Posts tagged science

TAU research finds that breastfed children are less likely to develop ADHD later in life

We know that breastfeeding has a positive impact on child development and health — including protection against illness. Now researchers from Tel Aviv University have shown that breastfeeding could also help protect against Attention Deficit/Hyperactivity Disorder (ADHD), the most commonly diagnosed neurobehavioral disorder in children and adolescents.

Seeking to determine if the development of ADHD was associated with lower rates of breastfeeding, Dr. Aviva Mimouni-Bloch, of Tel Aviv University’s Sackler Faculty of Medicine and Head of the Child Neurodevelopmental Center in Loewenstein Hospital, and her fellow researchers completed a retrospective study on the breastfeeding habits of parents of three groups of children: a group that had been diagnosed with ADHD; siblings of those diagnosed with ADHD; and a control group of children without ADHD and lacking any genetic ties to the disorder.

The researchers found a clear link between rates of breastfeeding and the likelihood of developing ADHD, even when typical risk factors were taken into consideration. Children who were bottle-fed at three months of age were found to be three times more likely to have ADHD than those who were breastfed during the same period. These results have been published in Breastfeeding Medicine.

Understanding genetics and environment

In their study, the researchers compared breastfeeding histories of children from six to 12 years of age at Schneider’s Children Medical Center in Israel. The ADHD group was comprised of children that had been diagnosed at the hospital, the second group included the siblings of the ADHD patients, and the control group included children without neurobehavioral issues who had been treated at the clinics for unrelated complaints.

In addition to describing their breastfeeding habits during the first year of their child’s life, parents answered a detailed questionnaire on medical and demographic data that might also have an impact on the development of ADHD, including marital status and education of the parents, problems during pregnancy such as hypertension or diabetes, birth weight of the child, and genetic links to ADHD.

Taking all risk factors into account, researchers found that children with ADHD were far less likely to be breastfed in their first year of life than the children in the other groups. At three months, only 43 percent of children in the ADHD group were breastfed compared to 69 percent of the sibling group and 73 percent of the control group. At six months, 29 percent of the ADHD group was breastfed, compared to 50 percent of the sibling group and 57 percent of the control group.

One of the unique elements of the study was the inclusion of the sibling group, says Dr. Mimouni-Bloch. Although a mother will often make the same breastfeeding choices for all her children, this is not always the case. Some children’s temperaments might be more difficult than their siblings’, making it hard for the mother to breastfeed, she suggests.

Added protection

While researchers do not yet know why breastfeeding has an impact on the future development of ADHD — it could be due to the breast milk itself, or the special bond formed between mother and baby during breastfeeding, for example — they believe this research shows that breastfeeding can have a protective effect against the development of the disorder, and can be counted as an additional biological advantage for breastfeeding.

Dr. Mimouni-Bloch hopes to conduct a further study on breastfeeding and ADHD, examining children who are at high risk for ADHD from birth and following up in six-month intervals until six years of age, to obtain more data on the phenomenon.

(Source: aftau.org)

Finding shows oxytocin strengthens bad memories and can increase fear and anxiety

It turns out the love hormone oxytocin is two-faced. Oxytocin has long been known as the warm, fuzzy hormone that promotes feelings of love, social bonding and well-being. It’s even being tested as an anti-anxiety drug. But new Northwestern Medicine® research shows oxytocin also can cause emotional pain, an entirely new, darker identity for the hormone.

Oxytocin appears to be the reason stressful social situations, perhaps being bullied at school or tormented by a boss, reverberate long past the event and can trigger fear and anxiety in the future.

That’s because the hormone actually strengthens social memory in one specific region of the brain, Northwestern scientists discovered.

If a social experience is negative or stressful, the hormone activates a part of the brain that intensifies the memory. Oxytocin also increases the susceptibility to feeling fearful and anxious during stressful events going forward. 

(Presumably, oxytocin also intensifies positive social memories and, thereby, increases feelings of well being, but that research is ongoing.)

The findings are important because chronic social stress is one of the leading causes of anxiety and depression, while positive social interactions enhance emotional health. The research, which was done in mice, is particularly relevant because oxytocin currently is being tested as an anti-anxiety drug in several clinical trials.

“By understanding the oxytocin system’s dual role in triggering or reducing anxiety, depending on the social context, we can optimize oxytocin treatments that improve well-being instead of triggering negative reactions,” said Jelena Radulovic, the senior author of the study and the Dunbar Professsor of Bipolar Disease at Northwestern University Feinberg School of Medicine. The paper was published July 21 in Nature Neuroscience.

This is the first study to link oxytocin to social stress and its ability to increase anxiety and fear in response to future stress. Northwestern scientists also discovered the brain region responsible for these effects — the lateral septum – and the pathway or route oxytocin uses in this area to amplify fear and anxiety.

The scientists discovered that oxytocin strengthens negative social memory and future anxiety by triggering an important signaling molecule — ERK (extracellular signal regulated kinases) — that becomes activated for six hours after a negative social experience. ERK causes enhanced fear, Radulovic believes, by stimulating the brain’s fear pathways, many of which pass through the lateral septum. The region is involved in emotional and stress responses.

The findings surprised the researchers, who were expecting oxytocin to modulate positive emotions in memory, based on its long association with love and social bonding.

“Oxytocin is usually considered a stress-reducing agent based on decades of research,” said Yomayra Guzman, a doctoral student in Radulovic’s lab and the study’s lead author. “With this novel animal model, we showed how it enhances fear rather than reducing it and where the molecular changes are occurring in our central nervous system.’

The new research follows three recent human studies with oxytocin, all of which are beginning to offer a more complicated view of the hormone’s role in emotions.

All the new experiments were done in the lateral septum. This region has the highest oxytocin levels in the brain and has high levels of oxytocin receptors across all species from mice to humans.

“This is important because the variability of oxytocin receptors in different species is huge,” Radulovic said. “We wanted the research to be relevant for humans, too.”

Experiments with mice in the study established that 1) oxytocin is essential for strengthening the memory of negative social interactions and 2) oxytocin increases fear and anxiety in future stressful situations.

Experiment 1: Oxytocin Strengthens Bad Memories

Three groups of mice were individually placed in cages with aggressive mice and experienced social defeat, a stressful experience for them. One group was missing its oxytocin receptors, essentially the plug by which the hormone accesses brain cells. The lack of receptors means oxytocin couldn’t enter the mice’s brain cells. The second group had an increased number of receptors so their brain cells were flooded with the hormone. The third control group had a normal number of receptors.

Six hours later, the mice were returned to cages with the aggressive mice. The mice that were missing their oxytocin receptors didn’t appear to remember the aggressive mice and show any fear. Conversely, when mice with increased numbers of oxytocin receptors were reintroduced to the aggressive mice, they showed an intense fear reaction and avoided the aggressive mice.

Experiment 2: Oxytocin Increases Fear and Anxiety in Future Stress

Again, the three groups of mice were exposed to the stressful experience of social defeat in the cages of other more aggressive mice. This time, six hours after the social stress, the mice were put in a box in which they received a brief electric shock, which startles them but is not painful. Then 24 hours later, the mice were returned to the same box but did not receive a shock.

The mice missing their oxytocin receptors did not show any enhanced fear when they re-entered the box in which they received the shock. The second group, which had extra oxytocin receptors showed much greater fear in the box. The third control group exhibited an average fear response.

“This experiment shows that after a negative social experience the oxytocin triggers anxiety and fear in a new stressful situation,” Radulovic said.

(Source: northwestern.edu)

For the first time scientists have identified how a pathway in the brain which is unique to humans allows us to learn new words.

The average adult’s vocabulary consists of about 30,000 words. This ability seems unique to humans as even the species closest to us - chimps - manage to learn no more than 100. 

It has long been believed that language learning depends on the integration of hearing and repeating words but the neural mechanisms behind learning new words remained unclear. Previous studies have shown that this may be related to a pathway in the brain only found in humans and that humans can learn only words that they can articulate. 

Now researchers from King’s College London Institute of Psychiatry, in collaboration with Bellvitge Biomedical Research Institute (IDIBELL) and the University of Barcelona, have mapped the neural pathways involved in word learning among humans. They found that the arcuate fasciculus, a collection of nerve fibres connecting auditory regions at the temporal lobe with the motor area located at the frontal lobe in the left hemisphere of the brain, allows the ‘sound’ of a word to be connected to the regions responsible for its articulation. Differences in the development of these auditory-motor connections may explain differences in people’s ability to learn words. 

The results of the study are published in the journal Proceedings of the National Academy of Sciences (PNAS).

Dr Marco Catani, co-author from the NatBrainLab at King’s College London Institute of Psychiatry said: “Often humans take their ability to learn words for granted. This research sheds new light on the unique ability of humans to learn a language, as this pathway is not present in other species. The implications of our findings could be wide ranging – from how language is taught in schools and rehabilitation from injury, to early detection of language disorders such as dyslexia. In addition these findings could have implications for other disorders where language is affected such as autism and schizophrenia.”

The study involved 27 healthy volunteers. Researchers used diffusion tensor imaging to image the structure of the brain before a word learning task and functional MRI, to  detect the regions in the brain that were most active during the task. They found a strong relationship between the ability to remember words and the structure of arcuate fasciculus, which connects two brain areas: the territory of Wernicke, related to auditory language decoding, and Broca’s area, which coordinates the movements associated with speech and the language processing.

In participants able to learn words more successfully their arcuate fasciculus was more myelinated i.e. the nervous tissue facilitated faster conduction of the electrical signal. In addition the activity between the two regions was more co-ordinated in these participants.

Dr Catani concludes, “Now we understand that this is how we learn new words, our concern is that children will have less vocabulary as much of their interaction is via screen, text and email rather than using their external prosthetic memory. This research reinforces the need for us to maintain the oral tradition of talking to our children.”

(Source: kcl.ac.uk)

Multiple sclerosis treatments that repair damage to the brain could be developed thanks to new research.

A study has shed light on how cells are able to regenerate protective sheaths around nerve fibres in the brain.

These sheaths, made up of a substance called myelin, are critical for the quick transmission of nerve signals, enabling vision, sensation and movement, but break down in patients with multiple sclerosis (MS).

In multiple sclerosis patients, the protective layer surrounding nerve fibres is stripped away and the nerves are exposed and damaged.

-Dr Veronique Miron(MRC for Regenerative Medicine at the University of Edinburgh)

Macrophages

The study, by the Universities of Edinburgh and Cambridge, found that immune cells, known as macrophages, help trigger the regeneration of myelin.

Researchers found that following loss of or damage to myelin, macrophages can release a compound called activin-A, which activates production of more myelin.

Approved therapies for multiple sclerosis work by reducing the initial myelin injury – they do not promote myelin regeneration. This study could help find new drug targets to enhance myelin regeneration and help to restore lost function in patients with multiple sclerosis.

-Dr Veronique Miron (Medical Council Centre for Regenerative Medicine at the University of Edinburgh)

Study

The study, which looked at myelin regeneration in human tissue samples and in mice, is published in Nature Neuroscience.

It was funded by the MS Society, the Wellcome Trust and the Multiple Sclerosis Society of Canada.

Scientists now plan to start further research to look at how activin-A works and whether its effects can be enhanced.

We urgently need therapies that can help slow the progression of MS and so we’re delighted researchers have identified a new, potential way to repair damage to myelin. We look forward to seeing this research develop further.

-Dr Susan Kohlhaas (Head of Biomedical Research at the MS Society)

We are pleased to fund MS research that may lead to treatment benefits for people living with MS. We look forward to advances in treatments that address repair specifically, so that people with MS may be able to manage the unpredictable symptoms of the disease.

-Dr Karen Lee (Vice-President, Research at the MS Society of Canada

(Source: ed.ac.uk)

Recycling is not only good for the environment, it’s good for the brain. A study using rat cells indicates that quickly clearing out defective proteins in the brain may prevent loss of brain cells.

Results of a study in Nature Chemical Biology suggest that the speed at which damaged proteins are cleared from neurons may affect cell survival and may explain why some cells are targeted for death in neurodegenerative disorders. The research was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

One of the mysteries surrounding neurodegenerative diseases is why some nerve cells are marked for destruction whereas their neighbors are spared. It is especially puzzling because the protein thought to be responsible for cell death is found throughout the brain in many of these diseases, yet only certain brain areas or cell types are affected.

In Huntington’s disease and many other neurodegenerative disorders, proteins that are misfolded (have abnormal shapes), accumulate inside and around neurons and are thought to damage and kill nearby brain cells. Normally, cells sense the presence of malformed proteins and clear them away before they do any damage. This is regulated by a process called proteostasis, which the cell uses to control protein levels and quality.

In the study, Andrey S. Tsvetkov and his colleagues from the University of California, San Francisco (UCSF) and Duke University, Durham, N.C., showed that differences in the rate of proteostasis may be the clue to understanding why certain nerve cells die in Huntington’s, a genetic brain disorder that leads to uncontrolled movements and death.

To measure how quickly proteins are cleared away from cells, the researchers developed a new technique called optical pulse-labeling, allowing them to follow specific proteins in individual living cells. To test the technique, they grew brain cells in a dish and turned on Dendra2, a photoswitchable protein that glows from green to red after being hit by a specific type of light. Both the red and green glow can be followed until the protein is cleared from the cell. In this way, the researchers could track the lifetime of newly produced Dendra2 (which glows green) and older, photoswitched Dendra2 (which glows red) until the protein was cleared away from the cell.

"Before this new technique, there was no way to look at individual neurons and their capacity to handle proteins. This method provides a real-time readout of how fast proteins are turned over in neurons and gives us a look at some of the mechanisms involved," said Margaret Sutherland, Ph.D., program director at NINDS.

The researchers followed Dendra2 in a set of striatal neurons, which they obtained from rats. The striatum (where striatal neurons are located) is a brain region involved in a number of brain functions including planning movements and is most heavily affected in Huntington’s disease. They discovered that the mean lifetime of the protein (how long it remained in the cell) varied three- to fourfold, suggesting that rates of proteostasis were different among individual neurons. In other words, some cells may process an identical protein much slower than others.

Then, the researchers investigated how cells deal with different forms of huntingtin, the protein involved in Huntington’s. They fused Dendra2 on the end of a normal or mutant version of huntingtin to track how long the protein remained in cells. The mutant version of huntingtin is longer, and contains three building blocks of the protein repeated an abnormal number of times. These repeats in huntingtin are what cause it to misfold, eventually leading to neuron death and the symptoms of the disease. As predicted, in their experiments, the mutant form of huntingtin caused more rat cells to die than did the normal form of the protein.

The researchers found that the amount of time the mutant protein remained in the cell predicted neuronal survival: shorter mean lifetimes of mutant huntingtin were associated with longer neuronal survival. A shorter mean lifetime indicates that a protein does not remain in the cell for a long time, and that proteostasis is working effectively to clear it away. This suggests that improving proteostasis in Huntington’s brains may improve neuronal survival.

To test this idea, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer.

"Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington’s model and it accelerates the clearance of mutant huntingtin," said Dr. Steven Finkbeiner, senior author of the paper.

Although both striatal and cortical neurons are affected by mutant huntingtin, striatal neurons are more susceptible to cell death. The investigators found that striatal neurons were not as effective as cortical neurons in recognizing and clearing away the mutant protein.

"One surprising finding from these experiments was the significance of single cells’ ability to clear mutant huntingtin. It turned out that this ability largely predicted their susceptibility, whether that neuron came from the most vulnerable region of the brain – the striatum, or the cortex, which is less vulnerable," said Dr. Finkbeiner. The findings indicate that the toxicity of the damaged proteins may cause neurodegeneration by interfering with the proteostasis system, affecting how quickly they are cleared from neurons.

"The results should remind us that focusing on the disease-causing proteins is only one side of the coin. To understand why some cells die and others are spared, we may need to recognize that there are major, largely unrecognized cell-specific differences in the ways that various types of neurons recognize and dispose of disease-causing proteins," continued Dr. Finkbeiner.

The researchers explored potential mechanisms behind differences in proteostasis. One way that cells normally get rid of proteins is through autophagy — a process in which proteins are packed up into spheres and then broken down. Results in this paper suggested that neurons increased the rate of autophagy when they sensed that the mutant form of huntingtin was accumulating, indicating the autophagy system may be a drug target.

"These findings provide evidence that our brains have powerful coping mechanisms to deal with disease-causing proteins. The fact that some of these diseases don’t cause symptoms we can detect until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms are pretty good," said Dr. Finkbeiner.

Future research is needed to determine why coping mechanisms fail as brain cells age and how neurons in the healthy brain keep the proteostasis system functioning.

"New research methods that help us understand how individual neurons function will increase our understanding of central nervous system disorders and help identify new treatments. It is critical to continue working on the methods such as those described in this paper," said Dr. Sutherland.

(Source: eurekalert.org)

The development of new drugs for improving treatment of Alzheimer’s and Parkinson’s disease is a step closer after recent research into how stem cells migrate and form circuits in the brain.

The results from a study by researchers at The University of Auckland’s Centre for Brain Research may hold important clues into why there is less plasticity in brains affected by Parkinson’s and Alzheimer’s disease, and links to insulin resistance and diabetes.

The major five-year project to understand how stem cells start and stop migrating in the brain has also helped to unlock the secrets of how stem cells migrate during development and in adulthood.

The study revealed new information on how connectivity between brain cells is improved or worsened, says senior study author, Dr Maurice Curtis who conceived and directed the research. The experiments were carried out at the Centre for Brain Research laboratories by Dr Hector Monzo. Collaborators included a director of the CBR, Distinguished Professor Richard Faull, Dr Thomas Park, Dr Birger Dieriks, Deidre Jansson and Professor Mike Dragunow.

“We have begun testing new novel drug compounds that target how polysialic acid is removed from the cell in the hope of improving neuron connectivity,” says Dr Curtis.

He explains that stem cells in the brain are immature brain cells that must migrate from their birthplace to a position in the brain where they will connect with other brain cells, turn into adult brain cells (neurons) and become part of the brain’s circuitry.

“Even once the neuron has found its location, the neuron’s tentacles (or dendrites) need to forage to find other neurons to connect with to form circuits. This would be easy except that in the adult brain the cells are surrounded by a fairly rigid matrix (extracellular matrix) and so migration or foraging becomes almost impossible in this high friction environment.”

“The way the cell overcomes this ‘friction’ is by placing large amounts of a special slippery molecule called ‘polysialic acid-neural cell adhesion molecule’ onto the cell surface,” says Dr Curtis. “This allows the cell to migrate or forage with only a fraction of the friction it once had and this also reduces the energy requirements of the cell.”

Once the cell has migrated to its destination, the slippery coating is removed and the cell becomes locked in place ready to connect with other cells. In the case of the dendritic foraging, the polysialic acid must be removed in order for the dendrite to connect with another cell (synapse formation).

“We have known for at least 20 years that this process occurs but despite extensive studies by a number of groups internationally we have been in the dark about what controls this process,” he says. “Studies in my laboratory have demonstrated what happens to the slippery molecules once the cell no longer needs them.”

There were three possibilities for this process:

• that enzymes cut them off the outside of the cell
• that the friction wears it off the cell or
• the cell internalises the slippery substance and recycles it ready for future use.

“For the past five years, we have systematically studied how this process is controlled,” says Dr Curtis. “Our findings have demonstrated that cells internalise the slippery molecule after receiving two specific cues.”

One of these cues is from collagen which makes up part of the rigid structure outside of the cell and the other is from a gaseous molecule called nitric oxide which triggers the outer membrane of the cell to internalise the slippery molecules.

“What we also discovered is that when there is an increased amount of insulin and insulin-like growth factor 1 (which has some similar functions to insulin) present in the culture, the cell cannot internalise the slippery molecules and instead they remain on the cell surface.”

“The key to the breakthrough was in determining that the process by which the polysialic acid is added to the cell surface was so persistent that it needed to be stopped in order to study how the polysialic acid was removed,” says Dr Curtis. “This required extensive trialling of many different cell growth conditions, enzyme concentrations and growing the cells in many different extracellular matrices.”

This is interesting because it is well known that in Parkinson’s disease and Alzheimer’s disease the brain is less sensitive to insulin, he says.

“In our studies in cells the insulin blocks the removal of polysialic acid and therefore the cell cannot connect properly and form synapses with other nearby cells.”

“This may hold major clues to why there is less plasticity in brains affected by Parkinson’s and Alzheimer’s disease in adults as well as helping to unlock the secrets of how stem cells migrate during development of the brain”, says Dr Curtis.

The Gus Fisher Postdoctoral Fellowship, the Auckland Medical Research Foundation and the Manchester Trust were the main sponsors of this research work.

The study results were published online this month in an ‘ahead of print’ version of The Journal of Neurochemistry.

(Source: auckland.ac.nz)

Borrowing a trick from nature, researchers have switched off the extra chromosome that causes Down syndrome in cells taken from patients with the condition.

Though not a cure, the technique, reported July 17 in Nature, has already produced insights into the disorder. In the long run it might even make the flaw that causes Down syndrome correctable through gene therapy.

“Gene therapy is now on the horizon,” says Elizabeth Fisher, a molecular geneticist at University College London. “But that horizon is very far away.”

Down syndrome, also called trisomy 21, occurs when people inherit three copies of chromosome 21 instead of the usual two. It is the most common chromosomal condition, affecting around one in every 700 babies born in the United States. People with the disorder typically have both physical and cognitive complications of having an extra chromosome.

“Down syndrome has been one of those disorders where people say, ‘Oh, there’s nothing you can do about it,’ ” says Jeanne Lawrence, a chromosome biologist and genetic counselor at the University of Massachusetts Medical School in Worcester, who led the study with colleagues Lisa Hall and Jun Jiang.

The researchers decided to see whether they could shut down the extra chromosome by drawing on a biological process called X inactivation. Women have two X chromosomes and men have only one X and a Y. To halve the amount of X chromosome products, female cells shut down one copy. Cells do that using a chunk of RNA called XIST, which is made by one X chromosome but not the other. The RNA works by pulling in proteins that essentially board up the chromosome like an abandoned building. The other X stays on by making a different RNA.

Lawrence and Hall thought that if they put XIST on another chromosome, it might shut that one down too. So Jiang put the gene for XIST onto one of the three copies of chromosome 21 carried by stem cells grown from a man with Down syndrome. That copy of the chromosome got switched off.

“It’s kind of surprising that it wasn’t done before. I’m smacking my own forehead and saying, ‘duh,’ ” says Roger Reeves, a geneticist at Johns Hopkins University.

One idea about why an extra chromosome 21 causes cognitive problems is that it may slow down the growth of brain cells. Jiang grew nerve cells from the Down patient’s stem cells to see how cells with one shut-down chromosome developed compared with cells bearing three active copies. The cells with only two working chromosomes grew faster, forming clusters of neurons in a day or two, while the uncorrected cells needed four or five days.

The work is an enormous step forward in Down syndrome research, Fisher says, and “may take us much closer to understanding the molecular basis of the disorder.” The technique could allow researchers to figure out which genes are involved in Down syndrome and how extra copies affect cells and ultimately the body, she says.

Reeves wants to use the technology in animal experiments, a critical step in determining whether it could find use as gene therapy for people with Down syndrome. He plans to work with Lawrence’s group to switch off the extra chromosome in mice engineered to have a disorder that simulates some features of Down syndrome.

But Reeves doubts that scientists could use the method to switch off the extra chromosome in every cell in the body. Doing so would probably require gene therapy at a very early stage of pregnancy, something scientists don’t know how to do. “I just don’t see how we would get there from where we are today,” Reeves says.

Such universal silencing of the extra chromosome may be necessary to forestall developmental problems. But other problems associated with Down syndrome might be prevented or reversed by shutting down the extra chromosome after birth. For instance, people with Down syndrome are at high risk of developing childhood leukemia and of getting Alzheimer’s disease. Gene therapy to turn off the extra chromosome in the bone marrow or the brain might prevent those problems.

Therapeutic possibilities are still far in the future and may never pan out, says William Mobley, a neurologist and neuroscientist at the University of California, San Diego. “We have to move cautiously and deliberately and not say that a cure for Down syndrome is on the horizon,” he says. “It’s not true, but gosh is there excitement that progress is being made.”

(Source: sciencenews.org)