New technique can rapidly turn genes on and off, helping scientists better understand their function.

Although human cells have an estimated 20,000 genes, only a fraction of those are turned on at any given time, depending on the cell’s needs — which can change by the minute or hour. To find out what those genes are doing, researchers need tools that can manipulate their status on similarly short timescales.

That is now possible, thanks to a new technology developed at MIT and the Broad Institute that can rapidly start or halt the expression of any gene of interest simply by shining light on the cells.

The work is based on a technique known as optogenetics, which uses proteins that change their function in response to light. In this case, the researchers adapted the light-sensitive proteins to either stimulate or suppress the expression of a specific target gene almost immediately after the light comes on.

“Cells have very dynamic gene expression happening on a fairly short timescale, but so far the methods that are used to perturb gene expression don’t even get close to those dynamics. To understand the functional impact of those gene-expression changes better, we have to be able to match the naturally occurring dynamics as closely as possible,” says Silvana Konermann, an MIT graduate student in brain and cognitive sciences.

The ability to precisely control the timing and duration of gene expression should make it much easier to figure out the roles of particular genes, especially those involved in learning and memory. The new system can also be used to study epigenetic modifications — chemical alterations of the proteins that surround DNA — which are also believed to play an important role in learning and memory.

Konermann and Mark Brigham, a graduate student at Harvard University, are the lead authors of a paper describing the technique in the July 22 online edition of Nature. The paper’s senior author is Feng Zhang, the W.M. Keck Assistant Professor in Biomedical Engineering at MIT and a core member of the Broad Institute and MIT’s McGovern Institute for Brain Research.

Shining light on genes

The new system consists of several components that interact with each other to control the copying of DNA into messenger RNA (mRNA), which carries genetic instructions to the rest of the cell. The first is a DNA-binding protein known as a transcription activator-like effector (TALE). TALEs are modular proteins that can be strung together in a customized way to bind any DNA sequence.

Fused to the TALE protein is a light-sensitive protein called CRY2 that is naturally found in Arabidopsis thaliana, a small flowering plant. When light hits CRY2, it changes shape and binds to its natural partner protein, known as CIB1. To take advantage of this, the researchers engineered a form of CIB1 that is fused to another protein that can either activate or suppress gene copying.

After the genes for these components are delivered to a cell, the TALE protein finds its target DNA and wraps around it. When light shines on the cells, the CRY2 protein binds to CIB1, which is floating in the cell. CIB1 brings along a gene activator, which initiates transcription, or the copying of DNA into mRNA. Alternatively, CIB1 could carry a repressor, which shuts off the process.

A single pulse of light is enough to stimulate the protein binding and initiate DNA copying. The researchers found that pulses of light delivered every minute or so are the most effective way to achieve continuous transcription for the desired period of time. Within 30 minutes of light delivery, the researchers detected an uptick in the amount of mRNA being produced from the target gene. Once the pulses stop, the mRNA starts to degrade within about 30 minutes.

In this study, the researchers tried targeting nearly 30 different genes, both in neurons grown in the lab and in living animals. Depending on the gene targeted and how much it is normally expressed, the researchers were able to boost transcription by a factor of two to 200.

Karl Deisseroth, a professor of bioengineering at Stanford University and one of the inventors of optogenetics, says the most important innovation of the technique is that it allows control of genes that naturally occur in the cell, as opposed to engineered genes delivered by scientists.

“You could control, at precise times, a particular genetic locus and see how everything responds to that, with high temporal precision,” says Deisseroth, who was not part of the research team.

Epigenetic modifications

Another important element of gene-expression control is epigenetic modification. One major class of epigenetic effectors is chemical modification of the proteins, known as histones, that anchor chromosomal DNA and control access to the underlying genes. The researchers showed that they can also alter these epigenetic modifications by fusing TALE proteins with histone modifiers.

Epigenetic modifications are thought to play a key role in learning and forming memories, but this has not been very well explored because there are no good ways to disrupt the modifications, short of blocking histone modification of the entire genome. The new technique offers a much more precise way to interfere with modifications of individual genes.

“We want to allow people to prove the causal role of specific epigenetic modifications in the genome,” Zhang says.

So far, the researchers have demonstrated that some of the histone effector domains can be tethered to light-sensitive proteins; they are now trying to expand the types of histone modifiers they can incorporate into the system.

“It would be really useful to expand the number of epigenetic marks that we can control. At the moment we have a successful set of histone modifications, but there are a good deal more of them that we and others are going to want to be able to use this technology for,” Brigham says.

(Source: web.mit.edu)

Novel microchips imitate the brain’s information processing in real time. Neuroinformatics researchers from the University of Zurich and ETH Zurich together with colleagues from the EU and US demonstrate how complex cognitive abilities can be incorporated into electronic systems made with so-called neuromorphic chips: They show how to assemble and configure these electronic systems to function in a way similar to an actual brain.

No computer works as efficiently as the human brain – so much so that building an artificial brain is the goal of many scientists. Neuroinformatics researchers from the University of Zurich and ETH Zurich have now made a breakthrough in this direction by understanding how to configure so-called neuromorphic chips to imitate the brain’s information processing abilities in real-time. They demonstrated this by building an artificial sensory processing system that exhibits cognitive abilities.

New approach: simulating biological neurons

Most approaches in neuroinformatics are limited to the development of neural network models on conventional computers or aim to simulate complex nerve networks on supercomputers. Few pursue the Zurich researchers’ approach to develop electronic circuits that are comparable to a real brain in terms of size, speed, and energy consumption. “Our goal is to emulate the properties of biological neurons and synapses directly on microchips,” explains Giacomo Indiveri, a professor at the Institute of Neuroinformatics (INI), of the University of Zurich and ETH Zurich.

The major challenge was to configure networks made of artificial, i.e. neuromorphic, neurons in such a way that they can perform particular tasks, which the researchers have now succeeded in doing: They developed a neuromorphic system that can carry out complex sensorimotor tasks in real time. They demonstrate a task that requires a short-term memory and context-dependent decision-making – typical traits that are necessary for cognitive tests. In doing so, the INI team combined neuromorphic neurons into networks that implemented neural processing modules equivalent to so-called “finite-state machines” – a mathematical concept to describe logical processes or computer programs. Behavior can be formulated as a “finite-state machine” and thus transferred to the neuromorphic hardware in an automated manner. “The network connectivity patterns closely resemble structures that are also found in mammalian brains,” says Indiveri.

Chips can be configured for any behavior modes

The scientists thus demonstrate for the first time how a real-time hardware neural-processing system where the user dictates the behavior can be constructed. “Thanks to our method, neuromorphic chips can be configured for a large class of behavior modes. Our results are pivotal for the development of new brain-inspired technologies,” Indiveri sums up. One application, for instance, might be to combine the chips with sensory neuromorphic components, such as an artificial cochlea or retina, to create complex cognitive systems that interact with their surroundings in real time.

Literature:

E. Neftci, J. Binas, U. Rutishauser, E. Chicca, G. Indiveri, R. J. Douglas. Synthesizing cognition in neuromorphic electronic systems. PNAS. July 22, 2013.

(Source: mediadesk.uzh.ch)

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)