Neuroscience

A drug that blocks the action of the enzyme Cdk5 could substantially reduce brain damage if administered shortly after a stroke, UT Southwestern Medical Center research suggests.

The findings, reported in the June 11 issue of the Journal of Neuroscience, determined in rodent models that aberrant Cdk5 activity causes nerve cell death during stroke.

“If you inhibit Cdk5, then the vast majority of brain tissue stays alive without oxygen for up to one hour,” said Dr. James Bibb, Associate Professor of Psychiatry and Neurology and Neurotherapeutics at UT Southwestern and senior author of the study. “This result tells us that Cdk5 is a central player in nerve cell death.”

More importantly, development of a Cdk5 inhibitor as an acute neuroprotective therapy has the potential to reduce stroke injury.

“If we could block Cdk5 in patients who have just suffered a stroke, we may be able to reduce the number of patients in our hospitals who become disabled or die from stroke. Doing so would have a major impact on health care,” Dr. Bibb said.

While several pharmaceutical companies worked to develop Cdk5 inhibitors years ago, these efforts were largely abandoned since research indicated blocking Cdk5 long-term could have detrimental effects. At the time, many scientists thought aberrant Cdk5 activity played a major role in the development of Alzheimer’s disease and that Cdk5 inhibition might be beneficial as a treatment.

Based on Dr. Bibb’s research and that of others, Cdk5 has both good and bad effects. When working normally, Cdk5 adds phosphates to other proteins that are important to healthy brain function. On the flip side, researchers have found that aberrant Cdk5 activity contributes to nerve cell death following brain injury and can lead to cancer.

“Cdk5 regulates communication between nerve cells and is essential for proper brain function. Therefore, blocking Cdk5 long-term may not be beneficial,” Dr. Bibb said. “Until now, the connection between Cdk5 and stroke injury was unknown, as was the potential benefit of acute Cdk5 inhibition as a therapy.”

In this study, researchers administered a Cdk5 inhibitor directly into dissected brain slices after adult rodents suffered a stroke, in addition to measuring the post-stroke effects in Cdk5 knockout mice. 

“We are not yet at a point where this new treatment can be given for stroke. Nevertheless, this research brings us a step closer to developing the right kinds of drugs,” Dr. Bibb said. “We first need to know what mechanisms underlie the disease before targeted treatments can be developed that will be effective. As no Cdk5 blocker exists that works in a pill form, the next step will be to develop a systemic drug that could be used to confirm the study’s results and lead to a clinical trial at later stages.”

Currently, there is only one FDA-approved drug for acute treatment of stroke, the clot-busting drug tPA. Other treatment options include neurosurgical procedures to help minimize brain damage.

Without a steady supply of blood, neurons can’t work. That’s why one of the culprits behind Alzheimer’s disease is believed to be the persistent blood clots that often form in the brains of Alzheimer’s patients, contributing to the condition’s hallmark memory loss, confusion and cognitive decline.

New experiments in Sidney Strickland’s Laboratory of Neurobiology and Genetics at Rockefeller University have identified a compound that might halt the progression of Alzheimer’s by interfering with the role amyloid-β, a small protein that forms plaques in Alzheimer’s brains, plays in the formation of blood clots. This work is highlighted in the July issue of Nature Reviews Drug Discovery.

For more than a decade, potential Alzheimer’s drugs have targeted amyloid-β, but, in clinical trials, they have either failed to slow the progression of the disease or caused serious side effects. However, by targeting the protein’s ability to bind to a clotting agent in blood, the work in the Strickland lab offers a promising new strategy, according to the highlight published in print on July 1.

This latest study builds on previous work in Strickland’s lab showing amyloid-β can interact with fibrinogen, the clotting agent, to form difficult-to-break-down clots that alter blood flow, cause inflammation and choke neurons.

“Our experiments in test tubes and in mouse models of Alzheimer’s showed the compound, known as RU-505, helped restore normal clotting and cerebral blood flow. But the big pay-off came with behavioral tests in which the Alzheimer’s mice treated with RU-505 exhibited better memories than their untreated counterparts,” Strickland says. “These results suggest we have found a new strategy with which to treat Alzheimer’s disease.”

RU-505 emerged from a pack of 93,716 candidates selected from libraries of compounds, the researchers write in the June issue of the Journal of Experimental Medicine. Hyung Jin Ahn, a research associate in the lab, examined these candidates with a specific goal in mind: Find one that interferes with the interaction between fibrinogen and amyloid-β. In a series of tests that began with a massive, automated screening effort at Rockefeller’s High Throughput Resource Center, Ahn and colleagues winnowed the 93,000 contenders to five. Then, test tube experiments whittled the list down to one contender: RU-505, a small, synthetic compound. Because RU-505 binds to amyloid-β and only prevents abnormal blood clot formation, it does not interfere with normal clotting. It is also capable of passing through the blood-brain barrier.

“We tested RU-505 in mouse models of Alzheimer’s disease that over-express amyloid-β and have a relatively early onset of disease. Because Alzheimer’s disease is a long-term, progressive disease, these treatments lasted for three months,” Ahn says. “Afterward, we found evidence of improvement both at the cellular and the behavioral levels.”

The brains of the treated mice had less of the chronic and harmful inflammation associated with the disease, and blood flow in their brains was closer to normal than that of untreated Alzheimer’s mice. The RU-505-treated mice also did better when placed in a maze. Mice naturally want to escape the maze, and are trained to recognize visual cues to find the exit quickly. Even after training, Alzheimer’s mice have difficulty in exiting the maze. After these mice were treated with RU-505, they performed much better.

“While the behavior and the brains of the Alzheimer’s mice did not fully recover, the three-month treatment with RU-505 prevents much of the decline associated with the disease,” Strickland says.

The researchers have begun the next steps toward developing a human treatment. Refinements to the compound are being supported by the Robertson Therapeutic Development Fund and the Tri-Institutional Therapeutic Discovery Institute. As part of a goal to help bridge critical gaps in drug discovery, these initiatives support the early stages of drug development, as is being done with RU-505.

“At very high doses, RU-505 is toxic to mice and even at lower doses it caused some inflammation at the injection site, so we are hoping to find ways to reduce this toxicity, while also increasing RU-505’s efficacy so smaller doses can accomplish similar results,” Ahn says.

NYU Langone Medical Center is now using a novel technology that serves as a “flight simulator” for neurosurgeons, allowing them to rehearse complicated brain surgeries before making an actual incision on a patient.

The new simulator, called the Surgical Rehearsal Platform (SRP), creates an individualized walkthrough for neurosurgeons based on 3D imaging taken from the patient’s CT and MRI scans. Surgeons then plan and rehearse the surgeries using the unique software, which combines life-like tissue reaction with accurate modeling of surgical tools and clamps, to enable them to navigate multiple-angled models of a patient’s brain and vasculature.

The SRP was developed by Surgical Theater of Cleveland, Ohio. This augmented reality technology may help improve safety and efficiency during surgeries for conditions including pituitary tumors, skull base tumors, intrinsic brain tumors, aneurysms, and arteriovenous malformations (AVMs), and could potentially allow surgeons from around the world to simultaneously collaborate on a patient’s case in real-time.

 ”We are excited to partner with Surgical Theater to bring their Surgery Rehearsal Platform to our institution,” said John G. Golfinos, MD, chair of the Department of Neurosurgery at NYU Langone Medical Center and associate professor of neurosurgery at NYU School of Medicine. “The reaction of tissue in these 3D images is incredibly life-like and modeling of surgical tools is equally impressive. The SRP also will enhance the training of medical students, residents and fellows and help them hone their skills in new and more meaningful ways.”

When using the SRP, surgeons can rehearse a specific patient’s case on computer monitors connected to controllers that simulate surgical tools. For example, when rehearsing a surgery for an aneurysm, the SRP reacts realistically when the surgeon virtually applies a clip to the blood vessel. The surgeon then can assess the tissue’s mechanical properties and view realistic microscopic characteristics including shadowing and texture to plan approaches, so that when the real surgery is being performed, doctors have rehearsed and already have a mental picture of what is being seen in the OR.

The SRP obtained clearance from the U.S. Food and Drug Administration (FDA) in February 2013 as a pre-operative software for simulating and evaluating surgical treatment options.

In addition, a newer-generation of this technology from Surgical Theater, the Surgical Navigation Advanced Platform (SNAP), has an application pending with the FDA to allow the tool to be taken into the operating room, so surgeons can see behind arteries and other critical structures in real-time.

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.