Neuroscience

Researchers at the University of Bristol and University College London found that lactate – essentially lactic acid – causes cells in the brain to release more noradrenaline (norepinephrine in US English), a hormone and neurotransmitter which is fundamental for brain function. Without it people can hardly wake up or focus on anything.

Production of lactate can be triggered by muscle use, which reinforces the connection between exercise and positive mental wellbeing.

Lactate was first discovered in sour milk by Swedish chemist, Carl Wilhelm Scheele in 1780. It is produced naturally by the body, for example when muscles are at work. In the brain, it has always been regarded as an energy source which can be delivered to neurones as fuel to keep them working when brain activity increases.

This research, published today [11 February] in Nature Communications, identifies a secondary function for lactate as a signal between brain cells. It implies that there is an as yet unknown receptor for lactate in the brain which must be present on noradrenaline cells to make them sensitive to lactate.

Professor Sergey Kasparov, from Bristol University’s School of Physiology and Pharmacology, said: “Our findings suggest that lactate has more than one incarnation - in addition to its role as an energy source, it is also a signal to neurones to release more noradrenaline.”

Dr Anja Teschemacher, also from the University of Bristol, added: “The next big task is to identify the receptor which mediates this effect because this will help to design drugs to block or stimulate this response. If we can regulate the release of noradrenaline – which is absolutely fundamental for brain function - then this could have important implications for the treatment of major health problems such as stress, blood pressure, pain and depression.”

Astrocytes, small non-neuronal star-shaped cells in the brain and spinal cord, are the principle source of brain lactate. The discovery that astrocytes communicate directly with neurones opens up a whole new area of pharmacology which has been little explored.

For the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study is published today in Molecular Psychiatry and may help scientists understand biological mechanisms behind some forms of intellectual impairment. 

The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified. 

An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence. 

Dr Sylvane Desrivières, from the MRC Social, Genetic and Developmental Psychiatry Centre at King’s College London’s Institute of Psychiatry and lead author of the study, said: “We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity – how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.”

She adds: “It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.” 

The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate. 

To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. The researchers found that the NPTN gene had a different activity in the left and right hemispheres of the brain, which may cause the left hemisphere to be more sensitive to the effects of NPTN mutations. Their findings suggest that some differences in intellectual abilities can result from the decreased function of the NPTN gene in particular regions of the left brain hemisphere.

The genetic variation identified in this study only accounts for an estimated 0.5% of the total variation in intelligence. However, the findings may have important implications for the understanding of biological mechanisms underlying several psychiatric disorders, such as schizophrenia, autism, where impaired cognitive ability is a key feature of the disorder. 

Scientists from the School of Medicine at The University of Texas Health Science Center at San Antonio have found a clue as to why muscles weaken with age. In a study published today in The Journal of Neuroscience, they report the first evidence that “set points” in the nervous system are not inalterably determined during development but instead can be reset with age. They observed a change in set point that resulted in significantly diminished motor function in aging fruit flies.

“The body has a set point for temperature (98.6 degrees), a set point for salt level in the blood, and other homeostatic (steady-state) set points that are important for maintaining stable functions throughout life,” said study senior author Ben Eaton, Ph.D., assistant professor of physiology at the Health Science Center. “Evidence also points to the existence of set points in the nervous system, but it has never been observed that they change, until now.”

Dr. Eaton and lead author Rebekah Mahoney, a graduate student, recorded changes in the neuromuscular junction synapses of aging fruit flies. These synapses are spaces where neurons exchange electrical signals to enable motor functions such as walking and smiling. “We observed a change in the synapse, indicating that the homeostatic mechanism had adjusted to maintain a new set point in the older animal,” Mahoney said.

The change was nearly 200 percent, and the researchers predicted that it would leave muscles more vulnerable to exhaustion.

Aside from impairing movement in aging animals, a new functional set point in neuromuscular junctions could put the synapse at risk for developing neurodegeneration — the hallmark of disorders such as Alzheimer’s and Parkinson’s diseases, Mahoney said.

“Observing a change in the set point in synapses alters our paradigms about how we think age affects the function of the nervous system,” she said.

It appears that a similar change could lead to effects on learning and memory in old age. An understanding of this phenomenon would be invaluable and could lead to development of novel therapies for those issues, as well.

A genetic disorder that affects about 1 in every 2,500 births can cause a bewildering array of clinical problems, including brain tumors, impaired vision, learning disabilities, behavioral problems, heart defects and bone deformities. The symptoms and their severity vary among patients affected by this condition, known as neurofibromatosis type 1 (NF1).

Image caption: A mutation in the gene that causes a human condition, neurofibromatosis type 1 (NF1), leads to shorter nerve cell branches (right) in the back of the eyes of female mice. The shorter branches, not seen in male mice with the mutation, make the cells more vulnerable. This may explain why girls with NF1 are more at risk of vision loss from brain tumors. (Credit: David H. Gutmann)

Now, researchers at Washington University School of Medicine in St. Louis have identified a patient’s gender as a clear and simple guidepost to help health-care providers anticipate some of the effects of NF1. The scientists report that girls with NF1 are at greater risk of vision loss from brain tumors. They also identified gender-linked differences in male mice that may help explain why boys with NF1 are more vulnerable to learning disabilities.

“This information will help us adjust our strategies for predicting the potential outcomes in patients with NF1 and recommending appropriate treatments,” said David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology, who treats NF1 patients at St. Louis Children’s Hospital.

The findings appear online in the Annals of Neurology.

Kelly Diggs-Andrews, PhD, a postdoctoral research associate in Gutmann’s laboratory, reviewed NF1 patient data collected at the Washington University Neurofibromatosis (NF) Center. In her initial assessment, Diggs-Andrews found that the number of boys and girls was almost equal in  a group of nearly 100 NF1 patients who had developed brain tumors known as optic gliomas. But vision loss occurred three times more often in girls with these tumors.

With help from David Wozniak, PhD, research professor of psychiatry, the scientists looked for an explanation in Nf1 mice (which, like NF1 patients, have a mutation in their Nf1 gene). They found that more nerve cells died in the eyes of female mice, and they linked the increased cell death to low levels of cyclic AMP, a chemical messenger that plays important roles in nerve function and health in the brain. In addition, Wozniak discovered that only female Nf1 mice had reduced vision, paralleling what was observed in children with NF1.

Two previous studies have shown that boys with NF1 are at higher risk of learning disorders than girls, including spatial learning and memory problems. To look for the causes of this gender-related difference, the scientists first confirmed that Nf1 mice had learning problems by testing the ability of the mice to find a hidden platform after training. After multiple trials, female Nf1 mice quickly found the hidden platform. In striking contrast, the male Nf1 mice did not, revealing that they had deficits in spatial learning and memory.

When the researchers examined the brain regions involved in learning and memory in the Nf1 mice, they identified biochemical abnormalities in the males but not in the females.

“We’re currently working to determine whether differences in the sex hormones are responsible for these abnormalities in vision and memory,” Gutmann said. “We’re talking about a disorder in young kids and in mice, where we normally would not expect sex hormones to play a major role, but we can’t rule them out yet.”

If hormones are responsible for these gender-linked distinctions in NF1, treatments that block hormonal function may be an option for use in patients with NF1, Gutmann added. 

“Moreover, these studies identify sex as one important factor that helps to predict clinical outcomes, such as vision loss and problems in cognitive function, in children with NF1,” Gutmann said. “Further understanding of the interplay between sex and NF1 may change the way we manage individuals with this common brain tumor predisposition syndrome.”

While the function of eating is to nourish the body, this is not what actually compels us to seek out food. Instead, it is hunger, with its stomach-growling sensations and gnawing pangs that propels us to the refrigerator – or the deli or the vending machine. Although hunger is essential for survival, abnormal hunger can lead to obesity and eating disorders, widespread problems now reaching near-epidemic proportions around the world.

Over the past 20 years, Beth Israel Deaconess Medical Center (BIDMC) neuroendocrinologist Bradford Lowell, MD, PhD, has been untangling the complicated jumble of neurocircuits in the brain that underlie hunger, working to create a wiring diagram to explain the origins of this intense motivational state. Key among his findings has been the discovery that Agouti-peptide (AgRP) expressing neurons – a group of nerve cells in the brain’s hypothalamus – are activated by caloric deficiency, and when either naturally or artificially stimulated in animal models, will cause mice to eat voraciously after conducting a relentless search for food.

Now, in a new study published on-line this week in the journal Nature, Lowell’s lab has made the surprising discovery that the hunger-inducing neurons that activate these AgRP neurons are located in the paraventricular nucleus — a brain region long thought to cause satiety, or feelings of fullness. This unexpected finding not only provides a critical addition to the overall wiring diagram, but adds an important extension to our understanding of what drives appetite.

"Our goal is to understand how the brain controls hunger," explains Lowell, an investigator in BIDMC’s Division of Endocrinology, Diabetes and Metabolism and Professor of Medicine at Harvard Medical School. "Abnormal hunger can lead to obesity and eating disorders, but in order to understand what might be wrong – and how to treat it – you first need to know how it works. Otherwise, it’s like trying to fix a car without knowing how the engine operates."

Hunger is notoriously complicated and questions abound: Why do the fed and fasted states of your body increase or decrease hunger? And how do the brain’s reward pathways come into play – why, as we seek out food, especially after an otherwise complete meal, do we prefer ice cream to lettuce?

"Psychologists have explained how cues from the environment and from the body interact, demonstrating that food and stimuli linked with food [such as a McDonald’s sign] are rewarding and therefore promote hunger," explains Lowell. "It’s clear that fasting increases the gain on how rewarding we find food to be, while a full stomach decreases this reward. But while this model has been extremely important in understanding the general features of the ‘hunger system,’ it’s told us nothing about what’s inside the ‘black box’ – the brain’s neural circuits that actually control hunger."

To deal with this particularly complex brain region – a dense and daunting tangle of circuits resembling a wildly colorful Jackson Pollack painting – the Lowell team is taking a step-by-step approach to find out how the messages indicating whether the body is in a state of feeding or fasting enter this system. Their search has been aided by a number of extremely powerful technologies, including rabies circuit mapping and channelrhodopsin-assisted circuit mapping, which enable their highly specific, neuron-by-neuron analysis of the region.

"By making use of these new technologies, we are able to follow the synapses, follow the axons, and see how it all works," says Lowell. "While this sounds like a relatively straightforward concept, it’s actually been a huge challenge for the neuroscience field."

In this new paper, first authors Michael Krashes, PhD, and Bhavik Shah, PhD, postdoctoral fellows in the Lowell lab, employed rabies circuit mapping, a technology in which a modified version of the rabies virus is engineered to “infect” just one type of neuron – in this case, the AgRP neurons that drive hunger. The virus moves upstream one synapse and identifies all neurons that are providing input to AgRP starter neurons. Then, using a host of different neuron-specific cre-recombinase expressing mice (a group of genetically engineered animals originally developed in the Lowell lab) the investigators were able to map inputs to just these nerve cells, and then manipulate these upstream neurons so that they could be targeted for activation by an external stimulus.

"We wanted to know, of all the millions of neurons in a mouse brain, which provided input to the AgRP neurons," explains Lowell. "And the shocking result was that there were only two sites in the brain that were involved – the dorsal medial hypothalamus and the paraventricular nucleus, with the input from the paraventricular neurons shown to be extremely strong."

With this new information, the investigators now had a model to pursue. “We hypothesized that neurons in the paraventricular nucleus were communicating with and turning on the AgRP neurons. We developed mice that expressed cre-recombinase in many subsets of the paraventricular neurons and then, mapping the neurons one-by-one, we determined which was talking to which,” says Lowell. Their results revealed that subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cylcase-activating polypeptide (PACAP) were in on the neuronal chatter.

Finally, through a chemogenetic technique known as DREADDs – Designer Receptor Exclusively Activated by Designer Drug – the authors used chemicals to specifically and selectively stimulate or inhibit these upstream neurons in the animal models. The fed mice, which had already consumed their daily meal and otherwise had no interest in food, proceeded to search out and voraciously eat after DREADD stimulation. Conversely, the fasting mice – which should have been hungry after a period of no food – ate very little when these upstream neurons were turned off.

"This has led us to the discovery of a novel, previously unknown means of activating AgRP neurons and producing hunger," explains Lowell. "Surprisingly, these hunger-inducing neurons were found in a region of the brain which has long been thought to have the opposite effect – causing satiety. This unexpected discovery, made possible only through the use of the new wiring diagram-elucidating technologies, highlights the importance of following the labeled neuronal lines of information flow. We are getting closer and closer to completing our wiring diagram, and the nearer we come to understanding how it all works, the better our chances of being able to treat obesity and eating disorders, the consequences of abnormal hunger."

Scientists have discovered a link between a largely unstudied gene and schizophrenia.

They also found a link between the same gene and bipolar disorder, depression and autism.

The University of Aberdeen-led research - published in the Journal of Cell Science - set out to look for genes that might be important for schizophrenia.

During analysis of five major patient cohorts, scientists picked out the poorly-understood gene ULK4 which has previously been associated with hypertension but never before with mental health disorders.

They discovered that a mutation of the gene ULK4 was found far more frequently in patients with schizophrenia.

Researchers also found mutation of ULK4 in some people with bipolar disorder, depression and autism.

First author Dr Bing Lang, Research Fellow at the University of Aberdeen, said: “Schizophrenia is a severe psychiatric disorder affecting about 1% of the population. Genetics are estimated to be between 60 and 80% responsible for the condition, but very few specific susceptibility genes for schizophrenia have been firmly confirmed in humans.

“However our results suggest that mutation of the gene UKL4 can be a rare genetic risk factor for schizophrenia as well as other psychiatric disorders.” 

The researchers found evidence that ULK4 regulates many important signalling pathways within nerve cells involved in schizophrenia and stress.

They also discovered that mutation of the gene reduced communication between brain cells.

Professor Colin McCaig, one of the researchers and Head of the University’s School of Medical Sciences, added: “This is an important discovery of a gene involved in major mental health disorders which affects basic nerve cell growth and nerve to nerve communication. We expect it will form another important piece of the jigsaw that will produce a fuller understanding of what goes wrong in the brain in conditions such as schizophrenia.”

Dr Lang added: “We are very excited by our findings. We still need to do much more work to understand the mechanisms underlying the role of UKL4 in schizophrenia in the hope that this may lead to the discovery of new drug targets for a condition that deprives some sufferers of the ability to lead normal, independent lives.”

Using auditory or tactile stimulation, Sensory Substitution Devices (SSDs) provide representations of visual information and can help the blind “see” colors and shapes. SSDs scan images and transform the information into audio or touch signals that users are trained to understand, enabling them to recognize the image without seeing it.

Currently SSDs are not widely used within the blind community because they can be cumbersome and unpleasant to use. However, a team of researchers at the Hebrew University of Jerusalem have developed the EyeMusic, a novel SSD that transmits shape and color information through a composition of pleasant musical tones, or “soundscapes.” A new study published in Restorative Neurology and Neuroscience reports that using the EyeMusic SSD, both blind and blindfolded sighted participants were able to correctly identify a variety of basic shapes and colors after as little as 2-3 hours of training.

Most SSDs do not have the ability to provide color information, and some of the tactile and auditory systems used are said to be unpleasant after prolonged use. The EyeMusic, developed by senior investigator Prof. Amir Amedi, PhD, and his team at the Edmond and Lily Safra Center for Brain Sciences (ELSC) and the Institute for Medical Research Israel-Canada at the Hebrew University, scans an image and uses musical pitch to represent the location of pixels. The higher the pixel on a vertical plane, the higher the pitch of the musical note associated with it. Timing is used to indicate horizontal pixel location. Notes played closer to the opening cue represent the left side of the image, while notes played later in the sequence represent the right side. Additionally, color information is conveyed by the use of different musical instruments to create the sounds: white (vocals), blue (trumpet), red (reggae organ), green (synthesized reed), yellow (violin); black is represented by silence.

“This study is a demonstration of abilities showing that it is possible to encode the basic building blocks of shape using the EyeMusic,” explains Prof. Amir Amedi. “Furthermore, the success in associating color to musical timbre holds promise for facilitating the representation of more complex shapes.” 

In addition to successfully identifying shapes and colors, users in the new EyeMusic study indicated they found the SSD’s soundscapes to be relatively pleasant and potentially tolerable for prolonged use. “In soundscapes generated from images,” notes Prof. Amedi, “there is a tendency for adjacent frequencies to be played together. Using a semitone western scale would then generate sounds that are perceived as highly dissonant. Therefore, to generate more pleasant soundscapes, we used the pentatonic musical scale that generates less dissonance when adjacent notes are played together.”

While this new study shows that the EyeMusic can enable the visually impaired to extract visual shape and color information using auditory soundscapes of objects, researchers feel that this device also holds great promise for the field of visual rehabilitation in general. By providing additional color information, the EyeMusic can help facilitate object recognition and scene segmentation, while the pleasant soundscapes offer the potential of prolonged use.

“There is evidence suggesting that the brain is organized as a task-machine and not as a sensory machine. This strengthens the view that SSDs can be useful for visual rehabilitation, and therefore we suggest that the time may be ripe for turning part of the SSD spotlight back on practical visual rehabilitation,” Prof. Amedi adds. “In the future, it would be intriguing to test whether the use of naturalistic sounds, like music and human voice, can facilitate learning and brain processing relying on the developed neural networks for music and human voice processing.”

Additionally, the researchers hope the EyeMusic can become a tool for future neuroscience research. “It would be intriguing to explore the plastic changes associated with learning to decode color information for auditory timbre in the congenitally blind, who never experience color in their life. The utilization of the EyeMusic and its added color information in the field of neuroscience could facilitate exploring several questions in the blind with the potential to expand our understanding of brain organization in general,” concludes Prof. Amedi.

A demonstration, “EyeMusic: Hearing colored shapes” is available from the AppStore.

All creatures great and small, including fruitflies, need sleep. Researchers have surmised that sleep – in any species — is necessary for repairing proteins, consolidating memories, and removing wastes from cells. But, really, sleep is still a great mystery.

Image caption: An alpha subunit of the nicotinic acetylcholine receptor accounts for the rye mutant phenotype. Expression pattern of redeye (green). Credit: Amita Sehgal and Mi Shi, PhD, Perelman School of Medicine, University of Pennsylvania

The timing of when we sleep versus are awake is controlled by cells in tune with circadian rhythms of light and dark. Most of the molecular components of that internal clock have been worked out. On the other hand, how much we sleep is regulated by another process called sleep homeostasis, however little is known about its molecular basis.

In a study published in eLIFE, Amita Sehgal, PhD, professor of Neuroscience at the Perelman School of Medicine, University of Pennsylvania, and colleagues, report a new protein involved in the homeostatic regulation of sleep in the fruitfly, Drosophila. Sehgal is also an investigator with the Howard Hughes Medical Institute (HHMI).

The researchers conducted a screen of mutant flies to identify short-sleeping individuals and found one, which they dubbed redeye. These mutants show a severe reduction in the amount of time they slumber, sleeping only half as long as normal flies. While the redeye mutants were able to fall asleep, they would wake again in only a few minutes.

The team found that the redeye gene encodes a subunit of the nicotinic acetylcholine receptor. This type of acetylcholine receptor consists of multiple protein subunits, which form an ion channel in the cell membrane, and, as the name implies, also binds to nicotine.  Although acetylcholine signaling — and cigarette smoking — typically promote wakefulness, the particular subunit studied in the eLIFE paper is required for sleep in Drosophila.

Levels of the redeye protein in the fly oscillate with the cycles of light and dark and peak at times of daily sleep. Normally, the redeye protein is expressed at times of increasing sleep need in the fly, right around the afternoon siesta and at the time of night-time sleep. From this, the team concluded that the redeye protein promotes sleep and is a marker for sleepiness – suggesting that redeye signals an acute need for sleep, and then helps to maintain sleep once it is underway.

In addition, cycling of the redeye protein is independent of the circadian clock in normal day:night cycles, but depends on the sleep homeostat. The team concluded this because redeye protein levels are upregulated in short-sleeping mutants as well as in wild-type animals following sleep deprivation. And, mutant flies had normal circadian rhythms, suggesting that their sleep problems were the result of disrupted sleep/wake homeostasis.

Ultimately the team wants to use the redeye gene to locate sleep homeostat neurons in the brain. “We propose that the homeostatic drive to sleep increases levels of the redeye protein, which responds to this drive by promoting sleep,” says Sehgal. Identification of molecules that reflect sleep drive could lead to the development of biomarkers for sleep, and may get us closer to revealing the mystery of the sleep homeostat.

Your memory is a wily time traveler, plucking fragments of the present and inserting them into the past, reports a new Northwestern Medicine® study. In terms of accuracy, it’s no video camera.

Rather, the memory rewrites the past with current information, updating your recollections with new experiences. 

Love at first sight, for example, is more likely a trick of your memory than a Hollywood-worthy moment.

“When you think back to when you met your current partner, you may recall this feeling of love and euphoria,” said lead author Donna Jo Bridge, a postdoctoral fellow in medical social sciences at Northwestern University Feinberg School of Medicine. “But you may be projecting your current feelings back to the original encounter with this person.”

The study is published Feb. 5 in the Journal of Neuroscience.

This the first study to show specifically how memory is faulty, and how it can insert things from the present into memories of the past when those memories are retrieved. The study shows the exact point in time when that incorrectly recalled information gets implanted into an existing memory.

To help us survive, Bridge said, our memories adapt to an ever-changing environment and help us deal with what’s important now.

“Our memory is not like a video camera,” Bridge said. “Your memory reframes and edits events to create a story to fit your current world. It’s built to be current.”

All that editing happens in the hippocampus, the new study found. The hippocampus, in this function, is the memory’s equivalent of a film editor and special effects team.

For the experiment, 17 men and women studied 168 object locations on a computer screen with varied backgrounds such as an underwater ocean scene or an aerial view of Midwest farmland. Next, researchers asked participants to try to place the object in the original location but on a new background screen. Participants would always place the objects in an incorrect location.

For the final part of the study, participants were shown the object in three locations on the original screen and asked to choose the correct location. Their choices were: the location they originally saw the object, the location they placed it in part 2 or a brand new location.

“People always chose the location they picked in part 2,” Bridge said. “This shows their original memory of the location has changed to reflect the location they recalled on the new background screen. Their memory has updated the information by inserting the new information into the old memory.”

Participants took the test in an MRI scanner so scientists could observe their brain activity. Scientists also tracked participants’ eye movements, which sometimes were more revealing about the content of their memories – and if there was conflict in their choices — than the actual location they ended up choosing.   

The notion of a perfect memory is a myth, said Joel Voss, senior author of the paper and an assistant professor of medical social sciences and of neurology at Feinberg.

“Everyone likes to think of memory as this thing that lets us vividly remember our childhoods or what we did last week,” Voss said. “But memory is designed to help us make good decisions in the moment and, therefore, memory has to stay up-to-date. The information that is relevant right now can overwrite what was there to begin with.”

Bridge noted the study’s implications for eyewitness court testimony. “Our memory is built to change, not regurgitate facts, so we are not very reliable witnesses,” she said.

A caveat of the research is that it was done in a controlled experimental setting and shows how memories changed within the experiment. “Although this occurred in a laboratory setting, it’s reasonable to think the memory behaves like this in the real world,” Bridge said.

Studies have shown that certain pesticides can increase people’s risk of developing Parkinson’s disease. Now, UCLA researchers have found that the strength of that risk depends on an individual’s genetic makeup, which, in the most pesticide-exposed populations, could increase a person’s chance of developing the debilitating disease two- to six-fold.

In an earlier study, published January 2013 in Proceedings of the National Academy of Sciences, the UCLA team discovered a link between Parkinson’s and the pesticide benomyl, a fungicide that has been banned by the U.S. Environmental Protection Agency. That study found that benomyl prevents the enzyme aldehyde dehydrogenase (ALDH) from converting aldehydes — organic compounds that are highly toxic to dopamine cells in the brain — into less toxic agents, thereby contributing to the risk of Parkinson’s.

For the current study, UCLA researchers tested a number of additional pesticides and found 11 that also inhibit ALDH and increase the risk of Parkinson’s — and at levels much lower than they are currently being used, said the study’s lead author, Jeff Bronstein, a professor of neurology and director of the movement disorders program at UCLA.

Bronstein said the team also found that people with a common genetic variant of the ALDH2 gene are particularly sensitive to the effects of ALDH-inhibiting pesticides and are two to six times more likely to develop Parkinson’s when exposed to these pesticides than those without the variant.

The results of the new epidemiological study appear Feb. 5 in the online issue of Neurology, the medical journal of the American Academy of Neurology.

"We were very surprised that so many pesticides inhibited ALDH and at quite low concentrations — concentrations that were way below what was needed for the pesticides to do their job," Bronstein said. "These pesticides are pretty ubiquitous and can be found on our food supply. They are used in parks and golf courses and in pest control inside buildings and homes. So this significantly broadens the number of people at risk."

The study compared 360 patients with Parkinson’s disease in three agriculture-heavy Central California counties and 816 people from the same area who did not have Parkinson’s. The researchers focused their analyses on individuals with ambient exposures to pesticides at work and at home, using information from the California Department of Pesticide Regulation.

In the previous PNAS study, Bronstein and his team had determined the mechanism that leads to increased risk. Exposure to pesticides starts a cascade of cellular events, preventing ALDH from keeping a lid on the aldehyde DOPAL, a toxin that naturally occurs in the brain. When ALDH does not detoxify DOPAL sufficiently, it accumulates, damages neurons and increases an individual’s risk of developing Parkinson’s.

"ALDH inhibition appears to be an important mechanism by which these environmental toxins contribute to Parkinson’s pathogenesis, especially in genetically vulnerable individuals," said study author Beate Ritz, a professor of epidemiology at UCLA’s Fielding School of Public Health. "This suggests several potential interventions to reduce Parkinson’s occurrence or to slow its progression."

In the current study, the research team developed a lab test to determine which pesticides inhibited ALDH. They then found that those participants in the epidemiologic study who had a genetic variant in the ALDH gene were at increased risk of Parkinson’s when exposed to these pesticides. Just having the variant alone, however, did not increase risk of the disease, Bronstein noted.

"This report provides evidence for the relevance of ALDH inhibition in Parkinson’s disease pathogenesis, identifies pesticides that should be avoided to reduce the risk of developing Parkinson’s disease and suggests that therapies modulating ALDH enzyme activity or otherwise eliminating toxic aldehydes should be developed and tested to potentially reduce Parkinson’s disease occurrence or slow its progression, particularly for patients exposed to pesticides," the study states.

University of Queensland researchers have made a surprise discovery about how the brain plans movement that may lead to more targeted treatments for patients with Parkinson’s disease.

The discovery was made by UQ’s Queensland Brain Institute (QBI) researcher Professor Pankaj Sah in collaboration with neurologist Professor Peter Silburn and neurosurgeon Associate Professor Terry Coyne from the UQ Centre for Clinical Research.

Professor Sah said the team examined the brains of 10 patients with Parkinson’s disease while the patients were awake during deep brain stimulation surgery, and found more than one part of the brain is responsible for planning movement.

“This study aimed to improve understanding of how different parts of the brain are involved in planning movement and controlling gait,” Professor Sah said.

The team was particularly interested in a part of the brain stem known as the pedunculopontine nucleus (PPN), which lies in the deepest part of the brain.

The PPN has previously been targeted as a treatment point for people with advanced Parkinson’s disease who are unable to walk.

“To date, we have known that walking is generally controlled by the outer part of the brain known as the cortex,” Professor Sah said.

“When you decide to walk, the cortex sends signals to your brain stem which in turn signals the spinal cord to initiate movement.

“We have also known that neurons in the PPN are activated during limb movement, but our study has shown they were also activated when patients were simply thinking about walking.

“This is a complete surprise, because general thinking has been that movement planning takes place in the cortex, but this study indicates it might be happening in the brain stem as well.”

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting more than six million people globally, and about 1 in 350 Australians.

Professor Sah said improved understanding of how the brain plans movement could lead to more targeted treatments for people with Parkinson’s.

“The cells involved in these networks seem to be one type of cell, so when thinking about drug treatments for Parkinson’s, maybe we should be targeting these cells,” Professor Sah said.

All the patients treated with deep brain stimulation also recorded positive outcomes with improvements with gait, highlighting the importance of neuroscientists working with clinicians.

Findings of the research are published in the Nature Neuroscience journal.

Stanford researchers may have solved a riddle about the inner workings of the brain, which consists of billions of neurons, organized into many different regions, with each region primarily responsible for different tasks.

The various regions of the brain often work independently, relying on the neurons inside that region to do their work. At other times, however, two regions must cooperate to accomplish the task at hand. The riddle is this: what mechanism allows two brain regions to communicate when they need to cooperate yet avoid interfering with one another when they must work alone?

In a paper published today in Nature Neuroscience, a team led by Stanford electrical engineering professor Krishna Shenoy reveals a previously unknown process that helps two brain regions cooperate when joint action is required to perform a task.

“This is among the first mechanisms reported in the literature for letting brain areas process information continuously but only communicate what they need to,” said Matthew T. Kaufman, who was a postdoctoral scholar in the Shenoy lab when he co-authored the paper.

Read More →

Drugs that modify DNA structure may be beneficial for treating Alzheimer’s Disease

In a study published this week in Nature Neuroscience, Bess Frost, PhD, and co-authors, identify abnormal expression of genes, resulting from DNA relaxation, that can be detected in the brain and blood of Alzheimer’s patients.

The protein tau is involved in a number of neurodegenerative disorders, including Alzheimer’s disease. Previous studies have implicated DNA damage as a cause of neuron, or cell, death in Alzheimer’s patients. Given that DNA damage can change the structure of DNA within cells, the researchers examined changes in DNA structure in tau-induced neurodegeneration. They used transgenic flies and mice expressing human tau to show that DNA is more relaxed in tauopathy. They then identified that the relaxation of tightly wound DNA and resulting abnormal gene expression are central events that cause neurons to die in Alzheimer’s disease.

The authors write, “Our work suggests that drugs that modify DNA structure may be beneficial for treating Alzheimer’s Disease.” The authors recommend, “A greater understanding of the pathway of DNA relaxation in tauopathies will allow us to identify the optimal target and explore the therapeutic potential of epigenetic-based drugs.”

A multicenter research team led by Cedars-Sinai neurologist Nancy Sicotte, MD, an expert in multiple sclerosis and state-of-the-art imaging techniques, used a new, automated technique to identify shrinkage of a mood-regulating brain structure in a large sample of women with MS who also have a certain type of depression.

In the study, women with MS and symptoms of “depressive affect” – such as depressed mood and loss of interest – were found to have reduced size of the right hippocampus. The left hippocampus remained unchanged, and other types of depression – such as vegetative depression, which can bring about extreme fatigue – did not correlate with hippocampal size reduction, according to an article featured on the cover of the January 2014 issue of Human Brain Mapping.

The research supports earlier studies suggesting that the hippocampus may contribute to the high frequency of depression in multiple sclerosis. It also shows that a computerized imaging technique called automated surface mesh modeling can readily detect thickness changes in subregions of the hippocampus. This previously required a labor-intensive manual analysis of MRI images.

Sicotte, the article’s senior author, and others have previously found evidence of tissue loss in the hippocampus, but the changes could only be documented in manual tracings of a series of special high-resolution MRI images. The new approach can use more easily obtainable MRI scans and it automates the brain mapping process.

“Patients with medical disorders – and especially those with inflammatory diseases such as MS – often suffer from depression, which can cause fatigue. But not all fatigue is caused by depression. We believe that while fatigue and depression often co-occur in patients with MS, they may be brought about by different biological mechanisms. Our studies are designed to help us better understand how MS-related depression differs from other types, improve diagnostic imaging systems to make them more widely available and efficient, and create better, more individualized treatments for our patients,” said Sicotte, director of Cedars-Sinai’s Multiple Sclerosis Program and the Neurology Residency Program. She received a $506,000 grant from the National Multiple Sclerosis Society last year to continue this research.