Neuroscience

An epilepsy drug shows promise in an animal model at preventing tinnitus from developing after exposure to loud noise, according to a new study by researchers at the University of Pittsburgh School of Medicine. The findings, reported this week in the early online version of the Proceedings of the National Academy of Sciences, reveal for the first time the reason the chronic and sometimes debilitating condition occurs.

An estimated 5 to 15 percent of Americans hear whistling, clicking, roaring and other phantom sounds of tinnitus, which typically is induced by exposure to very loud noise, said senior investigator Thanos Tzounopoulos, Ph.D., associate professor and member of the auditory research group in the Department of Otolaryngology, Pitt School of Medicine.

"There is no cure for it, and current therapies such as hearing aids don’t provide relief for many patients," he said. "We hope that by identifying the underlying cause, we can develop effective interventions."

The team focused on an area of the brain that is home to an important auditory center called the dorsal cochlear nucleus (DCN). From previous research in a mouse model, they knew that tinnitus is associated with hyperactivity of DCN cells — they fire impulses even when there is no actual sound to perceive. For the new experiments, they took a close look at the biophysical properties of tiny channels, called KCNQ channels, through which potassium ions travel in and out of the cell.

"We found that mice with tinnitus have hyperactive DCN cells because of a reduction in KCNQ potassium channel activity," Dr. Tzounopoulos said. "These KCNQ channels act as effective "brakes" that reduce excitability or activity of neuronal cells."

In the model, sedated mice are exposed in one ear to a 116-decibel sound, about the loudness of an ambulance siren, for 45 minutes, which was shown in previous work to lead to the development of tinnitus in 50 percent of exposed mice. Dr. Tzounopoulos and his team tested whether an FDA-approved epilepsy drug called retigabine, which specifically enhances KCNQ channel activity, could prevent the development of tinnitus. Thirty minutes into the noise exposure and twice daily for the next five days, half of the exposed group was given injections of retigabine.

Seven days after noise exposure, the team determined whether the mice had developed tinnitus by conducting startle experiments, in which a continuous, 70 dB tone is played for a period, then stopped briefly and then resumed before being interrupted with a much louder pulse. Mice with normal hearing perceive the gap in sounds and are aware something had changed, so they are less startled by the loud pulse than mice with tinnitus, which hear phantom noise that masks the moment of silence in between the background tones.

The researchers found that mice that were treated with retigabine immediately after noise exposure did not develop tinnitus. Consistent with previous studies, 50 percent of noise-exposed mice that were not treated with the drug exhibited behavioral signs of the condition.

"This is an important finding that links the biophysical properties of a potassium channel with the perception of a phantom sound," Dr. Tzounopoulos said. "Tinnitus is a channelopathy, and these KCNQ channels represent a novel target for developing drugs that block the induction of tinnitus in humans."

The KCNQ family is comprised of five different subunits, four of which are sensitive to retigabine. He and his collaborators aim to develop a drug that is specific for the two KCNQ subunits involved in tinnitus to minimize the potential for side effects.

"Such a medication could be a very helpful preventive strategy for soldiers and other people who work in situations where exposure to very loud noise is likely," Dr. Tzounopoulos said. "It might also be useful for other conditions of phantom perceptions, such as pain in a limb that has been amputated."

Researchers at the Stanford University School of Medicine have identified mutations in several new genes that might be associated with the development of spontaneously occurring cases of the neurodegenerative disease known as amyotrophic lateral sclerosis, or ALS. Also known as Lou Gehrig’s disease, the progressive, fatal condition, in which the motor neurons that control movement and breathing gradually cease to function, has no cure.

Although researchers know of some mutations associated with inherited forms of ALS, the majority of patients have no family history of the disease, and there are few clues as to its cause. The Stanford researchers compared the DNA sequences of 47 patients who have the spontaneous form of the disease, known as sporadic ALS, with those of their unaffected parents. The goal was to identify new mutations that were present in the patient but not in either parent that may have contributed to disease development.

Several suspects are mutations in genes that encode chromatin regulators — cellular proteins that govern how DNA is packed into the nucleus of a cell and how it is accessed when genes are expressed. Protein members of one these chromatin-regulatory complexes have recently been shown to play roles in normal development and some forms of cancer.

"The more we know about the genetic causes of the disorder, the greater insight we will have as to possible therapeutic targets," said Aaron Gitler, PhD, associate professor of genetics. "Until now, researchers have primarily relied upon large families with many cases of inherited ALS and attempted to pinpoint genetic regions that seem to occur only in patients. But more than 90 percent of ALS cases are sporadic, and many of the genes involved in these cases are unknown."

Gitler is the senior author of the study, published online May 26 in Nature Neuroscience. Postdoctoral scholar Alessandra Chesi, PhD, is the lead author. Gitler and Chesi collaborated with members of the laboratory of Gerald Crabtree, MD, professor of developmental biology and of pathology. Crabtree, a Howard Hughes Medical Institute investigator, is also a co-author of the study.

Chesi and Gitler combined deductive reasoning with recent advances in sequencing technology to conduct the work, which relied on the availability of genetic samples from not only ALS patients, but also the patients’ unaffected parents. Such trios can be difficult to obtain for diseases like sporadic ALS that strike well into adulthood when a patient’s parents may no longer be alive. Gitler and Chesi collaborated with researchers from Emory University and Johns Hopkins University to collect these samples.

The researchers compared the sequences of a portion of the genome called the exome, which directly contributes to the amino acid sequences of all the proteins in a cell. (Many genes contain intervening, non-protein-coding regions of DNA called introns that are removed prior to protein production.) Mutations found only in the patient’s exome, but not in that of his or her parents’, were viewed as potential disease-associated candidates - particularly if they affected the composition or structure of the resulting protein made from that gene.

Focusing on just the exome, which is about 1 percent of the total amount of DNA in each human cell, vastly reduced the total amount of DNA that needed to be sequenced and allowed the researchers to achieve relatively high coverage (or repeated sequencing to ensure accuracy) of each sample.

"We wanted to find novel changes in the patients," Chesi said. "These represent a class of mutations called de novo mutations that likely occurred during the production of the parents’ reproductive cells." As a result, these mutations would be carried in all the cells of patients, but not in their parents or siblings.

Using the exome sequencing technique, the researchers identified 25 de novo mutations in the ALS patients. Of these, five are known to be in genes involved in the regulation of the tightly packed form of DNA called chromatin — a proportion that is much higher than would have been expected by chance, according to Chesi.

Furthermore, one of the five chromatin regulatory proteins, SS18L1, is a member of a neuron-specific complex called nBAF, which has long been studied in Crabtree’s laboratory. This complex is strongly expressed in the brain and spinal cord, and affects the ability of the neurons to form branching structures called dendrites that are essential to nerve signaling.

"We found that, in one sporadic ALS case, the last nine amino acids of this protein are missing," Gitler said. "I knew that Gerald Crabtree’s lab had been investigating SS18L1, so I asked him about it. In fact, they had already identified these amino acids as being very important to the function of the protein."

When the researchers expressed the mutant SS18L1 in motor neurons isolated from mouse embryos, they found the neurons were unable to extend and grow new dendrites as robustly as normal neurons in response to stimuli. They also showed that SS18L1 appears to physically interact with another protein known to be involved in cases of familial, or inherited, ALS.

Although the results are intriguing, the researchers caution that more work is necessary to conclusively prove whether and how mutations in SS18L1 contribute to sporadic cases of ALS. But now they have an idea of where to look in other patients, without requiring the existence of patient and parent trios. They are planning to sequence SS18L1 and other candidates in an additional few thousand sporadic ALS cases.

"This is the first systematic analysis of ALS triads for the presence of de novo mutations," Chesi said. "Now we have a list of candidate genes we can pursue. We haven’t proven that these mutations cause ALS, but we’ve shown, at least in the context of SS18L1, that the mutation carried by some patients is damaging to the protein and affects the ability of mouse motor neurons to form dendrites."

The adult brain is far more malleable that we thought, and so learning can be child’s play if you know how.

Some 36-year-olds choose to collect vintage wine, vinyl records or sports memorabilia. For Richard Simcott, it is languages. His itch to learn has led him to study more than 30 foreign tongues – and he’s not ready to give up.

During our conversation in a London restaurant, he reels off sentences in Spanish, Turkish and Icelandic as easily as I can name the pizza and pasta on our menu. He has learned Dutch on the streets of Rotterdam, Czech in Prague and Polish during a house share with some architects. At home, he talks to his wife in fluent Macedonian.

What’s remarkable about Simcott isn’t just the number and diversity of languages he has mastered. It’s his age. Long before grey hairs appear and waistlines expand, the mind’s cogs are meant to seize up, making it difficult to pick up any new skill, be it a language, the flute, or archery. Even if Simcott had primed his mind for new languages while at school, he should have faced a steep decline in his abilities as the years went by – yet he still devours unfamiliar grammars and strange vocabularies to a high level. “My linguistic landscape is always changing,” he says. “If you’re school-aged, or middle-aged – I don’t think there’s a big difference.”

A decade ago, few neuroscientists would have agreed that adults can rival the learning talents of children. But we needn’t be so defeatist. The mature brain, it turns out, is more supple than anyone thought. “The idea that there’s a critical period for learning in childhood is overrated,” says Gary Marcus, a psychologist at New York University. What’s more, we now understand the best techniques to accelerate knowledge and skill acquisition in adults, so can perhaps unveil a few tricks of the trade of super-learners like Simcott. Whatever you want to learn, it’s never too late to charge those grey cells.

The idea that the mind fossilises as it ages is culturally entrenched. The phrase “an old dog will learn no tricks" is recorded in an 18th century book of proverbs and is probably hundreds of years older.

When researchers finally began to investigate the adult brain’s malleability in the 1960s, their results appeared to agree with the saying. Most insights came indirectly from studies of perception, which suggested that an individual’s visual abilities were capped at a young age. For example, restricting young animals’ vision for a few weeks after birth means they will never manage to see normally. The same is true for people born with cataracts or a lazy eye – repair too late, and the brain fails to use the eye properly for life. “For a very long time, it seemed that those constraints were set in stone after that critical period,” says Daphne Bavelier at the University of Rochester, New York.

These are extreme circumstances, of course, but the evidence suggested that the same neural fossilisation would stifle other kinds of learning. Many of the studies looked at language development – particularly in families of immigrants. While the children picked up new tongues with ease, their parents were still stuttering broken sentences. But if there is a critical period for foreign language learning, everyone should be affected equally; Simcott’s ability to master a host of languages should be as impossible as a dog playing the piano.

Bearing this in mind, Ellen Bialystok at York University in Toronto, Canada, recently turned to the US census records, which detailed the linguistic skills of more than 2 million Hispanic and Chinese immigrants. A “critical period” for learning a second language in infancy should have created a sharp difference between those who had moved country in early childhood and those who were uprooted in adolescence. In reality? “There was absolutely no discontinuity,” Bialystok says. Instead, she saw a very gradual decline with age among immigrants – which could reflect differences in environment as much as the adults’ rusty brain circuits. “People talk more slowly and clearly to children in short, simple sentences,” she says. “And the child’s entire social and educational network is organised around that language.”

Yet while Bialystok’s study suggested that adult brains are more pliable than had once been imagined, there was still the suspicion that children might have the edge in certain skills. Adult learners sometimes find it harder to learn to sing in tune, hit a home run or mimic an accent convincingly. At first glance, the problem might seem to lie in adults’ perception and motor skills. Learning involving these abilities differs from the acquisition of factual knowledge, because it needs us to rewire the eyes, ears and muscles.

It’s something that Marcus can identify with. At the age of 38, he devoted himself to learning the guitar, an experience he detailed in his book Guitar Zero. “My family’s initial response was laughter – but they soon saw I was making progress,” he says. Still, during his research, he attended a musical summer camp for 8 to 15-year-olds. He says he was quicker to catch on to the structure of songs, but his younger bandmates had better coordination and sense of pitch.

Yet the available evidence hints that children may not always be inherently better at such tasks. One study by Yang Zhang at the University of Minnesota in Minneapolis that focused on the acquisition of foreign accents in adults suggests we may simply be suffering from poor tuition. When the researchers gave them recordings that mimicked the exaggerated baby talk of cooing mothers, the adult learners progressed rapidly.

Nor do adults necessarily fumble over the intricate movements that are crucial for music or sport. When volunteers visiting Virginia Penhune's lab at Concordia University in Montreal, Canada, learned to press keys in a certain sequence, at certain times – essentially a boiled-down version of keyboard practice – the adults tended to outshine the younger volunteers.

During a more challenging test of hand-eye coordination, nearly 1000 volunteers of all age groups learned to juggle over a series of six training sessions. As you might expect, the senior citizens aged 60 to 80 began with some hesitation, but they soon caught up with the 30-year-olds and by the end of the trials all the adults were juggling more confidently than the 5 to 10-year-olds.

Old dogs, then, are much more adaptable than folklore would have it – and if we do have deficits, they aren’t insurmountable. The reason that children appear to be better learners may have more to do with their environment, and factors such as physical fitness (see “Faster body, faster mind”).

Indeed, many researchers believe that an adult’s lifestyle may be the biggest obstacle. “A child’s sole occupation is learning to speak and move around,” says Ed Cooke, a cognitive scientist who has won many memory contests. “If an adult had that kind of time to spend on attentive learning, I’d be very disappointed if they didn’t do a good job.”

A glut of free time and a carefree existence are out of reach for most of us, but there are other behaviours that boost children’s learning, and these habits can be easily integrated into even an adult’s schedule. For example, children are continually quizzed on what they know – and for good reason: countless studies have shown that testing doubles long-term recall, outperforming all other memory tactics. Yet most adults attempting to learn new skills will rely more on self-testing which, let’s be honest, happens less often.

That’s why Cooke developed a website, called Memrise, which helps take some of the pain out of testing and, crucially, can integrate learning into the adult day. It is designed to track your learning curve with cunningly timed tests that force you to retrieve the information just as you are about to forget it.

"Memrise engages your brain to the greatest possible extent," says Cooke, who has himself used the site to learn thousands of words of foreign vocabulary. Users can create their own courses – the topics range from art to zoology – and importantly, it is easy to load the site in the few spare minutes of your lunch break or while you are waiting for a train. Cooke also plans to launch a smartphone app.

What about tasks that involve perceptual learning or motor skills – like battling against a lifetime of tone deafness, or perfecting that golf swing? Here too, there are guiding principles that can help you rediscover the seemingly effortless learning of youth.

Adults can hamper progress with their own perfectionism: whereas children throw themselves into tasks, adults often agonise over the mechanics of the movements, trying to conceptualise exactly what is required. This could be one of our biggest downfalls. “Adults think so much more about what they are doing,” says Gabriele Wulf at the University of Nevada, Las Vegas. “Children just copy what they see.”

Wulf’s work over the past decade shows that you should focus on the outcome of your actions rather than the intricacies of the movements. She applies this finding in her own life: as a keen golfer, she has found it is better to think about the swing of the club, for instance, rather than the position of her hands. “I’m always trying to find where best to focus my attention,” she says. Similarly, if you are learning to sing, then you should concentrate on the tone of the voice, rather than on the larynx or the placement of the tongue. Study after study shows that simply shifting your mindset in this way accelerates your learning– perhaps by encouraging the subconscious, automatic movements that mark proficiency.

Misplaced conscientiousness may also lead adults to rely on overly rigid practice regimes that stifle long-term learning. The adult talent for perseverance, it seems, is not always a virtue. Left to their own devices, most people segment their sessions into separate blocks – when learning basketball, for instance, they may work on each shot in turn, perhaps because they feel a desire to master it. The approach may bring rapid improvements at first, but a host of studies have found that the refined technique is soon forgotten.

Instead, you do better to take a carousel approach, quickly rotating through the different skills to be practised without lingering too long on each one. Although the reason is still unclear, it seems that jumping between skills makes your mind work a little harder when applying what you’ve learned, helping you to retain the knowledge in the long term – a finding that has helped people improve in activities ranging from tennis and kayaking to pistol shooting.

Such an approach might not be to everyone’s taste – with intricate skills, it might feel like you are making no progress. But even if you do revert to stints of lengthy practice, you can still reap some of the same benefits by occasionally trying out your skills in an unfamiliar situation. In tennis, you might move to a different part of the court for a couple of serves before returning to the regular position; while playing scales on a musical instrument, you might switch hands temporarily. According to work by Arnaud Boutin at the Leibniz Research Centre for Working Environment and Human Factors in Dortmund, Germany, venturing out of your comfort zone in this way helps to ensure that you improve your overall performance rather than confining your progress to the single task at hand. “Otherwise, the longer you practise, the harder it becomes to transfer the skills that you’ve learned to new situations,” says Boutin.

If none of that helps you learn like a child, simply adopting the arrogance of youth may do no harm. “As we get older, we lose our confidence, and I’m convinced that has a big impact on performance,” says Wulf. To test the assumption, she recently trained a small group of people to pitch a ball. While half were given no encouragement, she offered the others a sham test, rigged to demonstrate that their abilities were above average. They learned to pitch on target with much greater accuracy than those who didn’t get an ego boost.

Whether your itch to learn will ever match Simcott’s appetite for foreign languages is another matter. “What I do – it’s like an extreme sport. There’s no need to learn that many languages,” he says. He has recently turned to Chinese, and has no plans to stop after that. “I’m like a linguistic butterfly. There’s always another, really far away, that suddenly feels appealing.”

Still, embrace the idea that your mind is as capable as Simcott’s, and the lure of extreme learning might take hold of you too.

-by David Robson, New Scientist

Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.

The results suggest a monthly window of opportunity that could potentially be targeted in efforts to prevent common mental health problems developing in women. The research is the first to show a potential link between psychological vulnerability and the timing of a biological cycle, in this case ovulation.

A common symptom of mood and anxiety problems is the tendency to experience repetitive and unwanted thoughts. These ‘intrusive thoughts’ often occur in the days and weeks after a stressful experience.

In this study, the researchers examined whether the effects of a stressful event are linked to different stages of the menstrual cycle. The participants were 41 women aged between 18 and 35 who had regular menstrual cycles and were not using the pill as a form of contraception. Each woman watched a 14-minute stressful film containing death or injury and provided a saliva sample so that hormone levels could be assessed. They were then asked to record instances of unwanted thoughts about the video over the following days.

“We found that women in the ‘early luteal’ phase, which falls roughly 16 to 20 days after the start of their period, had more than three times as many intrusive thoughts as those who watched the video in other phases of their menstrual cycle,” explains author Dr Sunjeev Kamboj, Lecturer in UCL’s Department of Clinical, Educational and Health Psychology.

“This indicates that there is actually a fairly narrow window within the menstrual cycle when women may be particularly vulnerable to experiencing distressing symptoms after a stressful event.”

The findings could have important implications for mental health problems and their treatment in women who have suffered trauma.

“Asking women who have experienced a traumatic event about the time since their last period might help identify those at greatest risk of developing recurring symptoms similar to those seen in psychological disorders such as depression and post-traumatic stress disorder (PTSD),” said Dr Kamboj.

“This work might have identified a useful line of enquiry for doctors, helping them to identify potentially vulnerable women who could be offered preventative therapies,” continued Dr Kamboj.

“However, this is only a first step. Although we found large effects in healthy women after they experienced a relatively mild stressful event, we now need to see if the same pattern is found in women who have experienced a real traumatic event. We also need further research to investigate how using the contraceptive pill affects this whole process.”

In Parkinson’s disease, the protein “alpha-synuclein” aggregates and accumulates within neurons. Specific areas of the brain become progressively affected as the disease develops and advances. The mechanism underlying this pathological progression is poorly understood but could result from spreading of the protein (or abnormal forms of it) along nerve projections connecting lower to upper brain regions. Scientists at the German Center for Neurodegenerative Diseases (DZNE) in Bonn have developed a novel experimental model that reproduces for the first time this pattern of alpha-synuclein brain spreading and provides important clues on the mechanisms underlying this pathological process. They triggered the production of human alpha-synuclein in the lower rat brain and were able to trace the spreading of this protein toward higher brain regions. The new experimental paradigm could promote the development of ways to halt or slow down disease development in humans. The research team headed by Prof. Donato Di Monte presents these results in the scientific journal “EMBO Molecular Medicine”.

Parkinson’s disease is a disorder of the nervous system. It typically manifests itself with motor disturbances, such as an uncontrollable trembling of the limbs, as well as non-motor symptoms, including sleep disorders and depression.

At the present, no cure exists for Parkinson’s disease, although symptomatic intervention, including treatment with dopamine agonists, can alleviate patients’ motor impairment. Parkinson’s is the second most common neurodegenerative disorder, after Alzheimer’s disease; it is estimated that 100,000 to 300,000 patients are affected by Parkinson’s disease in Germany alone.

In a small percentage of cases, Parkinson’s disease is due to genetic abnormalities carried within families. For the vast majority of patients, however, the cause of the disease remains unknown; the development of this sporadic form of the disease is likely promoted by both environmental and genetic risk factors. An intriguing characteristic of the brain of patients with sporadic Parkinson’s disease is the progressive accumulation of intraneuronal inclusions that were first described by a German neurologist, Friedrich Lewy, and are therefore called Lewy bodies.

“A major discovery in the late 90’s was that Lewy bodies are formed when the protein alpha-synuclein becomes aggregated,” says Di Monte. “Since then, it was also found that aggregates of alpha-synuclein are progressively accumulated within the patients’ brains during the course of the disease”.

Pathology studies from human brains show that the deposits usually start forming in the lower part of the brain, in an area named “medulla oblongata”. In subsequent disease stages, alpha-synuclein aggregates are observed in progressively higher (more rostral) brain regions, including the midbrain and cortical areas.

“This spreading appears to follow a typical pattern based on anatomical connections between regions of the brain,” says the neuroscientist. “For this reason, it has been hypothesized that alpha-synuclein or abnormal forms of it can be transferred between two interconnected neurons and hence migrate throughout the brain. But until now, there was no way of targeting the medulla oblongata to reproduce this spreading of alpha-synuclein in the laboratory. It is also unclear what conditions could trigger the inter-neuronal passage of the protein or its aggregates. We have now developed a new experimental paradigm which enables investigations on these fundamental issues.”

From the neck into the brain
The researchers’ concept is based on reproducing alpha-synuclein spreading in rats: for this, they transferred the blueprint of the human form of alpha-synuclein into the rat brain. The blueprint was transported by specifically engineered viral particles that the scientists injected into nerve fibres in the neck of the animals. The genetic code for the protein passed along these fibres into the medulla oblongata, where transfected rat neurons began producing high quantities of human alpha-synuclein.

“We have good reasons to believe that the medulla oblongata is a primary site of early disease development. This is why we wanted to activate production of alpha-synuclein specifically in this part of the brain. The medulla oblongata is difficult to reach via surgical procedures. For this reason, we injected the viral particles into the vagus nerve. This is a long nerve stretching from the abdomen via the neck to the medulla oblongata. The nerve consequently served as an entrance into the brain and, in particular, the medulla oblongata,” Di Monte explains.

A migrating protein
The researchers monitored the production and localization of human alpha-synuclein in rats’ brains over a period of four and a half months after injection of the viral particles. As predicted, the exogenous protein was synthesized only within neurons of the medulla oblongata connected to the vagus nerve. Starting at two months, however, human alpha-synuclein was observed also in brain areas more and more distant from the medulla oblongata. Caudo-rostral spreading involved inter-neuronal passage of the protein along specific nerve tracts and was accompanied by morphological alterations (such as swellings) of the neuronal projections taking up human alpha-synuclein.

The study, sponsored in part by the Blanche A. Paul Foundation, bears a number of critical implications. It reproduces a pattern of protein propagation that resembles the progressive spreading of pathological alpha-synuclein in Parkinson’s disease. As importantly, the process of protein transmission was triggered by overproduction of alpha-synuclein within a specific brain region.

“Overproduction of alpha-synuclein accompanies a variety of conditions, such as aging, neuronal injury or genetic polymorphisms, that could promote the development of Parkinson’s disease.” concludes Di Monte. “Thus, our results suggest a mechanistic link between disease risk factors, enhanced levels of alpha-synuclein, spreading of the protein and its pathological accumulation.”

Insight into the early stages of Parkinson’s
The new model mimics events that likely occur in the early stages of alpha-synuclein pathology in the absence of overt behavioural (in rats) or clinical (in patients) manifestations. “It will therefore become a valuable tool to investigate early mechanisms of disease pathogenesis that could be targeted for therapeutic intervention. Early intervention would have a greater probability to prevent or halt the spreading of pathology and progression of the disease,” says Di Monte.

The first symptoms of major depression may be behavioral, but the common mental illness is based in biology — and not limited to the brain.

In recent years, some studies have linked major, long-term depression with life-threatening chronic disease and with earlier death, even after lifestyle risk factors have been taken into account.

Now a research team led by Owen Wolkowitz, MD, professor of psychiatry at UC San Francisco, has found that within cells of the immune system, activity of an enzyme called telomerase is greater, on average, in untreated individuals with major depression. The preliminary findings from his latest, ongoing study was reported Wednesday at the annual meeting of the American Psychiatric Association in San Francisco.

Telomerase is an enzyme that lengthens protective end caps on the chromosomes’ DNA, called telomeres. Shortened telomeres have been associated with earlier death and with chronic diseases in population studies.

The heightened telomerase activity in untreated major depression might represent the body’s attempt to fight back against the progression of disease, in order to prevent biological damage in long-depressed individuals, Wolkowitz said.

The researchers made another discovery that may suggest a protective role for telomerase. Using magnetic resonance imaging (MRI), they found that, in untreated, depressed study participants, the size of the hippocampus, a brain structure that is critical for learning and memory, was associated with the amount of telomerase activity measured in the white blood cells. Such an association at a single point in time cannot be used to conclude that there is a cause-and-effect relationship with telomerase helping to protect the hippocampus, but it is plausible, Wolkowitz said.

Telomerase Activity and Antidepressants

Remarkably, the researchers also found that the enzyme’s activity went up when some patients began taking an antidepressant. In fact, depressed participants with lower telomerase activity at baseline — as well as those in whom enzyme activity increased the most with treatment — were the most likely to become less depressed with treatment.

“Our results are consistent with the beneficial effect of telomerase when it is boosted in animal studies, where it has been associated with the growth of new nerve cells in the hippocampus and with antidepressant-like effects, evidenced by increased exploratory behavior,” Wolkowitz said. He cautions that his new findings are preliminary due to the small size of the study and must be confirmed through further research.

The researchers also measured telomere length in the same immune cells. Only very chronically depressed individuals showed telomere shortening, Wolkowitz said.

“The longer people had been depressed, the shorter their telomeres were,” he said. “Shortened telomere length has been previously demonstrated in major depression in most, but not all, studies that have examined it. The duration of depression may be a critical factor.”

Ongoing Study

The 20 depressed participants enrolled in the study had been untreated for at least six weeks and had an average lifetime duration of depression of about 13 years. After baseline evaluation and laboratory measures, 16 of the depressed participants were treated with sertraline, a member of the most popular class of antidepressants, the serotonin-selective-reuptake-inhibitors (SSRIs), and then evaluated again after eight weeks. There were 20 healthy participants who served as controls.

The ongoing study still is accepting depressed participants who are not now taking antidepressants.

Wolkowitz’s team also studies chronic inflammation and the biochemical phenomenon of oxidative stress, which he said have often been reported in major depression. Wolkowitz is exploring the hypothesis that inflammation and oxidative stress play a role in telomere shortening and accelerated aging in depression.

“New insights into the mechanisms of these processes may well lead to new treatments — both pharmacological and behavioral — that will be distinctly different from the current generation of drugs prescribed to treat depression,” he said. “Additional studies might lead to simple blood tests that can measure accelerated immune-cell aging.”

Researchers at Lund University have succeeded in preventing very early symptoms of Huntington’s disease, depression and anxiety, by deactivating the mutated huntingtin protein in the brains of mice.

“We are the first to show that it is possible to prevent the depression symptoms of Huntington’s disease by deactivating the diseased protein in nerve cell populations in the hypothalamus in the brain. This is hugely exciting and bears out our previous hypotheses”, explains Åsa Petersén, Associate Professor of Neuroscience at Lund University.

Huntington’s is a debilitating disease for which there is still neither cure nor sufficient treatment. The dance-like movements that characterise the disease have long been the focus for researchers, but the emotional problems affect the patient earlier than the motor symptoms. These are now believed to stem from a different part of the brain – the small emotional centre called the hypothalamus.

“Now that we have been able to show in animal experiments that depression and anxiety occur very early in Huntington’s disease, we want to identify more specifically which nerve cells in the hypothalamus are critical in the development of these symptoms. In the long run, this gives us better opportunities to develop more accurate treatments that can attack the mutated huntingtin where it does the most damage”, says Åsa Petersén.

As the role of the hypothalamus in Huntington’s disease is gradually mapped, knowledge might be gained from drug research for other psychiatric diseases. It is likely that similar mechanisms control different types of depression, according to Åsa Petersén.

Publication:
Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntington’s disease
Human Molecular Genetics
Sofia Hult Lundh, Nathalie Nilsson, Rana Soylu, Deniz Kirik and Åsa Petersén

An anti-cancer drug about to be tested in a clinical trial by a biomedical company in Ohio as a possible treatment for Alzheimer’s disease has failed to work with the same type of brain plaques that plague Alzheimer’s patients, according to results of a study by University of Florida researchers.

David Borchelt, Ph.D., a professor of neuroscience affiliated with the Evelyn F. and William L. McKnight Brain Institute of the University of Florida, emphasized the importance of verifying promising research results before investing in clinical studies or testing potential therapies in people. Bexarotene has known side effects that include effects on the liver, blood and other metabolic systems.

“We wanted to repeat the study to see if we could build on it, and we couldn’t,” he said. “We thought it was important that something like this, which got a lot of publicity and patients were immediately looking to try to get access to this drug, that it was important to publish the fact that we couldn’t reproduce the most exciting part of the study. Maybe there should be some caution going forward in regard to patients.”

Borchelt and Kevin Felsenstein, Ph.D., an associate professor of neuroscience, said a drug called bexarotene that their team orally administered to mice did not reduce amyloid plaques, waxy buildups on the brain that are a key culprit in Alzheimer’s disease. Their findings will be published in the May 24, 2013 issue of the journal Science magazine, with two additional articles (1, 2) detailing similar results from other researchers.

The research follows up on a 2012 Science article that claimed bexarotene had reversed Alzheimer’s-like symptoms in mice afflicted with the plaques. Authors of that study also administered the drug orally.

The paper “indicated that with as little as three days of treatment, they basically cleared the amyloid deposits from these animals, as well as restored cognitive abilities,” Felsenstein said of the 2012 paper.He said the results of the original study were surprising, given decades of research that had failed to find a therapy successful in dismantling amyloid plaques.

“We can shut down the production of amyloid in these animal models and the deposits in these animal models don’t disappear,” Felsenstein said. “These deposits have been described by some as cement, and it will take a lot to get rid of them. The fact that something could actually make them disappear in literally a couple of days is — again — very remarkable.”

Interested to see how bexarotene might work to break down amyloid plaques, Felsenstein and Borchelt selected mice approximately the same age as those used in the 2012 study and orally administered the drug to the mice. Tests confirmed the drug had reached its target genes in the mice, and that it elevated levels of a protein called apolipoprotein E. Some scientists believe one of the forms of this protein may prevent the buildup of amyloid brain plaques in people who don’t have Alzheimer’s disease.

But elevated levels of the protein in the mice studied by UF researchers seemed to have no effect on the animals’ amyloid plaques. Samples taken after seven days of treatment with bexarotene showed no significant difference in the number or size of plaques in the animals’ brains. Two teams of researchers from other institutions also were unable to replicate the breakdown of amyloid plaques.

Felsenstein emphasized that his team does not claim the previous study indicating bexarotene’s effectiveness is “totally wrong.”

“We’re just saying right now it’s extremely difficult to replicate and there may be little nuances, that there’s something that we don’t quite understand,” he added. Felsenstein and Borchelt both work at UF’s Center for Translational Research in Neurodegenerative Disease.

Until now, little was scientifically known about the human potential to cultivate compassion — the emotional state of caring for people who are suffering in a way that motivates altruistic behavior.

A new study by researchers at the Center for Investigating Healthy Minds at the Waisman Center of the University of Wisconsin-Madison shows that adults can be trained to be more compassionate. The report, recently published online in the journal Psychological Science, is the first to investigate whether training adults in compassion can result in greater altruistic behavior and related changes in neural systems underlying compassion.

"Our fundamental question was, ‘Can compassion be trained and learned in adults? Can we become more caring if we practice that mindset?’" says Helen Weng, a graduate student in clinical psychology and lead author of the paper. "Our evidence points to yes."

In the study, the investigators trained young adults to engage in compassion meditation, an ancient Buddhist technique to increase caring feelings for people who are suffering. In the meditation, participants envisioned a time when someone has suffered and then practiced wishing that his or her suffering was relieved. They repeated phrases to help them focus on compassion such as, “May you be free from suffering. May you have joy and ease.”

Participants practiced with different categories of people, first starting with a loved one, someone whom they easily felt compassion for like a friend or family member. Then, they practiced compassion for themselves and, then, a stranger. Finally, they practiced compassion for someone they actively had conflict with called the “difficult person,” such as a troublesome coworker or roommate.

"It’s kind of like weight training," Weng says. "Using this systematic approach, we found that people can actually build up their compassion ‘muscle’ and respond to others’ suffering with care and a desire to help."

Compassion training was compared to a control group that learned cognitive reappraisal, a technique where people learn to reframe their thoughts to feel less negative. Both groups listened to guided audio instructions over the Internet for 30 minutes per day for two weeks. “We wanted to investigate whether people could begin to change their emotional habits in a relatively short period of time,” says Weng.

The real test of whether compassion could be trained was to see if people would be willing to be more altruistic — even helping people they had never met. The research tested this by asking the participants to play a game in which they were given the opportunity to spend their own money to respond to someone in need (called the “Redistribution Game”). They played the game over the Internet with two anonymous players, the “Dictator” and the “Victim.” They watched as the Dictator shared an unfair amount of money (only $1 out of $10) with the Victim. They then decided how much of their own money to spend (out of $5) in order to equalize the unfair split and redistribute funds from the Dictator to the Victim.

"We found that people trained in compassion were more likely to spend their own money altruistically to help someone who was treated unfairly than those who were trained in cognitive reappraisal," Weng says.

"We wanted to see what changed inside the brains of people who gave more to someone in need. How are they responding to suffering differently now?" asks Weng. The study measured changes in brain responses using functional magnetic resonance imaging (fMRI) before and after training. In the MRI scanner, participants viewed images depicting human suffering, such as a crying child or a burn victim, and generated feelings of compassion towards the people using their practiced skills. The control group was exposed to the same images, and asked to recast them in a more positive light as in reappraisal.

The researchers measured how much brain activity had changed from the beginning to the end of the training, and found that the people who were the most altruistic after compassion training were the ones who showed the most brain changes when viewing human suffering. They found that activity was increased in the inferior parietal cortex, a region involved in empathy and understanding others. Compassion training also increased activity in the dorsolateral prefrontal cortex and the extent to which it communicated with the nucleus accumbens, brain regions involved in emotion regulation and positive emotions.

"People seem to become more sensitive to other people’s suffering, but this is challenging emotionally. They learn to regulate their emotions so that they approach people’s suffering with caring and wanting to help rather than turning away," explains Weng.

Compassion, like physical and academic skills, appears to be something that is not fixed, but rather can be enhanced with training and practice. “The fact that alterations in brain function were observed after just a total of seven hours of training is remarkable,” explains UW-Madison psychology and psychiatry professor Richard J. Davidson, founder and chair of the Center for Investigating Healthy Minds and senior author of the article.

"There are many possible applications of this type of training," Davidson says. "Compassion and kindness training in schools can help children learn to be attuned to their own emotions as well as those of others, which may decrease bullying. Compassion training also may benefit people who have social challenges such as social anxiety or antisocial behavior."

Weng is also excited about how compassion training can help the general population. “We studied the effects of this training with healthy participants, which demonstrated that this can help the average person. I would love for more people to access the training and try it for a week or two — what changes do they see in their own lives?”

Both compassion and reappraisal trainings are available on the Center for Investigating Healthy Minds’ website. “I think we are only scratching the surface of how compassion can transform people’s lives,” says Weng.

It is known that signs of neurological disorders such as Alzheimer’s and Huntington’s disease can appear years before the disease becomes manifest; these signs take the form of subtle changes in the brain and behavior of individuals affected. For the first time, an international group of researchers led by the DZNE and the Bonn University Hospital has proven the existence of such signatures for motor disorders belonging to the group of “spinocerebellar ataxias”. The scientists report these findings in the current online edition of “The Lancet Neurology”. This pan-European study could open up new possibilities of early diagnosis and smooth the way for treatments which tackle diseases before the patient’s nervous system is irreparably damaged.

“Spinocerebellar ataxias” comprise a group of genetic diseases of the cerebellum and other parts of the brain. Persons affected only have limited control of their muscles. They also suffer from balance disorders and impaired speech. The symptoms originate from mutations in the patient’s genetic make-up. These cause nerve cells to become damaged and to die off. Such genetic defects are comparatively rare: it is estimated that about 3,000 people in Germany are affected.

It is known that there are various subtypes of these neurodegenerative diseases. The age at which the symptoms manifest consequently fluctuates between about 30 and 50. “Our aim was to find out whether specific signs can be recognized before a disease becomes obvious,” says project leader Prof. Thomas Klockgether, Director for Clinical Research at the DZNE and Director of the Clinic for Neurology at Bonn University Hospital.

Pan-European cooperation
The study, which involved 14 research centers in all, focused on the four most common forms of spinocerebellar ataxia. These account for more than half of all cases. More than 250 siblings and children of patients throughout Europe declared their willingness to participate in appropriate tests. These individuals had no obvious symptoms of ataxia. However, about half of them had inherited the genetic defects which invariably cause the disease to manifest in the long term.

With the aid of a mathematical model that considered the genetic mutations and their effects, the scientists were able to estimate the time remaining until the disease could be expected to manifest. In the test group, this “time to onset” varied from 2 to 24 years. These and all other test results remained anonymous: the data was not known to the test subjects, neither could the researchers assign it to specific participants. The same applied to individuals whose DNA turned out to be inconspicuous. “People in families with cases of ataxia usually have not taken a genetic test and they don’t want to know any results. This kind of information has to be treated very carefully for ethical reasons,” emphasizes Klockgether.

Extensive tests
The study participants made themselves available for various examinations including standardized tests of muscular coordination. These included measuring the time needed by the subjects to walk a specific distance. Another series of experiments involved inserting small pins into the holes of a board and taking them back out as quickly as possible. Yet another test measured how often the participants could repeat a certain sequence of syllables in ten seconds. “The tests were designed in such a way that they would provide significant information but still be easy to perform,” says Klockgether. “Tests like these can be performed anywhere without need for special technology.”

Technically complex methods were also used: all study participants were tested for the genetic defects relevant to ataxia. At some of the research centers involved in the study, it was also possible to examine the subjects with the aid of magnetic resonance imaging (MRI). This enabled researchers to measure the total brain volume as well as the dimensions of individual parts of the brain in about a third of the subjects.

Notable findings
In two of the four types of ataxia investigated, the scientists found signs of impending disease. “We found a loss in brain volume, particularly shrinkage in the area of the cerebellum and brain stem. These subjects also had subtle difficulties with coordination,” Klockgether summarizes the results. “This means that manifestations of this kind can be measured years before the disease is likely to become obvious.”

The findings for the other two types of ataxia were less conclusive. “I assume that there are indications also for these types of the disease. However, this subgroup of participants was relatively small. It is therefore difficult to make statistically reliable statements about these subjects,” says the Bonn-based researcher.

In his view, the study results testify to the modern-day view of neurodegenerative processes: “Neurodegeneration doesn’t begin when the symptoms surface. Rather, it is a stealthy disease which starts developing years or even decades beforehand.”

Klockgether believes that this gradual development offers certain opportunities: “If we intervened in this process by appropriate treatments and at a sufficiently early stage, it might be possible to slow down or even stop the disease process.”

More investigations planned
The current results will be the basis for long-term investigations. A new series of tests with the same group of individuals has already started; further tests are scheduled every two years. The scientists intend to monitor the study participants for as long as possible.

Researchers at Johns Hopkins have unraveled the molecular foundations of cocaine’s effects on the brain, and identified a compound that blocks cravings for the drug in cocaine-addicted mice. The compound, already proven safe for humans, is undergoing further animal testing in preparation for possible clinical trials in cocaine addicts, the researchers say.

“It was remarkably serendipitous that when we learned which brain pathway cocaine acts on, we already knew of a compound, CGP3466B, that blocks that specific pathway,” says Solomon Snyder, M.D., a professor of neuroscience in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. “Not only did CGP3466B help confirm the details of cocaine’s action, but it also may become the first drug approved to treat cocaine addiction.” Details of the research appear May 22 on the website of the journal Neuron.

Snyder, who won a 1978 Lasker Award for identifying the brain’s own opiate receptors, and his team have been studying the brain for decades. Twenty years ago, they discovered that the gas nitric oxide (NO) is a major player in the complex signaling network that lets our neurons coordinate activity with one another. Snyder and his team have since studied many of the proteins in that network that interact with NO, including GAPDH, a protein best known for regulating how cells store and use sugars.

A few years ago, Snyder’s team and other researchers found that if NO reacts with GAPDH, GAPDH can then bind to another protein that whisks GAPDH away from its humdrum sugar metabolism tasks and into the nucleus, the cell’s control center. There, depending on what other chemical signals are present, the GAPDH can either stimulate the neuron’s growth or activate a self-destruct program — called apoptosis — that will kill the neuron.

In his research on GAPDH, Snyder came across a paper published in 1998 by scientists at Novartis. The company had identified a molecule, CGP3466B, that in laboratory tests protected neurons from degeneration by inhibiting apoptosis, and had tested it in clinical trials on patients with Parkinson’s disease and amyotrophic lateral sclerosis, or ALS. But while the drug had few side effects, it wasn’t an effective treatment for either of the diseases. Before Novartis gave up on the drug, however, its scientists investigated which molecules it interacted with in the brain, hoping to learn the reasons for its neuroprotective effects. Their only hit was GAPDH, a result that no doubt left the researchers scratching their heads, Snyder says. After all, CGP3466B seemed so promising partly because its effects were so specific — it appeared to do nothing except protect neurons from self-destructing. How would it accomplish that by acting on GAPDH, a signaling molecule with such a broad role in sugar metabolism? Though the study seemed like a dead end, the researchers published it anyway.

When Snyder saw the paper, he connected it to his team’s findings, inferring that CGP3466B might work by preventing GAPDH from entering the nucleus to trigger cell death. In a study published in 2006, he and other Johns Hopkins researchers tested two compounds similar to CGP3466B to see if they would block GAPDH from triggering cell death under the types of highly stressful conditions that would normally cause apoptosis. The protective drugs worked, the team found, by disrupting with extraordinary potency the reaction between NO and GAPDH, which ultimately blocked GAPDH from binding to the protein that ferries it into the nucleus.

In the most recent study, M.D./Ph.D. student Risheng Xu worked with other members of Snyder’s team to investigate whether cocaine works through the NO signaling network, and if so, how. Using mice, they found that cocaine induces NO to react with GAPDH so that GAPDH moves into the nucleus. At low doses of cocaine, the GAPDH in the nucleus will stimulate the neuron, but at higher doses it activates the cell’s self-destruct pathway. “This explains why cocaine can have very different effects depending on the dosage,” Xu says.

The team then did experiments to see whether CGP3466B, which blocks the reaction between NO and GAPDH, would also block the effects of cocaine. In one experiment, they placed mice in a cage with two rooms, and trained them to expect occasional doses of cocaine in one of the rooms. When the mice began spending most of their time in that room, it showed they had become addicted to cocaine. But when treated with CGP3466B, the mice went back to spending roughly equal amounts of time in both rooms: Their cravings had abated, Xu says.

“What’s exciting is that this drug works at very low doses, and it also appears only to affect this specific pathway, making it unlikely to have unwanted side effects,” Xu notes. “We also know from Novartis’ early-stage clinical trials that the drug exhibits few documented side effects in people.”

CGP3466B is now owned by a different company. With the results of the current study in hand, Snyder has brokered a deal between that company and the National Institute on Drug Abuse (NIDA) for NIDA to test CGP3466B as a treatment for cocaine addiction. NIDA will first conduct more animal trials, and then, if all goes well, move on to clinical trials in addicts. “Our study’s results provide a direct demonstration that actions of a major psychotropic drug are mediated by the NO-GAPDH system and afford an unprecedented, straightforward approach to the treatment of cocaine abuse and neurotoxicity,” Snyder says.

Another member of the research team, Nilkanta Sen, Ph.D., cautions that more research is needed to see whether CGP3466B will fulfill its apparent promise. But, says Sen, now an assistant professor at Georgia Regents University, “what we cannot deny is that this study provides a new hope in the field of addiction research.”

New research shows that craving drugs such as nicotine can be visualized in specific regions of the brain that are implicated in determining the value of actions, in planning actions and in motivation. Dr. Alain Dagher, from McGill University, suggests abnormal interactions between these decision-making brain regions could underlie addiction. These results were presented at the 2013 Canadian Neuroscience Meeting, the annual meeting of the Canadian Association for Neuroscience - Association Canadienne des Neurosciences (CAN-ACN).

Neuroeconomics is a field of research which seeks to explain decision making in humans based on calculating costs and likely rewards or benefits of choices individuals make. Previous studies have suggested addicted individuals place greater value on immediate rewards (cigarette smoking) over delayed rewards (health benefits). Research done by Dr. Dagher and colleagues show how the value of the drug, which is indicated by the degree of craving, varies based on drug availability, decision to quit and other factors. He also shows that this perceived value of the drug at a given time can be visualized in the brains of addicted individuals by functional Magnetic Resonance Imaging (fMRI), and that imaging results can be used to predict subsequent consumption.

Dr. Dagher showed that a specific brain region called the dorsolateral prefrontal cortex (abbreviated DLPFC) regulates cigarette craving in response to drug cues - seeing people smoke, or smelling cigarettes - and that these induced cravings could be altered by inactivating the DLPFC by Transcranial Magnetic Stimulation (TMS). He suggests addiction may result from abberrant connections between the DLFPC and other brain region in susceptible individuals. These results could provide a rational basis for novel interventions to reduce cravings in addicted individuals, such as cognitive behavioral therapy or transcranial stimulation of the DLFPC.

Concluding quote from Dr. Dagher: “Policy debates have often centred on whether addictive behaviour is a choice or a brain disease. This research allows us to view addiction as a pathology of choice. Dysfunction in brain regions that assign value to possible options may lead to choosing harmful behaviours.”

Alteration of two genes, detectable by simple blood test during pregnancy, foretold illness with 85 percent certainty in small study

Johns Hopkins researchers say they have discovered specific chemical alterations in two genes that, when present during pregnancy, reliably predict whether a woman will develop postpartum depression.

The epigenetic modifications, which alter the way genes function without changing the underlying DNA sequence, can apparently be detected in the blood of pregnant women during any trimester, potentially providing a simple way to foretell depression in the weeks after giving birth, and an opportunity to intervene before symptoms become debilitating.

The findings of the small study involving 52 pregnant women are described online in the journal Molecular Psychiatry.

“Postpartum depression can be harmful to both mother and child,” says study leader Zachary Kaminsky, Ph.D., an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “But we don’t have a reliable way to screen for the condition before it causes harm, and a test like this could be that way.”

It is not clear what causes postpartum depression, a condition marked by persistent feelings of sadness, hopelessness, exhaustion and anxiety that begins within four weeks of childbirth and can last weeks, several months or up to a year. An estimated 10 to 18 percent of all new mothers develop the condition, and the rate rises to 30 to 35 percent among women with previously diagnosed mood disorders. Scientists long believed the symptoms were related to the large drop-off in the mother’s estrogen levels following childbirth, but studies have shown that both depressed and nondepressed women have similar estrogen levels.

By studying mice, the Johns Hopkins researchers suspected that estrogen induced epigenetic changes in cells in the hippocampus, a part of the brain that governs mood. Kaminsky and his team then created a complicated statistical model to find the candidate genes most likely undergoing those epigenetic changes, which could be potential predictors for postpartum depression. That process resulted in the identification of two genes, known as TTC9B and HP1BP3, about which little is known save for their involvement in hippocampal activity.

Kaminsky says the genes in question may have something to do with the creation of new cells in the hippocampus and the ability of the brain to reorganize and adapt in the face of new environments — two elements important in mood. In some ways, he says, estrogen can behave like an antidepressant, so that when inhibited, it adversely affects mood.

The researchers later confirmed their findings in humans by looking for epigenetic changes to thousands of genes in blood samples from 52 pregnant women with mood disorders. Jennifer L. Payne, M.D., director of the Johns Hopkins Women’s Mood Disorders Center, collected the blood samples. The women were followed both during and after pregnancy to see who developed postpartum depression.

The researchers noticed that women who developed postpartum depression exhibited stronger epigenetic changes in those genes that are most responsive to estrogen, suggesting that these women are more sensitive to the hormone’s effects. Specifically, two genes were most highly correlated with the development of postpartum depression. TTC9B and HP1BP3 predicted with 85 percent certainty which women became ill.

“We were pretty surprised by how well the genes were correlated with postpartum depression,” Kaminsky says. “With more research, this could prove to be a powerful tool.”

Kaminsky says the next step in research would be to collect blood samples from a larger group of pregnant women and follow them for a longer period of time. He also says it would be useful to examine whether the same epigenetic changes are present in the offspring of women who develop postpartum depression.

Evidence suggests that early identification and treatment of postpartum depression can limit or prevent debilitating effects. Alerting women to the condition’s risk factors — as well as determining whether they have a previous history of the disorder, other mental illness and unusual stress — is key to preventing long-term problems.

Research also shows, Kaminsky says, that postpartum depression not only affects the health and safety of the mother, but also her child’s mental, physical and behavioral health.

Kaminsky says that if his preliminary work pans out, he hopes a blood test for the epigenetic biomarkers could be added to the battery of tests women undergo during pregnancy, and inform decisions about the use of antidepressants during pregnancy. There are concerns, he says, about the effects of these drugs on the fetus and their use must be weighed against the potentially debilitating consequences to both the mother and child of foregoing them.

“If you knew you were likely to develop postpartum depression, your decisions about managing your care could be made more clearly,” he says.

Nutritional supplement delays advancement of Parkinson’s and Familial Dysautonomia, TAU researchers discover

Widely available in pharmacies and health stores, phosphatidylserine is a natural food supplement produced from beef, oysters, and soy. Proven to improve cognition and slow memory loss, it’s a popular treatment for older people experiencing memory impairment. Now a team headed by Prof. Gil Ast and Dr. Ron Bochner of Tel Aviv University’s Department of Human Molecular Genetics has discovered that the same supplement improves the functioning of genes involved in degenerative brain disorders, including Parkinson’s disease and Familial Dysautonomia (FD).

In FD, a rare genetic disorder that impacts the nervous system and appears almost exclusively in the Ashkenazi Jewish population, a genetic mutation prevents the brain from manufacturing healthy IKAP proteins — which likely have a hand in cell migration and aiding connections between nerves — leading to the early degeneration of neurons. When the supplement was applied to cells taken from FD patients, the gene function improved and an elevation in the level of IKAP protein was observed, reports Prof. Ast. These results were replicated in a second experiment which involved administering the supplement orally to mouse populations with FD.

The findings, which have been published in the journal Human Molecular Genetics, are very encouraging, says Prof. Ast. “That we see such an effect on the brain — the most important organ in relation to this disease — shows that the supplement can pass through the blood-brain barrier even when administered orally, and accumulate in sufficient amounts in the brain.”

Slowing the death of nerve cells

Already approved for use as a supplement by the FDA, phosphatidylserine contains a molecule essential for transmitting signals between nerve cells in the brain. Prof. Ast and his fellow researchers decided to test whether the same chemical, which is naturally synthesized in the body and known to boost memory capability, could impact the genetic mutation which leads to FD.

Researchers applied a supplement derived from oysters, provided by the Israeli company Enzymotec, to cells collected from FD patients. Noticing a robust effect on the gene, including a jump in the production of healthy IKAP proteins, they then tested the same supplement on mouse models of FD, engineered with the same genetic mutation that causes the disease in humans.

The mice received the supplement orally, every two days for a period of three months. Researchers then conducted extensive genetic testing to assess the results of the treatment. “We found a significant increase of the protein in all the tissues of the body,” reports Prof. Ast, including an eight-fold increase in the liver and 1.5-fold increase in the brain. “While the food supplement does not manufacture new nerve cells, it probably delays the death of existing ones,” he adds.

Therapeutic potential for Parkinson’s

That the supplement is able to improve conditions in the brain, even when given orally, is a significant finding, notes Prof. Ast. Most medications enter the body through the blood stream, but are incapable of breaking through the barrier between the blood and the brain.

In addition, the researchers say the supplement’s positive effects extend beyond the production of IKAP. Not only did phosphatidylserine impact the gene associated with FD, but it also altered the level of a total of 2400 other genes — hundreds of which have been connected to Parkinson’s disease in previous studies.

The researchers believe that the supplement may have a beneficial impact on a number of degenerative diseases of the brain, concludes Prof. Ast, including a major potential for the development of new medications which would help tens of millions of people worldwide suffering from these devastating diseases.

Salamanders’ immune systems are key to their remarkable ability to regrow limbs, and could also underpin their ability to regenerate spinal cords, brain tissue and even parts of their hearts, scientists have found.

In research published today in the Proceedings of the National Academy of Sciences researchers from the Australian Regenerative Medicine Institute (ARMI) at Monash University found that when immune cells known as macrophages were systemically removed, salamanders lost their ability to regenerate a limb and instead formed scar tissue.

Lead researcher, Dr James Godwin, a Fellow in the laboratory of ARMI Director Professor Nadia Rosenthal, said the findings brought researchers a step closer to understanding what conditions were needed for regeneration. 

"Previously, we thought that macrophages were negative for regeneration, and this research shows that that’s not the case - if the macrophages are not present in the early phases of healing, regeneration does not occur," Dr Godwin said. 

"Now, we need to find out exactly how these macrophages are contributing to regeneration. Down the road, this could lead to therapies that tweak the human immune system down a more regenerative pathway."

Salamanders deal with injury in a remarkable way. The end result is the complete functional restoration of any tissue, on any part of the body including organs. The regenerated tissue is scar free and almost perfectly replicates the injury site before damage occurred.

"We can look to salamanders as a template of what perfect regeneration looks like," Dr Godwin said. 

Aside from “holy grail” applications, such as healing spinal cord and brain injuries, Dr Godwin believes that studying the healing processes of salamanders could lead to new treatments for a number of common conditions, such as heart and liver diseases, which are linked to fibrosis or scarring. Promotion of scar-free healing would also dramatically improve patients’ recovery following surgery.

There are indications that there is the capacity for regeneration in a range of animal species, but it has, in most cases been turned off by evolution. 

"Some of these regenerative pathways may still be open to us. We may be able to turn up the volume on some of these processes," Dr Godwin said. 

"We need to know exactly what salamanders do and how they do it well, so we can reverse-engineer that into human therapies."