Neuroscience

Testosterone may trigger a brain chemical process linked to schizophrenia but the same sex hormone can also improve cognitive thinking skills in men with the disorder, two new studies show.

Scientists have long suspected testosterone plays an important role in schizophrenia, which affects more men than women. Men are also more likely to develop psychosis in adolescence, previous research has shown.

A new study on lab rodents by researchers from Neuroscience Research Australia analysed the impact increased testosterone had on levels of dopamine, a brain chemical linked to psychotic symptoms of schizophrenia.

The researchers found that testosterone boosted dopamine sensitivity in adolescent male rodents.

“From these rodent studies, we hypothesise that adolescent increases in circulating testosterone may be a driver of increased dopamine activity in the brains of individuals susceptible to psychosis and schizophrenia,” said senior Neuroscience Research Australia researcher and author of the study, Dr Tertia Purves-Tyson, who is presenting her work at the International Congress on Schizophrenia Research in Florida this week.

Dr Philip Mitchell, Scientia Professor and Head of the School of Psychiatry at the University of NSW, said the research was very interesting.

“The relationship between sex steroids, such as testosterone, and psychiatric disorders has long intrigued researchers. For example, we have known for many years that schizophrenia presents earlier in males than females, but the biological mechanism for this has been poorly understood,” said Dr Mitchell, who was not involved in the study.

“The rodent study by Professor Shannon Weickert from the School of Psychiatry at UNSW and NeuRA is therefore of particular interest. This study suggests an important interplay between circulating testosterone levels and the brain’s sensitivity to dopamine – a neurochemical which has been long implicated in the cause of schizophrenia,” said Dr Mitchell.

“This study suggests that it is the interplay between testosterone and dopamine which is critical. This is an important observation which may very well throw an important light on solving the puzzle of the biological causes of schizophrenia.”

Cognitive thinking

A separate study by Dr Thomas Weickert at Neuroscience Research Australia examined the role testosterone plays in the cognitive thinking skills of men with schizophrenia.

The researchers examined testosterone levels in a group of 29 chronically ill men with schizophrenia or schizoaffective disorder, and a control group of 20 healthy men and asked both groups to take a series of cognition tests.

“Circulating testosterone levels significantly predicted performance on verbal memory, processing speed, and working memory in men with schizophrenia … such that increased normal levels of testosterone were beneficial to thought processing in men with schizophrenia but circulating sex steroid levels did not appear to be related to cognitive function in healthy men,” the researchers reported.

“The results suggest that circulating sex steroids may influence thought processes in men with schizophrenia.”

Dr Melanie McDowall, a researcher at the University of Adelaide’s Robinson Institute, said the study added to a large body of evidence demonstrating a link between testosterone and schizophrenia.

“This is not surprising, given the link between testosterone and dopamine,” she said, adding that symptoms of schizophrenia predominantly began after puberty.

“However, as with most endocrine and mental illnesses, schizophrenia is multifaceted (genetic, environmental etc.), hence this may not be the be all and end.”

Neuroscientists at UB’s Hunter James Kelly Research Institute show how turning down synthesis of a protein improves nerve, muscle function in common neuropathy.

A potential new treatment strategy for patients with Charcot-Marie-Tooth disease is on the horizon, thanks to research by neuroscientists now at the University at Buffalo’s Hunter James Kelly Research Institute and their colleagues in Italy and England.

The institute is the research arm of the Hunter’s Hope Foundation, established in 1997 by Jim Kelly, Buffalo Bills Hall of Fame quarterback, and his wife, Jill, after their infant son Hunter was diagnosed with Krabbe Leukodystrophy, an inherited fatal disorder of the nervous system. Hunter died in 2005 at the age of eight. The institute conducts research on myelin and its related diseases with the goal of developing new ways of understanding and treating conditions such as Krabbe disease and other leukodystrophies.

Charcot-Marie-Tooth or CMT disease, which affects the peripheral nerves, is among the most common of hereditary neurological disorders; it is a disease of myelin and it results from misfolded proteins in cells that produce myelin.

The new findings were published online earlier this month in The Journal of Experimental Medicine.

They may have relevance for other diseases that result from misfolded proteins, including Alzheimer’s disease, Parkinson’s, multiple sclerosis, Type 1 diabetes, cancer and mad cow disease.

The paper shows that missteps in translational homeostasis, the process of regulating new protein production so that cells maintain a precise balance between lipids and proteins, may be how some genetic mutations in CMT cause neuropathy.

CMT neuropathies are common, hereditary and progressive; in severe cases, patients end up in wheelchairs. These diseases significantly affect quality of life but not longevity, taking a major toll on patients, families and society, the researchers note.

“It’s possible that our finding could lead to the development of an effective treatment not just for CMT neuropathies but also for other diseases related to misfolded proteins,” says Lawrence Wrabetz, MD, director of the institute and professor of neurology and biochemistry in UB’s School of Medicine and Biomedical Sciences and senior author on the paper. Maurizio D’Antonio, of the Division of Genetics and Cell Biology of the San Raffaele Scientific Institute in Milan is first author; Wrabetz did most of this research while he was at San Raffaele, prior to coming to UB.

The research finding centers around the synthesis of misfolded proteins in Schwann cells, which make myelin in nerves. Myelin is the crucial fatty material that wraps the axons of neurons and allows them to signal effectively. Many CMT neuropathies are associated with mutations in a gene known as P0, which glues the wraps of myelin together. Wrabetz has previously shown in experiments with transgenic mice that those mutations cause the myelin to break down, which in turn, causes degeneration of peripheral nerves and wasting of muscles.

When cells recognize that the misfolded proteins are being synthesized, cells respond by severely reducing protein production in an effort to correct the problem, Wrabetz explains. The cells commence protein synthesis again when a protein called Gadd34 gets involved.

“After cells have reacted to, and corrected, misfolding of proteins, the job of Gadd34 is to turn protein synthesis back on,” says Wrabetz. “What we have shown is that once Gadd34 is turned back on, it activates synthesis of proteins at a level that’s too high—that’s what causes more problems in myelination.

“We have provided proof of principle that Gadd34 causes a problem with translational homeostasis and that’s what causes some neuropathies,” says Wrabetz. “We’ve shown that if we just reduce Gadd34, we actually get better myelination. So, leaving protein synthesis turned partially off is better than turning it back on, completely.”

In both cultures and a transgenic mouse model of CMT neuropathies, the researchers improved myelin by reducing Gadd34 with salubrinal, a small molecule research drug. While salubrinal is not appropriate for human use, Wrabetz and colleagues at UB and elsewhere are working to develop derivatives that are appropriate.

“If we can demonstrate that a new version of this molecule is safe and effective, then it could be part of a new therapeutic strategy for CMT and possibly other misfolded protein diseases as well,” says Wrabetz.

And while CMT is the focus of this particular research, the work is helping scientists at the Hunter James Kelly Research Institute enrich their understanding of myelin disorders in general.

“What we learn in one disease, such as CMT, may inform how we think about toxins for others, such as Krabbe’s,” Wrabetz says. “We’d like to build a foundation and answer basic questions about where and when toxicity in diseases begin.”

The misfolded protein diseases are an interesting and challenging group of diseases to study, he continues. “CMT, for example, is caused by mutations in more than 40 different genes,” he says. “When there are so many different genes involved and so many different mechanisms, you have to find a unifying mechanism: this problem of Gadd34 turning protein synthesis on at too high a level could be one unifying mechanism. The hope is that this proof of principle applies to more than just CMT and may lead to improved treatments for Alzheimer’s, Parkinson’s, Type 1 diabetes and the other diseases caused by misfolded proteins.”

During fetal development of the mammalian brain, the cerebral cortex undergoes a marked expansion in surface area in some species, which is accommodated by folding of the tissue in species with most expanded neuron numbers and surface area. Researchers have now identified a key regulator of this crucial process.

Different regions of the mammalian brain are devoted to the performance of specific tasks. This in turn imposes particular demands on their development and structural organization. In the vertebrate forebrain, for instance, the cerebral cortex – which is responsible for cognitive functions – is remarkably expanded and extensively folded exclusively in mammalian species. The greater the degree of folding and the more furrows present, the larger is the surface area available for reception and processing of neural information. In humans, the exterior of the developing brain remains smooth until about the sixth month of gestation. Only then do superficial folds begin to appear and ultimately dominate the entire brain in humans. Conversely mice, for example, have a much smaller and smooth cerebral cortex.

“The mechanisms that control the expansion and folding of the brain during fetal development have so far been mysterious,” says Professor Magdalena Götz, a professor at the Institute of Physiology at LMU and Director of the Institute for Stem Cell Research at the Helmholtz Center Munich. Götz and her team have now pinpointed a major player involved in the molecular process that drives cortical expansion in the mouse. They were able to show that a novel nuclear protein called Trnp1 triggers the enormous increase in the numbers of nerve cells which forces the cortex to undergo a complex series of folds. Indeed, although the normal mouse brain has a smooth appearance, dynamic regulation of Trnp1 results in activating all necessary processes for the formation of a much enlarged and folded cerebral cortex.

Levels of Trnp1 control expansion and folding
“Trnp1 is critical for the expansion and folding of the cerebral cortex, and its expression level is dynamically controlled during development,” says Götz. In the early embryo, Trnp1 is locally expressed in high concentrations. This promotes the proliferation of self-renewing multipotent neural stem cells and supports tangential expansion of the cerebral cortex. The subsequent fall in levels of Trnp1 is associated with an increase in the numbers of various intermediate progenitors and basal radial glial cells. This results in the ordered formation and migration of a much enlarged number of neurons forming folds in the growing cortex.

The findings are particularly striking because they imply that the same molecule – Trnp1 – controls both the expansion and the folding of the cerebral cortex and is even sufficient to induce folding in a normally smooth cerebral cortex. Trnp1 therefore serves as an ideal starting point from which to dissect the complex network of cellular and molecular interactions that underpin the whole process. Götz and her colleagues are now embarking on the next step in this exciting journey - determination of the molecular function of this novel nuclear protein Trnp1 and how it is regulated. (Cell 2013)

Despite decades of research, relatively little is known about the identity of RNA molecules that are transported as part of the molecular process underpinning learning and memory.

Now, working together, scientists from the Florida campus of The Scripps Research Institute (TSRI), Columbia University and the University of Florida, Gainesville, have developed a novel strategy for isolating and characterizing a substantial number of RNAs transported from the cell-body of neuron (nerve cell) to the synapse, the small gap separating neurons that enables cell to cell communication.

Using this new method, the scientists were able to identify nearly 6,000 transcripts (RNA sequences) from the genome of Aplysia, a sea slug widely used in scientific investigation.

The scientists’ target is known as the synaptic transcriptome—roughly the complete set of RNA molecules transported from the neuronal cell body to the synapse.

In the study, published recently in the journal Proceedings of the National Academy of Sciences, the scientists focused on the RNA transport complexes that interact with the molecular motor kinesin; kinesin proteins move along filaments known as microtubules in the cell and carry various gene products during the early stage of memory storage.

While neurons use active transport mechanisms such as kinesin to deliver RNA cargos to synapses, once they arrive at their synaptic destination that service stops and is taken over by other, more localized mechanisms—in much the same way that a traveler’s bags gets handed off to the hotel doorman once the taxi has dropped them at the entrance.

The scientists identified thousands of these unique sequences of both coding and noncoding RNAs. As it turned out, several of these RNAs play key roles in the maintenance of synaptic function and growth.

The scientists also uncovered several antisense RNAs (paired duplicates that can inhibit gene expression), although what their function at the synapse might be remains unknown.

“Our analyses suggest that the transported RNAs are surprisingly diverse,” said Sathya Puthanveettil, a TSRI assistant professor who designed the study. “It also brings up an important question of why so many different RNAs are transported to synapses. One reason may be that they are stored there to be used later to help maintain long-term memories.”

The team’s new approach offers the advantage of avoiding the dissection of neuronal processes to identify synaptically localized RNAs by focusing on transport complexes instead, Puthanveettil said. This new approach should help in better understanding changes in localized RNAs and their role in local translation as molecular substrates, not only in memory storage, but also in a variety of other physiological conditions, including development.

“New protein synthesis is a prerequisite for maintaining long term memory,” he said, “but you don’t need this kind of transport forever, so it raises many questions that we want to answer. What molecules need to be synthesized to maintain memory? How long is this collection of RNAs stored? What localized mechanisms come into play for memory maintenance? ”

Melatonin injections delayed symptom onset and reduced mortality in a mouse model of the neurodegenerative condition amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, according to a new study by researchers at the University of Pittsburgh School of Medicine. In a report published online ahead of print in the journal Neurobiology of Disease, the team revealed that receptors for melatonin are found in the nerve cells, a finding that could launch novel therapeutic approaches.

Annually about 5,000 people are diagnosed with ALS, which is characterized by progressive muscle weakness and eventual death due to the failure of respiratory muscles, said senior investigator Robert Friedlander, M.D., UPMC Endowed Professor of neurosurgery and neurobiology and chair, Department of Neurological Surgery, Pitt School of Medicine. But the causes of the condition are not well understood, thwarting development of a cure or even effective treatments.

Melatonin is a naturally occurring hormone that is best known for its role in sleep regulation. After screening more than a thousand FDA-approved drugs several years ago, the research team determined that melatonin is a powerful antioxidant that blocks the release of enzymes that activate apoptosis, or programmed cell death.

"Our experiments show for the first time that a lack of melatonin and melatonin receptor 1, or MT1, is associated with the progression of ALS," Dr. Friedlander said. "We saw similar results in a Huntington’s disease model in an earlier project, suggesting similar biochemical pathways are disrupted in these challenging neurologic diseases."

Hoping to stop neuron death in ALS just as they did in Huntington’s, the research team treated mice bred to have an ALS-like disease with injections of melatonin or with a placebo. Compared to untreated animals, the melatonin group developed symptoms later, survived longer, and had less degeneration of motor neurons in the spinal cord.

"Much more work has to be done to unravel these mechanisms before human trials of melatonin or a drug akin to it can be conducted to determine its usefulness as an ALS treatment," Dr. Friedlander said. "I suspect that a combination of agents that act on these pathways will be needed to make headway with this devastating disease."

Using the fruit fly as a model organism, neurobiologists from the Friedrich Miescher Institute for Biomedical Research have identified the L1-type CAM neuroglian as an important regulator for synapse growth, function and stability. They show that the interaction of neuroglian with ankyrin provides a regulatory module to locally control synaptic connectivity and function.

A Drosophila neuromuscular junction. Motoneuron membrane (blue), synaptic vesicles (green), postsynaptic density (red)

From its earliest beginnings until an organism’s death, the nervous system changes. Connections between nerve cells are formed, stabilized and disassembled not only during the development of the brain in the womb and in early childhood, but also in adults as they learn or form memories. In this flow of change, cell adhesion molecules (CAMs), which mediate cell-cell interactions, are thought to provide stability and guidance in a Velcro-like-manner as synapses change.

Jan Pielage and his group at the Friedrich Miescher Institute for Biomedical Research have carried out an unbiased genetic screen to identify cell adhesion molecules that control synapse maintenance and plasticity, using the fruit fly, Drosophila. As they publish in the latest issue of PLOS Biology, they identified the cell adhesion molecule called neuroglian as a key regulator for synapse stability.

Neuroglian is a transmembrane protein with a large extracellular domain and an intracellular signaling domain. Through the extracellular domain interactions with CAMs on neighboring cells are established. This stabilizes the site and is a prerequisite for synapse formation. “We think that the extracellular interactions of neuroglian are essential for neurite outgrowth and axon targeting during early development,” explains Pielage.

The scientists could then show that the intracellular domain, which interacts with the adaptor molecule called ankyrin, modulates the stability of synapses. At the neuromuscular junction, where nerve cells innervate the muscle, the strength of the interaction of neuroglian with ankyrin modulates the balance between synapse growth and stability. As the binding affinity of ankyrin for neuroglian decreased, e.g. due to phosphorylation, the mobility of neuroglian within the motorneuron increased. This change in mobility caused the destabilization of synapses but at the same time, it allowed the formation of new synapses at other places. “This organization permits easy regulation, and allows the fine tuning of synaptic connectivity along one nerve cell without disrupting the neuronal network or impairing overall circuit stability,” said Pielage.

In the central nervous system, where synapses are formed between two neurons, a homophilic interaction of neuroglian is required to establish the contact between pre- and postsynaptic neurons. A differential regulation of ankyrin binding is then necessary to coordinate transsynaptic development and to enable synapse maturation and function. “Modulation of the neuroglian-ankyrin interaction might enable local and precise control of synaptic connectivity,” comments Pielage.

This comprehensive structure function study provides a molecular basis for previous observations linking mutations in the ankyrin binding domain of the human homologue of neuroglian, L1CAM, to neurological L1/CRASH disorders that include mental retardation.

Scientists funded by the National Institutes of Health have discovered a potential strategy for developing treatments to stem the disease process in Alzheimer’s disease. It’s based on unclogging removal of toxic debris that accumulates in patients’ brains, by blocking activity of a little-known regulator protein called CD33.

“Too much CD33 activity appears to promote late-onset Alzheimer’s by preventing support cells from clearing out toxic plaques, key risk factors for the disease,” explained Rudolph Tanzi, Ph.D., of Massachusetts General Hospital and Harvard University, a grantee of the NIH’s National Institute of Mental Health (NIMH) and National Institute on Aging (NIA). “Future medications that impede CD33 activity in the brain might help prevent or treat the disorder.”

Tanzi and colleagues report on their findings April 25, 2013 in the journal Neuron.

“These results reveal a previously unknown, potentially powerful mechanism for protecting neurons from damaging toxicity and inflammation,” said NIMH Director Thomas R. Insel, M.D. “Given increasing evidence of overlap between brain disorders at the molecular level, understanding such workings in Alzheimer’s disease may also provide insights into other mental disorders.”

Variation in the CD33 gene turned up as one of four prime suspects in the largest genome-wide dragnet of Alzheimer’s-affected families, reported by Tanzi and colleagues in 2008. The gene was known to make a protein that regulates the immune system, but its function in the brain remained elusive. To discover how it might contribute to Alzheimer’s, the researchers brought to bear human genetics, biochemistry and human brain tissue, mouse and cell-based experiments.

They found over-expression of CD33 in support cells, called microglia, in postmortem brains from patients who had late-onset Alzheimer’s disease, the most common form of the illness. The more CD33 protein on the cell surface of microglia, the more beta-amyloid protein and plaques – damaging debris – had accumulated in their brains. Moreover, the researchers discovered that brains of people who inherited a version of the CD33 gene that protected them from Alzheimer’s conspicuously showed reduced amounts of CD33 on the surface of microglia and less beta-amyloid.

Brain levels of beta-amyloid and plaques were also markedly reduced in mice engineered to under-express or lack CD33. Microglia cells in these animals were more efficient at clearing out the debris, which the researchers traced to levels of CD33 on the cell surface.

Evidence also suggested that CD33 works in league with another Alzheimer’s risk gene in microglia to regulate inflammation in the brain.

The study results – and those of a recent rat study that replicated many features of the human illness – add support to the prevailing theory that accumulation of beta-amyloid plaques are hallmarks of Alzheimer’s pathology. They come at a time of ferment in the field, spurred by other recent contradictory evidence suggesting that these presumed culprits might instead play a protective role.

Since increased CD33 activity in microglia impaired beta-amyloid clearance in late onset Alzheimer’s, Tanzi and colleagues are now searching for agents that can cross the blood-brain barrier and block it.

An Autistica consultation published this month found that 24% of children with autism were non-verbal or minimally verbal, and it is known that these problems can persist into adulthood. Professionals have long attempted to support the development of language in these children but with mixed outcomes. An estimated 600,000 people in the UK and 70 million worldwide have autism, a neuro-developmental condition which is life-long.

Today, scientists at the University of Birmingham publish a paper in Frontiers in Neuroscience showing that while not all of the current interventions used are effective, there is real hope for progress by using interventions based on understanding natural language development and the role of motor and “motor mirroring” behaviour in toddlers.

The researchers, led by Dr Joe McCleery, who is supported by autism research charity Autistica, examined over 200 published papers and more than 60 different intervention studies, and found that:

• Motor behaviours, such as banging toys and copying gestures or facial expressions (“mirroring”), play a key role in the learning of language.
• Children with autism show specific motor impairments, and less “mirroring” brain activity, particularly in relation to strangers in whom they show very little interest. This finding may hold the key to language problems overall.
• Despite extensive use of sign language training to improve speech and communication skills in non-verbal children with autism, there is very little evidence that it makes a positive impact, potentially due to the impairments in motor behaviours and mirroring.
• Picture exchange training can lead to improvements in speech. Here, children gradually learn to “ask” for things by exchanging pictures. This may work well because it does not depend on complex motor skills or mirroring.
• Play-based approaches which employ explicit teaching strategies and are developmentally based are particularly successful.
• New studies involving a focus on motor skills alongside speech and language intervention are showing promising preliminary results. This is exciting because these interventions utilise our new understanding of the role of motor behaviours in the development of speech and social interaction.

With the support of Autistica, the UK’s leading autism research charity, Dr McCleery’s team have now embarked on new work which builds on these findings to design interventions which specifically target the aspects of development where there are deficits in non-verbal autistic children.

Dr McCleery says: “We feel that the field is approaching a turning point, with potentially dramatic breakthroughs to come in both our understanding of communication difficulties in people with autism, and the potential ways we can intervene to make a real difference for those children who are having difficulties learning to speak.”

Christine Swabey, CEO of Autistica, says: “80% of the parents in our recent consultation wanted interventions straight after diagnosis. Dr McCleery’s work shows how critical it is for all intervention to be evidence-based, and that the best approaches are based on a real understanding of the development of difficulties in autism. We are proud to be supporting the next steps in this vital research which will improve the quality of life for people with autism.”

Alison Hardy, whose son Alfie is six, says: “As a parent of an autistic child, who is non-verbal, I feel quite vulnerable. People are always saying “try this, it worked wonders for us”. But you can’t try everything. We need a proper, scientific evidence base for what works and what does not. Then we can focus our time and our effort, with some confidence that we have a chance of helping our children. The publication of this research is an exciting step in giving us that confidence, it is great that Autistica is supporting this vital work.”

Scientists at the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw investigate mice with a very precisely modified genome. Because it is possible to turn off the Dicer gene in adult mice, they can be used to investigate the processes related to such cognitive functions such as learning and memory. Also Nencki scientists have just shown that the new transgenic mouse is suitable to study metabolic dysfunctions resulting in obesity.

Studies on the Dicer gene and its impact on the cognitive and metabolic processes are currently carried out at the Nencki Institute’s Laboratory of Animal Models, a core facility in the newly established Neurobiology Center. The Center has been built on Campus Ochota in Warsaw as part of a large European project called the Centre for Preclinical Research and Technology (CePT). This project, financed from the Operational Programme Innovative Economy, brings together 10 research institutions from Warsaw.

“No one needs convincing that knowledge about the function of individual human genes is absolutely fundamental in biology as well as medicine”, says Dr Witold Konopka, head of the Laboratory of Animal Models. “But how do we determine a gene’s function, if no genetic modifications in humans are allowed? The only method is to create an animal, for example a mouse with genes turned on or off to model the studied illness. This is easy to say, but difficult to do, especially when the involved genes are really important for each cell”.

For several years Dr Konopka has been involved in research on the Dicer gene in mice. This gene, the analogue of which can be found also in the human genome, is responsible for creating a protein which reduces RNA molecules to short, 20-nucleotide fragments, important in regulating the activity of other genes. The Dicer gene needs to be active for proper functioning of the cell. It cannot be simply turned off in zygote, because the resulting defect would make the proper development of the zygote impossible.

Preparation of a transgenic mouse, in which the Dicer gene could be blocked in adulthood, takes a year and a half. This process starts with surrounding the Dicer gene on the DNA chain with two sequences known as loxP. This is done on stem cells, which are then injected into the embryo. Since the Dicer gene remains active, the embryo develops normally. At the same time the animal zygote of the opposite sex is injected with a gene coding a protein known as recombinase Cre-ERT2. Molecules of this protein consist of a part containing the Cre enzyme and a fragment reacting to a chemical compound called tamoxifen, which prior to such reaction prohibits recombinase Cre-ERT2 from penetrating into the cell nucleus.

Adult mice of both types are then cross bred for progeny, which will inherit the Dicer gene surrounded with the loxP sequences as well as the gene coding for recombinase from its parents. A mouse of this type has been created thanks to a joint effort of research groups from different world research centres such as the German Cancer Research Center (DKFZ) in Germany or the Imperial College London in the United Kingdom.

In order to turn off the Dicer gene in such adult mouse, it is enough to administer tamoxifen to them for a few days, which accumulates in neurons and allows the recombinase to penetrate into the cell nucleus. The Cre enzyme recognises the loxP sequence and removes the coding fragment with the Dicer gene.

“The first mice, in which the Dicer gene could be switched off at any time, were received by me a few years ago during my postdoctoral fellowship in the German Cancer Research Center in Heidelberg. Currently we breed such mice also the Nencki’s Laboratory of Animal Models. But breeding such animals constitutes only a part of the task. If we want to use them for research, they have to be appropriately characterized”, explains Dr Konopka.

Traits of mice used for scientific research have to be well known. Without such knowledge researchers cannot determine whether a change observed in the appearance or behaviour of the animal is related to turning off the gene. “Two years ago we have characterized the cognitive processes of these new mice. We have determined that after turning off the Dicer gene the animals showed better memory than the controls”, says Dr Konopka. But about five months after deleting the Dicer gene from the brain, the mice scored below the level of the control group on their cognitive abilities, which could be related to dying neurons devoid of the Dicer gene. Currently scientists have just finished analysing changes occurring in metabolic processes of those new mice, which for 3-4 weeks after turning off the Dicer gene eat more and gain weight faster, whereupon their appetite goes back to normal, but higher weight of their bodies’ remains.

“Before we have established with the required accuracy, how our mice learn and remember. Now we are certain, that the same mice can be used to investigate obesity and we plan to do that soon. But in our new lab we will not only conduct studies on disease models. We would also like to generate new transgenic animals for other research centres”, emphasizes Dr Konopka.

BRAIN initiative aims to improve tools for studying neurons to answer questions about human thought and behavior

The images appearing on the computer screen were almost too detailed and fast-moving to take in, Misha B. Ahrens remembers. He and colleague Philipp J. Keller were recording the activity of about 80,000 neurons in a live zebrafish brain, the first time something on this scale had been done. Cross-sectional pictures of the young fish’s head flew by, dotted with splotches of light.

The Howard Hughes Medical Institute (HHMI) neuroscientists were using a zebra­fish larva with a fluorescent protein inserted in its neurons, and the protein was lighting up every time the cells fired. Their custom-built microscope imaged and recorded the resulting lightning storm in the fish’s brain in real time.

Ahrens commemorated the milestone experiment—which took place nearly seven months ago in a lab at the institute’s Janelia Farm Research Campus outside Washington, D.C.—by filming it with his iPhone. “It was mind-blowing to see the entire brain flash past our eyes,” he remembers.

Keller sat in awe at the computer, repeatedly pulling up and admiring slices of data the high-speed apparatus was collecting. The translucent zebrafish, immobilized in a glass tube filled with gel and nestled among the microscope’s optics, was completely unaware that its neural processing was causing such a stir.

Up until that point, scientists had been able to record simultaneous activity from only about 2 to 3% of the 100,000 neurons in a young zebrafish’s head, Keller says. He and Ahrens managed to capture 80%—a giant leap for fishkind.

On March 18, the duo reported their brain-imaging feat online at Nature Methods. Just 15 days later, President Barack Obama announced a large-scale neuroscience initiative to study the dynamics of brain circuits (C&EN, April 8, page 9).

Unlike the Human Connectome Project—a federal program that strives to uncover a static map of the brain’s circuits—this new initiative aims to uncover those circuits’ activity and interplay. BRAIN (Brain Research through Advancing Innovative Neurotechnologies), as the project is called, will get $100 million in federal support if Obama’s request is granted (see page 25), and it will get a similar amount from private foundations such as HHMI in 2014.

“It was a coincidence,” Keller says of the timing of the proposal. He and Ahrens weren’t involved in developing BRAIN, but their goal—to record all the activity from all the neurons in a simple organism’s brain at once—falls directly in line with the initiative.

Eighty-thousand neurons is a lot. But it’s nothing compared with the 85 billion nerve cells that humans have in their brains, or even the 75 million that mice have. To make the leap to measuring large swaths of the brain circuits of rodents or even humans, BRAIN researchers will need to develop new methods of measuring neuronal activity. They are already working on molecular tags to more accurately indicate nerve cell firing in real time. And scientists are developing miniaturized probes to monitor brain cells without disturbing the organ itself, as well as faster techniques for analyzing the flood of data generated by such a huge number of neurons.

Some imaging methods that monitor multitudes of neurons, like that of Ahrens and Keller, already exist. As do techniques for probing scads of nerve cells with tiny electrodes. BRAIN will likely build on these technologies, experts say. But it will also shoot to build “dream” technologies such as implantable nanomaterials that transmit the activity of individual neurons from inside the head.

At the moment, however, no one knows the exact scope of BRAIN. The National Institutes of Health has already appointed a team of neuroscientists to draw up a blueprint for what should be a multiyear initiative. Other federal agencies involved—the National Science Foundation and the Defense Advanced Research Projects Agency—have yet to announce their strategies.

“Neuroscience is getting to the point where researchers cannot take the next big step to understand neural circuits armed with traditional technology,” says Rafael Yuste, a neuron-imaging expert at Columbia University.

And taking that step, he argues, is vital to understanding human thought. “We have a suspicion that the brain is an emerging system,” Yuste says. In other words, how the brain produces memories or actions involves the interactions of all its neurons, rather than just one or even 1,000. It’s like watching television, Yuste adds. “You need to see all the pixels, or at least most of them, to figure out what’s playing.”

Along with five other scientists, Yuste made the original pitch for a public-private project to map the brain’s dynamics in a 2012 article in Neuron. The group argued that not only could this approach help reveal how the human mind works, but it might also offer some insight into what happens when the brain malfunctions. Knowing how the brain’s circuits are supposed to function, Yuste says, could help pinpoint what’s going wrong in conditions such as schizophrenia, which likely involve faulty circuitry.

BRAIN proponents also say areas outside of science and medicine could profit from the initiative. If successful, they claim, BRAIN could yield economic benefits similar to the Human Genome Project, a program launched in 1990 to sequence all the base pairs in a person’s DNA. “Every dollar we spent to map the human genome has returned $140 to our economy,” President Obama noted when he announced BRAIN.

As was the case for the Human Genome Project, BRAIN has been criticized by many scientists. In an already-tight fiscal climate, some researchers have voiced worries that paying for the initiative will mean losing their own funds. And others have expressed reservations that the project is going after too many neurons to yield interpretable, useful results.

But no one seems to dispute that better tools to record activity from nerve cells is a worthwhile goal. “There’s definitely room to grow in many of the techniques we use to record brain activity,” says Mark J. Schnitzer, a neuroscientist at Stanford University. So far, he says, progress has been made mainly by individual labs doing their own thing. But to get to the next level more rapidly, a coordinated effort like BRAIN—centers and labs of neuroscientists, chemists, and researchers in other disciplines working together—might be the ticket.

Until recently, the number of neurons being recorded simultaneously in experiments was doubling every seven years, according to a 2011 review in Nature Neuroscience. But the Janelia team blew this trend out of the water with its high-speed camera and microscope, which rapidly illuminates and images slices of the brain.

The Janelia experiment worked primarily because zebrafish larvae are transparent to light and can be easily immobilized without negative consequences to their brain activity. But moving to mice, which have more neurons and a light-impenetrable skull, will require some more serious innovation, Keller adds.

Some researchers have designed implantable prisms and fiber-optic probes to direct light into the depths of the mouse brain. But those optical tricks are still limited to measuring a few hundred neurons at once. Plus, the mouse has to be tethered to the fibers or prevented from moving altogether.

Stanford’s Schnitzer has overcome the mobility issue with a miniaturized microscope that he and his team designed to fit onto a mouse’s head. Standing three-quarters of an inch tall, the lightweight device, which contains its own light source and camera, gets implanted into the rodent’s brain, enabling researchers to track the freely moving animal’s nerve cell activity.

Early this year, Schnitzer’s group used the setup to follow the dynamics of roughly 1,000 neurons in a mouse’s brain for more than a month (Nat. Neurosci., DOI: 10.1038/nn.3329). The team learned that neurons in one part of the mouse’s brain fired in similar patterns whenever the mouse returned to a familiar spot in its enclosure.

Still, such optical techniques are invasive. “The most elegant experiment would be done from the outside, without mechanical disturbance to the brain,” Columbia’s Yuste says. He’d like to see BRAIN help develop new light sources that can penetrate farther into brain tissue than a few millimeters.

Also on Yuste’s neuron-imaging wish list is a better way to indicate cell firing. As in the Janelia experiment and Schnitzer’s microscope study, the imaging of neuronal activity is typically carried out with calcium indicators. These are molecules that move to the insides of neurons or are proteins engineered to reside there, both designed to fluoresce when they bind to calcium ions.

As a nerve cell fires, its ion channels open, allowing calcium ions to trickle inside and trigger the indicators.

However, “calcium imaging is flawed,” Yuste says. “It’s an indirect method of tracking neuronal firing.” The indicators can’t tell scientists whether a nerve cell fired a little or a lot, he argues. And they don’t track the cells’ electrical activity in real time because calcium diffusion and binding are comparatively slow.

So Yuste and others are working to develop dyes or nanomaterials, called voltage indicators, that bind within a neuron’s membrane and optically signal the cell’s electrical status. Progress is slow-going, however, because a cell’s membrane can hold only so many indicators on its surface and the resulting signal is low.

Another way neuroscientists are more directly measuring nerve cells’ electrical activity is with miniaturized electrodes and nanowires. These probes measure, at submillisecond speeds, the electrical current emitted by a neuron when it fires.

“But anytime you plunge anything into the brain, you have to worry about tissue damage,” says Sotiris Masmanidis, a neurobiologist at the University of California, Los Angeles. “The concern is, how much are you perturbing the system you’re studying?”

To minimize tissue disturbance, Masmanidis and others are lithographically fabricating arrays of microelectrodes that can record nerve cells’ electrical signals from 50 to 100 µm away. So far, the UCLA researcher says, electrode arrays are capable of measuring, at most, 100 to 1,000 neurons at a time.

Determining what types of nerve cells an arrayed microelectrode is measuring, however, is not exactly straightforward, given that it blindly measures any neuron in its vicinity, Masmanidis says. To figure it out, scientists have to take extra steps and monitor the cells’ reaction to drugs or other modulators.

But what good is measuring the dynamics of a slew of nerve cells without having any idea why they’re firing? BRAIN supporters think one way of getting an answer to which environmental cues or perceptions trigger certain neuronal activity patterns is a technique called optogenetics.

Hailed by Nature Methods as the “method of the year” in 2010, optogenetics enables scientists to activate particular nerve cells in the brains of animals with light. The researchers first engineer light-activated proteins into a mouse’s neurons and then trigger the macromolecules via fiber-optic arrays implanted in the rodent’s brain.

Once researchers have measured a firing pattern from an animal’s nerve cells, they can later play it back to see what happens, says Edward S. Boyden, an optogenetics pioneer and neurobiologist at Massachusetts Institute of Technology. “Once we ‘dial’ an activity pattern into the brain,” he says, “if we see that it’s enough to drive some behavior, that could be quite powerful for understanding which parts of the brain drive specific functions.”

Researchers have already been optogenetically stimulating clusters of a few hundred cells in mice, investigating the rodents’ decision-making abilities and aggressive tendencies.

But a brain is more than just electrical activity, says Anne M. Andrews, a psychiatry professor at UCLA. It also uses at least 100 types of neurotransmitters that are involved in triggering neuronal activity at cell junctions, or synapses. “If we want to understand how information is encoded in neuronal signaling, we have to study chemical neurotransmission at the level of synapses,” Andrews says.

And what better way to do that than with nanotechnology? asks Paul S. Weiss, a chemist and nanoscience expert, also at UCLA. After all, the junctions between neurons are just 10 nm wide, he adds.

Andrews and Weiss are hoping BRAIN will support the development of nanoscale sensors to measure the chemical activity at synapses. And they’re already in talks with UCLA’s Masmanidis to functionalize channels on his microelectrodes with molecules that could sense neurotransmitters.

No matter what BRAIN ends up encompassing, one thing is clear: Advances in the numbers of neurons monitored will necessitate improvements in data analysis and storage.

Take, for instance, the experiment done at Janelia. That single session of recording from a zebrafish brain generated 1 terabyte of data. “So you can fit two or three experiments on a computer hard drive,” Ahrens says. “It’s not a bottleneck yet, but when we start creating faster microscopes, computational power might become a problem.”

He and Keller also have just scratched the surface when it comes to analyzing the data they obtained from their initial experiments. As they reported in their Nature Methods paper, the pair found a circuit in the fish’s hindbrain functionally coupled to a specific part of its spinal cord. But determining what that means and what the rest of the brain is doing will require more study and help from computational neuroscientists.

“It’s apparent that to really understand what the brain is doing, you need to have as complete information as you can,” Ahrens says. “It’s a good goal to have, to measure as many neurons as possible.” But it’s a challenging one.

A multicenter study led by scientists at the University of Pittsburgh School of Medicine shows that mild traumatic brain injury after blast exposure produces inflammation, oxidative stress and gene activation patterns akin to disorders of memory processing such as Alzheimer’s disease. Their findings were recently reported in the online version of the Journal of Neurotrauma.

Blast-induced traumatic brain injury (TBI) has become an important issue in combat casualty care, said senior investigator Patrick Kochanek, M.D., professor and vice chair of critical care medicine and director of the Safar Center for Resuscitation Research at Pitt. In many cases of mild TBI, MRI scans and other conventional imaging technology do not show overt damage to the brain.

“Our research reveals that despite the lack of a lot of obvious neuronal death, there is a lot of molecular madness going on in the brain after a blast exposure,” Dr. Kochanek said. “Even subtle injuries resulted in significant alterations of brain chemistry.”

The research team developed a rat model to examine whether mild blast exposure in a device called a shock tube caused any changes in the brain even if there was no indication of direct cell death, such as bleeding. Brain tissues of rats exposed to blast and to a sham procedure were tested two and 24 hours after the injury.

Gene activity patterns, which shifted over time, resembled patterns seen in neurodegenerative diseases, particularly Alzheimer’s, Dr. Kochanek noted. Markers of inflammation and oxidative stress, which reflects disruptions of cell signaling, were elevated, but there was no indication of energy failure that would be seen with poor tissue oxygenation.

“It appears that although the neurons don’t die after a mild injury, they do sustain damage,” he said. “It remains to be seen what multiple exposures, meaning repeat concussions, do to the brain over the long term.”

One of the biggest challenges with Alzheimer’s disease (AD) is that by the time physicians can detect behavioral changes, the disease has already begun its irreversibly destructive course. Scientists know toxic brain lesions created by amyloid beta and tau proteins are involved. Yet, emerging therapies targeting these lesions have failed in recent clinical trials. These findings suggest that successful treatments will require diagnosis of disease at its earliest stages.

Now, by using computer-aided drug discovery, an Ohio State University molecular biochemist and molecular imaging chemist are collaborating to create an imaging chemical that attaches predominantly to tau-bearing lesions in living brain. Their hope is that the “designer” tracer will open the door for earlier diagnosis – and better treatments for Alzheimer’s, frontal temporal dementia and traumatic brain injuries like those suffered by professional athletes, all conditions in which tangled tau filaments accumulate in brain tissue.

“We’re creating agents that are specifically engineered to bind the surface of aggregated tau proteins so that we can see where and how much tau is collecting in the brain,” said Jeff Kuret, professor of molecular and cellular biochemistry at The Ohio State University College of Medicine. “We think the “tau signature” can be used to improve diagnosis and staging of disease.”

The study’s co-investigator, Michael Tweedle, a professor of radiology at Ohio State’s College of Medicine, notes that there may be more advantages to being able to image tau.

“Unlike beta amyloid, tau appears in specific brain regions in Alzheimer’s,” said Tweedle. “With a better view of how tau is distinct from amyloid, we’ll be able to create a much more accurate view of disease staging, and do a much better job getting the right therapeutics into the right populations at the right time.”

Tweedle notes that there are no drugs currently available that target tau, but that several are in development. Both investigators emphasized that being able to image tau in a living brain could be critical for identifying individuals that could benefit from tau-tackling drugs as they move into clinical trials.

The search for tau selective neuroimaging agents is proceeding with the help of a pilot grant awarded to the team by Ohio State’s Center for Clinical and Translational Science (CCTS). The award provided them with the funds needed to synthesize candidate radiotracers for testing. The team then received funding from the Alzheimer’s Drug Discovery Foundation to test how the compounds distribute throughout the body. This work also leverages several CCTS-funded core resources. So far, the team has prepared 12 ligands that have promising binding affinity for tau aggregates.

“It’s an iterative process, and each step gives us new information on what we need to be looking for,” said Tweedle. “Now we know what parts of the molecule to alter while trying to retain other good qualities.”

Tauopathies are neurodegenerative diseases associated with the accumulation of tau protein “tangles” in the human brain. Alzheimer’s disease is one of the most common tauopathies, but tau aggregates are also found in certain forms of frontal temporal dementia as well as traumatic brain injuries. Alzheimer’s disease has become one of the most common disorders in the aging population, and is predicted to be a major driver of health care costs in the coming decades.

Magnetic resonance imaging (MRI) measurements of atrophy in an important area of the brain are an accurate predictor of multiple sclerosis (MS), according to a new study published online in the journal Radiology. According to the researchers, these atrophy measurements offer an improvement over current methods for evaluating patients at risk for MS.

MS develops as the body’s immune system attacks and damages myelin, the protective layer of fatty tissue that surrounds nerve cells within the brain and spinal cord. Symptoms include visual disturbances, muscle weakness and trouble with coordination and balance. People with severe cases can lose the ability to speak or walk.

Approximately 85 percent of people with MS suffer an initial, short-term neurological episode known as clinically isolated syndrome (CIS). A definitive MS diagnosis is based on a combination of factors, including medical history, neurological exams, development of a second clinical attack and detection of new and enlarging lesions with contrast-enhanced or T2-weighted MRI.

"For some time we’ve been trying to understand MRI biomarkers that predict MS development from the first onset of the disease," said Robert Zivadinov, M.D., Ph.D., FAAN, from the Buffalo Neuroimaging Analysis Center of the University at Buffalo in Buffalo, N.Y. "In the last couple of years, research has become much more focused on the thalamus."

The thalamus is a structure of gray matter deep within the brain that acts as a kind of relay center for nervous impulses. Recent studies found atrophy of the thalamus in all different MS disease types and detected thalamic volume loss in pediatric MS patients.

"Thalamic atrophy may become a hallmark of how we look at the disease and how we develop drugs to treat it," Dr. Zivadinov said.

For this study, Dr. Zivadinov and colleagues investigated the association between the development of thalamic atrophy and conversion to clinically definite MS.

"One of the most important reasons for the study was to understand which regions of the brain are most predictive of a second clinical attack," he said. "No one has really looked at this over the long term in a clinical trial."

The researchers used contrast-enhanced MRI for initial assessment of 216 CIS patients. They performed follow-up scans at six months, one year and two years. Over two years, 92 of 216 patients, or 42.6 percent, converted to clinically definite MS. Decreases in thalamic volume and increase in lateral ventricle volumes were the only MRI measures independently associated with the development of clinically definite MS.

"First, these results show that atrophy of the thalamus is associated with MS," Dr. Zivadinov said. "Second, they show that thalamic atrophy is a better predictor of clinically definite MS than accumulation of T2-weighted and contrast-enhanced lesions."

The findings suggest that measurement of thalamic atrophy and increase in ventricular size may help identify patients at high risk for conversion to clinically definite MS in future clinical trials involving CIS patients.

"Thalamic atrophy is an ideal MRI biomarker because it’s detectable at very early stage," Dr. Zivadinov said. "It has very good predictive value, and you will see it used more and more in the future."

The research team continues to follow the study group, with plans to publish results from the four-year follow-up next summer. They are also trying to learn more about the physiology of the thalamic involvement in MS.

"The next step is to look at where the lesions develop over two years with respect to the location of the atrophy," Dr. Zivadinov said. "Thalamic atrophy cannot be explained entirely by accumulation of lesions; there must be an independent component that leads to loss of thalamus."

MS affects more than 2 million people worldwide, according to the Multiple Sclerosis International Foundation. There is no cure, but early diagnosis and treatment can slow development of the disease.

Deep brain stimulation (DBS) in a precise region of the brain appears to reduce caloric intake and prompt weight loss in obese animal models, according to a new study led by researchers at the University of Pennsylvania. The study, reported in the Journal of Neuroscience, reinforces the involvement of dopamine deficits in increasing obesity-related behaviors such as binge eating, and demonstrates that DBS can reverse this response via activation of the dopamine type-2 receptor.

"Based on this research, DBS may provide therapeutic relief to binge eating, a behavior commonly seen in obese humans, and frequently unresponsive to other approaches," said senior author Tracy L. Bale, PhD, associate professor of neuroscience in Penn’s School of Veterinary Medicine’s Department of Animal Biology and in the Perelman School of Medicine’s Department of Psychiatry. DBS is currently used to reduce tremors in Parkinson’s disease and is under investigation as a therapy for major depression and obsessive-compulsive disorder.

Nearly 50 percent of obese people binge eat, uncontrollably consuming palatable highly caloric food within a short period of time. In this study, researchers targeted the nucleus accumbens, a small structure in the brain reward center known to be involved in addictive behaviors. Mice receiving the stimulation ate significantly less of the high fat food compared to mice not receiving DBS. Following stimulation, mice did not compensate for the loss of calories by eating more. However, on days when the device was turned off, binge eating resumed.

Researchers also tested the long-term effects of DBS on obese mice that had been given unlimited access to high-fat food. During four days of continuous stimulation, the obese mice consumed fewer calories and, importantly, their body weight dropped. These mice also showed improvement in their glucose sensitivity, suggestive of a reversal of type 2 diabetes.

“These results are our best evidence yet that targeting the nucleus accumbens with DBS may be able to modify specific feeding behaviors linked to body weight changes and obesity,” Bale added.

“Once replicated in human clinical trials, DBS could rapidly become a treatment for people with obesity due to the extensive groundwork already established in other disease areas,” said lead author Casey Halpern, MD, resident in the Department of Neurosurgery of the Perelman School of Medicine at the University of Pennsylvania.

Scientists from King’s College London have identified patterns of epigenetic changes involved in autism spectrum disorder (ASD) by studying genetically identical twins who differ in autism traits.

The study, published in Molecular Psychiatry, is the largest of its kind and may shed light on the biological mechanism by which environmental influences regulate the activity of certain genes and in turn contribute to the development of ASD and related behaviour traits.

ASD affects approximately 1 in 100 people in the UK and involves a spectrum of disorders which manifest themselves differently in different people. People with ASD have varying levels of impairment across three common areas: deficits in social interactions and understanding, repetitive behaviour and interests, and impairments in language and communication development.

Evidence from twin studies shows there is a strong genetic component to ASD and previous studies suggest that genes that direct brain development may be involved in the disorder. In approximately 70% of cases, when one identical twin has ASD, so does the other. However, in 30% of cases, identical twins differ for ASD. Because identical twins share the same genetic code, this suggests non-genetic, or epigenetic, factors may be involved.

Epigenetic changes affect the expression or activity of genes without changing the underlying DNA sequence – they are believed to be one mechanism by which the environment can interact with the genome. Importantly, epigenetic changes are potentially reversible and may therefore provide targets for the development of new therapies.

The researchers studied an epigenetic mechanism called DNA methylation. DNA methylation acts to block the genetic sequences that drive gene expression, silencing gene activity. They examined DNA methylation at over 27,000 sites across the genome using samples taken from 50 identical twin pairs (100 individuals) from the UK Medical Research Council (MRC) funded Twins Early Development Study (TEDS): 34 pairs who differed for ASD or autism related behaviour traits, 5 pairs where both twins have ASD, and 11 healthy twin pairs.

Dr Chloe Wong, first author of the study from King’s College London’s Institute of Psychiatry, says: “We’ve identified distinctive patterns of DNA methylation associated with both autism diagnosis and related behaviour traits, and increasing severity of symptoms. Our findings give us an insight into the biological mechanism mediating the interaction between gene and environment in autism spectrum disorder.”

DNA methylation at some genetic sites was consistently altered for all individuals with ASD, and differences at other sites were specific to certain symptom groups. The number of DNA methylation sites across the genome was also linked to the severity of autism symptoms suggesting a quantitative relationship between the two. Additionally, some of the differences in DNA methylation markers were located in genetic regions that previous research has associated with early brain development and ASD.

Professor Jonathan Mill, lead author of the paper from King’s College London’s Institute of Psychiatry and the University of Exeter, says: “Research into the intersection between genetic and environmental influences is crucial because risky environmental conditions can sometimes be avoided or changed. Epigenetic changes are potentially reversible, so our next step is to embark on larger studies to see whether we can identify key epigenetic changes common to the majority of people with autism to help us develop possible therapeutic interventions.”

Dr Alycia Halladay, Senior Director of Environmental and Clinical Sciences from Autism Speaks who funded the research, says: “This is the first large-scale study to take a whole genome approach to studying epigenetic influences in twins who are genetically identical but have different symptoms. These findings open the door to future discoveries in the role of epigenetics – in addition to genetics – in the development of autism symptoms.”

New IBN Peptides May Help Researchers Combat Alzheimer’s, Diabetes and Cancer

Amyloids, or fibrous aggregates of abnormally folded proteins, are a common feature in degenerative diseases such as Alzheimer’s, diabetes and cancer. Amyloids occur naturally in the body, but despite decades of research, their mechanism of formation remains unknown, hampering drug development efforts. Now, a new class of ultrasmall peptides developed by the Institute of Bioengineering and Nanotechnology (IBN) offers scientists a platform for understanding this phenomenon, providing them with the insights required to design more effective treatments for these diseases.

IBN Executive Director Professor Jackie Y. Ying said, “Our researchers have been focusing on creating biomimetic materials for nanomedicine and cell and tissue engineering applications. The novel ultrasmall peptides developed by IBN are not only highly effective as synthetic cell culture substrates, but also as a model for studying the mystery of amyloid formation. Such fundamental understanding could contribute towards advancing medical treatment of amyloid-related disorders.”

First discovered in 2011 by IBN Team Leader and Principal Research Scientist Dr Charlotte Hauser, the peptides were formed from only 3-7 amino acids, making them the smallest ever reported class of self-assembling aliphatic compounds. Peptides perform a wide range of functions in the body, and are distinguished from proteins based on size. Building on this earlier research, IBN researchers have found a striking similarity between the structure of their synthetic peptides and the protein structure of naturally occurring amyloids in the latest study published in Proceedings of the National Academy of Sciences.

Dr Hauser elaborated, “This is the first proof-of-concept that our peptides self-assemble in the same way as naturally occurring amyloid sequences. Knowing that the process of amyloid formation is common across various chronic degenerative diseases, our goal is to identify the specific trigger so that we can design the appropriate drugs to inhibit and control the aggregate formation.”

The IBN team collaborated with researchers from the Institute of High Performance Computing and the European Synchrotron Radiation Facility to validate their peptides with the core protein sequences of three diseases: Alzheimer’s, diabetes and thyroid cancer.

The results revealed that the mechanism behind the self-assembly of amyloids from smaller intermediate structures into larger amyloid structures was similar to how the IBN peptides were formed. In addition, this study supports the growing evidence that early intermediates are more toxic than the final amyloid fibers, and may even be the driving force behind amyloid formation.

Patent applications have been filed on this research, and the next step of this project is pre-clinical evaluation of ultrasmall peptide therapeutics. IBN will also investigate other amyloid disorders such as corneal dystrophy, which can result in blindness.

Scientific progress in Huntington’s disease (HD) relies upon the availability of appropriate animal models that enable insights into the disease’s genetics and/or pathophysiology. Large animal models, such as domesticated farm animals, offer some distinct advantages over rodent models, including a larger brain that is amenable to imaging and intracerebral therapy, longer lifespan, and a more human-like neuro-architecture. Three articles in the latest issue of the Journal of Huntington’s Disease discuss the potential benefits of using large animal models in HD research and the implications for the development of gene therapy.

A review by Morton and Howland explores the advantages and drawbacks of small and large animal models of HD. In the same issue, Baxa et al. highlight the development of a transgenic minipig HD model that expresses a human mutant huntingtin (HTT) fragment through the central nervous system (CNS) and peripheral tissues and manifests neurochemical and reproductive changes with age. In another report, Van der Bom et al. describe a technique employing CT and MRI that allows precise intracerebral application of therapeutics to transgenic HD sheep.

Huntington’s disease (HD) is an inherited progressive neurological disorder for which there is presently no effective treatment. It is caused by a single dominant gene mutation an expanded CAG repeat in the HTT gene - leading to expression of mutant HTT protein. Expression of mutant HTT causes changes in cellular functions, which ultimately results in uncontrollable movements, progressive psychiatric difficulties, and loss of mental abilities.

The search for new large animal models of HD arises from the recognition that there are some practical limitations of rodent and other small animal models. Because neurodegenerative diseases like HD progress over a lifetime, a rodent’s short life span excludes the possibility of studying long-term changes. There are also important anatomic differences between the brains of humans and rodents that become especially relevant when studying HD, including the lack of a gyrencephalic (convoluted) cortex and differences in the structure and cellular characteristics of the basal ganglia compared to humans. Not only does a rodent’s small brain often preclude the use of advanced neuroimaging techniques, it is also not clear how intracerebral application of trophic factors, transplant therapies, and gene therapies in small animals might translate to the much larger human brain.

"Importantly, the brains of large animals can be studied using sensitive measures that should be highly translatable to the human condition, including MRI and PET imaging, EEG, and electrophysiology, as well as behavioral tests looking at motor and cognitive function," says Professor Jenny Morton, PhD, of the Department of Physiology, Development and Neuroscience at the University of Cambridge. "Moving to larger-brained animal models after promising results are obtained in rodents is a logical, and possibly necessary, step to optimize delivery and biodistribution, validating on-target mechanism of action, and assessing safety profiles," says Professor Morton

"Strategies directed against the huntingtin gene in the brain are an important part of CHDI’s therapeutic portfolio", says David Howland, PhD, Director of Model Systems at CHDI. "Translating preclinical results for gene-based therapies from rodent models to larger-brained models of HD is an important step along the path toward clinical testing."

Significant advances have been made in the creation and characterization of HD models in nonhuman primates (NHP). “The relevance to human biology of NHP models in Huntington’s disease hold great potential value for preclinical research and development, but we need to fully consider the substantial issues of cost, long-term housing of affected animals, access of the models to HD investigators, and ethical concerns with modeling in these species,” says Dr Howland. “CHDI has invested in efforts to expand modeling in large animals to include sheep and minipigs to work around some of these concerns about NHP models.”

Large domesticated farm animals offer some distinct advantages as models of HD. Sheep, for example, are domesticated, docile, live outdoors, are easy to care for, and relatively economical to maintain. A sheep’s brain is about the same size as a large primate’s, is gyrencephalic, and the basal ganglia that degenerate in HD are anatomically similar to those in humans. Sheep live long enough that the time available for studying progressive neurological diseases such as HD is much greater than is possible in rodents. HD transgenic sheep express HTT protein in the brain and abnormal HD-associated neurochemical changes. These HD sheep have been subject to advanced genomic techniques and, because they carry a human transgene that is expressed at both an mRNA and protein level, they are seen as suitable for testing gene therapy-based reagents directed against human HTT. A further advantage, says Professor Morton, is that “although sheep have a reputation for being stupid, this is probably undeserved they have very good memories and are capable of learning and remembering new tasks.”

In order to advance the use of the HD sheep model, I.M.J. van der Bom, PhD, from the Department of Radiology at the University of Massachusetts, and colleagues developed a multi-modal technique using skull markings seen with CT imaging and brain anatomy from MR imaging to allow more precise placement of intracerebral cannulae into sheep brain. The technique offers the ability to directly image micro-cannula placement to ensure accurate targeting of the therapeutic injection in the brain. With this technique, the authors hope to study the extent of optimal safety, spread and neuronal uptake of adeno-associated virus (AAV) based therapeutics.

"Pigs, and mainly minipigs, represent a viable model for preclinical drug trials and long-term safety studies," says Jan Motlik, DVM, PhD, DSc, from the Laboratory of Cell Regeneration and Plasticity of the Institute of Animal Physiology and Genetics in Libechov, Czech Republic. Advantages include its large brain size and long lifespan. Genetic advances have been made, including defining the porcine genome, with a 96% similarity between the porcine and human huntingtin genes. In addition to well-established methods for pig husbandry, they are economical to house and have body systems very similar to that of humans.

In the report by Baxa et al., a new HD minipig model using lentiviral infection of porcine embryos is described. The authors report that they successfully developed a heterozygote transgenic HD minipig that expresses a human mutant HTT fragment throughout the CNS and peripheral tissues through 4 successive generations. The model produces viable offspring, with a total neonatal mortality rate of 17%. The authors reported that one affected HD minipig showed a decline beginning at 16 months of a neuronal phosphoprotein, DARPP32, in the neostriatum, the brain region most affected by HD. A loss of fertility, possibly HD related, was also found.

The disrupted metabolism of sugar, fat and calcium is part of the process that causes the death of neurons in Alzheimer’s disease. Researchers from Karolinska Institutet in Sweden have now shown, for the first time, how important parts of the nerve cell that are involved in the cell’s energy metabolism operate in the early stages of the disease. These somewhat surprising results shed new light on how neuronal metabolism relates to the development of the disease.

In the Alzheimer’s disease brain, plaques consisting of so called amyloid-beta-peptide (Aβ) are accumulated. It is also a well-known fact that the nerve cells of patients with Alzheimer’s disease have problems metabolising for example glucose and calcium, and that these disorders are associated with cell death. The metabolism of these substances is the job of the cell mitochondria, which serve as the cell’s power plant and supply the cell with energy.

However, for the mitochondria to do this, they need good contact with another part of the cell called the endoplasmic reticulum (ER). The specialised region of ER that is in contact with mitochondria is called the MAM region. Earlier studies on yeast and other types of cells have shown that the deactivation of certain proteins in the MAM region disrupt the contact points between the mitochondria and the ER, preventing the delivery of energy to the cell and causing cell death.

Now for the first time, researchers at Karolinska Institutet have studied the MAM region in nerve cells, and examined the interaction between the mitochondria and the ER in early stage Alzheimer’s disease. Although at this point in the development of the disease Aβ has not formed large, lumpy plaques, symptoms still appear, implying that Aβ that has not yet formed plaque is toxic to neurons.

The team’s results are slightly surprising. When nerve cells are exposed to low doses of Aβ, it leads to an increase in the number of contact points between the mitochondria and the ER, causing more calcium to be transferred from the ER to the mitochondria. The resulting over-accumulation of calcium is toxic to the mitochondria and affects their ability to supply energy to the nerve cell.

“It’s urgent that we find out what causes neuronal death if we’re to develop molecules that check the disease,” says Maria Ankarcrona, docent and researcher at the Department of Neurobiology, Care Sciences and Society, and the Alzheimer’s Disease Research Centre of Karolinska Institutet. “In the long run we might be able to produce a drug that can arrest the progress of the disease at a stage when the patient is still able to manage their daily lives. If we can extend that period by a number of years, we’d have made great gains. Today there are no drugs that affect the actual disease process.”

The researchers conducted their studies on mice bred to develop symptoms of Alzheimer’s disease. They also studied nerve cells from deceased Alzheimer’s patients and neurons cultivated in the laboratory.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Hormones and hypnotism

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

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

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

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

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

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