Posts tagged science
Articles and news from the latest research reports.
Neuronal regeneration and the two-part design of nerves
Researchers at the University of Michigan have evidence that a single gene controls both halves of nerve cells, and their research demonstrates the need to consider that design in the development of new treatments for regeneration of nerve cells.
A paper published online in PLOS Biology by U-M Life Sciences Institute faculty member Bing Ye and colleagues shows that manipulating genes of the fruit fly Drosophila to promote the growth of one part of the neuron simultaneously stunts the growth of the other part.
Understanding this bimodal nature of neurons is important for researchers developing therapies for spinal cord injury, neurodegeneration and other nervous system diseases, Ye said.
Nerve cells look strikingly like trees, with a crown of “branches” converging at a “trunk.” The branches, called dendrites, input information from other neurons into the nerve cell. The trunk, or axon, transmits the signal to the next cell.
"If you want to regenerate an axon to repair an injury, you have to take care of the other end, too," said Ye, assistant professor in the Department of Cell and Developmental Biology at the U-M Medical School.
The separation of the nerve cell into these two parts is so fundamental to neuroscience that it’s known as the “neuron doctrine,” but how exactly neurons create, maintain and regulate these two separate parts and functions is still largely unknown.
While the body is growing, the neuronal network grows rapidly. But nerve cells don’t divide and replicate like other cells in the body (instead, a specific type of stem cell creates them). Adult nerve cells appear to no longer have the drive to grow, so the loss of neurons due to injury or neurodegeneration can be permanent.
Ye’s paper highlights the bimodal nature of neurons by explaining how a kinase that promotes axon growth surprisingly has the opposite effect of impeding dendrite growth of the same cell.
In the quest to understand the fundamentals of nerve cell growth in order to stimulate regrowth after injury, scientists have identified the genes responsible for axon growth and were able to induce dramatic growth of the long “trunk” of the cell, but less attention has been given to dendrites.
There are technical reasons that studying axons is easier than studying dendrites: The bundle of axons in a nerve is easier to track under the microscope, but to get an image of dendrites would require labeling single neurons.
Ye’s lab circumvented that obstacle by using Drosophila as a model. Using this simple model of the nervous system, the scientists were able to reliably label both axons and dendrites of single neurons and see what happened to nerve cells with various mutations of genes that are shared between the flies and humans.
One of the genes shared by Drosophila and people is the one that makes a protein called Dual Lucine Zipper Kinase, or DLK. As described previously by other groups, DLK is a product of the gene responsible for axon growth. Cells with more of the protein had very long axons, and those without the gene or protein had no regeneration after nerve injury. The DLK kinase seemed a promising target for therapies to regenerate nerve cells.
However, Ye’s lab found that the kinase had the opposite effect on the dendrites: Lots of DLK leads to diminished dendrites.
"This in vivo evidence of bimodal control of neuronal growth calls attention to the need to look at the other side of a neuron in terms of developing new therapies," Ye said. "If we use this kinase, DLK, as a drug target for axon growth, we’ll have to figure out a way to block its effect on dendrites."
Heart Health Matters to Your Brain
People suffering from type 2 diabetes and cardiovascular disease (CVD) are at an increased risk of cognitive decline, according to a new study from Wake Forest Baptist Medical Center.
Lead author Christina E. Hugenschmidt, Ph.D., an instructor of gerontology and geriatric medicine at Wake Forest Baptist, said the results from the Diabetes Heart Study-Mind (DHS-Mind) suggest that CVD is playing a role in cognition problems before it is clinically apparent in patients. The research appears online ahead of print in the Journal of Diabetes and Its Complications.
”There has been a lot of research looking at the links between type 2 diabetes and increased risk for dementia, but this is the first study to look specifically at subclinical CVD and the role it plays,” Hugenschmidt said. “Our research shows that CVD risk caused by diabetes even before it’s at a clinically treatable level might be bad for your brain.
"The results imply that additional CVD factors, especially calcified plaque and vascular status, and not diabetes status alone, are major contributors to type 2 diabetes related cognitive decline."
Hugenschmidt said DHS-Mind is a follow-up study to the Diabetes Heart Study (DHS), which examined relationships between cognitive function, vascular calcified plaque and other major diabetes risk factors associated with cognition. The DHS investigated CVD in siblings with a high incidence and prevalence of type 2 diabetes, where extensive measurements of CVD risk factors were obtained during exams that occurred from 1998 to 2006.
The study was supported by the National Institutes of Health through NINDS R01NS058700-02S109 and NIDDK 1F32DK083214-01.
The DHS-Mind study added cognitive testing to existing measures with the express purpose of exploring the relationships between measures of atherosclerosis and cognition in a population heavily affected by diabetes, a novel approach given that previous studies have focused on diabetes and cognition in the context of clinically evident CVD, Hugenschmidt said. The researchers followed up with as many of the original 1,443 DHS study participants as possible who had cardiovascular measures. Of that 516 total, 422 were affected with type 2 diabetes and 94 were unaffected.
Hugenschmidt said the researchers ran a battery of cognitive testing that looked at different kinds of thinking like memory and processing speed, as well as executive function, which is a set of mental skills coordinated in the brain’s frontal lobe that includes stop and think processes like managing time and attention, planning and organizing. She said that being able to look at data where the comparison group was siblings, some of whom had a high level of CVD themselves, made the results more clinically relevant because the participants shared the same environmental and genetic background.
"We still saw a difference between these two groups. Even compared to their own siblings who were not disease free, those with diabetes and subclinical cardiovascular disease had a higher risk of cognitive dysfunction," Hugenschmidt said.
CVD explains a lot of the cognitive problems that people with diabetes experience, Hugenschmidt said. “One possibility is that your brain requires a really steady blood flow and it’s possible that the cardiovascular disease that accompanies diabetes might be the main driver behind the cognitive deficits that we see.”
Hugenschmidt said the takeaway for clinicians is to take CVD risk factors into consideration when they’re treating patients with type 2 diabetes patients because even at borderline clinical levels, it might have long-term implications for peoples’ mental, cognitive health.
PET Finds Increased Cognitive Reserve Levels in Highly Educated Pre-Alzheimer’s Patients
Highly educated individuals with mild cognitive impairment that later progressed to Alzheimer’s disease cope better with the disease than individuals with a lower level of education in the same situation, according to research published in the June issue of The Journal of Nuclear Medicine. In the study “Metabolic Networks Underlying Cognitive Reserve in Prodromal Alzheimer Disease: A European Alzheimer Disease Consortium Project,”neural reserve and neural compensation were both shown to play a role in determining cognitive reserve, as evidenced by positron emission tomography (PET).
Cognitive reserve refers to the hypothesized capacity of an adult brain to cope with brain damage in order to maintain a relatively preserved functional level. Understanding the brain adaptation mechanisms underlying this process remains a critical question, and researchers of this study sought to investigate the metabolic basis of cognitive reserve in individuals with higher (more than 12 years) and lower (less than 12 years) levels of education who had mild cognitive impairment that progressed to Alzheimer’s disease, also known as prodromal Alzheimer’s disease.
“This study provides new insight into the functional mechanisms that mediate the cognitive reserve phenomenon in the early stages of Alzheimer’s disease,” said Silvia Morbelli, MD, lead author of the study. “A crucial role of the dorso-lateral prefrontal cortex was highlighted by demonstrating that this region is involved in a wide fronto-temporal and limbic functional network in patients with Alzheimer’s disease and high education, but not in poorly educated Alzheimer’s disease patients.”
In the study, 64 patients with prodromal Alzheimer’s disease and 90 control subjects—coming from the brain PET project (chaired by Flavio Nobili, MD, in Genoa, Italy) of the European Alzheimer Disease Consortium—underwentbrain 18F-FDG PET scans. Individuals were divided into a subgroup with a low level of education (42 controls and 36 prodromal Alzheimer’s disease patients) and a highly educated subgroup (40 controls and 28 prodromal Alzheimer’s disease patients). Brain metabolism was compared between education-matched groups of patients and controls, and then between highly and poorly educated prodromal Alzheimer’s disease patients.
Higher metabolic activity was shown in the dorso-lateral prefrontal cortex for prodromal Alzheimer’s disease patients. More extended and significant correlations of metabolism within the right dorso-lateral prefrontal cortex and other brain regions were found with highly educated than less educated prodromal Alzheimer’s disease patients or even highly educated controls.
This result suggests that neural reserve and neural compensation are activated in highly educated prodromal Alzheimer’s disease patients. Researchers concluded that evaluation of the implication of metabolic connectivity in cognitive reserve further confirms that adding a comprehensive evaluation of resting 18F-FDG PET brain distribution to standard inspection may allow a more complete comprehension of Alzheimer’s disease pathophysiology and possibly may increase 18F-FDG PET diagnostic sensitivity.
“This work supports the notion that employing the brain in complex tasks and developing our own education may help in forming stronger ‘defenses’ against cognitive deterioration once Alzheimer knocks at our door,” noted Morbelli.“It’s possible that, in the future, a combined approach evaluating resting metabolic connectivity and cognitive performance can be used on an individual basis to better predict cognitive decline or response to disease-modifying therapy.”
(Source: interactive.snm.org)
‘Back to sleep’ does not affect baby’s ability to roll
UAlberta research shows little change in babies’ ability to roll from their tummy to back and vice versa 20 years after “back to sleep” campaign.
Baby, keep on rolling. A campaign to put babies to bed on their backs to reduce the risk of sudden infant death syndrome has not impaired infants’ rolling abilities, according to University of Alberta research.
Johanna Darrah, a professor of physical therapy in the Faculty of Rehabilitation Medicine, says infants develop the ability to roll much the same today as they did 20 years ago when the “back to sleep” campaign was introduced and successfully reduced the occurrence of SIDS. Her research answers fears that the back to sleep campaign, which recommends putting babies to bed on their back instead of their stomach, would hurt an infant’s gross motor development, specifically the ability to roll from tummy to back and vice versa.
“Infant gross motor development hasn’t changed that much in 20 years,” says Darrah. “The thought that babies first roll from their tummy to their back, before they go from their back to their tummy, does not appear to be the case. For most babies, they happen very close together.”
Darrah first studied infant motor development in the early 1990s as a graduate student of former dean Martha Cook Piper when the pair published the Alberta Infant Motor Scale, an observational assessment scale used throughout the world to measure infant motor skill development from birth to walking.
More than 20 years later, Darrah revisited the work, studying the rolling abilities and motor skills development of 725 Canadian infants ranging in age from one week to eight months. One of her goals was to see whether the norms identified and developed 20 years ago still represent the age of emergence of gross motor skills.
Darah notes there is some concern in the physical therapy community that babies develop movement skills like rolling from tummy to back at later ages because of reduced time spent on their stomachs. Those concerns appear to be unfounded, she says, explaining that her results are particularly valuable for health-care practitioners specializing in early childhood development.
“Our results would suggest that gross motor skills emerge in the same order and at the same ages as 20 years ago. The environment is of course important to gross motor development, but the change in a sleeping position hasn’t made much difference as to when babies roll from stomach to back.”
Researchers Identify Genetic Signature of Deadly Brain Cancer
A multi-institutional team of researchers have pinpointed the genetic traits of the cells that give rise to gliomas – the most common form of malignant brain cancer. The findings, which appear in the journal Cell Reports, provide scientists with rich new potential set of targets to treat the disease.
“This study identifies a core set of genes and pathways that are dysregulated during both the early and late stages of tumor progression,” said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., the senior author of the study and co-director of the Center for Translational Neuromedicine. “By virtue of their marked difference from normal cells, these genes appear to comprise a promising set of targets for therapeutic intervention.”
As its name implies, gliomas arise from a cell type found in the central nervous system called the glial cell. Gliomas progress in severity over time and ultimately become highly invasive tumors known as glioblastomas, which are difficult to treat and almost invariably fatal. Current treatments, which include surgery, radiation therapy, and chemotherapy, can delay disease progression, but ultimately prove ineffective.
Cancer research has been transformed over the past several years by new concepts arising from stem cell biology. Scientists now appreciate that many cancers are the result of rogue stem cells or their offspring, known as progenitor cells. Traditional cancer therapies often do not prevent a recurrence of the disease since they may not effectively target and destroy the cancer-causing stem cells that lie at the heart of the tumors.
Gliomas are one such example. The source of the cancer is a cell found in the brain called the glial progenitor cell. The cells, which arise from and maintain characteristics of stem cells, comprise about three percent of the cell population of the human brain. When these cells become cancerous they are transformed into glioma stem cells, essentially glial progenitor cells whose molecular machinery has gone awry, resulting in uncontrolled cell division.
Goldman and his team have long studied normal glial progenitor cells. These cells produce glia, a category that includes both astrocytes – cells that support the function of neurons – and oligodendrocytes – cells that produces myelin, the fatty insulation that allows the long-distance conduction of neural impulses.
While Goldman’s group’s work has primarily focused on ways to use glial progenitor cells to treat neurological disorders such as multiple sclerosis, their understanding of the biology of these cells and mastery of the techniques required to sort, identify, and isolate these cells has also enabled them to explore the molecular and genetic changes that transform these cells into cancers.
Using human tissue samples representing the three principal stages of the cancer, the researchers were able to identify and isolate the cancer-inducing stem cells. Working with Goldman, lead authors Romane Auvergne, Ph.D. and Fraser Sim, Ph.D. then compared the gene expression profiles of these cancer stem cells to those of normal glial progenitor cells. The objective was to both pinpoint the earliest genetic changes associated with cancer formation and identify those genes that were unique to the cancer stem cells and were expressed at every stage of disease progression.
Out of a pool over 44,000 tested genes and sequences, the scientists identified a small set of genes in the cancerous glioma progenitor cells that were over-expressed at all stages of malignancy. These genes formed a unique “signature” that identified the tumor progenitor cells and enabled the scientists to define a corresponding set of potential therapeutic targets present throughout all stages of the cancer.
“One of the key things you are looking for in drug development in cancer is a protein or gene that is over-expressed, so that you can attempt to achieve therapeutic benefit by inhibiting it,” said Goldman.
The researchers chose to test this hypothesis by targeting one such gene, called SIX1, which was highly overexpressed in the glioma progenitor cells. While this particular gene is active in the early development of the nervous system, it had not been observed in the adult brain before. However, SIX1 signaling has been associated with breast and ovarian cancer, raising the possibility of its contribution to brain cancer as well. This turned out to indeed be the case. When the researchers blocked – or knocked down – the expression of this gene, the tumor cells ceased growing, and implanted tumors shrank.
“This study gives us a blueprint to develop new therapies,” said Goldman. “We can now devise a strategy to systematically and rationally analyze – and eliminate – glioma stem and progenitor cells using compounds that may selectively target these cells, relative to the normal glial progenitors from which they derive. By targeting genes like SIX1 that are expressed at all stages of glioma progression, we hope to be able to effectively treat gliomas regardless of their stage of malignancy. And by targeting the glioma-initiating cells in particular, we hope to lessen the likelihood of recurrence of these tumors, regardless of the stage at which we initiate treatment.”
(Source: urmc.rochester.edu)
Technique Could Identify Patients at High Risk of Stroke or Brain Hemorrhage
Measuring blood flow in the brain may be an easy, noninvasive way to predict stroke or hemorrhage in children receiving cardiac or respiratory support through a machine called ECMO, according to a new study by researchers at Nationwide Children’s Hospital. Early detection would allow physicians to alter treatment and take steps to prevent these complications—the leading cause of death for patients on ECMO.
Short for extracorporeal membrane oxygenation, ECMO is used when a patient is unable to sustain enough oxygen in the blood supply due to heart failure, septic shock, or other life-threatening condition, said Nicole O’Brien, MD, a physician and scientist in critical care medicine at Nationwide Children’s and lead author of the study, which appears in a recent issue of the journal Pediatric Critical Care Medicine. The patient is connected to ECMO with tubes that carry the patient’s blood from a vein through the machine, where it is oxygenated and funneled back to the patient via an artery or vein that then distributes the oxygen-rich blood to vital organs and tissues.
The disease processes that lead someone to need ECMO are different, O’Brien noted, but it is used only after traditional therapies, such as a ventilator, fail. One of the biggest risks of ECMO is bleeding in the brain. Only 36 percent of children who suffer this complication survive, many left with permanent neurologic injury.
“Most of these patients are critically ill before they go on ECMO and often have low oxygen levels, low blood pressure and poor heart function, all of which can certainly lead to strokes,” said O’Brien, also an associate professor of clinical medicine at The Ohio State University College of Medicine. “Still, some patients develop problems and others don’t and we don’t understand why.”
To better understand the cause for these brain bleeds, O’Brien launched a pilot study to monitor cerebral blood flow using a transcranial doplar ultrasound machine, a portable, noninvasive technology that uses sound waves to measure the amount and speed of blood flowing through the brain. All patients on ECMO experience a change in cranial blood flow, but O’Brien wanted to see if those variations offered any hint as to why some patients had complications while others didn’t.
She measured cranial blood flow in 18 ECMO patients, taking the first reading within the patient’s first 24 hours on the machine, then again each day they received the treatment and one more time after ECMO therapy ended.
When she compared these measurements to normal cerebral blood flow rates for children in the same age group, she found significant differences. Thirteen of the children in the study developed no neurologic complications while on ECMO. In these children, cerebral blood flow was 40 percent to 50 percent lower than normal. But in the five patients who had either a stroke or brain hemorrhage while on ECMO, cerebral blood flow was 100 percent higher than normal.
The age of the child, length of time on ECMO or the underlying illness didn’t seem to matter. The only difference was that cerebral blood flow was dramatically increased in patients who ultimately had problems. While O’Brien found that interesting, the most intriguing finding was that the increase in blood flow occurred as long as two to six days before the patient began bleeding in the brain.
“That could give us a lot of lead time to prevent the brain bleeds or hemorrhages,” said O’Brien.
Physicians may decide to try to wean a patient off ECMO a little more quickly or change the dosage of anti-coagulant medication that all ECMO patients take.
Although O’Brien is excited about the results, she is careful to note that the findings are preliminary. She is planning a multi-center trial to see if the outcome will be the same in a larger study population.
“We still need to understand why these kids bleed and why they stroke,” said O’Brien. “This little piece of information is the very tip of the iceberg in terms of why that happens.”
(Source: nationwidechildrens.org)
Blood Vessels in the Eye Linked With IQ, Cognitive Function
The width of blood vessels in the retina, located at the back of the eye, may indicate brain health years before the onset of dementia and other deficits, according to a new study published in Psychological Science, a journal of the Association for Psychological Science.
Research shows that younger people who score low on intelligence tests, such as IQ, tend to be at higher risk for poorer health and shorter lifespan, but factors like socioeconomic status and health behaviors don’t fully account for the relationship. Psychological scientist Idan Shalev of Duke University and colleagues wondered whether intelligence might serve as a marker indicating the health of the brain, and specifically the health of the system of blood vessels that provides oxygen and nutrients to the brain.
To investigate the potential link between intelligence and brain health, the researchers borrowed a technology from a somewhat unexpected domain: ophthalmology.
Shalev and colleagues used digital retinal imaging, a relatively new and noninvasive method, to gain a window onto vascular conditions in the brain by looking at the small blood vessels of the retina, located at the back of the eye. Retinal blood vessels share similar size, structure, and function with blood vessels in the brain and can provide a way of examining brain health in living humans.
The researchers examined data from participants taking part in the Dunedin Multidisciplinary Health and Development Study, a longitudinal investigation of health and behavior in over 1000 people born between April 1972 and March 1973 in Dunedin, New Zealand.
The results were intriguing.
Having wider retinal venules was linked with lower IQ scores at age 38, even after the researchers accounted for various health, lifestyle, and environmental risk factors that might have played a role.
Individuals who had wider retinal venules showed evidence of general cognitive deficits, with lower scores on numerous measures of neurospsychological functioning, including verbal comprehension, perceptual reasoning, working memory, and executive function.
Surprisingly, the data revealed that people who had wider venules at age 38 also had lower IQ in childhood, a full 25 years earlier.
It’s “remarkable that venular caliber in the eye is related, however modestly, to mental test scores of individuals in their 30s, and even to IQ scores in childhood,” the researchers observe.
The findings suggest that the processes linking vascular health and cognitive functioning begin much earlier than previously assumed, years before the onset of dementia and other age-related declines in brain functioning.
“Digital retinal imaging is a tool that is being used today mainly by eye doctors to study diseases of the eye,” Shalev notes. “But our initial findings indicate that it may be a useful investigative tool for psychological scientists who want to study the link between intelligence and health across the lifespan.”
The current study doesn’t address the specific mechanisms that drive the relationship between retinal vessels and cognitive functioning, but the researchers surmise that it may have to do with oxygen supply to the brain.
“Increasing knowledge about retinal vessels may enable scientists to develop better diagnosis and treatments to increase the levels of oxygen into the brain and by that, to prevent age-related worsening of cognitive abilities,” they conclude.
Positive Feedback: Researchers have found a new role for mTOR in autism-related disorders
Researchers have found a novel role for a protein that has been implicated in an autism-related disorder known as tuberous sclerosis complex (TSC).
The disease, which affects 1 in about 8,000 children, manifests itself in the form of mental retardation in addition to severe epileptic episodes. The disease is caused by mutations in two tumor-suppressing proteins, TSC1 and TSC2.
“Kids with this condition have benign tumors that grow all over the body,” said Bernardo Sabatini, the Takeda Professor of Neurobiology at Harvard Medical School and senior author of the study, “but we wanted to know what happened in the brain.”
The researchers found that when mutations in TSC1 and TSC2 adversely affected a third protein, mTOR, this mutation increased brain activity, which can result in epileptic seizures.
The findings were published in the May 8 issue of Neuron.
A protein kinase, mTOR is responsible for controlling cell growth in many parts of the body and has been widely implicated in epilepsy and autism. TSC1 and TSC2 normally repress the activity of mTOR to keep cell growth in check. In the case of TSC, there are mutations in TSC1 or TSC2, and mTOR’s ability to promote cell growth goes unchecked, resulting in tumors in regularly dividing cells.
“But neurons don’t divide,” said Sabatini. “So it was important to note the changes in these non-dividing cells.”
The researchers hypothesized that mTOR’s function in the brain related to homeostasis, the brain’s ability to maintain a controlled level of electrical activity. When there’s a lot of electrical activity, a negative feedback system switches on to suppress activity. Conversely, when levels are too low, other positive feedback pathways are engaged that bring the activity level back up.
“We went into this study with the specific hypothesis that mTOR would be part of the homeostatic loop in the brain,” explained Sabatini.
In the case of TSC patients, they thought that mTOR was incapable of maintaining homeostasis and kept adding to the level of electrical activity, leading to seizures.
“But we were wrong,” he added.
“What we actually found was that mTOR is part of a positive feedback pathway,” said Helen Bateup, HMS research fellow in neurobiology and first author on the study. “When a cell is active, mTOR gets turned on more frequently and makes the cell even more active by reducing the amount of inhibition that the neuron receives.”
In cells where TSC proteins are mutated, this positive feedback gets out of control, and the neuronal circuit remains overactive despite all the pathways that normally shut down activity being turned on.
“It’s like the circuit is trying to keep itself quiet, but it can’t,” said Sabatini. “The out-of-control mTOR causes some cells to loss all inhibition, something that can’t be compensated for by turning down excitation.”
The researchers think this key difference in how mTOR operates, in working to promote electrical activity, is important for the disease because patients end up with high levels of dysfunctional mTOR that makes for highly active circuits prone to epileptic fits. Furthermore, “we know that once a person has one seizure, they’re much more likely to have more, a concept known as kindling,” said Sabatini.
These findings are among the first to show that contrary to scientific consensus, mTOR does not play a part in everything.
“We have shown that one of the few things that mTOR does not seem to partake in is this negative feedback pathway,” said Sabatini.
Working in both in vitro and in vivo mouse models, the researchers think the next step would be tease out the molecular pathway of mTOR’s involvement in this positive feedback loop. “It’s also important to compare how this pathway works in normal brains versus a diseased model,” added Bateup.
“A huge challenge when studying the brain is that there are so many feedback pathways that a mutation in one gene can result in a hundred other secondary changes,” said Sabatini.
Rapamycin, a drug currently used to prevent organ rejection following transplants, targets mTOR and brings activity levels back to normal.
“We could use the drug to restore this excitatory-inhibitory balance in the brain,” said Bateup. “A lot of drugs that treat epilepsy try to make inhibition more powerful but given that the primary problem here is that a group of cells has lost inhibition, that approach won’t work,” she added. “What we might need is to target the excitation side. Or find ways of changing the biochemistry of the cells to make inhibitory synapses again.”
“For this disease, this is the right time to start looking at human cells,” said Sabatini. “We have really good data from the mouse model and it would be a really nice test to see if the mouse model is really predictive of human disorder and if it’s worth being continued.”
Manipulating Memory in the Hippocampus
Protein modification may help control Alzheimer’s and epilepsy, TAU researchers find
In the brain, cell-to-cell communication is dependent on neurotransmitters, chemicals that aid the transfer of information between neurons. Several proteins have the ability to modify the production of these chemicals by either increasing or decreasing their amount, or promoting or preventing their secretion. One example is tomosyn, which hinders the secretion of neurotransmitters in abnormal amounts.
Dr. Boaz Barak of Tel Aviv University’s Sagol School of Neuroscience, in collaboration with Prof. Uri Ashery, used a method for modifying the levels of this protein in the mouse hippocampus — the region of the brain associated with learning and memory. It had a significant impact on the brain’s activity: Over-production of the protein led to a sharp decline in the ability to learn and memorize information, the researchers reported in the journal NeuroMolecular Medicine.
"This study demonstrates that it is possible to manipulate various processes and neural circuits in the brain," says Dr. Barak, a finding which may aid in the development of therapeutic procedures for epilepsy and neurodegenerative diseases such as Alzheimer’s. Slowing the transmission rate of information when the brain is overactive during epileptic seizures could have a beneficial effect, and readjusting the levels of tomosyn in an Alzheimer’s patient may help increase cognition and combat memory loss.
A maze of memory loss
The researchers teamed up with a laboratory at the National Institutes of Health (NIH) in Baltimore to create a virus which produces the tomosyn protein. In the lab, the virus was injected into the hippocampus region in mice. Then, in order to test the consequences, they performed a series of behavioral tests designed to measure functions like memory, cognitive ability, and motor skills.
In one experiment, called the Morris Water Maze, mice had to learn to navigate to, and remember, the location of a hidden platform placed inside a pool with opaque water. During the first five days of testing, researchers found that the test group with an over-production of tomosyn had a significant problem in learning and memorizing the location of the platform, compared to a control group that received a placebo injection. And when the platform was removed from the maze, the test group spent less time swimming around the area where the platform once was, indicating that they had no memory of its existence. In comparison, the control group of mice searched for the missing platform in its previous location for two or even three days after its removal, notes Dr. Barak.
These findings were further verified by measuring electrical activity in the brains of both the test group and the control group. In the test group, researchers found decreased levels of transmissions between neurons in the hippocampus, a physiological finding that may explain the results of the behavioral tests.
Correcting neuronal processes
In the future, Dr. Barak believes that the ability to modify proteins directly in the brain will allow for more control over brain activities and the correction of neurodegenerative processes, such as providing stricter regulation in neuronal activity for epileptic patients or stimulating neurotransmitters to help with learning and memory loss in Alzheimer’s patients. Indeed, a separate study conducted by the researchers demonstrates that mouse models for Alzheimer’s disease do have an over-production of tomosyn in the hippocampus region, so countering the production of this protein could have a beneficial effect.
Now Dr. Barak and Prof. Ashery are working towards a method for artificially decreasing levels of the protein, which they believe will have the opposite effect on the cognitive ability of the mice. “We hypothesize that with an under-production in tomosyn, the mice will show a marked improvement in their performance in behavioral testing,” he says.
(Source: aftau.org)
Researchers focus on a brain protein and an antibiotic to block cocaine craving
A new study conducted by a team of Indiana University neuroscientists demonstrates that GLT1, a protein that clears glutamate from the brain, plays a critical role in the craving for cocaine that develops after only several days of cocaine use.
The study, appearing in The Journal of Neuroscience, showed that when rats taking large doses of cocaine are withdrawn from the drug, the production of GLT1 in the nucleus accumbens, a region of the brain implicated in motivation, begins to decrease. But if the rats receive ceftriaxone, an antibiotic used to treat meningitis, GLT1 production increases during the withdrawal period and decreases cocaine craving.
George Rebec, professor in the Department of Psychological and Brain Sciences, said drug craving depends on the release of glutamate, a neurotransmitter involved in motivated behavior. Glutamate is released in response to the cues associated with drug taking, so when addicts are exposed to these cues, their drug craving increases even if they have been away from the drug for some time.
The same behavior can be modeled in rats. When rats, who self-administer cocaine by pressing a lever that delivers the cocaine into their bodies, are withdrawn from the drug for several weeks, their craving returns if they are exposed to the cues that accompanied drug delivery in the past; in this case, a tone and light. But if the rats are treated with ceftriaxone during withdrawal, they no longer seek cocaine when the cues are presented.
Ceftriaxone appears to block craving by reversing the decrease in GLT1 caused by repeated exposure to cocaine. In fact, ceftriaxone increases GLT1, which allows glutamate to be cleared quickly from the brain. The Rebec research group localized this effect to the nucleus accumbens by showing that if GLT1 was blocked in this brain region even after ceftriaxone treatment, the rats would relapse.
While an earlier paper of Rebec’s group showed the effects of ceftriaxone on cocaine craving, the new paper was the first to localize the effects of ceftriaxone to the nucleus accumbens and was the first to show that ceftriaxone works after long withdrawal periods.
"The idea is that increasing GLT1 will prevent relapse. If we block GLT1, the ceftriaxone should not work," Rebec said. "We now have good evidence that ceftriaxone is acting on GLT1 and that the nucleus accumbens is the critical site."
Rebec said prior work on Huntington’s disease, a neurodegenerative disorder, alerted him and his team to the way ceftriaxone acts on the expression of GLT1, a protein that removes glutamate from the brain. Glutamate removal is a problem in Huntington’s disease, and Rebec’s team found that ceftriaxone increases GLT1 and improves neurological signs of the disease in mouse models.
It now is important to determine why cocaine decreases GLT1 and to see whether other drugs of abuse have the same effect. Rebec and colleagues have shown that ceftriaxone also can decrease the craving for alcohol in rats selectively bred to prefer alcohol.
Drug cues are one factor that can trigger relapse. Future work also will examine whether ceftriaxone can block drug craving induced by stress or by re-exposure to the drug. If so, it would mean that GLT1 could become an important target in the search for treatments to prevent drug relapse. Now, Rebec said, there are a number of factors to study. “We don’t yet know how long the effects of ceftriaxone last. Does an addict have to be on it for a month or will it lose its effectiveness? We don’t yet know what will happen.”
In the cocaine study, the rats self-administer cocaine for six hours a day for up to 11 days. Their behavior is much like that of a human addict.
"You might think that because they’re in there, they just take more, but they don’t just take more," Rebec said. "Like human addicts, they take the drug more and more rapidly and they want to get to it more and more quickly."
Withdrawal serves as an incubation period during which craving increases if it is activated by cues or other factors. “Something changes in the brain during that time to trigger the craving or make it more likely that you want the drug,” Rebec said. “That’s what ceftriaxone seems to be interfering with.”
Ceftriaxone is now in clinical trials on people with ALS, also known as Lou Gehrig’s disease, which has many mechanisms in common with other neurodegenerative diseases such as Huntington’s disease and Alzheimer’s.