Neuroscience

Researchers believe they have learned how mutations in the gene that causes Huntington’s disease kill brain cells, a finding that could open new opportunities for treating the fatal disorder. Scientists first linked the gene to the inherited disease more than 20 years ago.

Huntington’s disease affects five to seven people out of every 100,000. Symptoms, which typically begin in middle age, include involuntary jerking movements, disrupted coordination and cognitive problems such as dementia. Drugs cannot slow or stop the progressive decline caused by the disorder, which leaves patients unable to walk, talk or eat.

Lead author Hiroko Yano, PhD, of Washington University School of Medicine in St. Louis, found in mice and in mouse brain cell cultures that the disease impairs the transfer of proteins to energy-making factories inside brain cells. The factories, known as mitochondria, need these proteins to maintain their function. When disruption of the supply line disables the mitochondria, brain cells die.

“We showed the problem could be fixed by making cells overproduce the proteins that make this transfer possible,” said Yano, assistant professor of neurological surgery, neurology and genetics. “We don’t know if this will work in humans, but it’s exciting to have a solid new lead on how this condition kills brain cells.”

The findings are available online in Nature Neuroscience.

Huntington’s disease is caused by a defect in the huntingtin gene, which makes the huntingtin protein. Life expectancy after initial onset is about 20 years.

Scientists have known for some time that the mutated form of the huntingtin protein impairs mitochondria and that this disruption kills brain cells. But they have had difficulty understanding specifically how the gene harms the mitochondria.

For the new study, Yano and collaborators at the University of Pittsburgh worked with mice that were genetically modified to simulate the early stages of the disorder.

Yano and her colleagues found that the mutated huntingtin protein binds to a group of proteins called TIM23. This protein complex normally helps transfer essential proteins and other supplies to the mitochondria. The researchers discovered that the mutated huntingtin protein impairs that process.

The problem seems to be specific to brain cells early in the disease. At the same point in the disease process, the scientists found no evidence of impairment in liver cells, which also produce the mutated huntingtin protein.

The researchers speculated that brain cells might be particularly reliant on their mitochondria to power the production and recycling of the chemical signals they use to transmit information. This reliance could make the cells vulnerable to disruption of the mitochondria.

Other neurodegenerative conditions, including Alzheimer’s disease and amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, have been linked to problems with mitochondria. Scientists may be able to build upon these new findings to better understand these disorders.

A specific preparation of cocoa-extract called Lavado may reduce damage to nerve pathways seen in Alzheimer’s disease patients’ brains long before they develop symptoms, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published June 20 in the Journal of Alzheimer’s Disease (JAD).  

Specifically, the study results, using mice genetically engineered to mimic Alzheimer’s disease, suggest that Lavado cocoa extract prevents the protein β-amyloid- (Aβ) from gradually forming sticky clumps in the brain, which are known to damage nerve cells as Alzheimer’s disease progresses.

Lavado cocoa is primarily composed of polyphenols, antioxidants also found in fruits and vegetables, with past studies suggesting that they prevent degenerative diseases of the brain.  

The Mount Sinai study results revolve around synapses, the gaps between nerve cells. Within healthy nerve pathways, each nerve cell sends an electric pulse down itself until it reaches a synapse where it triggers the release of chemicals called neurotransmitters that float across the gap and cause the downstream nerve cell to “fire” and pass on the message.

The disease-causing formation of Aβ oligomers – groups of molecules loosely attracted to each other –build up around synapses. The theory is that these sticky clumps physically interfere with synaptic structures and disrupt mechanisms that maintain memory circuits’ fitness. In addition, Aβ triggers immune inflammatory responses, like an infection, bringing an on a rush of chemicals and cells meant to destroy invaders but that damage our own cells instead.

“Our data suggest that Lavado cocoa extract prevents the abnormal formation of Aβ into clumped oligomeric structures, to prevent synaptic insult and eventually cognitive decline,” says lead investigator Giulio Maria Pasinetti, MD, PhD, Saunders Family Chair and Professor of Neurology at the Icahn School of Medicine at Mount Sinai. “Given that cognitive decline in Alzheimer’s disease is thought to start decades before symptoms appear, we believe our results have broad implications for the prevention of Alzheimer’s disease and dementia.

Evidence in the current study is the first to suggest that adequate quantities of specific cocoa polyphenols in the diet over time may prevent the glomming together of Aβ into oligomers that damage the brain, as a means to prevent Alzheimer’s disease.  

The research team led by Dr. Pasinetti tested the effects of extracts from Dutched, Natural, and Lavado cocoa, which contain different levels of polyphenols. Each cocoa type was evaluated for its ability to reduce the formation of Aβ oligomers and to rescue synaptic function. Lavado extract, which has the highest polyphenol content and anti-inflammatory activity among the three, was also the most effective in both reducing formation of Aβ oligomers and reversing damage to synapses in the study mice.  

“There have been some inconsistencies in medical literature regarding the potential benefit of cocoa polyphenols on cognitive function,” says Dr. Pasinetti. “Our finding of protection against synaptic deficits by Lavado cocoa extract, but not Dutched cocoa extract, strongly suggests that polyphenols are the active component that rescue synaptic transmission, since much of the polyphenol content is lost by the high alkalinity in the Dutching process.”  

Because loss of synaptic function may have a greater role in memory loss than the loss of nerve cells, rescue of synaptic function may serve as a more reliable target for an effective Alzheimer’s disease drug, said Dr. Pasinetti.

The new study provides experimental evidence that Lavado cocoa extract may influence Alzheimer’s disease mechanisms by modifying the physical structure of Aβ oligomers. It also strongly supports further studies to identify the metabolites of Lavado cocoa extract that are active in the brain and identify potential drug targets.

In addition, turning cocoa-based Lavado into a dietary supplement may provide a safe, inexpensive and easily accessible means to prevent Alzheimer’s disease, even in its earliest, asymptomatic stages.

It has become increasingly common to hear reports that big brains are not necessary, or even an evolutionary fluke. However, the new article found that increases in the size of brain areas, such as the visual cortex, are an essential element of evolution.

As part of the study, the researchers found that an increase in the size of the visual part of the brain in different primate species, including humans, apes, and monkeys, is associated with enhanced visual processing.

It is controversial whether overall brain size can predict intelligence. However the size of specialised areas within the brain is associated with specific changes in behaviour such as reducing the susceptibility to visual illusions and increasing the visual acuity or fine details that can be seen.

First author, Dr Alexandra de Sousa explained: “Primates with a bigger visual cortex have better visual resolution, the precision of vision, and reduced visual illusion strength. In essence, the bigger the brain area, the better the visual processing ability.

“The size of brain areas predicts not only the number of neurons (brain cells) in that area, but also the likelihood of connections between neurons. These connections allow for increasingly complex computations to be made that allow for more accurate, and more difficult, visual perception.”

Co-author, Dr Michael Proulx, Senior Lecturer (Associate Professor) in Psychology, added: “This paper is a novel attempt to bring together the micro and macro anatomy of the brain with behaviour. We link visual abilities, the size of brain areas, and the number of neurons that make up those brain areas to provide a framework that ties brain structure and function together.

“The theory of brain size that we discuss can be tested in the future with more behavioural tests of other species, gathering more comparative neuroanatomical data, and by testing other senses and multi-sensory perception, too. We might be able to even predict how well extinct species could sense the world based on fossil data.”

For the study, Dr Alexandra de Sousa, an expert in brain evolution, provided brain size measurements from her and other’s neuroanatomical research. Dr Michael Proulx, an expert in perception, found psychological studies of visual illusions and visual acuity in the same species or general of animals.

The paper ‘What can volumes reveal about human brain evolution? A framework for bridging behavioral, histometric and volumetric perspectives’ is published today in Frontiers in Neuroanatomy – an online, open access journal.

Although deep brain stimulation can be an effective therapy for dystonia – a potentially crippling movement disorder – the treatment isn’t always effective, or benefits may not be immediate. Precise placement of DBS electrodes is one of several factors that can affect results, but few studies have attempted to identify the “sweet spot,” where electrode placement yields the best results.

Researchers led by investigators at Cedars-Sinai, using a complex set of data from records and imaging scans of patients who have undergone successful DBS implantation, have created 3-D, computerized models that map the brain region involved in dystonia. The models identify an anatomical target for further study and provide information for neurologists and neurosurgeons to consider when planning surgery and making device programming decisions.

“We know DBS works as a treatment for dystonia, but we don’t know exactly how it works or why some patients have better, quicker results than others. Patient age, disease duration and other underlying factors have a role, and we believe electrode positioning and device programming are critical, but there is no consensus on ideal device placement and optimal programming strategies,” said Michele Tagliati, MD, director of the Movement Disorders Program in the Department of Neurology at Cedars-Sinai.

“This modeling paves the way for the construction of practical therapeutic and investigational targets,” added Tagliati, senior author of an article now available on the online edition of Annals of Neurology.

Medications usually are the first line of treatment for dystonia and several other movement disorders, but if drugs fail – as frequently happens – or side effects are excessive, neurologists and neurosurgeons may supplement them with deep brain stimulation. Electrical leads are implanted deep in the brain, and a pulse generator is placed near the collarbone. The device is later programmed with a remote, hand-held controller.

To calm the disorganized muscle contractions of dystonia, doctors generally target a brain structure called the globus pallidus, but studies on precise positioning of electrode contacts and the best programming parameters – such as the intensity and frequency of electrical stimulation – are rare and conflicting. Finding the most effective settings can take months of fine-tuning.

In this retrospective study, investigators examined a database of 94 patients with the most common genetic form of dystonia, DYT1, who had been treated with DBS for at least a year. They selected 21 patients who had good responses to treatment, compiled their demographic and treatment information, and used magnetic resonance imaging scans to create 3-D anatomical models with a fine grid to show exact location of relevant brain structures.

The investigators then simulated the placement of electrodes as they were positioned in the patients’ brains and input the actual stimulation parameters into a computer program – a “volume of tissue activation” model – which calculated detailed information specific to each patient and each electrode. The model draws on principles of neurophysiology – the way nerve cells respond to DBS – the biophysics of voltage distribution from electrodes, and the anatomy of the globus pallidus and surrounding structures.

“We found that clinicians were applying relatively large amounts of energy to wide swaths of the globus pallidus, but the area in common among most individuals was much smaller. We interpret this as being the potential ‘target within the target,’ and if our results are validated in further research and clinical practice, computer modeling may offer a physiologically-based, data-driven, visualized approach to clinical decision-making,” Tagliati said.

There are new clues about malfunctions in brain cells that contribute to intellectual disability and possibly other developmental brain disorders.

(Image caption: False color image of a mouse hippocampal neuron (cell
body is at lower right) with branchlike dendrites that provide surfaces at which projections from other neurons can connect, by forming synapses. Van Aelst and colleagues have shown that when the OPHN1 protein is mutated, interfering with its ability to interact with another protein called Homer1b/c, AMPA receptors don’t recycle to the surface at synapses at the rate they normally do. This adversely impacts synaptic plasticity, the process by which neurons adjust the strength of their connections. Such pathology may play a role in X-linked mental retardation.)

Professor Linda Van Aelst of Cold Spring Harbor Laboratory (CSHL) has been scrutinizing how the normal version of a protein called OPHN1 helps enable excitatory nerve transmission in the brain, particularly at nerve-cell docking ports containing AMPA receptors (AMPARs). Her team’s new work, published June 24 in the Journal of Neuroscience, provides new mechanistic insight into how OPHN1 defects can lead to impairments in the maturation and adjustment of synaptic strength of AMPAR-expressing neurons, which are ubiquitous in the brain and respond to the excitatory neurotransmitter glutamate.

Mutations in a gene called oligophrenin-1 (OPHN1) – located on the X chromosome – have previously been linked to X-linked intellectual disability (also known as X-linked mental retardation), a condition that affects boys disproportionately and could account for as much as one-fifth of all intellectual disability among males.

Several different mutations in the OPHN1 gene have been identified to date, all of which perturb nerve cells’ manufacture of OPHN1 protein. Previously, Van Aelst and colleagues demonstrated that OPHN1 has a vital role in synaptic plasticity, the process through which adjacent nerve cells adjust the strength of their connections. Cells in the brain are constantly adjusting connection strength as they respond to streams of stimuli.

The new discovery shows how OPHN1 is involved in the trafficking of AMPARs, an essential feature of plasticity in neurons. Neurons move receptors away from synapses into their interior and then back to the surface of synapses to control connection strength. At the synaptic surface, receptors provide an opportunity for the docking of neurotransmitters, in this case glutamate molecules. After a cell has fired, surface receptors are typically brought back into the interior, where they are recycled for future use.

When OPHN1 is misshapen or missing due to genetic mutation, the CSHL team demonstrated, it can no longer properly perform its role in receptor recycling, thus also impairing neurons’ ability to maintain strong long-term connections with their neighbors, called long-term potentiation. 

Van Aelst’s new experiments explain how OPHN1 in complex with another protein called Homer1b/c should normally interact with an area called the endocytic zone (EZ) to provide a pool of AMPARs to be brought to the synapse at a location called the post-synaptic density (PSD). When OPHN1 is mutated, the pool does not form and receptors needed for strengthening synapses are not available. Long-term potentiation is impaired.

“This suggests a previously unknown way in which genetic defects in OPHN1 can lead to dysfunctions in the glutamate system,” says Dr. Van Aelst. “Our earlier studies had already shown that OPHN1 is essential in stabilizing AMPA receptors at the synapse. Together, these two essential roles suggest how defective OPHN1 protein may contribute to pathology that underlies X-linked intellectual disability.”

Pregnant women who lived in close proximity to fields and farms where chemical pesticides were applied experienced a two-thirds increased risk of having a child with autism spectrum disorder or other developmental delay, a study by researchers with the UC Davis MIND Institute has found. The associations were stronger when the exposures occurred during the second and third trimesters of the women’s pregnancies.

The large, multisite California-based study examined associations between specific classes of pesticides, including organophosphates, pyrethroids and carbamates, applied during the study participants’ pregnancies and later diagnoses of autism and developmental delay in their offspring. It is published online today in Environmental Health Perspectives.

“This study validates the results of earlier research that has reported associations between having a child with autism and prenatal exposure to agricultural chemicals in California,” said lead study author Janie F. Shelton, a UC Davis graduate student who now consults with the United Nations. “While we still must investigate whether certain sub-groups are more vulnerable to exposures to these compounds than others, the message is very clear: Women who are pregnant should take special care to avoid contact with agricultural chemicals whenever possible.”

California is the top agricultural producing state in the nation, grossing $38 billion in revenue from farm crops in 2010. Statewide, approximately 200 million pounds of active pesticides are applied each year, most of it in the Central Valley, north to the Sacramento Valley and south to the Imperial Valley on the California-Mexico border. While pesticides are critical for the modern agriculture industry, certain commonly used pesticides are neurotoxic and may pose threats to brain development during gestation, potentially resulting in developmental delay or autism.

The study was conducted by examining commercial pesticide application using the California Pesticide Use Report and linking the data to the residential addresses of approximately 1,000 participants in the Northern California-based Childhood Risk of Autism from Genetics and the Environment (CHARGE) Study. The study includes families with children between 2 and 5 diagnosed with autism or developmental delay or with typical development. It is led by principal investigator Irva Hertz-Picciotto, a MIND Institute researcher and professor and vice chair of the Department of Public Health Sciences at UC Davis. The majority of study participants live in the Sacramento Valley, Central Valley and the greater San Francisco Bay Area.

Twenty-one chemical compounds were identified in the organophosphate class, including chlorpyrifos, acephate and diazinon. The second most commonly applied class of pesticides was pyrethroids, one quarter of which was esfenvalerate, followed by lambda-cyhalothrin permethrin, cypermethrin and tau-fluvalinate. Eighty percent of the carbamates were methomyl and carbaryl.

For the study, researchers used questionnaires to obtain study participants’ residential addresses during the pre-conception and pregnancy periods. The addresses then were overlaid on maps with the locations of agricultural chemical application sites based on the pesticide-use reports to determine residential proximity. The study also examined which participants were exposed to which agricultural chemicals.

“We mapped where our study participants’ lived during pregnancy and around the time of birth. In California, pesticide applicators must report what they’re applying, where they’re applying it, dates when the applications were made and how much was applied,” Hertz-Picciotto said. “What we saw were several classes of pesticides more commonly applied near residences of mothers whose children developed autism or had delayed cognitive or other skills.”

The researchers found that during the study period approximately one-third of CHARGE Study participants lived in close proximity – within 1.25 to 1.75 kilometers – of commercial pesticide application sites. Some associations were greater among mothers living closer to application sites and lower as residential proximity to the application sites decreased, the researchers found.

Organophosphates applied over the course of pregnancy were associated with an elevated risk of autism spectrum disorder, particularly for chlorpyrifos applications in the second trimester. Pyrethroids were moderately associated with autism spectrum disorder immediately prior to conception and in the third trimester. Carbamates applied during pregnancy were associated with developmental delay.

Exposures to insecticides for those living near agricultural areas may be problematic, especially during gestation, because the developing fetal brain may be more vulnerable than it is in adults. Because these pesticides are neurotoxic, in utero exposures during early development may distort the complex processes of structural development and neuronal signaling, producing alterations to the excitation and inhibition mechanisms that govern mood, learning, social interactions and behavior.

“In that early developmental gestational period, the brain is developing synapses, the spaces between neurons, where electrical impulses are turned into neurotransmitting chemicals that leap from one neuron to another to pass messages along. The formation of these junctions is really important and may well be where these pesticides are operating and affecting neurotransmission,” Hertz-Picciotto said.

Research from the CHARGE Study has emphasized the importance of maternal nutrition during pregnancy, particularly the use of prenatal vitamins to reduce the risk of having a child with autism. While it’s impossible to entirely eliminate risks due to environmental exposures, Hertz-Picciotto said that finding ways to reduce exposures to chemical pesticides, particularly for the very young, is important.

“We need to open up a dialogue about how this can be done, at both a societal and individual level,” she said. “If it were my family, I wouldn’t want to live close to where heavy pesticides are being applied.”

Genes that increase the risk of developing schizophrenia may also increase the likelihood of using cannabis, according to a new study led by King’s College London, published today in Molecular Psychiatry. 

Previous studies have identified a link between cannabis use and schizophrenia, but it has remained unclear whether this association is due to cannabis directly increasing the risk of the disorder.

The new results suggest that part of this association is due to common genes, but do not rule out a causal relationship between cannabis use and schizophrenia risk. 

The study is a collaboration between King’s and the Queensland Institute of Medical Research in Australia, partly funded by the UK Medical Research Council (MRC). 

Mr Robert Power, lead author from the MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre at the Institute of Psychiatry at King’s, says: “Studies have consistently shown a link between cannabis use and schizophrenia. We wanted to explore whether this is because of a direct cause and effect, or whether there may be shared genes which predispose individuals to both cannabis use and schizophrenia.”

Cannabis is the most widely used illicit drug in the world, and its use is higher amongst people with schizophrenia than in the general population. Schizophrenia affects approximately 1 in 100 people and people who use cannabis are about twice as likely to develop the disorder. The most common symptoms of schizophrenia are delusions (false beliefs) and auditory hallucinations (hearing voices). Whilst the exact cause is unknown, a combination of physical, genetic, psychological and environmental factors can make people more likely to develop the disorder.

Previous studies have identified a number of genetic risk variants associated with schizophrenia, each of these slightly increasing an individual’s risk of developing the disorder.  

The new study included 2,082 healthy individuals of whom 1,011 had used cannabis. Each individual’s ‘genetic risk profile’ was measured – that is, the number of genes related to schizophrenia each individual carried. 

The researchers found that people genetically pre-disposed to schizophrenia were more likely to use cannabis, and use it in greater quantities than those who did not possess schizophrenia risk genes.

Power says: “We know that cannabis increases the risk of schizophrenia. Our study certainly does not rule this out, but it suggests that there is likely to be an association in the other direction as well – that a pre-disposition to schizophrenia also increases your likelihood of cannabis use.”

“Our study highlights the complex interactions between genes and environments when we talk about cannabis as a risk factor for schizophrenia. Certain environmental risks, such as cannabis use, may be more likely given an individual’s innate behaviour and personality, itself influenced by their genetic make-up. This is an important finding to consider when calculating the economic and health impact of cannabis.”

Vitamin D treatment acts in the brain to improve weight and blood glucose (sugar) control in obese rats, according to a new study being presented Saturday at the joint meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014 in Chicago.

“Vitamin D deficiency occurs often in obese people and in patients with Type 2 diabetes, yet no one understands if it contributes to these diseases,” said Stephanie Sisley, MD, the study’s principal investigator and an assistant professor at Baylor College of Medicine, Houston. “Our results suggest that vitamin D may play a role in the onset of both obesity and Type 2 diabetes by its action in the brain.”

“The brain is the master regulator of weight,” Sisley said. A region of the brain called the hypothalamus controls both weight and glucose, and has vitamin D receptors there.

In this study funded by the National Institutes of Health, Sisley and partners at the University of Cincinnati delivered vitamin D directly to the hypothalamus. The investigators administered the active, potent form of vitamin D—called 1,25-dihydroxyvitamin D3—to obese male rats through a cannula (thin tube) surgically inserted using anesthesia into the brain’s third ventricle. This narrow cavity lies within the hypothalamus. Rats recovered their presurgery body weight, and the researchers verified the correct cannula placement.

The animals received nothing to eat for four hours, so they could have a fasting blood sugar measurement. Afterward, 12 rats received vitamin D dissolved in a solution acting as a vehicle for drug delivery. Another 14 rats, matched in body weight to the first group, received only the vehicle, thus serving as controls. One hour later, all rats had a glucose tolerance test, in which they received an injection of dextrose, a sugar, in their abdomen, followed by measurement of their blood sugar levels again.

Compared with the control rats, animals that received vitamin D had improved glucose tolerance, which is how the body responds to sugar. In a separate experiment, these treated rats also had greatly improved insulin sensitivity, the body’s ability to successfully respond to glucose. When this ability decreases—called insulin resistance—it eventually leads to high blood sugar levels. Two of insulin’s main effects are to clear glucose from the bloodstream and decrease glucose production in the liver. In this study, vitamin D in the brain decreased the glucose created by the liver.

In a separate experiment of long-term vitamin D treatment, the researchers gave three rats vitamin D and four rats vehicle alone for four weeks. They observed a large decrease in food intake and weight in rats receiving vitamin D compared with the group that did not get vitamin D. Over 28 days, the treated group ate nearly three times less food and lost 24 percent of their weight despite not changing the way they burned calories, study data showed. The control group did not lose any weight.

“Vitamin D is never going to be the silver bullet for weight loss, but it may work in combination with strategies we know work, like diet and exercise,” Sisley commented.

She said more research is necessary to determine if obesity alters vitamin D transport into the brain or its action in the brain.

One of the deadliest forms of paediatric brain tumour, Group 3 medulloblastoma, is linked to a variety of large-scale DNA rearrangements which all have the same overall effect on specific genes located on different chromosomes. The finding, by scientists at the European Molecular Biology Laboratory (EMBL), the German Cancer Research Centre (DKFZ), both in Heidelberg, Germany, and Sanford-Burnham Medical Research Institute in San Diego, USA, is published online today in Nature.

To date, the only gene known to play an important role in Group 3 medulloblastoma was a gene called MYC, but that gene alone couldn’t explain some of the unique characteristics of this particular type of medulloblastoma, which has a higher metastasis rate and overall poorer prognosis than other types of this childhood brain tumour. To tackle the question, Jan Korbel’s group at EMBL and collaborators at DKFZ tried to identify new genes involved, taking advantage of the large number of medulloblastoma genome sequences now known.

“We were surprised to see that in addition to MYC there are two other major drivers of Group 3 medulloblastoma – two sister genes called GFI1B and GFI1,” says Korbel. “Our findings could be relevant for research on other cancers, as we discovered that those genes had been activated in a way that cancer researchers don’t usually look for in solid tumours.”

Rather than take the usual approach of looking for changes in individual genes, the team focused on large-scale rearrangements of the stretches of DNA that lie between genes. They found that the DNA of different patients showed evidence of different rearrangements: duplications, deletions, inversions, and even complex alterations involving many ‘DNA-shuffling’ events. This wide array of genetic changes had one effect in common: they placed GFI1B close to highly active enhancers – stretches of DNA that can dramatically increase gene activity. So large-scale DNA changes relocate GFI1B, activating this gene in cells where it would normally be switched off. And that, the researchers surmise, is what drives the tumour to form.

“Nobody has seen such a process in solid cancers before,” says Paul Northcott from DKFZ, “although it shares similarities with a phenomenon implicated in leukaemias, which has been known since the 80s.”

GFI1B wasn’t affected in all cases studied, but in many patients where it wasn’t, a related gene with a similar role, GFI1, was. GFI1B and GFI1 sit on different chromosomes, and interestingly, the DNA rearrangements affecting GFI1 put it next to enhancers sitting on yet other chromosomes. But the overall result was identical: the gene was activated, and appeared to drive tumour formation.

To confirm the role of GFI1B and GFI1 in causing medulloblastoma, the Heidelberg researchers turned to the expertise of Robert Wechsler-Reya’s group at Sanford-Burnham. Wechsler-Reya’s lab genetically modified neural stem cells to have either GFI1B or GFI1 turned on, together with MYC. When they inserted those modified cells into the brains of healthy mice, the rodents developed aggressive, metastasising brain tumours that closely resemble Group 3 medulloblastoma in humans.

These mice are the first to truly mimic the genetics of the human version of Group 3 medulloblastoma, and researchers can now use them to probe further. The mice could, for instance, be used to test potential treatments suggested by these findings. One interesting option to explore, the scientists say, is that highly active enhancers – like the ones they found were involved in this tumour – can be vulnerable to an existing class of drugs called bromodomain inhibitors. And, since neither GFI1B nor GFI1 is normally active in the brain, the study points to possible routes for diagnosing this brain tumour, too.

But the mice also raised another question the scientists are still untangling. For the rodents to develop medulloblastoma-like tumours, activating GFI1 or GFI1B was not enough; MYC also had to be switched on. In human patients, however, scientists have found a statistical link between MYC and GFI1, but not between MYC and GFI1B, so the team is now following up on this partial surprise.

“What we’re learning from this study is that clearly one has to think outside the box when trying to understand cancer genomes,” Korbel concludes.

Covert changes of mind can be discovered by tracking neural activity when subjects make decisions, researchers from New York University and Stanford University have found. Their results, which appear in the journal Current Biology, offer new insights into how we make decisions and point to innovative ways to study this process in the future.

“The methods used in this study allowed us to see the idiosyncratic nature of decision making that was inaccessible before,” explains Roozbeh Kiani, an assistant professor in NYU’s Center for Neural Science and the study’s lead author.

The study’s other authors included Christopher Cueva and John Reppas of Stanford’s Department of Neurobiology and William Newsome, who holds appointments at the university’s Department of Neurobiology and at the Howard Hughes Medical Institute at Stanford’s School of Medicine.

Previous work on the decision-making process—a plan of action based on evidence, prior knowledge, and payoff—has been methodologically limited. In earlier studies, scientists analyzed one neuron at a time, then averaged these results across neurons to develop an understanding of this activity. However, such a measurement offers only snapshots of neurological behavior and misses the fine-scale dynamics that lead up to a decision.

In the Current Biology study, the researchers examined many neurons at once, giving them a more detailed understanding of decision making.

“Now we can look at the nuances of this dynamic and track changes over a specified period,” explains Kiani. “Looking at one neuron at a time is ‘noisy’: results vary from trial to trial so you cannot get a clear picture of this complex activity. By recording multiple neurons at the same time, you can take out this noise and get a more robust picture of the underlying dynamics.”

The researchers studied macaque monkeys, running them through a series of tasks while monitoring the animals’ neuronal workings.

In the experiment, the monkeys viewed a patch of randomly moving dots on a computer screen. Following the stimulus, monkeys received a “Go” signal to report the motion direction by making an eye movement. The scientists sought to predict the monkeys’ choices purely based on the recorded neural responses before the Go signal. Their model achieved highly accurate predictions.

The same model was then used to study potential dynamics of the monkeys’ decision at different times before the Go signal. The scientists confirmed these predictions by stopping the decision-making process at arbitrary times and comparing the model predictions with the monkeys’ actual choices.

Surprisingly, the monkeys’ decisions were not always stable. Occasionally, they vacillated from one choice to another, indicating covert changes of mind during decision-making. These changes of mind closely matched the properties of human changes of mind, which were uncovered in a 2009 study. They were more frequent in uncertain conditions, more likely to correct an initial mistake, and more likely to happen earlier during a decision.

Twist and hold your neck to the left. Now down, and over to the right, until it hurts. Now imagine your neck – or arms or legs – randomly doing that on their own, without you controlling it.

That’s a taste of what children and adults with a neurological condition called dystonia live with every day – uncontrollable twisting and stiffening of neck and limb muscles.

The mystery of why this happens, and what can prevent or treat it, has long puzzled doctors, who have struggled to help their suffering dystonia patients. Now, new research from a University of Michigan Medical School team may finally open the door to answering those questions and developing new options for patients.

In a new paper in the Journal of Clinical Investigation, the researchers describe new strains of mice they’ve developed that almost perfectly mimic a human form of the disease. They also detail new discoveries about the basic biology of dystonia, made from studying the mice.

They’ll soon make the mice available for researchers everywhere to study, to accelerate understanding of all forms of dystonia and the search for better treatments. The lack of such mice has held back research on dystonia for years.

The U-M team’s success in creating a mouse model for the disease came only after 17 years of stubborn, persistent effort – often in the face of setbacks and failure.

Led by U-M neurologist William Dauer, M.D., the team tried to figure out how and why a gene defect leads to an inherited form of dystonia that, intriguingly, doesn’t start until the pre-teen or teen years, after which it progresses for many years but then stops getting worse after the person reaches their mid-20s.

The gene defect responsible, called DYT1, causes brain cells to make a less-active form of a protein called torsinA. But despite more than a decade of effort by Dauer’s team and many others around the world, no one has been able to translate this information into an animal model with dystonia’s characteristic movements.

Using the childhood onset as a clue, Dauer and his team used cutting-edge genetic technology to severely impair torsinA function during early brain development. This novel twist caused the new mice to closely mimic the human disease: they don’t develop dystonia until they reach preteen age in “mouse years,” and their symptoms stop getting worse after a while.

With this powerful tool in hand, Dauer’s team were now able to peer into the brains of these animals to begin to unravel the mysteries of the disease.

In an unexpected development, they found that the lack of torsinA in the brains of dystonic mice led to the death of neurons – a process called neurodegeneration – in just a few highly localized parts of the brain that control movement. Like the dystonic movements, this neurodegeneration began in young mice, progressed for a time, and then became fixed. 

“We’ve created a model for understanding why certain parts of the brain are more vulnerable to problems from a certain genetic insult,” says Dauer, an associate professor in the U-M departments of Neurology and Cell & Developmental Biology.

“In this case, we’re showing that in dystonia, the lack of this particular protein during a critical window of time is causing cell death. Every disease is telling us something about biology — one just has to listen carefully.”

(Image caption: The brains of the mice with dystonia (shown in the right column) had much higher levels of neuron death than those without the condition (left column) — and this neurodegeneration was limited to certain areas involved in controlling muscle movements.)

More discoveries to come

Dauer and his team don’t yet know why only one-third of human DYT1 gene mutation carriers develop primary dystonia during their school years, and why those who don’t develop the disease before their early 20s will never go on to develop it.

They believe some critical events during the brain’s development in infancy and childhood may have to do with it - and they’re already working to explore that question in mice.

They also believe their mouse model will help them and other researchers understand how dystonia occurs in people who have Parkinson’s disease, Huntington’s disease, or damage caused by a stroke or brain injury. Some people develop dystonia without either a known gene defect or any of these other diagnoses – a condition called idiopathic dystonia.

In all these cases, as in people with DYT1 mutations, dystonia’s twisting and curling motions likely arise from problems in the area of the brain that controls the body’s motor control system.

In other words, something’s going wrong in the process of sending signals to the nerves that control muscles involved in movement. Studying a “pure” form of dystonia using the mice will allow researchers to understand just what’s going on.

The team’s ultimate goal is to find new treatments for all kinds of dystonia. Currently, children, teens and young adults who develop it can take medications or even opt for a form of neurosurgery called deep brain stimulation. But the drugs carry major side effects and are only partially effective – and brain surgery carries its own risks. Dauer and his team are working to screen drug candidates.

In a report published today in Nature Communications, an Ottawa-led team of researchers describe the role of a specific gene, called Snf2h, in the development of the cerebellum. Snf2h is required for the proper development of a healthy cerebellum, a master control centre in the brain for balance, fine motor control and complex physical movements.

Athletes and artists perform their extraordinary feats relying on the cerebellum. As well, the cerebellum is critical for the everyday tasks and activities that we perform, such as walking, eating and driving a car. By removing Snf2h, researchers found that the cerebellum was smaller than normal, and balance and refined movements were compromised.

Led by Dr. David Picketts, a senior scientist at the Ottawa Hospital Research Institute and professor in the Faculty of Medicine at the University of Ottawa, the team describes the Snf2h gene, which is found in our brain’s neural stem cells and functions as a master regulator. When they removed this gene early on in a mouse’s development, its cerebellum only grew to one-third the normal size. It also had difficulty walking, balancing and coordinating its movements, something called cerebellar ataxia that is a component of many neurodegenerative diseases.

"As these cerebellar stem cells divide, on their journey toward becoming specialized neurons, this master gene is responsible for deciding which genes are turned on and which genes are packed tightly away," said Dr. Picketts. "Without Snf2h there to keep things organized, genes that should be packed away are left turned on, while other genes are not properly activated. This disorganization within the cell’s nucleus results in a neuron that doesn’t perform very well—like a car running on five cylinders instead of six."

The cerebellum contains roughly half the neurons found in the brain. It also develops in response to external stimuli. So, as we practice tasks, certain genes or groups of genes are turned on and off, which strengthens these circuits and helps to stabilize or perfect the task being undertaken. The researchers found that the Snf2h gene orchestrates this complex and ongoing process. These master genes, which adapt to external cues to adjust the genes they turn on and off, are known as epigenetic regulators.

"These epigenetic regulators are known to affect memory, behaviour and learning," said Dr. Picketts. "Without Snf2h, not enough cerebellar neurons are produced, and the ones that are produced do not respond and adapt as well to external signals. They also show a progressively disorganized gene expression profile that results in cerebellar ataxia and the premature death of the animal."

There are no studies showing a direct link between Snf2h mutations and diseases with cerebellar ataxia, but Dr. Picketts added that it “is certainly possible and an interesting avenue to explore.”

In 2012, Developmental Cell published a paper by Dr. Picketts’ team showing that mice lacking the sister gene Snf2l were completely normal, but had larger brains, more cells in all areas of the brain and more actively dividing brain stem cells. The balance between Snf2l and Snf2h gene activity is necessary for controlling brain size and for establishing the proper gene expression profiles that underlie the function of neurons in different regions, including the cerebellum.

The hormone progesterone could become part of therapy against the most aggressive form of brain cancer. High concentrations of progesterone kill glioblastoma cells and inhibit tumor growth when the tumors are implanted in mice, researchers have found.

The results were recently published in the Journal of Steroid Biochemistry and Molecular Biology.

Glioblastoma is the most common and the most aggressive form of brain cancer in adults, with average survival after diagnosis of around 15 months. Surgery, radiation and chemotherapy do prolong survival by several months, but targeted therapies, which have been effective with other forms of cancer, have not lengthened survival in patients fighting glioblastoma.

The lead author of the current paper is Fahim Atif, PhD, Assistant Professor of Emergency Medicine at Emory University. The findings with glioblastoma came out of Emory researchers’ work on progesterone as therapy for traumatic brain injury and more recently, stroke. Atif, Donald Stein and their colleagues have been studying progesterone for the treatment of traumatic brain injury for more than two decades, prompted by Stein’s initial observation that females recover from brain injury more readily than males. There is a similar tilt in glioblastoma as well: primary glioblastoma develops three times more frequently in males compared to females.

These results could pave the way for the use of progesterone against glioblastoma in a human clinical trial, perhaps in combination with standard-of-care therapeutic agents such as temozolomide. However, Stein says that more experiments are necessary with grafts of human tumor cells into animal brains first. His team identified a factor that may be important for clinical trial design: progesterone was not toxic to all glioblastoma cell lines, and its toxicity may depend on whether the tumor suppressor gene p53 is mutated.

Atif, Stein, and colleague Seema Yousuf found that low, physiological doses of progesterone stimulate the growth of glioblastoma tumor cells, but higher doses kill the tumor cells while remaining nontoxic for healthy cells. Similar effects have been seen with the progesterone antagonist RU486, but the authors cite evidence that progesterone is less toxic to healthy cells. Progesterone has also been found to inhibit growth of neuroblastoma cells (neuroblastoma is the most common cancer in infants), as well as breast, ovarian and colon cancers in cell culture and animal models.

For the first time, researchers have found that the ‘ERK pathway’ must be constantly active for salamander cells to be reprogrammed, and hence able to contribute to the regeneration of different body parts.

The team identified a key difference between the activity of this pathway in salamanders and mammals, which helps us to understand why humans can’t regrow limbs and sheds light on how regeneration of human cells can be improved.

The study published in Stem Cell Reports, demonstrates that the ERK pathway is not fully active in mammalian cells, but when forced to be constantly active, gives the cells more potential for reprogramming and regeneration. This could help researchers better understand diseases and design new therapies.

Lead researcher on the study, Dr Max Yun (UCL Institute of Structural & Molecular Biology) said: “While humans have limited regenerative abilities, other organisms, such as the salamander, are able to regenerate an impressive repertoire of complex structures including parts of their hearts, eyes, spinal cord, tails, and they are the only adult vertebrates able to regenerate full limbs.

We’re thrilled to have found a critical molecular pathway, the ERK pathway, that determines whether an adult cell is able to be reprogrammed and help the regeneration processes. Manipulating this mechanism could contribute to therapies directed at enhancing regenerative potential of human cells.”

The ERK pathway is a way for proteins to communicate a signal from the surface of a cell to the nucleus which contains the cell’s genetic material. Further research will focus on understanding how this important pathway is regulated during limb regeneration, and which other molecules are involved in the process.

A team of Stanford University investigators has linked a particular brain circuit to mammals’ tendency to interact socially. Stimulating this circuit — one among millions in the brain — instantly increases a mouse’s appetite for getting to know a strange mouse, while inhibiting it shuts down its drive to socialize with the stranger.

The new findings, published June 19 in Cell, may throw light on psychiatric disorders marked by impaired social interaction such as autism, social anxiety, schizophrenia and depression, said the study’s senior author, Karl Deisseroth, MD, PhD, a professor of bioengineering and of psychiatry and behavioral sciences. The findings are also significant in that they highlight not merely the role of one or another brain chemical, as pharmacological studies tend to do, but rather the specific components of brain circuits involved in a complex behavior. A combination of cutting-edge techniques developed in Deisseroth’s laboratory permitted unprecedented analysis of how brain activity controls behavior.

Deisseroth, the D.H. Chen Professor and a member of the interdisciplinary Stanford Bio-X institute, is a practicing psychiatrist who sees patients with severe social deficits. “People with autism, for example, often have an outright aversion to social interaction,” he said. They can find socializing — even mere eye contact — painful.

Deisseroth pioneered a brain-exploration technique, optogenetics, that involves selectively introducing light-receptor molecules to the surfaces of particular nerve cells in a living animal’s brain and then carefully positioning, near the circuit in question, the tip of a lengthy, ultra-thin optical fiber (connected to a laser diode at the other end) so that the photosensitive cells and the circuits they compose can be remotely stimulated or inhibited at the turn of a light switch while the animal remains free to move around in its cage.

Monitoring activity in real time

Using optogenetics and other methods he and his associates have invented, Deisseroth and his associates were able to both manipulate and monitor activity in specific nerve-cell clusters, and the fiber tracts connecting them, in mice’s brains in real time while the animals were exposed to either murine newcomers or inanimate objects in various laboratory environments. The mice’s behavioral responses were captured by video and compared with simultaneously recorded brain-circuit activity.

In some cases, the researchers observed activity in various brain centers and nerve-fiber tracts connecting them as the mice variously examined or ignored one another. Other experiments involved stimulating or inhibiting impulses within those circuits to see how these manipulations affected the mice’s social behavior.

To avoid confusing simple social interactions with mating- and aggression-related behaviors, the researchers restricted their experiments to female mouse pairs.

The scientists first examined the relationship between the mice’s social interactions and a region in the brain stem called the ventral tegmental area. The VTA is a key node in the brain’s reward circuitry, which produces sensations of pleasure in response to success in such survival-improving activities as eating, mating or finding a warm shelter in a cold environment.

The VTA transmits signals to other centers throughout the brain via tracts of fibers that secrete chemicals, including one called dopamine, at contact points abutting nerve cells within these faraway centers. When dopamine lands on receptors on those nerve cells, it can set off signaling activity within them.

Abnormal activity in the VTA has been linked to drug abuse and depression, for example. But much less is known about this brain center’s role in social behavior, and it had not previously been possible to observe or control activity along its connections during social behavior.

Deisseroth and his colleagues used mice whose dopamine-secreting, or dopaminergic, VTA nerve cells had been bioengineered to express optogenetic control proteins that could set off or inhibit signaling in the cells in response to light. They observed that enhancing activity in these cells increased a mouse’s penchant for social interaction. When a newcomer was introduced into its cage, it came, it saw, it sniffed. Inhibiting the dopaminergic VTA cells had the opposite effect: The host lost much of its interest in the guest.

Only social interaction affected

On the other hand, such manipulations of the VTA’s dopaminergic cells had no effect on the mice’s penchant for exploring novel objects (a golf ball, for example) placed in their cages. Nor did it change their overall propensity to move around. The effect appeared to be specific for social interaction.

Finding out exactly which dopaminergic projections from the VTA, traveling to which remote brain structures, were carrying the signals that generate exploratory social behavior required designing a new monitoring methodology. The signals traveling along such projections are extremely weak and confounded by background noise, especially when located deep within the brains of ambulatory animals. Deisseroth’s group overcame this by developing a highly sensitive technology capable of plucking these tiny signals out of the surrounding noise. The new technique, called fiber photometry, is a sophisticated way of measuring calcium flux, which invariably accompanies signaling activity along the fibers projecting from nerve cells.

Using a combination of optogenetics and fiber photometry, the investigators were able to demonstrate that a particular tract projecting from the VTA to a mid-brain structure called the nucleus accumbens (also strongly implicated in the reward system) was the relevant conduit carrying the impetus to social interaction in the mice.

A third technological trick helped determine which recipient nerve cells within the nucleus accumbens were involved in the social-behavior circuitry. That structure’s two types of dopamine-responsive cells are differentiated by the types of dopamine receptors, referred to as D1 and D2, on their surfaces. The team performed experiments in animals bioengineered so that the normally D1-containing cells instead expressed a modified, light-inducible version of that receptor. These experiments, along with complementary experiments blocking the D1 receptors with specific drug antagonists, showed that the D1 nucleus-accumbens nerve cells were mediating the changes in social behavior. Tripping off those receptors, either by optogenetically inducing incoming tracts to deliver dopamine to these receptors, or by directly stimulating light-activated forms of these receptors on the target cells, enhanced mice’s social exploration.

Helping to see how social behavior can go wrong

“Every behavior presumably arises from a pattern of activity in the brain, and every behavioral malfunction arises from malfunctioning circuitry,” said Deisseroth, who is also co-director of Stanford’s Cracking the Neural Code Program. “The ability, for the first time, to pinpoint a particular nerve-cell projection involved in the social behavior of a living, moving animal will greatly enhance our ability to understand how social behavior operates, and how it can go wrong.”

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shed light on how a specific kind of genetic mutation can cause damage during early brain development that results in lifelong learning and behavioral disabilities. The work suggests new possibilities for therapeutic intervention.

The study, which focuses on the role of a gene known as Syngap1, was published June 18, 2014, online ahead of print by the journal Neuron. In humans, mutations in Syngap1 are known to cause devastating forms of intellectual disability and epilepsy.

“We found a sensitive cell type that is both necessary and sufficient to account for the bulk of the behavioral problems resulting from this mutation,” said TSRI Associate Professor Gavin Rumbaugh, who led the study. “Because we found the root biological cause of this genetic brain disorder, we can now shift our research toward developing tailor-made therapies for people affected by Syngap1 mutations.”

In the study, Rumbaugh and his colleagues used a mouse model to show that mutations in Syngap1 damage the development of a kind of neuron known as glutamatergic neurons in the young forebrain, leading to intellectual disability. Higher cognitive processes, such as language, reasoning and memory arise in children as the forebrain develops.

Repairing damaging Syngap1 mutations in these specific neurons during development prevented cognitive abnormalities, while repairing the gene in other kinds of neurons and in other locations had no effect.

Rumbaugh noted prenatal diagnosis of some infant genetic disorders is on the horizon. Technological advances in genetic sequencing allow for individual genomes to be scanned for damaging mutations; it is possible to scan the entire genome of a child still in the womb. “Our research suggests that if Syngap1 function can be fixed very early in development, this should protect the brain from damage and permanently improve cognitive function,” said TSRI Research Associate Emin Ozkan, a first author of the study, along with TSRI Research Associate Thomas Creson. “In theory, patients then wouldn’t have to be subjected to a lifetime of therapies and worry that the drugs might stop working or have side effects from chronic use.”

Mutations to Syngap1 are a leading cause of “sporadic intellectual disability,” resulting from new, random mutations arising spontaneously in genes, rather than faulty genes inherited from parents. Intellectual disability affects approximately one to three percent of the population worldwide.

Rumbaugh and his colleagues are continuing to investigate. “Our findings have also identified exciting potential biomarkers in the brain of cognitive failure, allowing us to test new therapeutic strategies in our Syngap1 animal model,” said Creson.

Young adult men who watched more violence on television showed indications of less mature brain development and poorer executive functioning, according to the results of an Indiana University School of Medicine study published online in the journal Brain and Cognition.

The researchers used psychological testing and MRI scans to measure mental abilities and volume of brain regions in 65 healthy males with normal IQ between the age of 18 and 29, specifically chosen because they were not frequent video game players.

Lead author Tom A. Hummer, Ph.D., assistant research professor in the IU Department of Psychiatry, said the young men provided estimates of their television viewing over the past year and then kept a detailed diary of their TV viewing for a week. Participants also completed a series of psychological tests measuring inhibitory control, attention and memory. At the conclusion, MRI scans were used to measure brain structure.

Executive function is the broad ability to formulate plans, make decisions, reason and problem-solve, regulate attention, and inhibit behavior in order to achieve goals.

"We found that the more violent TV viewing a participant reported, the worse they performed on tasks of attention and cognitive control," Dr. Hummer said. "On the other hand, the overall amount of TV watched was not related to performance on any executive function tests."

Dr. Hummer noted that these executive functioning abilities can be important for controlling impulsive behaviors, including aggression. “The worry is that more impulsivity does not mix well with the behaviors modeled in violent programming.”

Tests that measured working memory, another subtype of executive functioning, were not found to be related to overall or violent TV viewing.

Comparing TV habits to brain images also produced results that Dr. Hummer and colleagues believe are significant.

"When we looked at the brain scans of young men with higher violent television exposure, there was less volume of white matter connecting the frontal and parietal lobes, which can be a sign of less maturity in brain development," he said.

White matter is tissue in the brain that insulates nerve fibers connecting different brain regions, making functioning more efficient. In typical development, the amount or volume of white matter increases as the brain makes more connections until about age 30, improving communication between regions of the brain. Connections between the frontal and parietal lobes are thought to be especially important for executive functioning.

"The take-home message from this study is the finding of a relationship between how much violent television we watch and important aspects of brain functioning like controlled attention and inhibition," Dr. Hummer said.

Dr. Hummer cautions that more research is needed to better understand the study findings.

"With this study we could not isolate whether people with poor executive function are drawn to programs with more violence or if the content of the TV viewing is responsible for affecting the brain’s development over a period of time," Dr. Hummer said. "Additional longitudinal work is necessary to resolve whether individuals with poor executive function and slower white matter growth are more drawn to violent programming or if exposure to media violence modifies development of cognitive control," Dr. Hummer said.

A neuroscientist from Trinity College Dublin has proposed a new, ground-breaking explanation for the fundamental process of ‘habituation’, which has never been completely understood by neuroscientists.

Typically, our response to a stimulus is reduced over time if we are repeatedly exposed to it. This process of habituation enables organisms to identify and selectively ignore irrelevant, familiar objects and events that they encounter again and again. Habituation therefore allows the brain to selectively engage with new stimuli, or those that it ‘knows’ to be relevant. For example, the unusual sensation created by a spider walking over our skin should elicit an appropriate evasive response, but the touch of a shirt or blouse on the same skin should be functionally ignored by the nervous system. If habituation does not occur, then such unimportant stimuli become distracting, which means that complex environments can become overwhelming.

The new perspective on the way habituation occurs has implications for our understanding of neuropsychiatric conditions, because normal habituation, emotional responses and attentional abilities are altered in several of these conditions. In particular, hypersensitivity to complex environments is common in individuals on the autism spectrum.

Habituation has long been recognised as the most fundamental form of learning, but it has never been satisfactorily explained. In a Perspective article just published in the leading international journal Neuron (embargoed copy), Professor of Neurogenetics in the School of Genetics & Microbiology at Trinity, Mani Ramaswami, explains habituation through what he terms the ‘negative-image model’. The model proposes and explains how a repeated activation of any group of neurons that respond to a given stimulus results in the build-up of ‘negative activation’, which inhibits responses from this same group of cells.

For example, the first view of an unfamiliar and scary face can trigger a fearful response. However after multiple exposures, the group of neurons activated by the face is less effective at activating fear centres because of increased inhibition on this same group of neurons. Significantly, a strong response to new faces persists for much longer in people on the autism spectrum. This matched increase in inhibition (the ‘negative image’), proposed to underlie habituation, is not normally consciously perceived but it can be revealed under particular conditions (see accompanying video for a visual example here).

Professor Ramaswami said: “This Perspective outlines scalable circuit mechanisms that can account for habituation to stimuli encoded by very small or very large assemblies of neurons. Its strength is its simplicity, its basis in experimental data, and its ability to explain many features of habituation. However, more high-quality studies of habituation mechanisms will be required to establish its generality.”

Professor of Experimental Brain Research at Trinity, and Director of the Trinity College Institute for Neuroscience, Shane O’Mara, said: “The arguments and ideas expressed by Professor Ramaswami should lead to additions and changes to our current text-book sections on habituation, which is a process of great relevance to cognition, attention and psychiatric disease. It is possible that highlighting the process of negative image formation as crucial for habituation will prove useful to clinical genetic studies of autism, by helping to place diverse autism susceptibility genes in a common biological pathway.”

When a woman experiences a stressful event early in pregnancy, the risk of her child developing autism spectrum disorders or schizophrenia increases. Yet how maternal stress is transmitted to the brain of the developing fetus, leading to these problems in neurodevelopment, is poorly understood. 

New findings by University of Pennsylvania School of Veterinary Medicine scientists suggest that an enzyme found in the placenta is likely playing an important role. This enzyme, O-linked-N-acetylglucosamine transferase, or OGT, translates maternal stress into a reprogramming signal for the brain before birth.

(Image caption: Mice with reduced OGT in their placenta were shorter and leaner than their normal counterparts.)

“By manipulating this one gene, we were able to recapitulate many aspects of early prenatal stress,” said Tracy L. Bale, senior author on the paper and a professor in the Department of Animal Biology at Penn Vet. “OGT seems to be serving a role as the ‘canary in the coal mine,’ offering a readout of mom’s stress to change the baby’s developing brain.”

Bale also holds an appointment in the Department of Psychiatry in Penn’s Perelman School of Medicine. Her co-author is postdoctoral researcher Christopher L. Howerton. The paper was published online in PNAS this week.

OGT is known to play a role in gene expression through chromatin remodeling, a process that makes some genes more or less available to be converted into proteins. In a study published last year in PNAS, Bale’s lab found that placentas from male mice pups had lower levels of OGT than those from female pups, and placentas from mothers that had been exposed to stress early in gestation had lower overall levels of OGT than placentas from the mothers’ unstressed counterparts.

“People think that the placenta only serves to promote blood flow between a mom and her baby, but that’s really not all it’s doing,” Bale said. “It’s a very dynamic endocrine tissue and it’s sex-specific, and we’ve shown that tampering with it can dramatically affect a baby’s developing brain.”

To elucidate how reduced levels of OGT might be transmitting signals through the placenta to a fetus, Bale and Howerton bred mice that partially or fully lacked OGT in the placenta. They then compared these transgenic mice to animals that had been subjected to mild stressors during early gestation, such as predator odor, unfamiliar objects or unusual noises, during the first week of their pregnancies.

The researchers performed a genome-wide search for genes that were affected by the altered levels of OGT and were also affected by exposure to early prenatal stress using a specific activational histone mark and found a broad swath of common gene expression patterns.

They chose to focus on one particular differentially regulated gene called Hsd17b3, which encodes an enzyme that converts androstenedione, a steroid hormone, to testosterone. The researchers found this gene to be particularly interesting in part because neurodevelopmental disorders such as autism and schizophrenia have strong gender biases, where they either predominantly affect males or present earlier in males.

Placentas associated with male mice pups born to stressed mothers had reduced levels of the enzyme Hsd17b3, and, as a result, had higher levels of androstenedione and lower levels of testosterone than normal mice.

“This could mean that, with early prenatal stress, males have less masculinization,” Bale said. “This is important because autism tends to be thought of as the brain in a hypermasculinized state, and schizophrenia is thought of as a hypomasculinized state. It makes sense that there is something about this process of testosterone synthesis that is being disrupted.”

Furthermore, the mice born to mothers with disrupted OGT looked like the offspring of stressed mothers in other ways. Although they were born at a normal weight, their growth slowed at weaning. Their body weight as adults was 10-20 percent lower than control mice.

Because of the key role that that the hypothalamus plays in controlling growth and many other critical survival functions, the Penn Vet researchers then screened the mouse genome for genes with differential expression in the hypothalamus, comparing normal mice, mice with reduced OGT and mice born to stressed mothers.

They identified several gene sets related to the structure and function of mitochrondria, the powerhouses of cells that are responsible for producing energy. And indeed, when compared by an enzymatic assay that examines mitochondria biogenesis, both the mice born to stressed mothers and mice born to mothers with reduced OGT had dramatically reduced mitochondrial function in their hypothalamus compared to normal mice. These studies were done in collaboration with Narayan Avadhani’s lab at Penn Vet.

Such reduced function could explain why the growth patterns of mice appeared similar until weaning, at which point energy demands go up.

“If you have a really bad furnace you might be okay if temperatures are mild,” Bale said. “But, if it’s very cold, it can’t meet demand. It could be the same for these mice. If you’re in a litter close to your siblings and mom, you don’t need to produce a lot of heat, but once you wean you have an extra demand for producing heat. They’re just not keeping up.”

Bale points out that mitochondrial dysfunction in the brain has been reported in both schizophrenia and autism patients.

In future work, Bale hopes to identify a suite of maternal plasma stress biomarkers that could signal an increased risk of neurodevelopmental disease for the baby.

“With that kind of a signature, we’d have a way to detect at-risk pregnancies and think about ways to intervene much earlier than waiting to look at the term placenta,” she said.

UT Arlington researchers have successfully used a portable brain-mapping device to show limited prefrontal cortex activity among student veterans with Post Traumatic Stress Disorder when they were asked to recall information from simple memorization tasks.

The study by bioengineering professor Hanli Liu and Alexa Smith-Osborne, an associate professor of social work, and two other collaborators was published in the May 2014 edition of NeuroImage: Clinical. The team used functional near infrared spectroscopy to map brain activity responses during cognitive activities related to digit learning and memory retrial.

Smith-Osborne has used the findings to guide treatment recommendations for some veterans through her work as principal investigator for UT Arlington’s Student Veteran Project, which offers free services to veterans who are undergraduates or who are considering returning to college.

“When we retest those student veterans after we’ve provided therapy and interventions, they’ve shown marked improvement,” Smith-Osborne said. “The fNIRS data have shown improvement in brain functions and responses after the student veterans have undergone treatment.”

Liu said this type of brain imaging allows us to “see” which brain region or regions fail to memorize or recall learned knowledge in student veterans with PTSD.

“It also shows how PTSD can affect the way we learn and our ability to recall information, so this new way of brain imaging advances our understanding of PTSD.” Liu said.

This study is multi-disciplinary, associating objective brain imaging with neurological disorders and social work.

While UT Arlington bioengineering faculty associate Fenghua Tian is the primary author assisted by bioengineering graduate research assistant Amarnath Yennu, collaborators of the study include UT Austin psychology professor Francisco Gonzalez-Lima and psychology professor Carol North with UT Southwestern Medical Center and the Veterans Administration North Texas Health Care System.

Khosrow Behbehani, dean of the UT Arlington College of Engineering, said this collaborative research is “allowing the researchers to objectively measure the changes in the level of oxygen in the brain and relate them to some of the brain functions that may have been adversely affected by trauma or stress.”  

Numerous neuropsychological studies have linked learning dysfunctions – such as memory loss, attention deficits and learning disabilities – with PTSD.

The new study involved 16 combat veterans previously diagnosed with PTSD who were experiencing distress and functional impairment affecting cognitive and related academic performance.  The veterans were directed to perform a series of number-ordering tasks on a computer while researchers monitored their brain activity through near infrared spectroscopy, a noninvasive neuroimaging technology.

The research found that participants with PTSD experienced significant difficulty recalling the given digits compared with a control group. This deficiency is closely associated with dysfunction of a portion in the right frontal cortex. The team also determined that near infrared spectroscopy was an effective tool for measuring cognitive dysfunction associated with PTSD.

With that information, Smith-Osborne said mental healthcare providers could customize a treatment plan best suited for that individual.

“It’s not a one-size-fits-all treatment plan but a concentrated effort to tailor the treatment based on where that person is on the learning scale,” Smith-Osborne said.

Smith-Osborne and Liu hope that their research results lead to better and more comprehensive care for veterans and a better college education.