Neuroscience

Most people equate “gray matter” with the brain and its higher functions, such as sensation and perception, but this is only one part of the anatomical puzzle inside our heads. Another cerebral component is the white matter, which makes up about half the brain by volume and serves as the communications network.

The gray matter, with its densely packed nerve cell bodies, does the thinking, the computing, the decision-making. But projecting from these cell bodies are the axons—the network cables. They constitute the white matter. Its color derives from myelin—a fat that wraps around the axons, acting like insulation.

Alex Schelgel, first author on a paper in the August 2012 Journal of Cognitive Neuroscience, has been using the white matter as a landscape on which to study brain function. An important result of the research is showing that you can indeed “teach old dogs new tricks.” The brain you have as an adult is not necessarily the brain you are always going to have. It can still change, even for the better.

"This work is contributing to a new understanding that the brain stays this plastic organ throughout your life, capable of change," Schlegel says. "Knowing what actually happens in the organization of the brain when you are learning has implications for the development of new models of learning as well as potential interventions in cases of stroke and brain damage."

Schlegel is a graduate student working under Peter Tse, an associate professor of psychological and brain sciences and a coauthor on the paper. “This study was Peter’s idea,” Schlegel says. “He wanted to know if we could see white matter change as a result of a long-term learning process. Chinese seemed to him like the most intensive learning experience he could think of.”

Twenty-seven Dartmouth students were enrolled in a nine-month Chinese language course between 2007 and 2009, enabling Schlegel to study their white matter in action. While many neuroscientists use magnetic resonance imaging (MRI) in brain studies, Schlegel turned to a new MRI technology, called diffusion tensor imaging (DTI). He used DTI to measure the diffusion of water in axons, tracking the communication pathways in the brain. Restrictions in this diffusion can indicate that more myelin has wrapped around an axon.

"An increase in myelination tells us that axons are being used more, transmitting messages between processing areas," Schlegel says. "It means there is an active process under way."

Their data suggest that white matter myelination is precisely what was seen among the language students. There is a structural change that goes along with this learning process. While some studies have shown that changes in white matter occurred with learning, these observations were made in simple skill learning and strictly on a “before and after” basis.

"This was the first study looking at a really complex, long-term learning process over time, actually looking at changes in individuals as they learn a task," says Schlegel. "You have a much stronger causal argument when you can do that."

The work demonstrates that significant changes are occurring in adults who are learning. The structure of their brains undergoes change.

"This flies in the face of all these traditional views that all structural development happens in infancy, early in childhood," Schlegel says. "Now that we actually do have tools to watch a brain change, we are discovering that in many cases the brain can be just as malleable as an adult as it is when you are a child or an adolescent."

NIH study of rats shows DNA regions thought inactive highly involved in body’s clock

Long stretches of DNA once considered inert dark matter appear to be uniquely active in a part of the brain known to control the body’s 24-hour cycle, according to researchers at the National Institutes of Health.

Working with material from rat brains, the researchers found some expanses of DNA contained the information that generate biologically active molecules. The levels of these molecules rose and fell, in synchrony with 24-hour cycles of light and darkness. Activity of some of the molecules peaked at night and diminished during the day, while the remainder peaked during the day and diminished during the night.

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Lithium is a ‘gold standard’ drug for treating bipolar disorder, however not everyone responds in the same way. New research published in BioMed Central’s open access journal Biology of Mood & Anxiety Disorders finds that this is true at the levels of gene activation, especially in the activation or repression of genes which alter the level the apoptosis (programmed cell death). Most notably BCL2, known to be important for the therapeutic effects of lithium, did not increase in non-responders. This can be tested in the blood of patients within four weeks of treatment.

A research team from Yale University School of Medicine measured the changing levels of gene activity in the blood of twenty depressed adult subjects with bipolar disorder before treatment, and then fortnightly once treatment with lithium carbonate had begun.

Over the eight weeks of treatment there were definite differences in the levels of gene expression between those who responded to lithium (measured using the Hamilton Depression Rating Scale) and those who failed to respond. Dr Robert Beech who led this study explained, “We found 127 genes that had different patterns of activity (turned up or down) and the most affected cellular signalling pathway was that controlled programmed cell death (apoptosis).”

For people who responded to lithium the genes which protect against apoptosis, including Bcl2 and IRS2, were up regulated, while those which promote apoptosis were down regulated, including BAD and BAK1.

The protein coded by BAK1 can open an anion channel in mitochondrial walls which leads to leakage of mitochondrial contents and activation of cell death pathways. Damage similar to this has been seen within the prefrontal cortex of the brain of patients with bipolar disorder. BAD protein is thought to promote BAK1 activity, while Bcl2 binds to BAK1 and prevents its ability to bind to the channel.

Dr Beech continued, “This positive swing in regulation of apoptosis for lithium responders was measurable as early as four weeks after the start of treatment, while in non-responders there was a measureable shift in the opposite direction. It seems then, that increased expression of BCL2 and related genes is  necessary for the therapeutic effects of lithium. Understanding these differences in genes expression may lead towards personalized treatment for bipolar disorder in the future.”

The real culprits of colour blindness are vision cells rather than unusual wiring in the eye and brain, recent research has shown.

The discovery brings scientists a step closer to restoring full colour vision for people who are colour blind – a condition that affects close to two million Australians, says Professor Paul Martin from The Vision Centre and The University of Sydney.

It may also help pave the way for an answer to one of the most common causes of blindness – age-related macular degeneration (AMD), which accounts for half of the legal blindness cases in Australia.

“There are millions of cones in our eyes – vision cells that pick up bright light and allow us to see colour,” Prof. Martin says. “They are nicknamed red, green and blue cones because they are sensitive to different wavelengths of light.

“We now know that in the macular region of the eye, each cone has its own ’private line’ into the optic nerve and the brain. Just as a painter can mix from three tubes of paint to produce a wide and vivid palette, our brain uses the ‘private lines’ from the three cone types to create thousands of colour sensations.

Scientists previously thought that full colour vision depends on specialised nerve wiring in the eye and brain, but animal studies show that the wiring is identical for monkeys whether they have normal or abnormal colour vision, Prof. Martin says.

“This tells us that there’s nothing wrong in the brain – it’s only working with the signals that it receives on the ‘private lines’,” he says. “So the only difference in normal and abnormal colour vision is caused by the first stage of sight, which points to faulty cones. Either they have failed to develop, or else they are picking up abnormal wavelengths.

“Now that we know faulty wiring isn’t the cause, we can concentrate on fixing the cones, which are controlled by genes – and thus prone to mutation or mistakes during cell replication. There are already promising results from gene therapy as a way to restore full colour vision in colour blind monkeys.”

“While we have still have some way to go, the benefits of this gene therapy – if successful – can potentially extend beyond providing complete colour vision,” he says.

“If we can get these genes to work in human eyes, it means that the same approach might be possible for other visual problems – including blinding diseases such as macular degeneration.”

"In macular degeneration, energy supplies to the macula can’t keep up with demand. So the ‘private line’ system must be very energy-intensive. Gene therapy could be used to turn down the cones’ energy demand, or to increase energy supply from supporting cells to cone cells,” Prof. Martin says.

“Together with clinical researchers at the Save Sight Institute, we are now working hard to find out exactly how many ‘private lines’ there are in humans. That can point us to where energy demand is highest and we can target gene therapy to the right place.

"So animal research on ‘private lines’ for colour vision has given new clues for understanding one of the most important visual diseases – macular degeneration – in humans."

By Sabrina Richards | September 20, 2012

Researchers find that photoreceptors expressed in zebrafish hypothalamus contribute to light-dependent behavior.

Juvenile zebrafish.

Zebrafish larvae without eyes or pineal glands can still respond to light using photopigments located deep within their brains.  Published in Current Biology, the findings are the first to link opsins, photoreceptors located in the hypothalamus and other brain areas, to increased swimming in response to darkness, a behavior researchers hypothesize may help the fish move toward better-lit environments.

“[It’s a] strong demonstration that opsin-dependent photoreceptors in deep brain areas affect behaviors,” said Samer Hattar, who studies light reception in mammals at Johns Hopkins University but did not participate in the research.

Photoreceptors in eyes enable vision, and photoreceptors in the pineal gland, a small endocrine gland located in the center of the vertebrate brain, regulate circadian rhythms. But photoreceptors are also found in other brain areas of both invertebrates and vertebrate lineages. The function of these extraocular photoreceptors has been best studied in birds, where they regulate seasonal reproduction, explained Harold Burgess, a behavioral neurogeneticist at the Eunice Kennedy Shriver National Institute for Child Health and Human Development.

Many opsins have been reported in the brains of tiny and transparent larval zebrafish, raising the possibility that light could be stimulating the photoreceptors even deep in the brain. To test for behaviors that may be regulated by deep brain photoreceptors, Burgess and his colleagues in Wolfgang Driever’s lab at the University of Freiburg removed the eyes of zebrafish larvae, and compared their behavior to larvae that retained their eyes. Although most light-dependent behavior required eyes, the eyeless larvae did respond when the lights were turned off, increasing their activity for a several minutes, though to a somewhat lesser extent than control larvae. But the fact that they responded at all suggests that non-retinal photoreceptors contributed to the behavior.

To confirm the role of the deep brain photoreceptors, the researchers also tested eyeless larvae that had been genetically modified to block expression of photoreceptors in the pineal gland. This fish still showed this jump in activity for several minutes after entering darkness.

Two different types of opsins—melanopsin and multiple tissue opsin—are expressed in the same type of neuron in zebrafish hypothalamus. Burgess and his colleagues looked at zebrafish missing the transcription factor Orthopedia, which is unique to these neurons, and found that the darkness-induced activity boost is nearly absent in these fish. To further narrow the search for the responsible photoreceptors, the researchers overexpressed melanopsin in hypothalamus neurons that co-express Orthopedia and melanopsin, and found that it increased the sensitivity of eyeless zebrafish to reductions in light. The results point to both melanopsin and Orthopedia as key players in modulating this behavior and pinpoint the location to neurons that coexpress these factors in the zebrafish hypothalamus.

Interestingly, the hypothalamus is one of the oldest parts of the vertebrate brain, said Detlev Arendt, a developmental biologist at the European Molecular Biology Laboratory in Heidelberg. “It’s very possible that this is one of the oldest functions”—one that evolved in “non-visual organisms” that had no eyes but still needed to sense light.

Although not as directed and efficient as eye-dependent behaviors that help fish swim toward light, Burgess speculates that deep brain opsins can still benefit zebrafish larvae. “You could imagine situation where it can’t see light, if a leaf falls on it and it doesn’t know where to swim. I think this behavior puts it in a hyperactive state where it swims wildly for several minutes until it reaches enough light for eyes to take over,” he explained, noting that such behavior is common in invertebrates.

It remains to be seen whether these deep brain opsins regulate other behaviors, perhaps in similar fashion to seasonal hormonal regulation in birds, but Hattar believes it is likely. “It’s beyond reasonable doubt there are many functions for these deep brain photoreceptors.”

People with degenerative neurological conditions could benefit from research that shows why their brain cells stop communicating properly.

Scientists believe that the findings could help to develop treatments that slow the progress of a broad range of brain disorders such as Huntington’s, Alzheimer’s and Parkinson’s diseases.

The team at the University, led by Professor Tom Gillingwater, analysed how connection points between brain cells break down during disease and identified six proteins that control the process.

Sending Signals

When connection points in the brain, known as synapses, stop working - because of injury or disease - the chain of brain signalling breaks down and cannot be repaired.

The research from The Roslin Institute and Centre for Integrative Physiology at the University will help scientists identify drugs that target these proteins.

This could eventually enable clinicians to slow the progress of these disorders.

This study has identified key proteins that may control what goes wrong in a range of brain disorders. We now hope to identify drugs that prevent the breakdown of communication between brain cells and, as a result, halt the progress of these devastating neurodegenerative conditions. — Dr Thomas Wishart Career Track Fellow, The Roslin Institute at the University

Millions of Americans take antidepressants such as Prozac, Effexor, and Paxil, but the explanations for how they work never satisfied René Hen, a professor of psychiatry, neuroscience and pharmacology.

So the French-born researcher began a series of experiments a decade ago that are now helping to overturn conventional wisdom about the class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) and providing new insights into the biological mechanisms in the brain that affect mood and cognition.

Adult-born neurons in the hippocampus have been engineered to express channelrhodopsin (red), a protein that allows the activation of these neurons and the study of their impact on pattern separation and mood. (Image credit: Mazen Kheirbek and René Hen)

SSRIs, it has long been thought, work by inhibiting brain cells from reabsorbing serotonin, a signaling agent in the brain associated with positive mood. Yet unlike with psychoactive substances, the effects of the drugs take weeks to be felt—even though the increase in serotonin circulating in the brain begins almost immediately. Something more, Hen concluded, must be happening after that to create such a profound effect in depressed patients.

In 2003, Hen demonstrated an important finding in mice: The change in mood—measured by the amount of time it took the animals to overcome anxiety and feed in new environments—appeared to be due in part to the production of new brain cells in the hippocampus, an area of the brain associated with learning and memory. And those new brain cells, Hen thinks, are the result of growth-stimulating chemicals released in the brain, in response to the increased serotonin.

Last year, Hen published another groundbreaking study, suggesting how these new brain cells might affect mood. The new brain cells are located in the dentate gyrus, an area of the hippocampus involved in pattern separation, a cognitive process that helps us to recognize that something is new and different from similar experiences and stimuli. This information is then sent to other brain regions where the new stimulus is assigned a positive or negative emotional value.

Using genetic manipulations that block or enhance the production of brain cells in the dentate gyrus, Hen demonstrated that the new brain cells led to a marked improvement not just in the cognitive abilities of mice, but also in their mood. “What we think, even though it hasn’t been proven yet, is that some depressed human patients also have a problem with pattern separation,” Hen says. “What we are hoping is, if we can boost production of new neurons in their hippocampus, maybe we can improve pattern separation in patients and decrease general symptoms.”

Hen sees numerous ways that a disruption in pattern separation might lead to negative emotions such as anxiety and depression. The hippocampus is located next to, and is strongly linked with, another brain structure, the almond-shaped amygdala, thought to be the seat of our emotions.

If wrong judgments were assigned to novel stimuli in the amygdala, that could easily trigger the brain’s fight-or-flight instinct or, at the very least, produce fear. That might help explain features of anxiety disorders—why survivors of the 9/11 terrorist attacks suffering from post-traumatic stress disorder, for instance, might be hit with a panic attack whenever they see an airplane fly over a skyscraper, Hen says.

A deficit in pattern separation might also help explain why depressed patients often are unable to experience pleasure, exhibit a lack of interest in novel experiences, and feel profound malaise. Perhaps they are simply unable to register an experience as novel or pleasurable because they are unable to recognize it as sufficiently different from prior experiences.

Hen is quick to point out that new brain cell production in the hippocampus is just one effect of a cascade of neurochemical changes unleashed by SSRIs. Other researchers have demonstrated, among other things, that the drugs also have a strong impact on the prefrontal cortex, the area of the brain associated with executive functions such as decision-making and restraint.

Even so, Hen hopes his findings will have significant implications for some depressed patients—and perhaps even reveal why certain antidepressants work for some people and not others. Over the next several years, he plans to explore his hypotheses further by evaluating the pattern-separation abilities of depressed patients before and after they are treated with SSRIs.

“There is still a long way to go, but we are at least starting to provide a theoretical framework,” Hen says. “With complex disorders such as anxiety and depression, you are dealing with many parts of the brain. We think we have identified the biological basis for one of the symptoms present in a subgroup of patients, and maybe by targeting it, we will be able to help them.”

A new oral medication to treat patients in the early stages of multiple sclerosis has shown considerable promise in two clinical trials, researchers announced on Wednesday.

The medication is on track to become just the third oral drug available to M.S. patients, and potentially the safest and most effective, experts said. The second oral drug, called Aubagio, was approved just last week.

M.S. was virtually untreatable only two decades ago, but today nine “disease modifying” drugs are available for early-stage patients; a half-dozen more are in the late stages of development. Most patients in the early stage of the disease, a form called relapsing-remitting M.S., take drugs by injection.

The two new studies, published online in The New England Journal of Medicine, found that the drug BG-12, developed by Biogen Idec, reduced relapse rates in patients with relapsing M.S. by about 50 percent. The drug also significantly reduced the frequency of new brain lesions often associated with these attacks, and slowed the progression of disease compared with a placebo.

The studies were Phase 3 trials, a last step on the road to drug approval. The Food and Drug Administration is required to make a decision about the drug’s approval before the end of this year.

“This drug is clearly quite effective in managing disease and reducing disability, and the safety profile looks quite good,” said Timothy Coetzee, the chief research officer at the National Multiple Sclerosis Society, who was not involved in the studies.

Multiple sclerosis is often a progressive disease in which the immune system damages neurons in the brain and spinal cord. A majority of people with M.S. have relapsing-remitting M.S., characterized by flare-ups that cause lesions in the brain to develop and neurological symptoms to emerge or worsen. Eventually, more than half of patients develop a progressive form of M.S., leading to permanent disabilities.

Interferons, the drugs most commonly used in relapsing M.S., reduce relapses by about 30 percent, and have not been shown to slow the progression of the disease and disability. The newly approved Aubagio also reduces relapses by about 30 percent, and it has the advantage of being an oral drug.

Two drugs that are substantially more effective, Tysabri and Gilenya, come with serious risks including, in rare cases, death. They are used as second-line treatments when an initial approach fails, and patients require some monitoring.

In the new studies, called Define and Confirm, patients were randomized into two groups, taking 240 milligrams of BG-12 either twice or three times a day. Patients in a third group took a placebo. The combined results showed that the drug reduced the relapse rate by about 50 percent. There was minimal difference between the twice-daily and thrice-daily regimens.

Taking BG-12 twice a day reduced the number of new or newly enlarging brain lesions by 71 percent to 99 percent, depending on the type of lesion and the study. The Define study found a statistically significant 38 percent reduction in the progression to disability.

The most frequent side effects were a temporary flushing and warm feeling and gastrointestinal symptoms including nausea, diarrhea, cramping and vomiting. Though both types of side effects were common, they tended to diminish after the first few weeks of use and were tolerated by most patients.

BG-12 is an anti-inflammatory that works by protecting nerves against injury. It is a fumaric acid, very similar to one widely used in Germany for the treatment of psoriasis. “The safety track record is well known and appears to be very strong,” said Dr. Robert Fox, lead author of one of the two new studies and medical director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

“It’s a bright day for M.S. patients, but there is a gray cloud in that we still don’t have anything for those with progressive M.S.,” he added.