSHL Professor, to single out VIP-expressing neurons in the vast diversity of cortical neurons. This enabled Kepecs’ group, led by postdocs Hyun Jae Pi and Balazs Hangya, to employ advanced optogenetic techniques using color-coded laser light to specifically activate VIP neurons. The activity of the cells was monitored via electrophysiological recordings in behaving animals to study their function, and in vitro to probe their circuit properties.

These VIP neurons are long sought “disinhibitory” cells: they inhibit other classes of inhibitory neurons; but they do not directly cause excitation to occur in brain. Dr. Kepecs and colleagues propose that the disinhibitory control mediated by VIP neurons represents a fundamental “motif” in cerebral cortex.

The difference between neural excitation and disinhibition is akin to the difference between hitting the gas pedal and taking your foot off the breaks. Cells that specialize in releasing the brakes, Dr. Kepecs explains, provide the means for balancing between excitation and inhibition. Kepecs calls this function “gain modulation,” which brings to mind the fine control that a dimmer switch provides.

The team wondered when VIP neurons are activated during behavior. When, in other words, is the “cortical dimmer switch” engaged? To learn the answer the scientists recorded VIP neurons while mice were making simple decisions, discriminating between sounds of different pitches. When they made correct choices, the mice earned a drop of water; for incorrect choices, a mild puff of air. Surprisingly, the team found that in auditory cortex, a region involved in processing sounds, VIP neurons were activated by rewards and punishments. Thus these neurons appeared to mediate the impact of reinforcements and “turn up the lights” on principal cells, to use the dimmer-switch analogy.

“Linking specific neuronal types to well-defined behaviors has proved extremely difficult,” says Kepecs. These results, he says, potentially link the circuit-function of VIP neurons in gain control to an important behavioral function: learning.

It’s not visible to the naked eye and you can’t feel it, but up to 40 per cent of your body’s energy goes into supplying the microscopic sodium-potassium pump with the energy it needs. The pump is constantly doing its job in every cell of all animals and humans. It works much like a small battery which, among other things, maintains the sodium balance which is crucial to keep muscles and nerves working.

The sodium-potassium pump transports sodium out and potassium into the cell in a fixed cycle. During this process the structure of the pump changes. It is well-established that the pump has a sodium and a potassium form. But the structural differences between the two forms have remained a mystery, and researchers have been unable to explain how the pump distinguishes sodium from potassium.

Structure solves the mystery

Thanks to the international collaboration between Professor Chikashi Toyoshima’s group at the University of Tokyo and researchers from Aarhus University, the structure of the sodium-bound form of the protein has now been described. For the first time ever, the sodium ions can be studied at a resolution so high - 0.28 nanometres - that researchers can actually see the sodium ions and observe where they bind in the structure of the pump. In 2000, Professor Chikashi Toyoshima’s group described the structure of a calcium-pump for the first time, and in 2007 and 2009 research groups from Aarhus University and Toyoshima’s group described the potassium-bound form of the sodium-potassium pump.

"The new protein structure shows how the smaller sodium ions are bound and subsequently transported out of the cell, whereas the access of the slightly larger potassium ions is blocked. We now understand how the pump distinguishes between sodium and potassium at the molecular level. This is a great leap forward for research into ion pumps and may help us understand and treat serious neurological conditions associated with mutations of the sodium-potassium pump, including a form of Parkinsonism and alternating hemiplegia of childhood in which sodium binding is defective," explains Bente Vilsen, a professor at Aarhus University who spearheaded the project’s activities in Aarhus with Associate Professor Flemming Cornelius.

Impressed Nobel Prize winner

The vital pump was discovered in 1957 by Professor Jens Christian Skou of Aarhus University, who received the Nobel Prize for his discovery in 1997. The new result is the culmination of five or six decades of research aimed at the mechanism behind this vital motor of the cells.

"Years ago, when the first electron microscopic images were taken in which the enzyme was but a millimetre-sized dot at 250,000 magnifications, I thought, how on earth will we ever be able to establish the structure of the enzyme. The pump transports potassium into and sodium out of the cells, so it must be capable of distinguishing between the two ions. But until now, it has been a mystery how this was possible," says retired Professor Jens Christian Skou, who - even at 94 years of age - keeps up to date with new developments in the field of research which he initiated more than 50 years ago.

"Now, the researchers have described the structure that allows the enzyme to identify sodium and this may pave the way for a more detailed understanding of how the pump works. It is an impressive achievement and something I haven’t even dared dream of," concludes Jens Christian Skou.

Study brings to 110 known risk factors and provides important insight into disease mechanism

Scientists of the International Multiple Sclerosis Genetics Consortium (IMSGC) have identified an additional 48 genetic variants influencing the risk of developing multiple sclerosis. This work nearly doubles the number of known genetic risk factors and thereby provides additional key insights into the biology of this debilitating neurological condition. The genes implicated by the newly identified associations underline the central role played by the immune system in the development of multiple sclerosis and show substantial overlap with genes known to be involved in other autoimmune diseases.

Published online September 29 in the journal Nature Genetics, the study, “Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis,” is the largest investigation of multiple sclerosis genetics to date. Led by the University of Miami Miller School of Medicine, this study relied upon an international team of 193 investigators from 84 research groups in 13 countries and was funded by more than 40 local and national agencies and foundations.

Multiple sclerosis (MS) is a chronic disabling neurological condition that affects over 2.5 million individuals worldwide. The disease results in patchy inflammation and damage to the central nervous system that causes problems with mobility, balance, sensation and cognition depending upon where the damage to the central nervous system occurs. Neurological symptoms are often intermittent in the early stages of the disease but tend to persist and progressively worsen with the passage of time for the majority of patients. The risk of developing multiple sclerosis is increased in those who have a family history of the disease. Research studies in twins and adopted individuals have shown that this increased risk is primarily the result of genetic risk factors.

The findings released in this study nearly double the number of confirmed susceptibility loci, underline the critical role played by the immune system in the development of multiple sclerosis, and highlight the marked similarities between the genetic architecture underlying susceptibility to this and the many other autoimmune diseases.

The present study takes advantage of custom designed technology known as ImmunoChip—a high-throughput genotyping array specifically designed to interrogate a targeted set of genetic variants linked to one or more autoimmune diseases. IMSGC researchers used the ImmunoChip platform to analyze the DNA from 29,300 individuals with multiple sclerosis and 50,794 unrelated healthy controls, making this the largest genetics study ever performed for multiple sclerosis. In addition to identifying 48 new susceptibility variants, the study also confirmed and further refined a similar number of previously identified genetic associations.

With these new findings, there are now 110 genetic variants associated with MS. Although each of these variants individually confers only a very small risk of developing multiple sclerosis, collectively they explain approximately 20 percent of the genetic component of the disease.

Explaining the significance of the work and the nature of the collaboration, the Miller School’s Jacob McCauley, Ph.D., who led the study on behalf of the IMSGC, said, “With the release of these new data, our ongoing effort to elucidate the genetic components of this complex disease has taken a major step forward. Describing the genetic underpinnings of any complex disease is a complicated but critical step. By further refining the genetic landscape of multiple sclerosis and identifying novel genetic associations, we are closer to being able to identify the cellular and molecular processes responsible for MS and therefore the specific biological targets for future drug treatment strategies. These results are the culmination of a thoroughly collaborative effort. A study of this size and impact is only possible because of the willingness of so many hard working researchers and thousands of patients to invest their time and energy in a shared goal.”

Scientists discover key function in molecule that regulates sleep, metabolism and hunger

Why does hunger keep us awake and a full belly make us tired? Why do people with sleep disorders such as insomnia often binge eat late at night? What can sleep patterns tell us about obesity?

Sleep, hunger and metabolism are closely related, but scientists are still struggling to understand how they interact. Now, Brandeis University researchers have discovered a function in a molecule in fruit flies that may provide insight into the complicated relationship between sleep and food.

In the October issue of the journal Neuron, Brandeis scientists report that sNPF, a neuropeptide long known to regulate food intake and metabolism, is also an important component in regulating and promoting sleep. When researchers activated sNPF in fruit flies, the insects fell asleep almost immediately, awaking only long enough to eat before nodding off again. The flies were so sleepy that once they found a food source, they slept right on top of it for days — like falling asleep on a giant hamburger bun and waking up long enough to take a few nibbles before falling back to sleep.

When researchers returned sNPF functions to normal, the flies resumed their normal level of activity, leaving behind their couch potato ways.

The researchers, led by professor of biology Leslie Griffith, concluded that sNPF has an important regulatory function in sleep in addition to its previously known function coordinating behaviors such as eating and metabolism.

"This paper provides a nice bridge between feeding behavior and sleep behavior with just a single molecule," says Nathan Donelson, a post doctoral fellow in Griffith’s lab and one of the study’s lead authors.

Neurons use neuropeptides to communicate a range of brain functions including learning, metabolism, memory and social behaviors. In humans, Neuropeptide Y functions similarly to sNPF and has been studied as a possible drug target for obesity treatment.

But scientists don’t fully understand how regulating neuropeptide function at specific times and in specific cells affects sleeping and eating. By studying sNPF in fruit flies, scientists can learn which cells, neurotransmitters and genes are involved in eating and sleeping; what processes turn on and inhibit the behaviors, and how sleep cells are relevant to hunger drive.

"Our paper makes a significant step into tying all these things together," says Donelson, "and that is extremely important down the road to our understanding of human health."

The membranes surrounding and inside cells are involved in every aspect of biological function. They separate the cell’s various metabolic functions, compartmentalize the genetic material, and drive evolution by separating a cell’s biochemical activities. They are also the largest and most complex structures that cells synthesize.

Understanding the myriad biochemical roles of membranes requires the ability to prepare synthetic versions of these complex multi-layered structures, which has been a long-standing challenge.

In a study published this week by Nature Chemistry, scientists at The Scripps Research Institute (TSRI) report a highly programmable and controlled platform for preparing and experimentally probing synthetic cellular structures.

“Layer-by-layer membrane assembly allows us to create synthetic cells with membranes of arbitrary complexity at the molecular and supramolecular scale,” said TSRI Assistant Professor Brian Paegel, who authored the study with Research Associate Sandro Matosevic. “We can now control the molecular composition of the inner and outer layers of a bilayer membrane, and even assemble multi-layered membranes that resemble the envelope of the cell nucleus.”

Starting with a technique commonly used to deposit molecules on a solid surface, Langmuir-Blodgett deposition, the scientists repurposed the approach to work on liquid objects.

The scientists engineered a microfluidic device containing an array of microscopic cups, each trapping a single droplet of water bathed in oil and lipids, the molecules that make up cellular membranes. The trapped droplets are then ready to serve as a foundation for building up a series of lipid layers like coats of paint.

The lipid-coated water droplets are first bathed in water. As the water/oil interface encounters the trapped droplets, a second lipid layer coats the droplets and transforms them into what are known as unilamellar or single-layer vesicles. Bathing the vesicles in oil/lipid deposits a third lipid layer, and followed by a final layer of lipids that is deposited on the trapped drops to yield double-bilayer vesicles.

“The computer-controlled microfluidic circuits we have constructed will allow us to assemble synthetic cells not only from biologically derived lipids, but from any amphiphile and to measure important chemical and physical parameters, such as permeability and stability,” said Paegel.

A team of scientists led by Dr. Antoine Adamantidis, a researcher at the Douglas Mental Health University Institute and an assistant professor at McGill University, has released the findings from their latest study, which will appear in the October issue of the prestigious scientific journal Nature Neuroscience.

(Image: iStockphoto)

Previous studies had established an association between the activity of certain types of neurons and the phase of sleep known as REM (rapid eye movement). Researchers on the team of Dr. Antoine Adamantidis identified, for the first time, a precise causal link between neuronal activity in the lateral hypothalamus (LH) and the state of REM sleep. Using optogenetics, they were able to induce REM sleep in mice and modulate the duration of this sleep phase by activating the neuronal network in this area of the brain.

This achievement is an important contribution to the understanding of sleep mechanisms in the brains of mammals, as well as the underlying neuronal network, which is still not well understood despite recent breakthroughs in neuroscience.

Better understanding how sleep is modulated to reduce sleep disorders

“These research findings could help us better grasp how the brain controls sleep and better understand the role of sleep in humans. These results could also lead to new therapeutic strategies to treat sleep disorders along with associated neuropsychiatric problems,” stated Dr. Antoine Adamantidis, who is also the Canada Research Chair in Neural Circuits and Optogenetics.

What is REM (rapid eye movement) sleep?

There are two types of sleep: REM and non-REM sleep. In humans, non-REM sleep has four stages. REM sleep, or deep sleep, is generally associated with dreaming and is a phase when the brain is very active, even though people are in a heavy sleep, their eyes move rapidly (hence the name), and their bodies have an almost total loss of muscle tonus.
Although our understanding of the mechanisms that control the wake and sleep cycle has progressed in recent years, many frontiers remain unexplored. However, we do know that a disruption in sleep can lead to adverse effects on physical and mental health in humans.

Optogenetics, a revolutionary technology

In 2010 in the journal Nature, optogenetics was recognized as one of the coming decade’s most promising techniques to better understand brain function. This new field of research and application integrates optics and genetics methodologies to modulate the activity of neural circuits. Optogenetics involves controlling neuronal activity with light. This technique is therefore used to manipulate a specific type of cell without affecting neighbouring cells. A researcher who uses optogenetics is therefore like a conductor who decides to change the sheet music for an instrument to observe the effects, however insignificant they may seem, on the orchestra’s entire performance.

As Baby Boomers age, many experience difficulty in hearing and understanding conversations in noisy environments such as restaurants. People who are hearing-impaired and who wear hearing aids or cochlear implants are even more severely impacted. Researchers know that the ability to locate the source of a sound with ease is vital to hear well in these types of situations, but much more information is needed to understand how hearing works to be able to design devices that work better in noisy environment.  

Researchers from the Eaton-Peabody Laboratories of the Massachusetts Eye and Ear, Harvard Medical School, and Research Laboratory of Electronics, Massachusetts Institute of Technology have gained new insight into how localized hearing works in the brain. Their research is published in the Oct. 2, 2013 issue of the Journal of  Neuroscience. 

“Most people are able to locate the source of a sound with ease, for example, a snapping twig on the left, or a honking horn on the right. However this is actually a difficult problem for the brain to solve,” said Mitchell L. Day, Ph.D., investigator in the Eaton-Peabody Laboratories at Mass. Eye and Ear and instructor of Otology and Laryngology at Harvard Medical School “The higher levels of the brain that decide the direction a sound is coming from do not have access to the actual sound, but only the representation of that sound in the electrical activity of neurons at lower levels in the brain. How higher levels of the brain use information contained in the electrical activity of these lower-level neurons to create the perception of sound location is not known.” 

In the experiment, researchers recorded the electrical activity of individual neurons in an essential lower-level auditory brain area called the inferior colliculus (IC) while an animal listened to sounds coming from different directions. They found that the location of a sound source could be accurately predicted from the pattern of activation across a population of less than 100 IC neurons – i.e., a particular pattern of IC activation indicated a particular location in space. Researchers further found that the pattern of IC activation could correctly distinguish whether there was a single sound source present or two sources coming from different directions – i.e., the pattern of IC activation could segregate concurrent sources. 

“Our results show that higher levels of the brain may be able to accurately segregate and localize sound sources based on the detection of patterns in a relatively small population of IC neurons,” said Dr. Day. “We hope to learn more so that someday we can design devices that work better in noisy environments.”

Johns Hopkins researchers, working with mice, say they have identified a chemical compound that reduces the risk of dangerous, potentially stroke-causing blood vessel spasms that often occur after the rupture of a bulging vessel in the brain.

They say their findings offer clues about the biological mechanisms that cause vasospasm, or constriction of blood vessels that reduces oxygen flow to the brain, as well as potential means of treating the serious condition in humans.

When an aneurysm — essentially a blister-like bulge in the wall of a blood vessel — bursts, blood spills into the fluid-filled space that cushions the brain inside the skull. If a patient survives a ruptured aneurysm, between 20 and 40 percent of the time, this brain bleed, called a subarachnoid hemorrhage, will lead to an ischemic stroke within four to 21 days, even when the aneurysm is surgically clipped.

“We’re a long way from applying this to humans, but it’s a good start,” says Johns Hopkins neurosurgery resident Tomas Garzon-Muvdi, M.D., M.Sc., one of the authors of the study led by Rafael J. Tamargo, M.D., and described in the October issue of the journal Neurosurgery.

To conduct their experiments, Garzon-Muvdi and his colleagues took blood from mouse leg arteries and injected it behind their necks to mimic what happens in a subarachnoid hemorrhage. Then they gave the mice a compound called (S)-4-carboxyphenylglycine (S-4-CPG), a placebo or nothing at all. The mice given S-4-CPG developed less vasospasm, looked better and were more active than those in the other two groups.

The scientists also found concentrations of the drug in the brains of the mice, showing that it was able to cross the often impermeable blood-brain barrier. The researchers chose the compound because it is similar to drugs that have been used in stroke research in rodents. It is not approved for any use in humans.

Garzon-Muvdi explains that when blood vessels break anywhere but the brain, the body’s immune cells easily clear the blood cells and their remnants from the area. This is what happens with a bruise, when immune cells rush to the area, and a chemical cascade scavenges and disperses the remnants of excess blood components.

When a blood vessel bursts in the space around the brain, however, the blood is trapped. A subsequent inflammatory response brings key immune system cells into the space, where they secrete the neurotransmitter glutamate outside of the blood vessels where it shouldn’t be, promoting dangerous vasospasm in those blood vessels. This can lead to ischemic stroke, the most common type of stroke, caused by a blockage of a blood vessel in the brain. Death or serious disability may result.

The Johns Hopkins researchers say S-4-CPG keeps glutamate “in check,” prevents or reduces vasospasm and allows oxygen-filled blood to continue flowing into the brain.

According to the National Institutes of Health, subarachnoid hemorrhage caused by a cerebral aneurysm that breaks open occurs in about 40 to 50 out of 100,000 people over age 30. Patients may die immediately, but those who survive are still at elevated risk for developing an ischemic stroke in the days afterward. These patients are often watched very carefully in the intensive care unit for one to two weeks to search for early signs of vasospasm so that doctors can take steps to prevent or limit damage from a stroke.

In the ICU, doctors can order regular angiograms or ultrasounds to measure blood flow in vessels. If need be, they can increase blood pressure to send blood through vessels faster in the hopes of counteracting the constriction.

A drug to prevent stroke after a serious subarachnoid hemorrhage that follows the rupture of an aneurysm would improve quality of life for patients, Garzon-Muvdi says, and could potentially save millions of dollars in health care costs if patients don’t have to endure extensive hospital stays to monitor for a delayed stroke.

A group of really brainy scientists have moved closer to growing “therapeutic” brain cells in the laboratory that can be re-integrated back into patients’ brains to treat a wide range of neurological conditions. According to new research published online in The FASEB Journal, brain cells from a small biopsy can be used to grow large numbers of new personalized cells that are not only “healthy,” but also possess powerful attributes to preserve and protect the brain from future injury, toxins and diseases. Scientists are hopeful that ultimately these cells could be transformed in the laboratory to yield specific cell types needed for a particular treatment, or to cross the “blood-brain barrier” by expressing specific therapeutic agents that are released directly into the brain.

"This work is an example of how integrating basic science and clinical care may reveal privileged opportunities for biomedical research," said Matthew O. Hebb, M.D., Ph.D., FRCSC, a researcher involved in the work from the Departments of Clinical Neurological Sciences (Neurosurgery), Oncology and Otolaryngology at the University of Western Ontario in Ontario, Canada. "It is our hope that the results of this study provide a footing for further advancement of personalized, cell-based treatments for currently incurable and devastating neurological disorders."

Scientists enrolled patients with Parkinson’s disease who were scheduled to have deep brain stimulation (DBS) surgery, a commonly used procedure that involves placing electrodes into the brain. Before the electrodes were implanted, small biopsies were removed near the surface of the brain and multiplied in culture to generate millions of patient-specific cells that were then subjected to genetic analysis. These cells were complex in their make-up, but exhibited regeneration and characteristics of a fundamental class of brain cells, called glia. They expressed a broad array of natural and potent protective agents, called neurotrophic factors.

"From an extremely small amount of brain tissue, we will one day be able to do very big things," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “For centuries, treating the brain effectively and safely has been elusive. This advance opens the doors to not only new therapies for a myriad of brain diseases, but new ways of delivering therapies as well.”

Researchers at The University of Texas at Dallas have taken a step toward developing a new treatment to aid the recovery of limb function after strokes.

In a study published online in the journal Neurobiology of Disease, researchers report the full recovery of forelimb strength in animals receiving vagus nerve stimulation.

“Stroke is a leading cause of disability worldwide,” said Dr. Navid Khodaparast, a postdoctoral researcher in the School of Behavioral and Brain Sciences and lead author of the study. “Every 40 seconds, someone in the U.S. has a stroke. Our results mark a major step in the development of a possible treatment.”

Vagus nerve stimulation (VNS) is an FDA-approved method for treating various illnesses, such as depression and epilepsy. It involves sending a mild electric pulse through the vagus nerve, which relays information about the state of the body to the brain.

Khodaparast and his colleagues used vagus nerve stimulation precisely timed to coincide with rehabilitative movements in rats. Each of the animals had previously experienced a stroke that impaired their ability to pull a handle.

Stimulation of the vagus nerve causes the release of chemicals in the brain known to enhance learning and memory called neurotransmitters, specifically acetylcholine and norepinephrine. Pairing this stimulation with rehabilitative training allowed Khodaparast and colleagues to improve recovery.

Many rehabilitative interventions try to enhance neuroplasticity (the brain’s ability to change) in conjunction with physical rehabilitation to drive the recovery of lost functions, according to Khodaparast. Unfortunately, up to 70 percent of stroke patients still display long-term impairment in arm function after traditional rehabilitation.

“For years, the majority of stroke patients have received treatment with various drugs and/or physical rehabilitation,” Khodaparast said. “Medications can have widespread effects in the brain and the effects can last for long periods of time. In some cases the side effects outweigh the benefits. Through the use of VNS, we are able to use the brain’s natural way of changing its neural circuitry and provide specific and long lasting effects.”

Khodaparast acknowledged the study has some limitations. For example, the animals were young and lacked some of the other illnesses that accompany an aged human population, such as diabetes or hypertension. But Khodaparast and his colleagues said they are optimistic about vagus nerve stimulation as a future tool. They will continue testing in chronically impaired animals with the hopes of translating the technique for stroke patients. Working with MicroTransponder Inc., a partner company in the current study, researchers at the University of Glasgow in Scotland have begun a small-scale trial in humans.

“There is strong evidence that VNS can be used safely in stroke patients because of its extensive use in the treatment of other neurological conditions,” said Dr. Michael Kilgard, professor in neuroscience at UT Dallas and senior author of the study.

Kilgard is also conducting clinical trials using vagus nerve stimulation to treat tinnitus, the medical condition of unexplained ringing in the ears. Kilgard’s lab first demonstrated the ability of vagus nerve stimulation to enhance brain adaptability in a 2011 Nature paper.

About 70 percent of a person’s intelligence can be explained by their DNA — and those genetic influences only get stronger with age, according to new research from The University of Texas at Austin.

The study, authored by psychology researchers Elliot Tucker-Drob, Daniel Briley and Paige Harden, shows how genes can be stimulated or suppressed depending on the child’s environment and could help bridge the achievement gap between rich and poor students. The findings are published online in Current Directions in Psychological Science.

To investigate the underlying mechanisms at work, Tucker-Drob and his colleagues analyzed data from several studies tracking the cognitive ability and environmental circumstances of twin and sibling pairs. According to the findings, genetic factors account for 80 percent of cognition for children in economically advantaged households. Yet disadvantaged children – who rank lower in cognitive performance across the board – show almost no progress attributable to their genetic makeup.

This doesn’t mean disadvantaged children are genetically inferior. Instead, they have less high-quality opportunities, such as learning resources and parental involvement, to reach their genetic potential, Tucker-Drob says. 

“Genetic influences on cognitive ability are maximized when people are free to select their own learning experiences,” says Tucker-Drob, who is an assistant professor of psychology. “We were born with blueprints; the question is how are we using our experiences to build upon our genetic makeup?”

In a related study, Daniel Briley, a psychology doctoral student, examined how genetic and environmental influences on cognition change over time. Using meta-analytic procedures — the statistical methods used to analyze and combine results from previous, related literature — Briley examined genetic and environmental influences on cognition in twin and sibling pairs from infancy to adolescence.

According to his findings, published in the July issue of Psychological Science, genes influencing cognition become activated during the first decade of life and accelerate over time. The results emphasize the importance of early literacy and education during the first decade of life.

“As children get older, their parents and teachers give them increasing autonomy to do their homework to the best of their ability, pay attention in class, and choose their peer group,” says Briley. “Each of these behaviors likely influences their academic development. If these types of behaviors are influenced by genes, then it would explain why the heritability of cognitive ability increases as children age.”

Tucker-Drob says this research highlights the possibilities for bridging the achievement gap between the rich and poor.

“The conventional view is that genes place an upper limit on the effects of social intervention on cognitive development,” says Tucker-Drob. “This research suggests the opposite. As social, educational and economic opportunities increase in a society, more children will have access to the resources they need to maximize their genetic potentials.”

Findings in bacteria, yeast, mice show how flawed transport gene contributes to the condition

Researchers say it’s clear that some cases of autism are hereditary, but have struggled to draw direct links between the condition and particular genes. Now a team at the Johns Hopkins University School of Medicine, Tel Aviv University and Technion-Israel Institute of Technology has devised a process for connecting a suspect gene to its function in autism.

In a report in the Sept. 25 issue of Nature Communications, the scientists say mutations in one such autism-linked gene, dubbed NHE9, which is involved in transporting substances in and out of structures within the cell, causes communication problems among brain cells that likely contribute to autism.

“Autism is considered one of the most inheritable neurological disorders, but it is also the most complex,” says Rajini Rao, Ph.D., a professor of physiology in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. “There are hundreds of candidate genes to sort through, and a single genetic variant may have different effects even within the same family. This makes it difficult to separate the chaff from the grain, to distinguish harmless variations from disease-causing mutations. We were able to use a new process to screen variants in one candidate gene that has been linked to autism, and figure out how they might contribute to the disorder.”

An estimated one in 88 children in the United States is affected by autism spectrum disorders, a group of neurological development conditions marked by varying degrees of social, communication and behavioral problems. Scientists for years have looked for the biological roots of the problem using tools such as genome-wide association studies and gene-linkage analysis, which crunch genetic and health data from thousands of people in an effort to pinpoint disease-causing genetic variants. But while such techniques have turned up a number of gene mutations that may be linked to autism, none of them appear in more than 1 percent of people with the condition. With numbers that low, researchers need a way to screen variants in order to make a definitive link, Rao says.

For the new study, Rao and her collaborators focused on NHE9, which other researchers had flagged as a suspect in attention-deficit hyperactivity disorder, addiction and epilepsy as well as autism spectrum disorders. The gene was already known to be involved in transporting hydrogen, sodium and potassium ions in and out of cellular compartments called endosomes, and the team wondered how this function might be related to neurological conditions.

Rao’s collaborators at Tel Aviv University and Technion-Israel Institute of Technology constructed a computer model of the NHE9 protein based on previous research on a distant relative in bacteria. They then used the model to predict how autism-linked variants in the NHE9 gene would affect the protein’s shape and function. Some of them were predicted to cause dramatic changes, while other changes appeared to be more subtle.

Rao’s team next tested how these variant forms of NHE9 would affect a relatively simple organism often used in genetic studies: yeast. “Using yeast to screen the function of variants was a quick, easy and inexpensive way of figuring out which were worth further study, and which we could ignore because they didn’t have any effect,” Rao says. To do that, the team engineered the yeast form of NHE9 to have the variants seen in autistic people.

For those mutations that did have a detectable effect on the yeast, the team moved on to a third and more challenging step, in mouse brains. They homed in on astrocytes, a type of brain cell that clears the signaling molecule glutamate out of the way after it has performed its job of delivering a message across a synapse between two nerve cells. Using lab-grown mouse astrocytes with variant forms of NHE9, the researchers found a change in the pH (acidity) inside cellular compartments called endosomes, which in turn altered the ability of cells to take up glutamate. Because endosomes are the vehicles that deliver cargo essential for communication between brain cells, changing their pH alters traffic to and from the cell surface, which could affect learning and memory, Rao says. “Elevated glutamate levels are known to trigger seizures, perhaps explaining why autistic patients with mutations in NHE9 and related genes also have seizures,” she notes.

Rao and her team hope that pinpointing the importance of this trafficking mechanism in autism spectrum disorders may lead to the development of new drugs for autism that alter endosomal pH. As the use of genomic data becomes increasingly commonplace in the future, the step-wise strategy devised by her team can be used to screen gene variants and identify at-risk patients, she says.

A mix of serendipity and dogged laboratory work allowed a diverse team of University of Pittsburgh scientists to report in the Oct. 1 issue of Nature Cell Biology that they had solved the mystery of a basic biological function essential to cellular health.

By discovering a mechanism by which mitochondria – tiny structures inside cells often described as “power plants” – signal that they are damaged and need to be eliminated, the Pitt team has opened the door to potential research into cures for disorders such as Parkinson’s disease that are believed to be caused by dysfunctional mitochondria in neurons.

"It’s a survival process. Cells activate to get rid of bad mitochondria and consolidate good mitochondria. If this process succeeds, then the good ones can proliferate and the cells thrive," said Valerian Kagan, Ph.D., D.Sc., a senior author on the paper and professor and vice chair of the Pitt Graduate School of Public Health’s Department of Environmental and Occupational Health. "It’s a beautiful, efficient mechanism that we will seek to target and model in developing new drugs and treatments."

Dr. Kagan, who, as a recipient of a Fulbright Scholar grant, currently is serving as visiting research chair in science and the environment at McMaster University in Ontario, Canada, likened the process to cooking a Thanksgiving turkey.

"You put the turkey in the oven and the outside becomes golden, but you can’t just look at it to know it’s ready. So you put a thermometer in, and when it pops up, you know you can eat it," he said. "Mitochondria give out a similar ‘eat me’ signal to cells when they are done functioning properly."

Cardiolipins, named because they were first found in heart tissue, are a component on the inner membrane of mitochondria. When a mitochondrion is damaged, the cardiolipins move from its inner membrane to its outer membrane, where they encourage the cell to destroy the entire mitochondrion.

However, that is only part of the process, says Charleen T. Chu, M.D., Ph.D., professor and the A. Julio Martinez Chair in Neuropathology in the Pitt School of Medicine’s Department of Pathology, another senior author of the study. “It’s not just the turkey timer going off; it’s a question of who’s holding the hot mitt to bring it to the dining room?” That turns out to be a protein called LC3. One part of LC3 binds to cardiolipin, and LC3 causes a specialized structure to form around the mitochondrion to carry it to the digestive centers of the cell.

The research arose nearly a decade ago when Dr. Kagan had a conversation with Dr. Chu at a research conference. Dr. Chu, who studies autophagy, or “self-eating,” in Parkinson’s disease, was seeking a change on the mitochondrial surface that could signal to LC3 to bring in the damaged organelle for recycling. It turned out they were working on different sides of the same puzzle.

Together with Hülya Bayır, M.D., research director of pediatric critical care medicine, Children’s Hospital of Pittsburgh of UPMC and professor, Pitt’s Department of Critical Care Medicine, and a team of nearly two dozen scientists, the three senior authors worked out how the pieces of the mitochondria signaling problem fit together.

Now that they’ve worked out the basic mechanism, Dr. Chu indicates that many more research directions will likely follow.

"There are so many follow-up questions," she said. "What is the process that triggers the cardiolipin to move outside the mitochondria? How does this pathway fit in with other pathways that affect onset of diseases like Parkinson’s? Interestingly, two familial Parkinson’s disease genes also are linked to mitochondrial removal."

Dr. Bayir explained that while this process may happen in all cells with mitochondria, it is particularly important that it functions correctly in neuronal cells because these cells do not divide and regenerate as readily as cells in other parts of the body.

"I think these findings have huge implications for brain injury patients," she said. "The mitochondrial ‘eat me’ signaling process could be a therapeutic target in the sense that you need a certain level of clearance of damaged mitochondria. But, on the other hand, you don’t want the clearing process to go on unchecked. You must have a level of balance, which is something we could seek to achieve with medications or therapy if the body is not able to find that balance itself."

The logo of the 1984 Los Angeles Olympics includes red, white and blue stars, but the white star is not really there: It is an illusion. Similarly, the “S” in the USA Network logo is wholly illusory.

Both of these logos take advantage of a common perceptual illusion where the brain, when viewing a fragmented background, frequently sees shapes and surfaces that don’t really exist.

“It’s hallucinating without taking drugs,” said Alexander Maier, assistant professor of psychology at Vanderbilt University, who headed a team of neuroscientists who has pinpointed the area of the brain that is responsible for these “illusory contours.”

In the Sept. 30 online early edition of the Proceedings of the National Academy of Sciences, Maier’s team reported that they have discovered groups of neurons in a region of the visual cortex called V4 that fire when an individual is viewing a pattern that produces such an illusion and remain quiescent when viewing an almost identical pattern that doesn’t.

Studies have shown that a diverse range of species, including monkeys, cats, owls, goldfish and even honeybees perceive these illusory contours. This has led scientists to propose that they are the byproduct of methods that the brain has evolved to spot predators or prey hiding in the bushes, a capability with considerable survival value.

Although scientists discovered illusory contours more than a century ago, it is only in the last 30 years that they have begun studying them because they reveal the internal mechanisms that the brain uses to interpret sensory input.

The gold square marks the location in the V4 region of a macaque’s visual cortex, where the neurons respond to visual contours. (Alex Maier, Donna Pritchett / Vanderbilt)

In mammals, visual stimuli is processed in the back of the brain in an area called the visual cortex. Efforts to map this area have found that it is made up of five different regions at the back of brain (labeled V1 to V5.)

The primary visual cortex, V1, takes the stimuli coming from the eyes and sorts it by a variety of basic properties, including orientation, color and spatial variation. It also splits the information into two pathways, called the dorsal and ventral streams.

From V1, both streams are routed to the second major area of the visual cortex. V2 performs many of the same functions as V1 but adds some more complex processing, such as recognizing the disparities in the signals coming from the two eyes that produce binocular vision.

From V2, one pathway, sometimes called the “Where Pathway,” goes to V5 and is associated with object location and motion detection. The other pathway, sometimes called the “What Pathway,” goes to V4 and is associated with object representation and form recognition.

“Studies have shown that V4 is involved in both object recognition and visual attention, so we thought it might also be involved with illusory contours,” said Michele Cox, the Vanderbilt graduate student who is first author on the study.

A Kanizsa square (Courtesy of D. Alan Stubbs, University of Maine)

First, the researchers searched for the neurons in V4 that were associated with different locations in the retinas of macaque monkeys. Once these maps were complete, they rewarded the monkeys for staring at a screen containing an example of an illusory contour called a Kanizsa square. This consists of four “Pac-Man” figures with their “mouths” oriented to form the corners of a square. When black Pac-Men are placed on a white background, the brain creates a bright white square connecting them.

While the monkeys were looking at the Kanizsa square, the researchers discovered that the neurons that represented the area in the middle of the Pac-Men, the area covered by the illusory square, began firing. However, when the monkeys viewed the same four Pac-Men with their mouths facing outward – an orientation that doesn’t produce the illusion – these central neurons remained silent.

“Basically, the brain is acting like a detective,” said Maier. “It is responding to cues in the environment and making its best guesses about how they fit together. In the case of these illusions, however, it comes to an incorrect conclusion.”

Two graphs show the activity of neurons in V4 associated with the position of the illusory Kanizsa square. The percentage of neurons firing more than doubles when the monkey views pac-men with their mouths facing inward to produce the illusion (top) compared to their activity level when the monkey is viewing pac-men with their mouths facing outward (bottom). (Michelle Cox and Alex Maier / Vanderbilt)

New Danish/Italian research shows how medicine for the brain can be absorbed through the nose. This paves the way to more effective treatment of neurological diseases like Alzheimer’s and tumors in the brain.

A big challenge in medical science is to get medicine into the brain when treating patients with neurological diseases. The brain will do everything to keep foreign substances out and therefore the brains of neurological patients fight a constant, daily battle to throw out the medicine prescribed to help the patients.

The problem is the so-called blood-brain barrier, which prevents the active substances in medicine from travelling from the blood into the brain.

"The barrier is created because there is extremely little space between the cells in the brain’s capillar walls. Only very small molecules can enter through these openings and become active in the brain. And for the substances which finally get in, a new problem arises: The brain will do anything to throw them out again", explains assistant professor, Massimiliano di Cagno from in the Department of Physics, Chemistry and Pharmacy.

On this background science is looking for alternative pathways to the brain - and the nose is a candidate receiving much attention. From cocaine abusers it is well known that a substance can be absorbed through the nose and reach the brain extremely effective.

"It is very interesting to investigate if medical drugs can do the same", says di Cagno.

In recent years research has shown that it can be a very good idea to send medicine to the brain via the nose. The medicine can be sprayed into the nose and absorbed through the olfactory bulb, which is positioned at the front of the underside of the brain. Once the medicine passes the olfactory bulb there is direct access to the brain.

But there are many challenges to be solved before patients can be prescribed medication to be taken nasally.

"One of the biggest challenges is getting the olfactory bulb to absorb the substances aimed for the brain", explains di Cagno.
Together with Barbara Luppi from the University of Bologna in Italy he therefore investigated how to improve access to the olfactory bulb.

"It’s all done at nano-level, and the challenge is to find the vehicles that can transport the required medicine to the brain. In our attempts to come up with efficient vehicles we now point at some special liposomes and polymers that can bring an active substance to the olfactory bulb more than 2-3 times more efficiently than when using the standard techniques", explains di Cagno.

Liposomes are small spheres of fat, which is often used to protect active substance and carry them into the body. Polymers are long molecules that can be attached to the liposomes so that they can be made to look like water and thus not be rejected by the body’s immune system.

The improved efficiency is very important for the development of future medicines for neurological diseases. Today a pill has to contain millions of times more active ingredients than the brain needs to fight the disease. But because the blood-brain barrier is so effective and the brain so good at throwing foreign substances out, you have to send an extreme amount of active substances towards the brain.

"In a pill patients receive extremely more medicine than they need, and when we talk about medicines with severe and unpleasant side effects, it is not good. It is therefore very important that we get better at delivering exactly the amount of active substances needed - and no more", says di Cagno.

The new liposomes and polymers from his and Barbara Luppi’s work can not only carry the active ingredients efficiently through the slimy mucosa of a nose, so that they can reach the olfactory bulb. They can also do it over a longer time.

"We want to develop a vehicle that can release the active ingredients over a long time, over many hours, so the patients do not have to spray their nose too many times a day. In our experiments we still saw active substances being released after three hours, and we are very happy with that. One must remember that the nasal mucosa is constantly working to remove foreign objects and substances", says di Cagno.

The researchers performed their tests on the mucous membranes (mucosa) of sheep. Sheep and human mucosa and the mucinous secretions it produces in the nose are very similar. The sheep’s mucosa were cleaned, distributed on a tissue and then stretched over a container. In the container the researchers placed an active substance, hydrocortisone, that had been put inside different kinds of vehicles. After this the researchers observed how effectively and for how long time the various vehicles transported the hydrocortisone through the mucosa.

In the era of globalization, bilingualism is becoming more and more frequent, and it is considered a plus. However, can this skill turn into a disadvantage, when someone acquires aphasia? More precisely, if a bilingual person suffers brain damage (i.e. stroke, head trauma, dementia) and this results in a language impairment called aphasia, then the two languages can be disrupted, thus increasing the challenge of language rehabilitation. According to Dr. Ana Inés Ansaldo, researcher at the Research Centre of the Institut universitaire de gériatrie de Montréal (IUGM), and a professor at the School of Speech Therapy and Audiology at Université de Montréal, research evidence suggests that bilingualism can be a lever—and not an obstacle—to aphasia recovery. A recent critical literature review conducted by Ana Inés Ansaldo and Ladan Ghazi Saidi -Ph.D student- points to three interventional avenues to promote cross-linguistic effects of language therapy (the natural transfer effects that relearning one language has on the other language).

It is important for speech-language pathologists to clearly identify a patient’s mastery of either language before and after aphasia onset, in order to decide which language to stimulate to achieve better results. Overall, the studies reviewed show that training the less proficient language (before or after aphasia onset)—and not the dominant language—results in bigger transfer effects on the untreated language.

Moreover, similarities between the two languages, at the levels of syntax, phonology, vocabulary, and meaning, will also facilitate language transfer. Specifically, working on “cognates,” or similar words in both languages, facilitates cross-linguistic transfer of therapy effects. For example, stimulating the word “table” in French will also help the retrieval of  the word “table” in English, as these words have the same meaning and similar sounds in French and English. However, training “non-cognates” (words that sound alike, but do not share the same meanings) can be confusing for the bilingual person with aphasia.

In general, semantic therapy approaches, based on stimulating word meanings, facilitate transfer of therapy effects from the treated language to the untreated one. In other words, drilling based on the word’s semantic properties can help recovering both the target word and its cross-linguistic equivalent. For example, when the speech-language pathologist cues the patient to associate the word “dog” to the ideas of “pet,” “four legs” and “bark,”, the French word “chien”is as well activated, and will be more easily retrieved than by simply repeating the word “dog”.

“In the past, therapists would ask patients to repress or stifle one of their two languages, and focus on the target language. Today, we have a better understanding of how to use both languages, as one can support the other. This is a more complex approach, but it gives better results and respects the inherent abilities of bilingual people. Considering that bilinguals may soon represent the majority of our clients, this is definitely a therapeutic avenue we need to pursue,” explained Ana Inés Ansaldo, who herself is quadrilingual.

People with mental illness smoke at much higher rates than the overall population. But the popular belief that they are self-medicating is most likely wrong, according to researchers at the Indiana University School of Medicine. Instead, they report, research indicates that psychiatric disease makes the brain more susceptible to addiction.

As smoking rates in the general population have fallen below 25 percent, smoking among the mentally ill has remained pervasive, encompassing an estimated half of all cigarettes sold. Despite the well-known health dangers of tobacco consumption, smoking among the mentally ill has long been widely viewed as “self-medication,” reducing the incentive among health care professionals to encourage such patients to quit.

"This is really a devastating problem for people with mental illness because of the broad health consequences of nicotine addiction," said R. Andrew Chambers, M.D., associate professor of psychiatry at the IU School of Medicine. "Nicotine addiction is the number one cause of premature illness and death in the United States, and most of that morbidity and mortality is concentrated in people with mental illness."

In a report published recently in the journal Addiction Biology, the research team lead by Dr. Chambers reported the results of experiments using an established animal model of schizophrenia in which rats display a neuropsychiatric syndrome that closely resembles the disease.

Both the schizophrenia-model rats and normal rats were given access to intravenous self-administration of nicotine.

"The mentally ill rats acquired nicotine use faster and consumed more nicotine," Dr. Chambers said. "Then when we cut them off from access to nicotine, they worked much harder to restore access to nicotine than did the normal ‘control’ rats."

In additional testing, the researchers found that administration of nicotine provided equal, but minimal, cognitive benefits to both groups of rats when performing a memory test. When the nicotine was withdrawn, however, both groups of rats were more cognitively impaired, so that any cognitive benefits to nicotine administration were “paid for” by cognitive impairments later.

“These results strongly suggest that what has changed in mental illness to cause smoking at such high rates results in a co-morbid addiction to which the mentally ill are highly biologically vulnerable. The evidence suggests that the vulnerability is an involuntary biological result of the way the brain is designed and how it develops after birth, rather than it being about a rational choice to use nicotine as a medicine,” Dr. Chambers said.

The data, he said, point to neuro-developmental mechanisms that increase the risk of addiction. Better understanding of those mechanisms could lead to better prevention and treatment strategies, especially among mentally ill smokers, Dr. Chambers said.

A video interview of Dr. Chambers discussing his research is available here.

New research from the University of Sheffield could offer solutions into slowing down the progression of motor neurone disease (MND).

Scientists from the University of Sheffield’s Institute for Translational Neuroscience (SITraN) conducted pioneering research assessing how the devastating debilitating disease affects individual patients.

MND is an incurable disease destroying the body’s cells which control movement causing progressive disability. Present treatment options for those with MND only have a modest effect in improving the patient’s quality of life.

Professor Pamela Shaw, Director of SITraN, and her research team worked in collaboration with a fellow world leading MND scientist Dr Caterina Bendotti and her group at the Mario Negri Institute for Pharmacological Research in Milan, Italy. Together they investigated why the progression of MND following onset of symptoms varies in speed, even in the presence of a known genetic cause of the condition.

The research, published in the scientific journal Brain, investigated two mouse models of MND caused by an alteration in the SOD1 gene, a known cause of MND in humans. One of the strains had a rapidly progressing disease course and the other a much slower change in the symptoms of MND. The teams from Sheffield and Milan looked at the factors which might explain the differences observed in speed and severity in the progression of the disease. They used a scientific technique known as gene expression profiling to identify factors within motor neurones that control vulnerability or resistance to MND in order to shed light on the factors important for the speed of motor neurone injury in human patients.

The study, funded by the Motor Neurone Disease Association, revealed new evidence, at the point of onset of the disease, before muscle weakness was observed, showing key differences in major molecular pathways and the way the protective systems of the body responded, between the profiles of the rapid progressing and slow progressing mouse models. In the case of the model with rapidly progressing MND the motor neurones showed reduced functioning of the cellular systems for energy production, disposal of waste proteins and neuroprotection. Motor neurones from the model with more slowly progressing MND showed an increase in protective inflammation and immune responses and increased function of the mechanisms that protect motor neurones from damage.

The research provides valuable clues about mechanisms that have the effect of slowing down the progression of disabling symptoms in MND.

Professor Shaw said that the state-of-the-art Functional Genomics laboratory in SITraN had enabled the research team to use a cutting edge technique called gene expression profiling.
“This enables us to ‘get inside’ the motor neurones in health and disease and understand better what is happening to cause motor neurone injury in MND,” she said.

“This project was a wonderful collaboration, supported by the MND Association, between research teams in Sheffield and Milan. We are very excited about the results which have given us some new ideas for treatment strategies which may help to slow disease progression in human MND.”

Dr Caterina Bendotti said: “MND is a clinically heterogenous disease with a high variability in its course which makes assessments of potential therapies difficult. Thanks to the recent evidence in our laboratory of a difference in the speed of symptom progression in two MND models carrying the same gene mutation and the successful collaboration with Professor Pamela Shaw and her team, we have identified some mechanisms that may help to predict the disease duration and eventually to slow it down.

“I strongly believe that the new hypotheses generated by this study and our ongoing collaboration are the prerequisites to be able to fight this disease.”

Brian Dickie from MND Association added: “These new and important findings in mice open up the possibility for new treatment approaches in man. It is heartening to see such a productive collaboration between two of the leading MND research labs in Europe, combining their unique specialist knowledge and technical expertise in the fight against this devastating disease.”

MND affects more than 6,000 sufferers in the UK with the majority of cases being sporadic but approximately five per cent of cases are familial or inherited with an identifiable genetic cause. Sufferers may lose their ability to walk, talk, eat and breathe.

A diagnosis of multiple sclerosis (MS) is a hard lot. Patients typically get the diagnosis around age 30 after experiencing a series of neurological problems such as blurry vision, wobbly gait or a numb foot. From there, this neurodegenerative disease follows an unforgiving course.

Many people with MS start using some kind of mobility aid — cane, walker, scooter or wheelchair — by 45 or 50, and those with the most severe cases are typically bed-bound by 60. The medications that are currently available don’t do much to slow the relentless march of the disease.

In search of a better option for MS patients, a team of UW-Madison biochemists has discovered a promising vitamin D-based treatment that can halt — and even reverse — the course of the disease in a mouse model of MS. The treatment involves giving mice that exhibit MS symptoms a single dose of calcitriol, the active hormone form of vitamin D, followed by ongoing vitamin D supplements through the diet. The protocol is described in a scientific article that was published online in August in the Journal of Neuroimmunology.

"All of the animals just got better and better, and the longer we watched them, the more neurological function they regained," says biochemistry professor Colleen Hayes, who led the study.

MS afflicts around 400,000 people nationwide, with 200 new cases diagnosed each week. Early on, this debilitating autoimmune disease, in which the immune system attacks the myelin coating that protects the brain’s nerve cells, causes symptoms including weakness, loss of dexterity and balance, disturbances to vision, and difficulty thinking and remembering. As it progresses, people can lose the ability to walk, sit, see, eat, speak and think clearly.

Current FDA-approved treatments only work for some MS patients and, even among them, the benefits are modest. “And in the long term they don’t halt the disease process that relentlessly eats away at the neurons,” Hayes adds. “So there’s an unmet need for better treatments.”

While scientists don’t fully understand what triggers MS, some studies have linked low levels of vitamin D with a higher risk of developing the disease. Hayes has been studying this “vitamin D hypothesis” for the past 25 years with the long-term goal of uncovering novel preventive measures and treatments. Over the years, she and her researchers have revealed some of the molecular mechanisms involved in vitamin D’s protective actions, and also explained how vitamin D interactions with estrogen may influence MS disease risk and progression in women.

In the current study, which was funded by the National Multiple Sclerosis Society, Hayes’ team compared various vitamin D-based treatments to standard MS drugs. In each case, vitamin D-based treatments won out. Mice that received them showed fewer physical symptoms and cellular signs of disease.

First, Hayes’ team compared the effectiveness of a single dose of calcitriol to that of a comparable dose of a glucocorticoid, a drug now administered to MS patients who experience a bad neurological episode. Calcitriol came out ahead, inducing a nine-day remission in 92 percent of mice on average, versus a six-day remission in 58 percent for mice that received glucocorticoid.

"So, at least in the animal model, calcitriol is more effective than what’s being used in the clinic right now," says Hayes.

Next, Hayes’ team tried a weekly dose of calcitriol. They found that a weekly dose reversed the disease and sustained remission indefinitely.

But calcitriol can carry some strong side effects — it’s a “biological sledgehammer” that can raise blood calcium levels in people, Hayes says — so she tried a third regimen: a single dose of calcitriol, followed by ongoing vitamin D supplements in the diet. This one-two punch “was a runaway success,” she says. “One hundred percent of mice responded.”

Hayes believes that the calcitriol may cause the autoimmune cells attacking the nerve cells’ myelin coating to die, while the vitamin D prevents new autoimmune cells from taking their place.

While she is excited about the prospect of her research helping MS patients someday, Hayes is quick to point out that it’s based on a mouse model of disease, not the real thing. Also, while rodents are genetically homogeneous, people are genetically diverse.

"So it’s not certain we’ll be able to translate (this discovery to humans)," says Hayes. "But I think the chances are good because we have such a broad foundation of data showing protective effects of vitamin D in humans."

The next step is human clinical trials, a step that must be taken by a medical doctor, a neurologist. If the treatment works in people, patients with early symptoms of MS may never need to receive an official diagnosis.

"It’s my hope that one day doctors will be able to say, ‘We’re going to give you an oral calcitriol dose and ramp up the vitamin D in your diet, and then we’re going to follow you closely over the next few months. You’re just going to have this one neurological episode and that will be the end of it,’" says Hayes. "That’s my dream."

Understanding RNA biology in dendrites may inform neurological and psychiatric illness therapeutics

Protein synthesis in the extensions of nerve cells, called dendrites, underlies long-term memory formation in the brain, among other functions. “Thousands of messenger RNAs reside in dendrites, yet the dynamics of how multiple dendrite messenger RNAs translate into their final proteins remain elusive,” says James Eberwine, PhD, professor of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, and co-director of the Penn Genome Frontiers Institute.

Dendrites, which branch from the cell body of the neuron, play a key role in the communication between cells of the nervous system, allowing for many neurons to connect with each other. Dendrites detect the electrical and chemical signals transmitted to the neuron by the axons of other neurons. The synapse is the neuronal structure where this chemical connection is formed, and investigators surmise that it is here where learning and memory occur.

These structural and chemical changes – called synaptic plasticity — require rapid, new synthesis of proteins. Cells may use different rates of translation in different types of mRNA to produce the right amounts and ratios of required proteins.

Knowing how proteins are made to order – as it were - at the synapse can help researchers better understand how memories are made. Nevertheless, the role of this “local” environment in regulating which messenger RNAs are translated into proteins in a neuron’s periphery is still a mystery.

Eberwine, first author Tae Kyung Kim, PhD, a postdoc in the Eberwine lab, and colleagues including Jai Yoon Sul, PhD, assistant professor in Pharmacology, showed that protein translation of two dendrite mRNAs is complex in space and time, as reported online in Cell Reports this week. 

“We needed to look at more than one RNA at the same time to get a better handle on real- world processes, and this is the first study to do that in a live neuron,” Eberwine explains.

At Home in the Hippocampus

“It’s not always one particular RNA that dominates at a translation hotspot versus another type of RNA,” says Eberwine. “Since there are 1,000 to 3,000 different mRNA types present in the dendrite overall, but not 1,000 to 3,000 different translational hot spots, do the mRNAs ‘take turns’ being translated in space and time at the ribosomes at the hotspots?”

The researchers engineered the glutamate receptor RNAs to contain different fluorescent proteins that are independently detectable, as well as a photo-switchable protein to determine when new proteins were being made. In the case of the photo-switchable protein studies, when an mRNA for the glutamate receptor protein is marked green, it means it has already been translated.

When a laser is passed over the green protein, it changes to red as a way of tagging when it has been been translated, and new proteins synthesized at that hotspot would be green, which is visible by the appearance of yellow fluorescence (green + red, as measured by light on the visible spectrum). These tricks of the light allow the team to keep track of newly made proteins over time and space.

“This is the first time this method of protein labeling has been used to measure the act of translation of multiple proteins over space and time in a quantitative way,” says Eberwine. “We call it quantitative functional genomics of live cell translation.”

“Our results suggest that the location of the translational hotspot is a regulator of the simultaneous translation of multiple messenger RNAs in nerve cell dendrites and therefore synaptic plasticity,” says Sul.

Laying the Groundwork

Almost 10 years ago, the Eberwine lab discovered that nerve-cell dendrites have the capacity to splice messenger RNA, a process once believed to take place only in the nucleus of cells. Here, a gene is copied into mRNA, which possesses both exons (mature mRNA regions that code for proteins) and introns (non-coding regions). mRNA splicing works by cutting out introns and merging the remaining exon pieces, resulting in an mRNA capable of being translated into a specific protein.

The vast array of proteins within the human body arises in part from the many ways that mRNAs can be spliced and reconnected. Specifically, splicing removes pieces of intron and exon regions from the RNA. The resulting spliced RNA is made into protein.

If the RNA has different exons spliced in and out of it, then different proteins can be made from this RNA. The Eberwine lab was successful in showing that splicing can occur in dendrites because they used sensitive technologies developed in their lab, which permits them to detect and quantify RNA splicing, as well as the translated protein in single isolated dendrites.

Understanding the dynamics of RNA biology and protein translation in dendrites promises to provide insight into regulatory mechanisms that may be modulated for therapeutic purposes in neurological and psychiatric illnesses. The directed development of therapeutics requires this detailed knowledge, says Eberwine.