Posts tagged science

New research from the University of Rochester Medical Center describes how exposure to air pollution early in life produces harmful changes in the brains of mice, including an enlargement of part of the brain that is seen in humans who have autism and schizophrenia.  

As in autism and schizophrenia, the changes occurred predominately in males. The mice also performed poorly in tests of short-term memory, learning ability, and impulsivity.

The new findings are consistent with several recent studies that have shown a link between air pollution and autism in children. Most notably, a 2013 study in JAMA Psychiatry reported that children who lived in areas with high levels of traffic-related air pollution during their first year of life were three times as likely to develop autism.

“Our findings add to the growing body of evidence that air pollution may play a role in autism, as well as in other neurodevelopmental disorders,” said Deborah Cory-Slechta, Ph.D., professor of Environmental Medicine at the University of Rochester and lead author of the study, published in the journal Environmental Health Perspectives.

In three sets of experiments, Cory-Slechta and her colleagues exposed mice to levels of air pollution typically found in mid-sized U.S. cities during rush hour. The exposures were conducted during the first two weeks after birth, a critical time in the brain’s development. The mice were exposed to polluted air for four hours each day for two four-day periods.

In one group of mice, the brains were examined 24 hours after the final pollution exposure. In all of those mice, inflammation was rampant throughout the brain, and the lateral ventricles — chambers on each side of the brain that contain cerebrospinal fluid — were enlarged two-to-three times their normal size.

“When we looked closely at the ventricles, we could see that the white matter that normally surrounds them hadn’t fully developed,” said Cory-Slechta. “It appears that inflammation had damaged those brain cells and prevented that region of the brain from developing, and the ventricles simply expanded to fill the space.”

The problems were also observed in a second group of mice 40 days after exposure and in another group 270 days after exposure, indicating that the damage to the brain was permanent. Brains of mice in all three groups also had elevated levels of glutamate, a neurotransmitter, which is also seen in humans with autism and schizophrenia.

Most air pollution is made up mainly of carbon particles that are produced when fuel is burned by power plants, factories, and cars. For decades, research on the health effects of air pollution has focused on the part of the body where the damage is most obvious — the lungs. That research began to show that different-sized particles produce different effects.  Larger particles — the ones regulated by the Environmental Protection Agency (EPA) — are actually the least harmful because they are coughed up and expelled.  But many researchers believe that smaller particles known as ultrafine particles —  which are not regulated by the EPA — are more dangerous, because they are small enough to travel deep into the lungs and be absorbed into the bloodstream, where they can produce toxic effects throughout the body.

That assumption led Cory-Slechta to design a set of experiments that would show whether ultrafine particles have a damaging effect on the brain, and if so, to reveal the mechanism by which they inflict harm. Her study published today is the first scientific work to do both.

“I think these findings are going to raise new questions about whether the current regulatory standards for air quality are sufficient to protect our children,” said Cory-Slechta.

(Source: urmc.rochester.edu)

University of Toronto biologists leading an investigation into the cells that regulate proper brain function, have identified and located the key players whose actions contribute to afflictions such as epilepsy and schizophrenia. The discovery is a major step toward developing improved treatments for these and other neurological disorders.

“Neurons in the brain communicate with other neurons through synapses, communication that can either excite or inhibit other neurons,” said Professor Melanie Woodin in the Department of Cell and Systems Biology at the University of Toronto (U of T), lead investigator of a study published today in Cell Reports. “An imbalance among the levels of excitation and inhibition – a tip towards excitation, for example – causes improper brain function and can produce seizures. We identified a key complex of proteins that can regulate excitation-inhibition balance at the cellular level.”

This complex brings together three key proteins – KCC2, Neto2 and GluK2 – required for inhibitory and excitatory synaptic communication. KCC2 is required for inhibitory impulses, GluK2 is a receptor for the main excitatory transmitter glutamate, and Neto2 is an auxiliary protein that interacts with both KCC2 and GluK2. The discovery of the complex of three proteins is pathbreaking as it was previously believed that KCC2 and GluK2 were in separate compartments of the cell and acted independently of each other.

“Finding that they are all directly interacting and can co-regulate each other’s function reveals for the first time a system that can mediate excitation-inhibition balance among neurons themselves,” said Vivek Mahadevan, a PhD candidate in Woodin’s group and lead author of the study.

Mahadevan and fellow researchers made the discovery via biochemistry, fluorescence imaging and electrophysiology experiments on mice brains. The most fruitful technique was the application of an advanced sensitive gel system to determine native protein complexes in neurons, called Blue Native PAGE. The process provided the biochemical conditions necessary to preserve the protein complexes that normally exist in neurons. Blue Native PAGE is advantageous over standard gel electrophoresis, where proteins are separated from their normal protein complexes based on their molecular weights.

“The results reveal the proteins that can be targeted by drug manufacturers in order to reset imbalances that occur in neurological disorders such as epilepsy, autism spectrum disorder, schizophrenia and neuropathic pain,” said Woodin. “There is no cure for epilepsy; the best available treatments only control its effects, such as convulsions and seizures. We can now imagine preventing them from occurring in the first place.”

“It was the cellular mechanisms that determine the excitation-inhibition balance that needed to be identified. Now that we know the key role played by KCC2 in moderating excitatory activity, further research can be done into its occasional dysfunction and how it can also be regulated by excitatory impulses,” said Mahadevan.

(Source: media.utoronto.ca)

“Where does it hurt?” is the first question asked to any person in pain.

A new UCL study defines for the first time how our ability to identify where it hurts, called “spatial acuity”, varies across the body, being most sensitive at the forehead and fingertips.

Using lasers to cause pain to 26 healthy volunteers without any touch, the researchers produced the first systematic map of how acuity for pain is distributed across the body. The work is published in the journal Annals of Neurology and was funded by the Wellcome Trust.

With the exception of the hairless skin on the hands, spatial acuity improves towards the centre of the body whereas the acuity for touch is best at the extremities. This spatial pattern was highly consistent across all participants.

The experiment was also conducted on a rare patient lacking a sense of touch, but who normally feels pain. The results for this patient were consistent with those for healthy volunteers, proving that acuity for pain does not require a functioning sense of touch.

“Acuity for touch has been known for more than a century, and tested daily in neurology to assess the state of sensory nerves on the body. It is striking that until now nobody had done the same for pain,” says lead author Dr Flavia Mancini of the UCL Institute of Cognitive Neuroscience. “If you try to test pain with a physical object like a needle, you are also stimulating touch. This clouds the results, like taking an eye test wearing sunglasses. Using a specially-calibrated laser, we stimulate only the pain nerves in the upper layer of skin and not the deeper cells that sense touch.”

Volunteers were blindfolded and had specially-calibrated pairs of lasers targeted at various parts of their body. These lasers cause a brief sensation of pinprick pain. Sometimes only one laser would be activated, and sometimes both would be, unknown to participants. They were asked whether they felt one ‘sting’ or two, at varying distances between the two beams. The researchers recorded the minimum distance between the beams at which people were able to accurately say whether it was one sting or two.

“This measure tells us how precisely people can locate the source of pain on different parts of their body,” explains senior author Dr Giandomenico Iannetti of the UCL Department of Neuroscience, Physiology and Pharmacology. “Touch and pain are mediated by different sensory systems. While tactile acuity has been well studied, pain acuity has been largely ignored, beyond the common textbook assertion that pain has lower acuity than touch. We found the opposite: acuity for touch and pain are actually very similar. The main difference is in their gradients across the body. For example, pain acuity across the arm is much higher at the shoulder than at the wrist, whereas the opposite is true for touch.”

Acuity for both touch and pain normally correlates with the density of the relevant nerve fibres in each part of the body. However, the fingertips remain highly sensitive despite having a low density of pain-sensing nerve cells.

“The high pain acuity of the fingertips is something of a mystery that requires further investigation,” says Dr Mancini. “This may be because people regularly use their fingertips, and so the central nervous system may learn to process the information accurately.”

The findings have important implications for the assessment of both acute and chronic pain. Dr Roman Cregg of the UCL Centre for Anaesthesia, who was not involved in the research, is a clinical expert who treats patients with chronic pain.

“Chronic pain affects around 10 million people in the UK each year according to the British Pain Society, but we still have no reliable, reproducible way to test patients’ pain acuity,” says Dr Cregg. “This method offers an exciting, non-invasive way to test the state of pain networks across the body. Chronic pain is often caused by damaged nerves, but this is incredibly difficult to monitor and to treat. The laser method may enable us to monitor nerve damage across the body, offering a quantitative way to see if a condition is getting better or worse. I am excited at the prospect of taking this into the clinic, and now hope to work with Drs Mancini and Iannetti to translate their study to the chronic pain setting.”

(Source: ucl.ac.uk)

In laboratory tests, researchers have used electrical stimulation of retinal cells to produce the same patterns of activity that occur when the retina sees a moving object. Although more work remains, this is a step toward restoring natural, high-fidelity vision to blind people, the researchers say. The work was funded in part by the National Institutes of Health.

(Image caption: Chichilnisky and colleagues used an electrode array to record activity from retinal ganglion cells (yellow and blue) and feed it back to them, reproducing the cells’ responses to visual stimulation. Credit: E.J. Chichilnisky, Stanford.)

Just 20 years ago, bionic vision was more a science fiction cliché than a realistic medical goal. But in the past few years, the first artificial vision technology has come on the market in the United States and Western Europe, allowing people who’ve been blinded by retinitis pigmentosa to regain some of their sight. While remarkable, the technology has its limits. It has enabled people to navigate through a door and even read headline-sized letters, but not to drive, jog down the street, or see a loved one’s face.

A team based at Stanford University in California is working to improve the technology by targeting specific cells in the retina—the neural tissue at the back of the eye that converts light into electrical activity.

"We’ve found that we can reproduce natural patterns of activity in the retina with exquisite precision," said E.J. Chichilnisky, Ph.D., a professor of neurosurgery at Stanford’s School of Medicine and Hansen Experimental Physics Laboratory. The study was published in Neuron, and was funded in part by NIH’s National Eye Institute (NEI) and National Institute of Biomedical Imaging and Bioengineering (NIBIB).

The retina contains several cell layers. The first layer contains photoreceptor cells, which detect light and convert it into electrical signals. Retinitis pigmentosa and several other blinding diseases are caused by a loss of these cells. The strategy behind many bionic retinas, or retinal prosthetics, is to bypass the need for photoreceptors and stimulate the retinal ganglion cell layer, the last stop in the retina before visual signals are sent to the brain.

Several types of retinal prostheses are under development. The Argus II, which was developed by Second Sight Therapeutics with more than $25 million in support from NEI, is the best known of these devices. In the United States, it was approved for treating retinitis pigmentosa in 2013, and it’s now available at a limited number of medical centers throughout the country. It consists of a camera, mounted on a pair of goggles, which transmits wireless signals to a grid of electrodes implanted on the retina. The electrodes stimulate retinal ganglion cells and give the person a rough sense of what the camera sees, including changes in light and contrast, edges, and rough shapes.

"It’s very exciting for someone who may not have seen anything for 20-30 years. It’s a big deal. On the other hand, it’s a long way from natural vision," said Dr. Chichilnisky, who was not involved in development of the Argus II.

Current technology does not have enough specificity or precision to reproduce natural vision, he said. Although much of visual processing occurs within the brain, some processing is accomplished by retinal ganglion cells. There are 1 to 1.5 million retinal ganglion cells inside the retina, in at least 20 varieties. Natural vision—including the ability to see details in shape, color, depth and motion—requires activating the right cells at the right time.

The new study shows that patterned electrical stimulation can do just that in isolated retinal tissue. The lead author was Lauren Jepson, Ph.D., who was a postdoctoral fellow in Dr. Chichilnisky’s former lab at the Salk Institute in La Jolla, California. The pair collaborated with researchers at the University of California, San Diego, the Santa Cruz Institute for Particle Physics, and the AGH University of Science and Technology in Krakow, Poland.

They focused their efforts on a type of retinal ganglion cell called parasol cells. These cells are known to be important for detecting movement, and its direction and speed, within a visual scene. When a moving object passes through visual space, the cells are activated in waves across the retina.

The researchers placed patches of retina on a 61-electrode grid. Then they sent out pulses at each of the electrodes and listened for cells to respond, almost like sonar. This enabled them to identify parasol cells, which have distinct responses from other retinal ganglion cells. It also established the amount of stimulation required to activate each of the cells. Next, the researchers recorded the cells’ responses to a simple moving image—a white bar passing over a gray background. Finally, they electrically stimulated the cells in this same pattern, at the required strengths. They were able to reproduce the same waves of parasol cell activity that they observed with the moving image.

"There is a long way to go between these results and making a device that produces meaningful, patterned activity over a large region of the retina in a human patient," Dr. Chichilnisky said. "But if we can handle the many technical hurdles ahead, we may be able to speak to the nervous system in its own language, and precisely reproduce its normal function."

Such advances could help make artificial vision more natural, and could be applied to other types of prosthetic devices, too, such as those being studied to help paralyzed individuals regain movement. NEI supports many other projects geared toward retinal prosthetics.

"Retinal prosthetics hold great promise, but this research is a marathon, not a sprint," said Thomas Greenwell, Ph.D., a program director in retinal neuroscience at NEI. "This important study helps illustrate the challenges of restoring high-quality vision, one group’s progress toward that goal, and the continued need to for the entire field to keep innovating."

(Source: nei.nih.gov)

St. Jude Children’s Research Hospital scientists have identified problems in a connection between brain structures that may predispose individuals to hearing the “voices” that are a common symptom of schizophrenia. The work appears in the June 6 issue of the journal Science.

(Image: Getty Images)

Researchers linked the problem to a gene deletion. This leads to changes in brain chemistry that reduce the flow of information between two brain structures involved in processing auditory information.

The research marks the first time that a specific circuit in the brain has been linked to the auditory hallucinations, delusions and other psychotic symptoms of schizophrenia. The disease is a chronic, devastating brain disorder that affects about 1 percent of Americans and causes them to struggle with a variety of problems, including thinking, learning and memory.

The disrupted circuit identified in this study solves the mystery of how current antipsychotic drugs ease symptoms and provides a new focus for efforts to develop medications that quiet “voices” but cause fewer side effects.

“We think that reducing the flow of information between these two brain structures that play a central role in processing auditory information sets the stage for stress or other factors to come along and trigger the ‘voices’ that are the most common psychotic symptom of schizophrenia,” said the study’s corresponding author Stanislav Zakharenko, M.D., Ph.D., an associate member of the St. Jude Department of Developmental Neurobiology. “These findings also integrate several competing models regarding changes in the brain that lead to this complex disorder.”

The work was done in a mouse model of the human genetic disorder 22q11 deletion syndrome. The syndrome occurs when part of chromosome 22 is deleted and individuals are left with one rather than the usual two copies of about 25 genes. About 30 percent of individuals with the deletion syndrome develop schizophrenia, making it one of the strongest risk factors for the disorder. DNA is the blueprint for life. Human DNA is organized into 23 pairs of chromosomes that are found in nearly every cell.

Earlier work from Zakharenko’s laboratory linked one of the lost genes, Dgcr8, to brain changes in mice with the deletion syndrome that affect a structure important for learning and memory. They found evidence that the same mechanism was at work in patients with schizophrenia. Dgcr8 carries instructions for making small molecules called microRNAs that help regulate production of different proteins.

For this study, researchers used state-of-the-art tools to link the loss of Dgcr8 to changes that affect a different brain structure, the auditory thalamus. For decades antipsychotic drugs have been known to work by binding to a protein named the D2 dopamine receptor (Drd2). The binding blocks activity of the chemical messenger dopamine. Until now, however, how that quieted the “voices” of schizophrenia was unclear.

Working in mice with and without the 22q11 deletion, researchers showed that the strength of the nerve impulse from neurons in the auditory thalamus was reduced in mice with the deletion compared to normal mice. Electrical activity in other brain regions was not different.

Investigators showed that Drd2 levels were elevated in the auditory thalamus of mice with the deletion, but not in other brain regions. When researchers checked Drd2 levels in tissue from the same structure collected from 26 individuals with and without schizophrenia, scientists reported that protein levels were higher in patients with the disease.

As further evidence of Drd2’s role in disrupting signals from the auditory thalamus, researchers tested neurons in the laboratory from different brain regions of mutant and normal mice by adding antipsychotic drugs haloperidol and clozapine. Those drugs work by targeting Drd2. Originally nerve impulses in the mutant neurons were reduced compared to normal mice. But the nerve impulses were almost universally enhanced by antipsychotics in neurons from mutant mice, but only in neurons from the auditory thalamus.

When researchers looked more closely at the missing 22q11 genes, they found that mice that lacked the Dgcr8 responded to a loud noise in a similar manner as schizophrenia patients. Treatment with haloperidol restored the normal startle response in the mice, just as the drug does in patients.

Studying schizophrenia and other brain disorders advances understanding of normal brain development and the missteps that lead to various catastrophic diseases, including pediatric brain tumors and other problems.

(Source: stjude.org)