Posts tagged science

Researchers at Northeastern University in Boston have developed a gene therapy approach that may one day stop Parkinson’s disease (PD) in it tracks, preventing disease progression and reversing its symptoms. The novelty of the approach lies in the nasal route of administration and nanoparticles containing a gene capable of rescuing dying neurons in the brain. Parkinson’s is a devastating neurodegenerative disorder caused by the death of dopamine neurons in a key motor area of the brain, the substantia nigra (SN). Loss of these neurons leads to the characteristic tremor and slowed movements of PD, which get increasingly worse with time. Currently, more than 1% of the population over age 60 has PD and approximately 60,000 Americans are newly diagnosed every year. The available drugs on the market for PD mimic or replace the lost dopamine but do not get to the heart of the problem, which is the progressive loss of the dopamine neurons.

The focus of Dr. Barbara Waszczak’s lab at Northeastern University in Boston is to find a way to harvest the potential of glial cell line-derived neurotrophic factor (GDNF) as a treatment for PD. GDNF is a protein known to nourish dopamine neurons by activating survival and growth-promoting pathways inside the cells. Not surprisingly, GDNF is able to protect dopamine neurons from injury and restore the function of damaged and dying neurons in many animal models of PD. However, the action of GDNF is limited by its inability to cross the blood-brain barrier (BBB), thus requiring direct surgical injection into the brain. To circumvent this problem, Waszczak’s lab is investigating intranasal delivery as a way to bypass the BBB. Their previous work showed that intranasal delivery of GDNF protects dopamine neurons from damage by the neurotoxin, 6-hydroxydopamine (6-OHDA), a standard rat model of PD.

Taking this work a step further, Brendan Harmon, working in Waszczak’s lab, has adapted the intranasal approach so that cells in the brain can continuously produce GDNF. His work utilized nanoparticles, developed by Copernicus Therapeutics, Inc., which are able to transfect brain cells with an expression plasmid carrying the gene for GDNF (pGDNF). When given intranasally to rats, these pGDNF nanoparticles increase GDNF production throughout the brain for long periods, avoiding the need for frequent re-dosing. Now, in new research presented on April 20 at 12:30 pm during Experimental Biology 2013 in Boston, MA, Harmon reports that intranasal administration of Copernicus’ pGDNF nanoparticles results in GDNF expression sufficient to protect SN dopamine neurons in the 6-OHDA model of PD.

Waszczak and Harmon believe that intranasal delivery of Copernicus’ nanoparticles may provide an effective and non-invasive means of GDNF gene therapy for PD, and an avenue for transporting other gene therapy vectors to the brain. This work, which was funded in part by the Michael J. Fox Foundation for Parkinson’s Research and Northeastern University, has the potential to greatly expand treatment options for PD and many other central nervous system disorders.

(Source: eurekalert.org)

For the first time, human embryonic stem cells have been transformed into nerve cells that helped mice regain the ability to learn and remember.

A study at UW-Madison is the first to show that human stem cells can successfully implant themselves in the brain and then heal neurological deficits, says senior author Su-Chun Zhang, a professor of neuroscience and neurology.

Once inside the mouse brain, the implanted stem cells formed two common, vital types of neurons, which communicate with the chemicals GABA or acetylcholine. “These two neuron types are involved in many kinds of human behavior, emotions, learning, memory, addiction and many other psychiatric issues,” says Zhang.

The human embryonic stem cells were cultured in the lab, using chemicals that are known to promote development into nerve cells — a field that Zhang has helped pioneer for 15 years. The mice were a special strain that do not reject transplants from other species.

After the transplant, the mice scored significantly better on common tests of learning and memory in mice. For example, they were more adept in the water maze test, which challenged them to remember the location of a hidden platform in a pool.

The study began with deliberate damage to a part of the brain that is involved in learning and memory.

Three measures were critical to success, says Zhang: location, timing and purity. “Developing brain cells get their signals from the tissue that they reside in, and the location in the brain we chose directed these cells to form both GABA and cholinergic neurons.”

The initial destruction was in an area called the medial septum, which connects to the hippocampus by GABA and cholinergic neurons. “This circuitry is fundamental to our ability to learn and remember,” says Zhang.

The transplanted cells, however, were placed in the hippocampus — a vital memory center — at the other end of those memory circuits. After the transferred cells were implanted, in response to chemical directions from the brain, they started to specialize and connect to the appropriate cells in the hippocampus.

The process is akin to removing a section of telephone cable, Zhang says. If you can find the correct route, you could wire the replacement from either end.

For the study, published in the current issue of Nature Biotechnology, Zhang and first author Yan Liu, a postdoctoral associate at the Waisman Center on campus, chemically directed the human embryonic stem cells to begin differentiation into neural cells, and then injected those intermediate cells. Ushering the cells through partial specialization prevented the formation of unwanted cell types in the mice.

Ensuring that nearly all of the transplanted cells became neural cells was critical, Zhang says. “That means you are able to predict what the progeny will be, and for any future use in therapy, you reduce the chance of injecting stem cells that could form tumors. In many other transplant experiments, injecting early progenitor cells resulted in masses of cells — tumors. This didn’t happen in our case because the transplanted cells are pure and committed to a particular fate so that they do not generate anything else. We need to be sure we do not inject the seeds of cancer.”

Brain repair through cell replacement is a Holy Grail of stem cell transplant, and the two cell types are both critical to brain function, Zhang says. “Cholinergic neurons are involved in Alzheimer’s and Down syndrome, but GABA neurons are involved in many additional disorders, including schizophrenia, epilepsy, depression and addiction.”

Though tantalizing, stem-cell therapy is unlikely to be the immediate benefit. Zhang notes that “for many psychiatric disorders, you don’t know which part of the brain has gone wrong.” The new study, he says, is more likely to see immediate application in creating models for drug screening and discovery.

(Source: news.wisc.edu)

A contact lens on the bathroom floor, an escaped hamster in the backyard, a car key in a bed of gravel: How are we able to focus so sharply to find that proverbial needle in a haystack? Scientists at the University of California, Berkeley, have discovered that when we embark on a targeted search, various visual and non-visual regions of the brain mobilize to track down a person, animal or thing.

That means that if we’re looking for a youngster lost in a crowd, the brain areas usually dedicated to recognizing other objects such as animals, or even the areas governing abstract thought, shift their focus and join the search party. Thus, the brain rapidly switches into a highly focused child-finder, and redirects resources it uses for other mental tasks.

“Our results show that our brains are much more dynamic than previously thought, rapidly reallocating resources based on behavioral demands, and optimizing our performance by increasing the precision with which we can perform relevant tasks,” said Tolga Cukur, a postdoctoral researcher in neuroscience at UC Berkeley and lead author of the study published today (Sunday April 21) in the journal Nature Neuroscience.

“As you plan your day at work, for example, more of the brain is devoted to processing time, tasks, goals and rewards, and as you search for your cat, more of the brain becomes involved in recognition of animals,” he added.

The findings help explain why we find it difficult to concentrate on more than one task at a time. The results also shed light on how people are able to shift their attention to challenging tasks, and may provide greater insight into neurobehavioral and attention deficit disorders such as ADHD.

These results were obtained in studies that used functional Magnetic Resonance Imaging (fMRI) to record the brain activity of study participants as they searched for people or vehicles in movie clips. In one experiment, participants held down a button whenever a person appeared in the movie. In another, they did the same with vehicles.

The brain scans simultaneously measured neural activity via blood flow in thousands of locations across the brain. Researchers used regularized linear regression analysis, which finds correlations in data, to build models showing how each of the roughly 50,000 locations near the cortex responded to each of the 935 categories of objects and actions seen in the movie clips. Next, they compared how much of the cortex was devoted to detecting humans or vehicles depending on whether or not each of those categories was the search target.

They found that when participants searched for humans, relatively more of the cortex was devoted to humans, and when they searched for vehicles, more of the cortex was devoted to vehicles. For example, areas that were normally involved in recognizing specific visual categories such as plants or buildings switched to become attuned to humans or vehicles, vastly expanding the area of the brain engaged in the search.

“These changes occur across many brain regions, not only those devoted to vision. In fact, the largest changes are seen in the prefrontal cortex, which is usually thought to be involved in abstract thought, long-term planning, and other complex mental tasks,” Cukur said.

The findings build on an earlier UC Berkeley brain imaging study that showed how the brain organizes thousands of animate and inanimate objects into what researchers call a “continuous semantic space.” Those findings challenged previous assumptions that every visual category is represented in a separate region of the visual cortex. Instead, researchers found that categories are actually represented in highly organized, continuous maps.

The latest study goes further to show how the brain’s semantic space is warped during a visual search, depending on the search target. Researchers have posted their results in an interactive, online brain viewer. Other co-authors of the study are UC Berkeley neuroscientists Jack Gallant, Alexander Huth and Shinji Nishimoto. Funding for the research was provided by the National Eye Institute of the National Institutes of Health.

When the brains of those who have succumbed to age-related neurodegeneration are analyzed post-mortem, they typically show significant atrophy on all scales. Not only is the cortex thinner and sparser, but the hollow ventricles inside the brain are grossly enlarged. In the absence of any specific disease, these general trends are still familiar. It has traditionally been assumed that the dynamic microfeatures of aged brains—the growth of the fine neurites and the synapses they make—would similarly be degenerate. In other words, synaptic growth would have either entered some form of stasis, or alternatively, a state of permanent decay with replacement by matrix or scar tissue. Contrary to these expectations, recent research shows increased structural plasticity in the axonal component of synapses in the aged mouse cortex. Reporting in the current issues of PNAS, researchers provide evidence that the observed behavioral deficits in these animals may be due to an inability to maintain persistent synaptic structure, rather than because of a loss of plasticity.

Specifically, the researchers found dramatic increases in the rates of synapse formation and elimination. They used two-photon microscopy to image axonal arbors and boutons in aged brains over time. Compared to young adult brains, established synaptic boutons in aged brain showed 10-fold higher rates of destabilization, and 20-fold higher turnover. The researchers also demonstrated, that while the size and density of synapses was comparable, size fluctuations were significantly higher in the aged brains.

Changes in synaptic structure are believed to be the mechanism for encoding long-term memory in the brain. In the absence of the full molecular picture underlying the way they change and grow, macroscopic appearance (size) is a convenient stand-in used to gauge relative importance of a particular synapse. Among other things, a larger synapse has greater resource at its disposal to reliably match incoming spikes to transmitter release. Not only can a larger synapse generally do this matching faster, they can do it for a longer time. The new studies suggest, however, that decreased ability to form new memories, or learn new behaviors, results from synapses being too fickle, rather than from loss of flexibility.

Clearly the full behavior of synapses is far from understood, despite it being one of the central preoccupations of experimental neuroscience. It is generally believed that the average synapse is at best able to match an incoming spike with fusion of a vesicle (and subsequent transmitter release) roughly half of the time. Many theoretical efforts have been made to account for this fact. One approach has been to do a strict accounting analysis of the energetic use of ATP by a neuron’s entire signalling tree. In other words, estimate how a neuron partitions its ATP budget between transmitting information in the form of spikes down the axon, and that spent in completing the hand-off to the next neuron at the synapse.

Detailed and painstaking measurements of axonal structural dynamics, as done here by the authors, is critical ground-floor work towards understand neural circuits. Isolated molecular details, while important, will never be sufficient to completely understand how learning and memory emerge from architectural changes. The current efforts of the BRAIN Initiative to map the complete connectome of a brain, together with a full activity map, will also need to include efforts to create what might be called, a theory of neurons. The ways in which neurons budget their energy, is likely to a central component of such a theory.

As a start, one postulate of a theory of neurons, that is consistent with the one-half probability for synaptic information transfer, might be the following: neurons tend to match the energy spent in sending spikes through their entire axonal arbor, with the sum total of the energy spent at all terminal boutons of that axon. The temporal aspects of how synapses are generated and eliminated in a short-lived animal, like a mouse, may be far different than those in a human. Understanding how these processes change with age, and with the amount of energy available to synapses to effect that change, will help complete the larger picture.

(Source: medicalxpress.com)

Up to 10 per cent of the population are affected by specific learning disabilities (SLDs), such as dyslexia, dyscalculia and autism, translating to 2 or 3 pupils in every classroom according to a new study.

The study – by academics at UCL and Goldsmiths - also indicates that children are frequently affected by more than one learning disability.

The research, published in Science, helps to clarify the underlying causes of learning disabilities and the best way to tailor individual teaching and learning for affected individuals and education professionals.

Specific learning disabilities arise from atypical brain development with complicated genetic and environmental causes, causing such conditions as dyslexia, dyscalculia, attention-deficit/hyperactivity disorder, autism spectrum disorder and specific language impairment.

While these conditions in isolation already provide a challenge for educators, an additional problem is that specific learning disabilities also co-occur for more often that would be expected. As, for example, in children with attention-deficit/hyperactivity disorder, 33 to 45 per cent also suffer from dyslexia and 11 per cent from dyscalculia.

Lead author Professor Brian Butterworth (UCL Institute of Cognitive Neuroscience) said: “We now know that there are many disorders of neurological development that can give rise to learning disabilities, even in children of normal or even high intelligence, and that crucially these disabilities can also co-occur far more often that you’d expect based on their prevalence.

"We are also finally beginning to find effective ways to help learners with one or more SLDs, and although the majority of learners can usually adapt to the one-size-fits-all approach of whole class teaching, those with SLDs will need specialised support tailored to their unique combination of disabilities."

As part of the study, Professor Butterworth and Dr Yulia Kovas (Goldsmiths) have summarised what is currently known about SLD’s neural and genetic basis to help clarify what is causing these disabilities to develop, helping to improve teaching for individual learners, and also training for school psychologists, clinicians and teachers.

What the team hope is that by developing an understanding of how individual differences in brain development interact with formal education, and also adapting learning pathways to individual needs, those with specific learning disabilities will produce more tailored education for such learners.

Professor Butterworth said: “Each child has a unique cognitive and genetic profile, and the educational system should be able to monitor and adapt to the learner’s current repertoire of skills and knowledge.

"A promising approach involves the development of technology-enhanced learning applications – such as games - that are capable of adapting to individual needs for each of the basic disciplines."

(Source: eurekalert.org)

People with genes that make it tough for them to engage socially with others seem to be better than average at hypnotizing themselves. A study published today in Psychoneuroendocrinology concludes that such individuals are particularly good at becoming absorbed in their own internal world, and might also be more susceptible to other distortions of reality.

Psychologist Richard Bryant of the University of New South Wales in Sydney and his colleagues tested the hypnotizability of volunteers with different forms of the receptor for oxytocin, a hormone that increases trust and social bonding. (Oxytocin’s association with emotional attachment also earned it the nickname of ‘love hormone’.) Those with gene variants linked to social detachment and autism were found to be most susceptible to hypnosis.

Hypnosis has intrigued scientists since the nineteenth-century physician James Braid used it to alleviate pain in a variety of medical conditions, but it has never been fully understood. Hypnotized people can undergo a range of unusual experiences, including amnesia, anaesthesia and the loss of the ability to move their limbs. But some individuals are more affected by hypnosis than others — and no one knows why.

Hormones and hypnotism

How susceptible someone is to persuasion is an important factor in how easily they can be hypnotized by someone else. Bryant and his colleagues have previously shown that spraying a shot of oxytocin up people’s noses makes them more hypnotizable, and more likely to engage in potentially embarrassing activities such as swearing or dancing at a hypnotist’s suggestion.

When it comes to self-hypnosis, however, the team wondered whether people who can easily disengage from the external world and become lost in their own imagination might do better. In their latest study, they asked 185 volunteers to hypnotize themselves with the aid of an audio recording, then assessed the depth of their hypnosis using checks such as whether they were unable to open their eyes, or could hallucinate a sound.

The researchers used a questionnaire to test the participants’ ability to become absorbed in internal and imagined experiences, and tested them for variants of the oxytocin-receptor gene at two places in the gene sequence — rs53576 and rs2254298 — that that increase the risk of social detachment and autism. Participants with these variants scored highest for hypnotizability and absorption.

Bryant suggests that as well as being more hypnotizable, such individuals might “be influenced to have a range of experiences that more reality-based people cannot”. For example, this capacity might help to explain why some people respond better to placebos, or are more likely to accept paranormal or religious experiences.

“At this point we do not know anything about genetic bases of suggestibility per se,” says Bryant. “The current finding does provide some direction for exploring this.”

Aleksandr Kogan of the University of Cambridge, UK, who works on the genetics of social psychology, says that the results fit well with what is known about the oxytocin-receptor gene, particularly for variants at site rs53576. Among white people, these influence an individual’s sensitivity to social cues, he says. “That this would reflect a difference in internal experiences makes sense.”

(Source: nature.com)