Neuroscience
Month
For the first time, researchers have found that the ‘ERK pathway’ must be constantly active for salamander cells to be reprogrammed, and hence able to contribute to the regeneration of different body parts.
The team identified a key difference between the activity of this pathway in salamanders and mammals, which helps us to understand why humans can’t regrow limbs and sheds light on how regeneration of human cells can be improved.
The study published in Stem Cell Reports, demonstrates that the ERK pathway is not fully active in mammalian cells, but when forced to be constantly active, gives the cells more potential for reprogramming and regeneration. This could help researchers better understand diseases and design new therapies.
Lead researcher on the study, Dr Max Yun (UCL Institute of Structural & Molecular Biology) said: “While humans have limited regenerative abilities, other organisms, such as the salamander, are able to regenerate an impressive repertoire of complex structures including parts of their hearts, eyes, spinal cord, tails, and they are the only adult vertebrates able to regenerate full limbs.
We’re thrilled to have found a critical molecular pathway, the ERK pathway, that determines whether an adult cell is able to be reprogrammed and help the regeneration processes. Manipulating this mechanism could contribute to therapies directed at enhancing regenerative potential of human cells.”
The ERK pathway is a way for proteins to communicate a signal from the surface of a cell to the nucleus which contains the cell’s genetic material. Further research will focus on understanding how this important pathway is regulated during limb regeneration, and which other molecules are involved in the process.
A team of Stanford University investigators has linked a particular brain circuit to mammals’ tendency to interact socially. Stimulating this circuit — one among millions in the brain — instantly increases a mouse’s appetite for getting to know a strange mouse, while inhibiting it shuts down its drive to socialize with the stranger.
The new findings, published June 19 in Cell, may throw light on psychiatric disorders marked by impaired social interaction such as autism, social anxiety, schizophrenia and depression, said the study’s senior author, Karl Deisseroth, MD, PhD, a professor of bioengineering and of psychiatry and behavioral sciences. The findings are also significant in that they highlight not merely the role of one or another brain chemical, as pharmacological studies tend to do, but rather the specific components of brain circuits involved in a complex behavior. A combination of cutting-edge techniques developed in Deisseroth’s laboratory permitted unprecedented analysis of how brain activity controls behavior.
Deisseroth, the D.H. Chen Professor and a member of the interdisciplinary Stanford Bio-X institute, is a practicing psychiatrist who sees patients with severe social deficits. “People with autism, for example, often have an outright aversion to social interaction,” he said. They can find socializing — even mere eye contact — painful.
Deisseroth pioneered a brain-exploration technique, optogenetics, that involves selectively introducing light-receptor molecules to the surfaces of particular nerve cells in a living animal’s brain and then carefully positioning, near the circuit in question, the tip of a lengthy, ultra-thin optical fiber (connected to a laser diode at the other end) so that the photosensitive cells and the circuits they compose can be remotely stimulated or inhibited at the turn of a light switch while the animal remains free to move around in its cage.
Monitoring activity in real time
Using optogenetics and other methods he and his associates have invented, Deisseroth and his associates were able to both manipulate and monitor activity in specific nerve-cell clusters, and the fiber tracts connecting them, in mice’s brains in real time while the animals were exposed to either murine newcomers or inanimate objects in various laboratory environments. The mice’s behavioral responses were captured by video and compared with simultaneously recorded brain-circuit activity.
In some cases, the researchers observed activity in various brain centers and nerve-fiber tracts connecting them as the mice variously examined or ignored one another. Other experiments involved stimulating or inhibiting impulses within those circuits to see how these manipulations affected the mice’s social behavior.
To avoid confusing simple social interactions with mating- and aggression-related behaviors, the researchers restricted their experiments to female mouse pairs.
The scientists first examined the relationship between the mice’s social interactions and a region in the brain stem called the ventral tegmental area. The VTA is a key node in the brain’s reward circuitry, which produces sensations of pleasure in response to success in such survival-improving activities as eating, mating or finding a warm shelter in a cold environment.
The VTA transmits signals to other centers throughout the brain via tracts of fibers that secrete chemicals, including one called dopamine, at contact points abutting nerve cells within these faraway centers. When dopamine lands on receptors on those nerve cells, it can set off signaling activity within them.
Abnormal activity in the VTA has been linked to drug abuse and depression, for example. But much less is known about this brain center’s role in social behavior, and it had not previously been possible to observe or control activity along its connections during social behavior.
Deisseroth and his colleagues used mice whose dopamine-secreting, or dopaminergic, VTA nerve cells had been bioengineered to express optogenetic control proteins that could set off or inhibit signaling in the cells in response to light. They observed that enhancing activity in these cells increased a mouse’s penchant for social interaction. When a newcomer was introduced into its cage, it came, it saw, it sniffed. Inhibiting the dopaminergic VTA cells had the opposite effect: The host lost much of its interest in the guest.
Only social interaction affected
On the other hand, such manipulations of the VTA’s dopaminergic cells had no effect on the mice’s penchant for exploring novel objects (a golf ball, for example) placed in their cages. Nor did it change their overall propensity to move around. The effect appeared to be specific for social interaction.
Finding out exactly which dopaminergic projections from the VTA, traveling to which remote brain structures, were carrying the signals that generate exploratory social behavior required designing a new monitoring methodology. The signals traveling along such projections are extremely weak and confounded by background noise, especially when located deep within the brains of ambulatory animals. Deisseroth’s group overcame this by developing a highly sensitive technology capable of plucking these tiny signals out of the surrounding noise. The new technique, called fiber photometry, is a sophisticated way of measuring calcium flux, which invariably accompanies signaling activity along the fibers projecting from nerve cells.
Using a combination of optogenetics and fiber photometry, the investigators were able to demonstrate that a particular tract projecting from the VTA to a mid-brain structure called the nucleus accumbens (also strongly implicated in the reward system) was the relevant conduit carrying the impetus to social interaction in the mice.
A third technological trick helped determine which recipient nerve cells within the nucleus accumbens were involved in the social-behavior circuitry. That structure’s two types of dopamine-responsive cells are differentiated by the types of dopamine receptors, referred to as D1 and D2, on their surfaces. The team performed experiments in animals bioengineered so that the normally D1-containing cells instead expressed a modified, light-inducible version of that receptor. These experiments, along with complementary experiments blocking the D1 receptors with specific drug antagonists, showed that the D1 nucleus-accumbens nerve cells were mediating the changes in social behavior. Tripping off those receptors, either by optogenetically inducing incoming tracts to deliver dopamine to these receptors, or by directly stimulating light-activated forms of these receptors on the target cells, enhanced mice’s social exploration.
Helping to see how social behavior can go wrong
“Every behavior presumably arises from a pattern of activity in the brain, and every behavioral malfunction arises from malfunctioning circuitry,” said Deisseroth, who is also co-director of Stanford’s Cracking the Neural Code Program. “The ability, for the first time, to pinpoint a particular nerve-cell projection involved in the social behavior of a living, moving animal will greatly enhance our ability to understand how social behavior operates, and how it can go wrong.”
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shed light on how a specific kind of genetic mutation can cause damage during early brain development that results in lifelong learning and behavioral disabilities. The work suggests new possibilities for therapeutic intervention.
The study, which focuses on the role of a gene known as Syngap1, was published June 18, 2014, online ahead of print by the journal Neuron. In humans, mutations in Syngap1 are known to cause devastating forms of intellectual disability and epilepsy.
“We found a sensitive cell type that is both necessary and sufficient to account for the bulk of the behavioral problems resulting from this mutation,” said TSRI Associate Professor Gavin Rumbaugh, who led the study. “Because we found the root biological cause of this genetic brain disorder, we can now shift our research toward developing tailor-made therapies for people affected by Syngap1 mutations.”
In the study, Rumbaugh and his colleagues used a mouse model to show that mutations in Syngap1 damage the development of a kind of neuron known as glutamatergic neurons in the young forebrain, leading to intellectual disability. Higher cognitive processes, such as language, reasoning and memory arise in children as the forebrain develops.
Repairing damaging Syngap1 mutations in these specific neurons during development prevented cognitive abnormalities, while repairing the gene in other kinds of neurons and in other locations had no effect.
Rumbaugh noted prenatal diagnosis of some infant genetic disorders is on the horizon. Technological advances in genetic sequencing allow for individual genomes to be scanned for damaging mutations; it is possible to scan the entire genome of a child still in the womb. “Our research suggests that if Syngap1 function can be fixed very early in development, this should protect the brain from damage and permanently improve cognitive function,” said TSRI Research Associate Emin Ozkan, a first author of the study, along with TSRI Research Associate Thomas Creson. “In theory, patients then wouldn’t have to be subjected to a lifetime of therapies and worry that the drugs might stop working or have side effects from chronic use.”
Mutations to Syngap1 are a leading cause of “sporadic intellectual disability,” resulting from new, random mutations arising spontaneously in genes, rather than faulty genes inherited from parents. Intellectual disability affects approximately one to three percent of the population worldwide.
Rumbaugh and his colleagues are continuing to investigate. “Our findings have also identified exciting potential biomarkers in the brain of cognitive failure, allowing us to test new therapeutic strategies in our Syngap1 animal model,” said Creson.
Young adult men who watched more violence on television showed indications of less mature brain development and poorer executive functioning, according to the results of an Indiana University School of Medicine study published online in the journal Brain and Cognition.
The researchers used psychological testing and MRI scans to measure mental abilities and volume of brain regions in 65 healthy males with normal IQ between the age of 18 and 29, specifically chosen because they were not frequent video game players.
Lead author Tom A. Hummer, Ph.D., assistant research professor in the IU Department of Psychiatry, said the young men provided estimates of their television viewing over the past year and then kept a detailed diary of their TV viewing for a week. Participants also completed a series of psychological tests measuring inhibitory control, attention and memory. At the conclusion, MRI scans were used to measure brain structure.
Executive function is the broad ability to formulate plans, make decisions, reason and problem-solve, regulate attention, and inhibit behavior in order to achieve goals.
"We found that the more violent TV viewing a participant reported, the worse they performed on tasks of attention and cognitive control," Dr. Hummer said. "On the other hand, the overall amount of TV watched was not related to performance on any executive function tests."
Dr. Hummer noted that these executive functioning abilities can be important for controlling impulsive behaviors, including aggression. “The worry is that more impulsivity does not mix well with the behaviors modeled in violent programming.”
Tests that measured working memory, another subtype of executive functioning, were not found to be related to overall or violent TV viewing.
Comparing TV habits to brain images also produced results that Dr. Hummer and colleagues believe are significant.
"When we looked at the brain scans of young men with higher violent television exposure, there was less volume of white matter connecting the frontal and parietal lobes, which can be a sign of less maturity in brain development," he said.
White matter is tissue in the brain that insulates nerve fibers connecting different brain regions, making functioning more efficient. In typical development, the amount or volume of white matter increases as the brain makes more connections until about age 30, improving communication between regions of the brain. Connections between the frontal and parietal lobes are thought to be especially important for executive functioning.
"The take-home message from this study is the finding of a relationship between how much violent television we watch and important aspects of brain functioning like controlled attention and inhibition," Dr. Hummer said.
Dr. Hummer cautions that more research is needed to better understand the study findings.
"With this study we could not isolate whether people with poor executive function are drawn to programs with more violence or if the content of the TV viewing is responsible for affecting the brain’s development over a period of time," Dr. Hummer said. "Additional longitudinal work is necessary to resolve whether individuals with poor executive function and slower white matter growth are more drawn to violent programming or if exposure to media violence modifies development of cognitive control," Dr. Hummer said.
A neuroscientist from Trinity College Dublin has proposed a new, ground-breaking explanation for the fundamental process of ‘habituation’, which has never been completely understood by neuroscientists.
Typically, our response to a stimulus is reduced over time if we are repeatedly exposed to it. This process of habituation enables organisms to identify and selectively ignore irrelevant, familiar objects and events that they encounter again and again. Habituation therefore allows the brain to selectively engage with new stimuli, or those that it ‘knows’ to be relevant. For example, the unusual sensation created by a spider walking over our skin should elicit an appropriate evasive response, but the touch of a shirt or blouse on the same skin should be functionally ignored by the nervous system. If habituation does not occur, then such unimportant stimuli become distracting, which means that complex environments can become overwhelming.
The new perspective on the way habituation occurs has implications for our understanding of neuropsychiatric conditions, because normal habituation, emotional responses and attentional abilities are altered in several of these conditions. In particular, hypersensitivity to complex environments is common in individuals on the autism spectrum.
Habituation has long been recognised as the most fundamental form of learning, but it has never been satisfactorily explained. In a Perspective article just published in the leading international journal Neuron (embargoed copy), Professor of Neurogenetics in the School of Genetics & Microbiology at Trinity, Mani Ramaswami, explains habituation through what he terms the ‘negative-image model’. The model proposes and explains how a repeated activation of any group of neurons that respond to a given stimulus results in the build-up of ‘negative activation’, which inhibits responses from this same group of cells.
For example, the first view of an unfamiliar and scary face can trigger a fearful response. However after multiple exposures, the group of neurons activated by the face is less effective at activating fear centres because of increased inhibition on this same group of neurons. Significantly, a strong response to new faces persists for much longer in people on the autism spectrum. This matched increase in inhibition (the ‘negative image’), proposed to underlie habituation, is not normally consciously perceived but it can be revealed under particular conditions (see accompanying video for a visual example here).
Professor Ramaswami said: “This Perspective outlines scalable circuit mechanisms that can account for habituation to stimuli encoded by very small or very large assemblies of neurons. Its strength is its simplicity, its basis in experimental data, and its ability to explain many features of habituation. However, more high-quality studies of habituation mechanisms will be required to establish its generality.”
Professor of Experimental Brain Research at Trinity, and Director of the Trinity College Institute for Neuroscience, Shane O’Mara, said: “The arguments and ideas expressed by Professor Ramaswami should lead to additions and changes to our current text-book sections on habituation, which is a process of great relevance to cognition, attention and psychiatric disease. It is possible that highlighting the process of negative image formation as crucial for habituation will prove useful to clinical genetic studies of autism, by helping to place diverse autism susceptibility genes in a common biological pathway.”
When a woman experiences a stressful event early in pregnancy, the risk of her child developing autism spectrum disorders or schizophrenia increases. Yet how maternal stress is transmitted to the brain of the developing fetus, leading to these problems in neurodevelopment, is poorly understood.
New findings by University of Pennsylvania School of Veterinary Medicine scientists suggest that an enzyme found in the placenta is likely playing an important role. This enzyme, O-linked-N-acetylglucosamine transferase, or OGT, translates maternal stress into a reprogramming signal for the brain before birth.
(Image caption: Mice with reduced OGT in their placenta were shorter and leaner than their normal counterparts.)
“By manipulating this one gene, we were able to recapitulate many aspects of early prenatal stress,” said Tracy L. Bale, senior author on the paper and a professor in the Department of Animal Biology at Penn Vet. “OGT seems to be serving a role as the ‘canary in the coal mine,’ offering a readout of mom’s stress to change the baby’s developing brain.”
Bale also holds an appointment in the Department of Psychiatry in Penn’s Perelman School of Medicine. Her co-author is postdoctoral researcher Christopher L. Howerton. The paper was published online in PNAS this week.
OGT is known to play a role in gene expression through chromatin remodeling, a process that makes some genes more or less available to be converted into proteins. In a study published last year in PNAS, Bale’s lab found that placentas from male mice pups had lower levels of OGT than those from female pups, and placentas from mothers that had been exposed to stress early in gestation had lower overall levels of OGT than placentas from the mothers’ unstressed counterparts.
“People think that the placenta only serves to promote blood flow between a mom and her baby, but that’s really not all it’s doing,” Bale said. “It’s a very dynamic endocrine tissue and it’s sex-specific, and we’ve shown that tampering with it can dramatically affect a baby’s developing brain.”
To elucidate how reduced levels of OGT might be transmitting signals through the placenta to a fetus, Bale and Howerton bred mice that partially or fully lacked OGT in the placenta. They then compared these transgenic mice to animals that had been subjected to mild stressors during early gestation, such as predator odor, unfamiliar objects or unusual noises, during the first week of their pregnancies.
The researchers performed a genome-wide search for genes that were affected by the altered levels of OGT and were also affected by exposure to early prenatal stress using a specific activational histone mark and found a broad swath of common gene expression patterns.
They chose to focus on one particular differentially regulated gene called Hsd17b3, which encodes an enzyme that converts androstenedione, a steroid hormone, to testosterone. The researchers found this gene to be particularly interesting in part because neurodevelopmental disorders such as autism and schizophrenia have strong gender biases, where they either predominantly affect males or present earlier in males.
Placentas associated with male mice pups born to stressed mothers had reduced levels of the enzyme Hsd17b3, and, as a result, had higher levels of androstenedione and lower levels of testosterone than normal mice.
“This could mean that, with early prenatal stress, males have less masculinization,” Bale said. “This is important because autism tends to be thought of as the brain in a hypermasculinized state, and schizophrenia is thought of as a hypomasculinized state. It makes sense that there is something about this process of testosterone synthesis that is being disrupted.”
Furthermore, the mice born to mothers with disrupted OGT looked like the offspring of stressed mothers in other ways. Although they were born at a normal weight, their growth slowed at weaning. Their body weight as adults was 10-20 percent lower than control mice.
Because of the key role that that the hypothalamus plays in controlling growth and many other critical survival functions, the Penn Vet researchers then screened the mouse genome for genes with differential expression in the hypothalamus, comparing normal mice, mice with reduced OGT and mice born to stressed mothers.
They identified several gene sets related to the structure and function of mitochrondria, the powerhouses of cells that are responsible for producing energy. And indeed, when compared by an enzymatic assay that examines mitochondria biogenesis, both the mice born to stressed mothers and mice born to mothers with reduced OGT had dramatically reduced mitochondrial function in their hypothalamus compared to normal mice. These studies were done in collaboration with Narayan Avadhani’s lab at Penn Vet.
Such reduced function could explain why the growth patterns of mice appeared similar until weaning, at which point energy demands go up.
“If you have a really bad furnace you might be okay if temperatures are mild,” Bale said. “But, if it’s very cold, it can’t meet demand. It could be the same for these mice. If you’re in a litter close to your siblings and mom, you don’t need to produce a lot of heat, but once you wean you have an extra demand for producing heat. They’re just not keeping up.”
Bale points out that mitochondrial dysfunction in the brain has been reported in both schizophrenia and autism patients.
In future work, Bale hopes to identify a suite of maternal plasma stress biomarkers that could signal an increased risk of neurodevelopmental disease for the baby.
“With that kind of a signature, we’d have a way to detect at-risk pregnancies and think about ways to intervene much earlier than waiting to look at the term placenta,” she said.
UT Arlington researchers have successfully used a portable brain-mapping device to show limited prefrontal cortex activity among student veterans with Post Traumatic Stress Disorder when they were asked to recall information from simple memorization tasks.
The study by bioengineering professor Hanli Liu and Alexa Smith-Osborne, an associate professor of social work, and two other collaborators was published in the May 2014 edition of NeuroImage: Clinical. The team used functional near infrared spectroscopy to map brain activity responses during cognitive activities related to digit learning and memory retrial.
Smith-Osborne has used the findings to guide treatment recommendations for some veterans through her work as principal investigator for UT Arlington’s Student Veteran Project, which offers free services to veterans who are undergraduates or who are considering returning to college.
“When we retest those student veterans after we’ve provided therapy and interventions, they’ve shown marked improvement,” Smith-Osborne said. “The fNIRS data have shown improvement in brain functions and responses after the student veterans have undergone treatment.”
Liu said this type of brain imaging allows us to “see” which brain region or regions fail to memorize or recall learned knowledge in student veterans with PTSD.
“It also shows how PTSD can affect the way we learn and our ability to recall information, so this new way of brain imaging advances our understanding of PTSD.” Liu said.
This study is multi-disciplinary, associating objective brain imaging with neurological disorders and social work.
While UT Arlington bioengineering faculty associate Fenghua Tian is the primary author assisted by bioengineering graduate research assistant Amarnath Yennu, collaborators of the study include UT Austin psychology professor Francisco Gonzalez-Lima and psychology professor Carol North with UT Southwestern Medical Center and the Veterans Administration North Texas Health Care System.
Khosrow Behbehani, dean of the UT Arlington College of Engineering, said this collaborative research is “allowing the researchers to objectively measure the changes in the level of oxygen in the brain and relate them to some of the brain functions that may have been adversely affected by trauma or stress.”
Numerous neuropsychological studies have linked learning dysfunctions – such as memory loss, attention deficits and learning disabilities – with PTSD.
The new study involved 16 combat veterans previously diagnosed with PTSD who were experiencing distress and functional impairment affecting cognitive and related academic performance. The veterans were directed to perform a series of number-ordering tasks on a computer while researchers monitored their brain activity through near infrared spectroscopy, a noninvasive neuroimaging technology.
The research found that participants with PTSD experienced significant difficulty recalling the given digits compared with a control group. This deficiency is closely associated with dysfunction of a portion in the right frontal cortex. The team also determined that near infrared spectroscopy was an effective tool for measuring cognitive dysfunction associated with PTSD.
With that information, Smith-Osborne said mental healthcare providers could customize a treatment plan best suited for that individual.
“It’s not a one-size-fits-all treatment plan but a concentrated effort to tailor the treatment based on where that person is on the learning scale,” Smith-Osborne said.
Smith-Osborne and Liu hope that their research results lead to better and more comprehensive care for veterans and a better college education.
Researchers from Emory’s Rollins School of Public Health discovered that an increase in the protein that helps store dopamine, a critical brain chemical, led to enhanced dopamine neurotransmission and protection from a Parkinson’s disease-related neurotoxin in mice.
Dopamine and related neurotransmitters are stored in small storage packages called vesicles by the vesicular monoamine transporter (VMAT2). When released from these packages dopamine can help regulate movement, pleasure and emotional response. Low dopamine levels are associated with neurodegenerative diseases such as Parkinson’s disease and recent research has shown that VMAT2 function is impaired in people with the disease.
Lead researcher Gary W. Miller, PhD professor and associate dean for research at the Rollins School of Public Health and his team generated transgenic mice with increased levels of VMAT2 and found it led to an increase in dopamine release. In addition, the group found improved outcomes on anxiety and depressive behaviors, increased movement, and protection from MPTP, the chemical that can cause Parkinson’s disease-related damage in the brain.
The complete study is available in the June 17, 2014 edition of Proceedings of the National Academy of Sciences (PNAS).
According to Miller, “This work suggests that enhanced vesicular filling can be sustained over time and may be a viable therapeutic approach for a variety of central nervous system disorders that involve the storage and release of dopamine, serotonin or norepinephrine.”
From animated ads on Main Street to downtown intersections packed with pedestrians, the eyes of urban drivers have much to see.
But while city streets have become increasingly crowded with distractions, our ability to process visual information has remained unchanged for millions of years. Can modern eyes keep up?
Encouragingly, a new study suggests that even as we’re processing a million things at once, we are still sensitive to certain kinds of changes in our visual environment — even while performing a difficult task.
In a paper published in Visual Cognition, researchers from Concordia University, Kansas State University, the University of Findlay, the University of Central Florida and the University of Illinois prove that we can automatically detect changes in blur across our field of view.
To investigate, the research team focused on the common problem of blurred sight, which can be caused by factors like changes in distance between objects, as well as vision disorders like near-sightedness, far-sightedness and astigmatism.
“Blur is normally compensated for by adjusting the lens of the eye to bring the image back into focus,” says study co-author Aaron Johnson, a professor in the Department of Psychology at Concordia.
“We wanted to know if the detection of this blur by the brain happens automatically, because previous research had resulted in two conflicting views.”
Those views suggest:
“If blur is detected automatically and doesn’t require attention, then performing another cognitive task — driving, say — at the same time shouldn’t change our ability to detect the blur,” Johnson says.
To determine which of these two theories was correct, he and his colleagues used a new technique that presented different amounts of blur to various regions of the eye.
The researchers showed study participants (individuals with normal, or corrected-to-normal, vision) 1,296 distinct images — pictures of things ranging from forests to building interiors — and used a window that moved based on the their eye movements to give the pictures two levels of resolution.
As they changed the resolution from blurry to sharp, the researchers gave participants mental tasks of varying degree of difficulty. Regardless of the difficulty levels, though, the subjects’ ability to detect blur in these pictures was unchanged.
“Our study proves that, much like other simple visual features such as colour and size, blur in an image doesn’t seem to require mental effort to detect,” Johnson says.
“The process may be what we call ‘pre-attentive’ — that is, little or no attention is required to detect it. As such, this research provides insight into a key task, compensating for blur, that the visual system must perform on a daily basis. In the future, I hope to study how blur detection changes with age.”
An international team of researchers has discovered a significant genetic component of Idiopathic Generalized Epilepsy (IGE), the most common form of epilepsy. Epilepsy is a neurological disorder characterized by sudden, uncontrolled electrical discharges in the brain expressed as a seizure. The new research, published in this week’s issue of EMBO Reports, implicates a mutation in the gene for a protein, known as cotransporter KCC2.
KCC2 maintains the correct levels of chloride ions in neurons, playing a major part in regulating excitation and inhibition of neurons. The results indicate that a genetic mutation of KCC2 might be a risk factor for developing IGE.
“We found a clear statistical association between two variants of KCC2 and severe IGE in a large French-Canadian patient sample,” said Dr. Guy Rouleau, Director of the Montreal Neurological Institute and Hospital (The Neuro) at McGill University and the McGill University Health Centre, and senior author of the study. “Our data not only corroborate recent findings by other groups but vastly extend them from genetic, physiological and biochemical standpoints.” The first authors on the paper are Dr. Kristopher Kahle, chief neurosurgery resident at Massachusetts General Hospital and post-doctoral fellow at Harvard University, and Dr. Nancy Merner, a former post-doctoral fellow in Dr. Rouleau’s laboratory and now a professor at Auburn University.
The study examined 380 French Canadians with IGE living in Montreal and Quebec City. Results were compared to data from a control group of more than 1,200 people. “KCC2 is a hot topic in neuroscience given its important role in neuronal signaling and in its potential role in neurological diseases such as epilepsy, neuropathic pain, and other diseases,” said Dr. Rouleau.
Each day in Canada, an average of 42 people learn that they have epilepsy. In 50 – 60% of cases, the cause of epilepsy is unknown. The major form of treatment is long-term drug therapy. Drugs are not a cure and can have numerous, sometimes severe, side effects. Brain surgery is recommended only when medication fails and when the seizures are confined to one area of the brain where brain tissue can be safely removed without damaging personality or function.
The hippocampus is a small structure in the brains of mammals that plays a crucial role in processing input from our senses and allows perceptions to be stored as memories. Nerve cells that inhibit the activity of other cells have now been shown to play a much larger and more complex role in these processes than previously assumed. Teams led by Prof. Dr. Marlene Bartos from the Cluster of Excellence BrainLinks-BrainTools at the University of Freiburg and Prof. Dr. Imre Vida from the Cluster of Excellence NeuroCure at the hospital Charité in Berlin report these findings in the current issue of the Journal of Neuroscience.
(Image caption: Three different cell types in the hippocampus (BC, HCP, and HIPP) were previously known to have different morphologies (top). New research shows that they respond to electrical stimulation (black traces) by inhibiting other nerve cells in very different patterns (bottom), allowing for more powerful information processing. Credit: BrainLinks-BrainTools)
In their study, the scientists investigated how special types of so-called interneurons build connections with each other within the hippocampus and how their function influences the network of nerve cells as a whole. Interneurons do not prompt other nerve cells to become active but, on the contrary, inhibit them. This kind of suppression plays an important role in brain activity in general. Information processing would not be possible otherwise, because a brain in which all nerve cells are active at the same time is effectively put out of order.
The hippocampus is home to a variety of different inhibitory cells, which were known so far to differ greatly in their form and function. But up to now it has been generally assumed that their actual influence on the activity of the brain structure they belong to is rather small. By combining several different experimental methods, Bartos, Vida, and their teams succeeded in showing that these cells are actually able to strongly interfere with the activity and the timing of activity patterns within the hippocampus. Moreover, the various possible combinations of connections between these different cell types show markedly different characteristics in their function. This makes the inhibition within the hippocampus much more flexible and versatile than previously assumed. The team of scientists suspects that this also makes the capability to process information within the hippocampus much bigger. The results published in this study are from experiments conducted in acute slice preparations of the hippocampus. Up next for the researchers will be the task of verifying these results within the actual brain.
A study group at the Medical University of Vienna’s Centre for Brain Research has investigated the function of an intracellular dopamine pump in Parkinson’s patients compared to a healthy test group. It turned out that this pump is less effective at pumping out dopamine and storing it in the brain cells of Parkinson’s sufferers. If dopamine is not stored correctly, however, it can cause self-destruction of the affected nerve cells.
In the brain, dopamine mediates the exchange of information between different neurons and, to help it do this, it is continuously reformed at the contact points between the corresponding nerve cells. It is stored in structures known as vesicles (intracellular bubbles) and it is released when required. In people with Parkinson’s disease, the death of these nerve cells causes a lack of dopamine, and this in turn causes the familiar movement problems such as motor retardation, stiffness of the muscles and tremors.
More than 50 years ago, in the Institute of Pharmacology at the University of Vienna (now the MedUni Vienna), Herbert Ehringer and Oleh Hornykiewicz discovered that Parkinson’s disease is caused by a lack of dopamine in certain regions of the brain. This discovery enabled Hornykiewicz to introduce the amino acid L-DOPA into the treatment of Parkinson’s to substitute the dopamine and make the symptoms of the condition manageable for years.
The reasons for the death of nerve cells in Parkinson’s disease are not yet fully understood, however, which is why it is still not possible to prevent the disease from developing. Nevertheless, dopamine itself, if it is not stored correctly in vesicles, can cause self-destruction of the affected nerve cells.
Now, a further step forward has been taken in the research into the causes of this disease: a study at the MedUni Vienna’s Centre for Brain Research, led by Christian Pifl and the now 87-year-old Oleh Hornykiewicz, compared the brains of deceased Parkinson’s patients with those of a neurologically healthy control group. For the first time, it was possible to prepare the dopamine-storing vesicles from the brains so that their ability to store dopamine by pumping it in could be measured in quantitative terms.
It turned out that the pumps in the vesicles of Parkinson’s sufferers pumped the dopamine out less efficiently. “This pump deficiency and the associated reduction in dopamine storage capacity of the Parkinson’s vesicles could lead to dopamine collecting in the nerve cells, developing its toxic effect and destroying the nerve cells,” explains Christian Pifl.
The amygdala is a key “fear center” in the brain. Alterations in the development of the amygdala during childhood may have an important influence on the development of anxiety problems, reports a new study in the current issue of Biological Psychiatry.
Researchers at the Stanford University School of Medicine recruited 76 children, 7 to 9 years of age, a period when anxiety-related traits and symptoms can first be reliably identified. The children’s parents completed assessments designed to measure the anxiety levels of the children, and the children then underwent non-invasive magnetic resonance imaging (MRI) scans of brain structure and function.
The researchers found that children with high levels of anxiety had enlarged amygdala volume and increased connectivity with other brain regions responsible for attention, emotion perception, and regulation, compared to children with low levels of anxiety. They also developed an equation that reliably predicted the children’s anxiety level from the MRI measurements of amygdala volume and amygdala functional connectivity.
The most affected region was the basolateral portion of the amygdala, a subregion of the amygdala implicated in fear learning and the processing of emotion-related information.
“It is a bit surprising that alterations to the structure and connectivity of the amygdala were so significant in children with higher levels of anxiety, given both the young age of the children and the fact that their anxiety levels were too low to be observed clinically,” commented Dr. Shaozheng Qin, first author on this study.
Dr. John Krystal, Editor of Biological Psychiatry, commented, “It is critical that we move from these interesting cross-sectional observations to longitudinal studies, so that we can separate the extent to which larger and better connected amygdalae are risk factors or consequences of increased childhood anxiety.”
“However, our study represents an important step in characterizing altered brain systems and developing predictive biomarkers in the identification for young children at risk for anxiety disorders,” Qin added. “Understanding the influence of childhood anxiety on specific amygdala circuits, as identified in our study, will provide important new insights into the neurodevelopmental origins of anxiety in humans.”
Orexin proteins, which are blamed for spontaneous daytime sleepiness, also play a crucial role in bone formation, according to findings by UT Southwestern Medical Center researchers. The findings could potentially give rise to new treatments for osteoporosis, the researchers say.
Orexins are a type of protein used by nerve cells to communicate with each other. Since their discovery at UT Southwestern more than 15 years ago, they have been found to regulate a number of behaviors, including arousal, appetite, reward, energy expenditure, and wakefulness. Orexin deficiency, for example, causes narcolepsy – spontaneous daytime sleepiness. Thus, orexin antagonists are promising treatments for insomnia, some of which have been tested in Phase III clinical trials.
UT Southwestern researchers, working with colleagues in Japan, now have found that mice lacking orexins also have very thin and fragile bones that break easily because they have fewer cells called osteoblasts, which are responsible for building bones.
“Osteoporosis is highly prevalent, especially among post-menopausal women. We are hoping that we might be able to take advantage of the already available orexin-targeting small molecules to potentially treat osteoporosis,” said Dr. Yihong Wan, Assistant Professor of Pharmacology, the Virginia Murchison Linthicum Scholar in Medical Research, and senior author for the study, published in the journal Cell Metabolism.
Osteoporosis, the most common type of bone disease in which bones become fragile and susceptible to fracture, affects more than 10 million Americans. The disease, which disproportionately affects seniors and women, leads to more than 1.5 million fractures and some 40,000 deaths annually. In addition, the negative effects impact productivity, mental health, and quality of life. One in five people with hip fractures, for example, end up in nursing homes.
Orexins seem to play a dual role in the process: they both promote and block bone formation. On the bones themselves, orexins interact with another protein, orexin receptor 1 (OX1R), which decreases the levels of the hunger hormone ghrelin. This slows down the production of new osteoblasts and, therefore, blocks bone formation locally. At the same time, orexins interact with orexin receptor 2 (OX2R) in the brain. In this case, the interaction reduces the circulating levels of leptin, a hormone known to decrease bone mass, and thereby promotes bone formation. Therefore, osteoporosis prevention and treatment may be achieved by either inhibiting OX1R or activating OX2R.
“We were very intrigued by this yin-yang-style dual regulation,” said Dr. Wan, a member of the Cecil H. and Ida Green Center for Reproductive Biology Sciences and UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center. “It is remarkable that orexins manage to regulate bone formation by using two different receptors located in two different tissues.”
The central nervous system regulation through OX2R, and therefore promotion of bone formation, was actually dominant over regulation through OX1R. So when the group examined mice lacking both OX1R and OX2R, they had very fragile bones with decreased bone formation. Similarly, when they assessed mice that expressed high levels of orexins, those mice had increased numbers of osteoblasts and enhanced bone formation.
In a remarkable series of experiments on a fungus that causes cryptococcal meningitis, a deadly infection of the membranes that cover the spinal cord and brain, investigators at UC Davis have isolated a protein that appears to be responsible for the fungus’ ability to cross from the bloodstream into the brain.
The discovery — published online June 3 in mBio, the open-access, peer-reviewed journal of the American Society for Microbiology — has important implications for developing a more effective treatment for Cryptococcus neoformans, the cause of the condition, and other brain infections, as well as for brain cancers that are difficult to treat with conventional medications.
“This study fills a significant gap in our understanding of how C. neoformans crosses the blood-brain barrier and causes meningitis,” said Angie Gelli, associate professor of pharmacology at UC Davis and principal investigator of the study. “It is our hope that our findings will lead to improved treatment for this fungal disease as well as other diseases of the central nervous system.”
Normally the brain is protected from bacterial, viral and fungal pathogens in the bloodstream by a tightly packed layer of endothelial cells lining capillaries within the central nervous system — the so-called blood-brain barrier. Relatively few organisms — and drugs that could fight brain infections or cancers — can breach this protective barrier.
The fungus studied in this research causes cryptococcal meningoencephalitis, a usually fatal brain infection that annually affects some 1 million people worldwide, most often those with an impaired immune system. People typically first develop an infection in the lungs after inhalation of the fungal spores of C. neoformans in soil or pigeon droppings. The pathogen then spreads to the brain and other organs.
Unique protein identified
In an effort to discover how C. neoformans breaches the blood-brain barrier, the investigators isolated candidate proteins from the cryptococcal cell surface. One was a previously uncharacterized metalloprotease that they named Mpr1. (A protease is an enzyme — a specialized protein — that promotes a chemical reaction; a metalloprotease contains a metal ion — in this case zinc — that is essential for its activity.) The M36 class of metalloproteases to which Mpr1 belongs is unique to fungi and does not occur in mammalian cells.
The investigators next artificially generated a strain of C. neoformans that lacked Mpr1 on the cell surface. Unlike the normal wild-type C. neoformans, the strain without Mpr1 could not cross an artificial model of the human blood-brain barrier.
They next took a strain of common baking yeast — Saccharomyces cerevisiae — that does not cross the blood-brain barrier and does not normally express Mpr1, and modified it to express Mpr1 on its cell surface. This strain then gained the ability to cross the blood-brain barrier model.
Investigators then infected mice with either the C. neoformans that lacked Mpr1 or the wild-type strain by injecting the organisms into their bloodstream. Comparing the brain pathology of mice 48 hours later, they found numerous cryptococci-filled cysts throughout the brain tissue of mice infected with the wild-type strain; these lesions were undetectable in those infected with the strain lacking Mpr1. In another experiment, after 37 days of being infected by the inhalation route, 85 percent of the mice exposed to the wild-type C. neoformans had died, while all of those given the fungus without Mpr1 were alive.
“Our studies are the first clear demonstration of a specific role for a fungal protease in invading the central nervous system,” said Gelli. “The details of exactly how it crosses is an important new area under investigation.”
New targeted therapies possible
According to Gelli, their discovery has significant therapeutic potential via two important mechanisms. Either Mpr1 — or an aspect of the mechanism by which it crosses the blood-brain barrier — could be a target of new drugs for treating meningitis caused by C. neoformans. In a person who develops cryptococcal lung infection, such a treatment would ideally make the fungus less likely to enter the brain and lead to a rapidly fatal meningitis.
Secondly, Mpr1 could be developed as part of a drug-delivery vehicle for brain infections and cancers. An antibiotic or cancer-fighting drug that is unable to cross the blood-brain barrier on its own could be attached to a nanoparticle containing Mpr1, allowing it to hitch a ride and deliver its goods to where it is needed.
“The biggest obstacle to treating many brain cancers and infections is getting good drugs through the blood-brain barrier,” said Gelli. “If we could design an effective delivery system into the brain, the impact would be enormous for treating some of these terrible diseases.”
Gelli’s group is currently pursuing such a nanoparticle drug-delivery system using Mpr1. They are also further investigating the exact molecular mechanism by which Mpr1 breaches the blood-brain barrier.
In a new study, scientists at the National Institutes of Health took a molecular-level journey into microtubules, the hollow cylinders inside brain cells that act as skeletons and internal highways. They watched how a protein called tubulin acetyltransferase (TAT) labels the inside of microtubules. The results, published in Cell, answer long-standing questions about how TAT tagging works and offer clues as to why it is important for brain health.
(Image caption: NIH scientists watched the inside of brain cell tubes, called microtubules, get tagged by a protein called TAT. Tagging is a critical process in the health and development of nerve cells. Credit: Courtesy of the Roll-Mecak lab, NINDS, Bethesda, MD)
Microtubules are constantly tagged by proteins in the cell to designate them for specialized functions, in the same way that roads are labeled for fast or slow traffic or for maintenance. TAT coats specific locations inside the microtubules with a chemical called an acetyl group. How the various labels are added to the cellular microtubule network remains a mystery. Recent findings suggested that problems with tagging microtubules may lead to some forms of cancer and nervous system disorders, including Alzheimer’s disease, and have been linked to a rare blinding disorder and Joubert Syndrome, an uncommon brain development disorder.
“This is the first time anyone has been able to peer inside microtubules and catch TAT in action,” said Antonina Roll-Mecak, Ph.D., an investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and the leader of the study.
Microtubules are found in all of the body’s cells. They are assembled like building blocks, using a protein called tubulin. Microtubules are constructed first by aligning tubulin building blocks into long strings. Then the strings align themselves side by side to form a sheet. Eventually the sheet grows wide enough that it closes up into a cylinder. TAT then bonds an acetyl group to alpha tubulin, a subunit of the tubulin protein.
Some microtubules are short-lived and can rapidly change lengths by adding or removing tubulin pieces along one end, whereas others remain unchanged for longer times. Recognizing the difference may help cells function properly. For example, cells may send cargo along stable microtubules and avoid ones that are being rebuilt. Cells appear to use a variety of chemical labels to describe the stability of microtubules.
“Our study uncovers how TAT may help cells distinguish between stable microtubules and ones that are under construction,” said Dr. Roll-Mecak. According to Dr. Roll-Mecak, high levels of microtubule tagging are unique to nerve cells and may be the reason that they have complex shapes allowing them to make elaborate connections in the brain.
For decades scientists knew that the insides of long-lived microtubules were often tagged with acetyl groups by TAT. Changes in acetylation may influence the health of nerve cells. Some studies have shown that blocking this form of microtubule tagging leads to nerve defects, brain abnormalities or degeneration of nerve fibers. Since the discovery of microtubule acetylation, scientists have been puzzled about how TAT accesses the inside of the microtubules and how the tagging reaction happens.
To watch TAT at work, Dr. Roll-Mecak and her colleagues took high resolution movies of individual TAT molecules interacting with microtubules in real time. They saw that TAT surfs through the inside of microtubules and although it can find acetylation sites quickly, the process of adding the tag occurs very slowly.
In general, tagging reactions work like keys fitting into locks: the better the key fits, the faster the lock can open. Similarly, the rate of the reactions is determined by how well TAT molecules fit around tagging sites.
Dr. Roll-Mecak’s team investigated this idea by using a technique called X-ray crystallography to look at how atoms on TAT molecules interact with acetylation sites on tubulin molecules. Their results suggested that TAT fit poorly around the sites.
“It looks as though TAT can easily journey through microtubules spotting acetylation sites but may only label those that are stable for longer periods of time,” said Dr. Roll-Mecak.
This may help cells identify the microtubules they need to rapidly change shapes or send cargo to other places. Further studies may help researchers understand how microtubule tagging influences nerve cells in health and disease.
Researchers have determined that a copper compound known for decades may form the basis for a therapy for amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.
In a new study just published in the Journal of Neuroscience, scientists from Australia, the United States (Oregon), and the United Kingdom showed in laboratory animal tests that oral intake of this compound significantly extended the lifespan and improved the locomotor function of transgenic mice that are genetically engineered to develop this debilitating and terminal disease.
In humans, no therapy for ALS has ever been discovered that could extend lifespan more than a few additional months. Researchers in the Linus Pauling Institute at Oregon State University say this approach has the potential to change that, and may have value against Parkinson’s disease as well.
“We believe that with further improvements, and following necessary human clinical trials for safety and efficacy, this could provide a valuable new therapy for ALS and perhaps Parkinson’s disease,” said Joseph Beckman, a distinguished professor of biochemistry and biophysics in the OSU College of Science.
“I’m very optimistic,” said Beckman, who received the 2012 Discovery Award from the OHSU Medical Research Foundation as the leading medical researcher in Oregon.
ALS was first identified as a progressive and fatal neurodegenerative disease in the late 1800s and gained international recognition in 1939 when it was diagnosed in American baseball legend Lou Gehrig. It’s known to be caused by motor neurons in the spinal cord deteriorating and dying, and has been traced to mutations in copper, zinc superoxide dismutase, or SOD1. Ordinarily, superoxide dismutase is an antioxidant whose proper function is essential to life.
When SOD1 is lacking its metal co-factors, it “unfolds” and becomes toxic, leading to the death of motor neurons. The metals copper and zinc are important in stabilizing this protein, and can help it remain folded more than 200 years.
“The damage from ALS is happening primarily in the spinal cord and that’s also one of the most difficult places in the body to absorb copper,” Beckman said. “Copper itself is necessary but can be toxic, so its levels are tightly controlled in the body. The therapy we’re working toward delivers copper selectively into the cells in the spinal cord that actually need it. Otherwise, the compound keeps copper inert.”
“This is a safe way to deliver a micronutrient like copper exactly where it is needed,” Beckman said.
By restoring a proper balance of copper into the brain and spinal cord, scientists believe they are stabilizing the superoxide dismutase in its mature form, while improving the function of mitochondria. This has already extended the lifespan of affected mice by 26 percent, and with continued research the scientists hope to achieve even more extension.
The compound that does this is called copper (ATSM), has been studied for use in some cancer treatments, and is relatively inexpensive to produce.
“In this case, the result was just the opposite of what one might have expected,” said Blaine Roberts, lead author on the study and a research fellow at the University of Melbourne, who received his doctorate at OSU working with Beckman.
“The treatment increased the amount of mutant SOD, and by accepted dogma this means the animals should get worse,” he said. “But in this case, they got a lot better. This is because we’re making a targeted delivery of copper just to the cells that need it.
“This study opens up a previously neglected avenue for new disease therapies, for ALS and other neurodegenerative disease,” Roberts said.
A new study from Karolinska Institutet shows that a part of the nervous system, the parasympathetic nervous system, is formed in a way that is different from what researchers previously believed. In this study, which is published in the journal Science, a new phenomenon is investigated within the field of developmental biology, and the findings may lead to new medical treatments for congenital disorders of the nervous system.
Almost all of the body’s functions are controlled by the autonomous, involuntary nervous system, for example the heart and blood vessels, liver and gastrointestinal system. At rest, the body is set up for energy saving functions, which is regulated by the parasympathetic part of the autonomous nervous system.
Current understanding is that many important types of cells, including the parasympathetic nerve cells in various organs, originate in early progenitor cells that move short distances while the embryo is still small. But this model does not explain how many of our organs – which develop relatively late, when the embryo is large – are furnished with cells that form the parasympathetic neurons.
This study alters a fundamental principal of our understanding of how the peripheral nervous system develops in the body. Researchers at Karolinska Institutet have made three-dimensional reconstructions of mouse embryos. These show that the parasympathetic neurons are formed from immature glial cells known as Schwann cell precursors that travel along the peripheral nerves out to the body’s tissues and organs. The immature cells have the properties of stem cells and may be the origin of several different types of cells. For example, the researchers behind this new study have previously demonstrated that the majority of our melanocytes (pigment cells) are born from these cells.
New principal of developmental biology
"Our study focuses on a new principal of developmental biology, a targeted recruitment of cells that are probably also used in the reconstruction of tissue. Despite the elegance, simplicity and beauty of this principal, it is still unclear how the number of parasympathetic neurons is controlled and why only some of the cells transported by nerves are transformed into that which becomes an important part of the nervous system", says Igor Adameyko at the Department of Physiology and Pharmacology who, together with Patrik Ernfors at the Department of Medical Biochemistry and Biophysics, is responsible for the study.
Somewhat surprisingly, the researchers found that the entire parasympathetic nervous system arises from these progenitor cells that travel along the peripheral nerves. The researchers hope that this discovery will open up the possibility of new ways to treat congenital disorders of the autonomous nervous system using regenerative medicine.
In a new study published online in the Journal of the American Heart Association June 12, 2014, researchers at Columbia Engineering report that they have identified a new component of the biological mechanism that controls blood flow in the brain. Led by Elizabeth M. C. Hillman, associate professor of biomedical engineering, the team has demonstrated, for the first time, that the vascular endothelium plays a critical role in the regulation of blood flow in response to stimulation in the living brain.
(Image caption: In-vivo two-photon microscopy image of endothelial cells lining surface arteries in the brain (green, TIE-2/GFP). Red cells are astrocytes labeled with sulphorhodamine. New results suggest that the continuous pathway of endothelial cells within the brain’s arteries is essential for propagating signals that orchestrate local dilation and increases in blood flow in response to local neuronal activity. Credit: Image courtesy of Elizabeth Hillman)
“We think we’ve found a missing link in our understanding of how the brain dynamically tunes its blood flow to stay in sync with the activity of neurons,” says Hillman, who has a joint appointment in Radiology. She is also a member of the Zuckerman Mind Brain Behavior Institute and the Kavli Institute for Brain Science at Columbia. Hillman has spent more than 10 years using advanced imaging tools to study how blood flow is controlled in the brain. “Earlier studies identified small pieces of the puzzle, but we didn’t believe they formed a cohesive ‘big picture’ that unified everybody’s observations. Our new finding seems to really connect the dots.”
Understanding how and why the brain regulates its blood flow could provide important clues to understanding early brain development, disease, and aging. The brain increases local blood flow when neurons fire, and this increase is what is detected by a functional magnetic resonance imaging (fMRI) scan. Hillman found that the vascular endothelium, the inner layer of blood vessels, plays a critical role in propagating and shaping the blood flow response to local neuronal activity. While the vascular endothelium is known to do this in other areas of the body, until now the brain was thought to use a different, more specialized mechanism and researchers in the field were focused on the cells surrounding the vessels in the brain.
“Once we realized the importance of endothelial signaling in the regulation of blood flow in the brain,” Hillman adds, “we wondered whether overlooking the vascular endothelium might have led researchers to misinterpret their results.”
“As we identified this pathway, so many things fell into place,” she continues, “We really hope that our work will encourage others to take a closer look at the vascular endothelium in the brain. So far, we think that our findings have far-reaching and really exciting implications for neuroscience, neurology, cardiovascular medicine, radiology, and our overall understanding of how the brain works.”
This research was carried out in Hillman’s Laboratory for Functional Optical Imaging, led by PhD student and lead author on the study, Brenda Chen. Other lab members who assisted with the study included PhD and MD/PhD students from Columbia Engineering, Neurobiology and Behavior, and Columbia University Medical Center. The group combined their engineering skills with their expertise in neuroscience, biology, and medicine to understand this new aspect of brain physiology.
To tease apart the role of endothelial signaling in the living brain, they had to develop new ways to both image the brain at very high speeds, and also to selectively alter the ability of endothelial cells to propagate signals within intact vessels. The team achieved this through a range of techniques that use light and optics, including imaging using a high-speed camera with synchronized, strobed LED illumination to capture changes in the color, and thus the oxygenation level of flowing blood. Focused laser light was used in combination with a fluorescent dye within the bloodstream to cause oxidative damage to the inner endothelial layer of blood brain arterioles, while leaving the rest of the vessel intact and responsive. The team showed that, after damaging a small section of a vessel using their laser, the vessel no longer dilated beyond the damaged point. When the endothelium of a larger number of vessels was targeted in the same way, the overall blood flow response of the brain to stimulation was significantly decreased.
“Our finding unifies what is known about blood flow regulation in the rest of the body with how it is regulated in the brain,” Hillman explains. “This has wider reaching implications since there are many disease states known to affect blood flow regulation in the rest of the body that, until now, were not expected to directly affect brain health.” For instance, involvement of the endothelium might explain neural deficits in diabetics; a clue that could lead to new diagnostics tests and treatments for neurological conditions associated with broader cardiovascular problems.
“Improving our fundamental understanding of how and why the brain regulates its blood flow is key to understanding how and when this mechanism could be altered or broken,” she says. “We think this could extend to studies of early brain development, aging, and diseases such as Alzheimer’s and dementia.”
The team’s research findings may also explain the effects of some drugs on the brain, and on the fMRI response to stimulation, since the vascular endothelium is exposed to chemicals in the bloodstream. “Overall, this work could dramatically improve our ability to interpret fMRI data collected in humans, perhaps making it a better tool for doctors to understand brain disease,” she adds. Hillman’s work in this area is also featured in an upcoming review in the 2014 edition of the Annual Review of Neuroscience, as well as an article in Scientific American MIND (July/August 2014).
Hillman plans next to address the broad range of implications her latest finding may have. She wants to explore the effects of drugs and disease states on the coupling of blood flow to neuronal activity in the brain, and is now starting studies to explore fMRI data from a range of different disease states to see whether she can find signs of neurovascular dysfunction. She is also working on characterizing the co-evolution of neuronal and hemodynamic activity during brain development and is beginning to develop new imaging tools that will enable non-invasive, inexpensive monitoring of brain hemodynamics in infants and children who cannot be imaged within an MRI scanner.
“Our latest finding gives us a new way of thinking about brain disease—that some conditions assumed to be caused by faulty neurons could actually be problems with faulty blood vessels,” Hillman adds. “This gives us a new target to focus on to explore treatments for a wide range of disorders that have, until now, been thought of as impossible to treat. The brain’s vasculature is a critical partner in normal brain function. We hope that we are slowly getting closer to untangling some of the mysteries of the human brain.”