Posts tagged neuroscience
Articles and news from the latest research reports.
Gene discovered that could cure jet lag
A gene has been discovered which stops our body clock from resetting, paving the way for new drugs to combat jet lag
The gene slows our body’s adaptation to new time zones, the team from the University of Oxford found, acting as a safety mechanism to prevent our internal clock from getting out of synch, a process which is linked to chronic diseases.
However, turning the gene off could prevent the symptoms jet lag, tests on mice indicated.
Our bodies, like those of most life forms on earth, operate to the circadian clock, a natural 24 cycle which tells us when to sleep or wake up.
This responds to natural light - but when we rapidly move to a different time zone, such as on a long haul flight, it is thrown into disarray.
The circadian clock is governed by an area of the brain called the suprachiasmatic nuclei (SCN), which in turn receives information from a specialised system in the eyes which detects environmental light, according to the report in the journal Cell.
This allows the body to synchronise with the night and day cycle. However, scientists were unable to explain why it took so long for the body clock to ‘reset’ to different time zones - sometimes as long as a day for each hour the actual clock shifted.
Now a team from the University of Oxford have identified a gene in mice which appears to stop the body clock from adjusting too quickly.
This is because it can take some days for the brain to be convinced the new data about the night/day cycle is reliable, they say.
Dr Stuart Peirson said: “We’ve identified a system that actively prevents the body clock from re-adjusting.
"If you think about, it makes sense to have a buffering mechanism in place to provide some stability to the clock. The clock needs to be sure that it is getting a reliable signal, and if the signal occurs at the same time over several days it probably has biological relevance.
"But it is this same buffering mechanism that slows down our ability to adjust to a new time zone and causes jet lag."
They studied gene expression in the SCN in mice, who were exposed to light and darkness.
They identified around 100 genes that were switched on in response to light, revealing a sequence of events that act to retune the circadian clock.
Amongst these, they identified one molecule, SIK1, that terminates this response, acting as a brake to limit the effects of light on the clock.
When they blocked the activity of SIK1, the mice adjusted faster to changes in light cycle.
Dr Russell Foster said that we were still a long way off from a jet lag cure, but added it was a step towards developing drugs for interrupted sleep cycles.
Disruptions in the circadian system have been linked to chronic diseases including cancer, diabetes, and heart disease, as well as weakened immunity to infections and impaired cognition.
More recently, researchers are uncovering that circadian disturbances are a common feature of several mental illnesses, including schizophrenia and bipolar disorder.
Dr Foster said: “We’re still several years away from a cure for jet-lag but understanding the mechanisms that generate and regulate our circadian clock gives us targets to develop drugs to help bring our bodies in tune with the solar cycle.
"Such drugs could potentially have broader therapeutic value for people with mental health issues."
Poor concentration: Poverty reduces brainpower needed for navigating other areas of life
Poverty and all its related concerns require so much mental energy that the poor have less remaining brainpower to devote to other areas of life, according to research based at Princeton University. As a result, people of limited means are more likely to make mistakes and bad decisions that may be amplified by — and perpetuate — their financial woes.
Published in the journal Science, the study presents a unique perspective regarding the causes of persistent poverty. The researchers suggest that being poor may keep a person from concentrating on the very avenues that would lead them out of poverty. A person’s cognitive function is diminished by the constant and all-consuming effort of coping with the immediate effects of having little money, such as scrounging to pay bills and cut costs. Thusly, a person is left with fewer “mental resources” to focus on complicated, indirectly related matters such as education, job training and even managing their time.
In a series of experiments, the researchers found that pressing financial concerns had an immediate impact on the ability of low-income individuals to perform on common cognitive and logic tests. On average, a person preoccupied with money problems exhibited a drop in cognitive function similar to a 13-point dip in IQ, or the loss of an entire night’s sleep.
But when their concerns were benign, low-income individuals performed competently, at a similar level to people who were well off, said corresponding author Jiaying Zhao, who conducted the study as a doctoral student in the lab of co-author Eldar Shafir, Princeton’s William Stewart Tod Professor of Psychology and Public Affairs. Zhao and Shafir worked with Anandi Mani, an associate professor of economics at the University of Warwick in Britain, and Sendhil Mullainathan, a Harvard University economics professor.
"These pressures create a salient concern in the mind and draw mental resources to the problem itself. That means we are unable to focus on other things in life that need our attention," said Zhao, who is now an assistant professor of psychology at the University of British Columbia.
"Previous views of poverty have blamed poverty on personal failings, or an environment that is not conducive to success," she said. "We’re arguing that the lack of financial resources itself can lead to impaired cognitive function. The very condition of not having enough can actually be a cause of poverty."
The mental tax that poverty can put on the brain is distinct from stress, Shafir explained. Stress is a person’s response to various outside pressures that — according to studies of arousal and performance — can actually enhance a person’s functioning, he said. In the Science study, Shafir and his colleagues instead describe an immediate rather than chronic preoccupation with limited resources that can be a detriment to unrelated yet still important tasks.
"Stress itself doesn’t predict that people can’t perform well — they may do better up to a point," Shafir said. "A person in poverty might be at the high part of the performance curve when it comes to a specific task and, in fact, we show that they do well on the problem at hand. But they don’t have leftover bandwidth to devote to other tasks. The poor are often highly effective at focusing on and dealing with pressing problems. It’s the other tasks where they perform poorly."
The fallout of neglecting other areas of life may loom larger for a person just scraping by, Shafir said. Late fees tacked on to a forgotten rent payment, a job lost because of poor time-management — these make a tight money situation worse. And as people get poorer, they tend to make difficult and often costly decisions that further perpetuate their hardship, Shafir said. He and Mullainathan were co-authors on a 2012 Science paper that reported a higher likelihood of poor people to engage in behaviors that reinforce the conditions of poverty, such as excessive borrowing.
"They can make the same mistakes, but the outcomes of errors are more dear," Shafir said. "So, if you live in poverty, you’re more error prone and errors cost you more dearly — it’s hard to find a way out."
The first set of experiments took place in a New Jersey mall between 2010 and 2011 with roughly 400 subjects chosen at random. Their median annual income was around $70,000 and the lowest income was around $20,000. The researchers created scenarios wherein subjects had to ponder how they would solve financial problems, for example, whether they would handle a sudden car repair by paying in full, borrowing money or putting the repairs off. Participants were assigned either an “easy” or “hard” scenario in which the cost was low or high — such as $150 or $1,500 for the car repair. While participants pondered these scenarios, they performed common fluid-intelligence and cognition tests.
Subjects were divided into a “poor” group and a “rich” group based on their income. The study showed that when the scenarios were easy — the financial problems not too severe — the poor and rich performed equally well on the cognitive tests. But when they thought about the hard scenarios, people at the lower end of the income scale performed significantly worse on both cognitive tests, while the rich participants were unfazed.
To better gauge the influence of poverty in natural contexts, between 2010 and 2011 the researchers also tested 464 sugarcane farmers in India who rely on the annual harvest for at least 60 percent of their income. Because sugarcane harvests occur once a year, these are farmers who find themselves rich after harvest and poor before it. Each farmer was given the same tests before and after the harvest, and performed better on both tests post-harvest compared to pre-harvest.
The cognitive effect of poverty the researchers found relates to the more general influence of “scarcity” on cognition, which is the larger focus of Shafir’s research group. Scarcity in this case relates to any deficit — be it in money, time, social ties or even calories — that people experience in trying to meet their needs. Scarcity consumes “mental bandwidth” that would otherwise go to other concerns in life, Zhao said.
"These findings fit in with our story of how scarcity captures attention. It consumes your mental bandwidth," Zhao said. "Just asking a poor person to think about hypothetical financial problems reduces mental bandwidth. This is an acute, immediate impact, and has implications for scarcity of resources of any kind."
"We documented similar effects among people who are not otherwise poor, but on whom we imposed scarce resources," Shafir added. "It’s not about being a poor person — it’s about living in poverty."
Many types of scarcity are temporary and often discretionary, said Shafir, who is co-author with Mullainathan of the book, “Scarcity: Why Having Too Little Means So Much,” to be published in September. For instance, a person pressed for time can reschedule appointments, cancel something or even decide to take on less.
"When you’re poor you can’t say, ‘I’ve had enough, I’m not going to be poor anymore.’ Or, ‘Forget it, I just won’t give my kids dinner, or pay rent this month.’ Poverty imposes a much stronger load that’s not optional and in very many cases is long lasting," Shafir said. "It’s not a choice you’re making — you’re just reduced to few options. This is not something you see with many other types of scarcity."
The researchers suggest that services for the poor should accommodate the dominance that poverty has on a person’s time and thinking. Such steps would include simpler aid forms and more guidance in receiving assistance, or training and educational programs structured to be more forgiving of unexpected absences, so that a person who has stumbled can more easily try again.
"You want to design a context that is more scarcity proof," said Shafir, noting that better-off people have access to regular support in their daily lives, be it a computer reminder, a personal assistant, a housecleaner or a babysitter.
"There’s very little you can do with time to get more money, but a lot you can do with money to get more time," Shafir said. "The poor, who our research suggests are bound to make more mistakes and pay more dearly for errors, inhabit contexts often not designed to help."
Scientists Succeed in Growing Human Brain Tissue in “Test Tubes”
Complex human brain tissue has been successfully developed in a three-dimensional culture system established in an Austrian laboratory. The method described in the current issue of NATURE allows pluripotent stem cells to develop into cerebral organoids – or “mini brains” – that consist of several discrete brain regions. Instead of using so-called patterning growth factors to achieve this, scientists at the renowned Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW) fine-tuned growth conditions and provided a conducive environment. As a result, intrinsic cues from the stem cells guided the development towards different interdependent brain tissues. Using the “mini brains”, the scientists were also able to model the development of a human neuronal disorder and identify its origin – opening up routes to long hoped-for model systems of the human brain.
The development of the human brain remains one of the greatest mysteries in biology. Derived from a simple tissue, it develops into the most complex natural structure known to man. Studies of the human brain’s development and associated human disorders are extremely difficult, as no scientist has thus far successfully established a three-dimensional culture model of the developing brain as a whole. Now, a research group lead by Dr. Jürgen Knoblich at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) has changed just that.
Brain Size Matters
Starting with established human embryonic stem cell lines and induced pluripotent stem (iPS) cells, the group identified growth conditions that aided the differentiation of the stem cells into several brain tissues. While using media for neuronal induction and differentiation, the group was able to avoid the use of patterning growth factor conditions, which are usually applied in order to generate specific cell identities from stem cells. Dr. Knoblich explains the new method: “We modified an established approach to generate so-called neuroectoderm, a cell layer from which the nervous system derives. Fragments of this tissue were then maintained in a 3D-culture and embedded in droplets of a specific gel that provided a scaffold for complex tissue growth. In order to enhance nutrient absorption, we later transferred the gel droplets to a spinning bioreactor. Within three to four weeks defined brain regions were formed.”
Already after 15 – 20 days, so-called “cerebral organoids” formed which consisted of continuous tissue (neuroepithelia) surrounding a fluid-filled cavity that was reminiscent of a cerebral ventricle. After 20 – 30 days, defined brain regions, including a cerebral cortex, retina, meninges as well as choroid plexus, developed. After two months, the mini brains reached a maximum size, but they could survive indefinitely (currently up to 10 months) in the spinning bioreactor. Further growth, however, was not achieved, most likely due to the lack of a circulation system and hence a lack of nutrients and oxygen at the core of the mini brains.
Microcephaly in Mini Brains
The new method also offers great potential for establishing model systems for human brain disorders. Such models are urgently needed, as the commonly used animal models are of considerably lower complexity, and often do not adequately recapitulate the human disease. Knoblich’s group has now demonstrated that the mini brains offer great potential as a human model system by analysing the onset of microcephaly, a human genetic disorder in which brain size is significantly reduced. By generating iPS cells from skin tissue of a microcephaly patient, the scientists were able to grow mini brains affected by this disorder. As expected, the patient derived organoids grew to a lesser size. Further analysis led to a surprising finding: while the neuroepithilial tissue was smaller than in mini brains unaffected by the disorder, increased neuronal outgrowth could be observed. This lead to the hypothesis that, during brain development of patients with microcephaly, the neural differentiation happens prematurely at the expense of stem and progenitor cells which would otherwise contribute to a more pronounced growth in brain size. Further experiments also revealed that a change in the direction in which the stem cells divide might be causal for the disorder.
"In addition to the potential for new insights into the development of human brain disorders, mini brains will also be of great interest to the pharmaceutical and chemical industry," explains Dr. Madeline A. Lancaster, team member and first author of the publication. "They allow for the testing of therapies against brain defects and other neuronal disorders. Furthermore, they will enable the analysis of the effects that specific chemicals have on brain development."
Hospital scientists identify ALS disease mechanism
Study strengthens link between amyotrophic lateral sclerosis (ALS) and problems in protein production machinery of cells and identifies possible treatment strategy
Researchers have tied mutations in a gene that causes amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders to the toxic buildup of certain proteins and related molecules in cells, including neurons. The research, published recently in the scientific journal Cell, offers a new approach for developing treatments against these devastating diseases.
Scientists at St. Jude Children’s Research Hospital and the University of Colorado, Boulder, led the work.
The findings provide the first evidence that a gene named VCP plays a role in the break-up and clearance of protein and RNA molecules that accumulate in temporary structures called RNA granules. RNAs perform a variety of vital cell functions, including protein production. RNA granules support proper functioning of RNA.
In ALS and related degenerative diseases, the process of assembling and clearing RNA granules is impaired. The proteins and RNAs associated with the granules often build up in nerve cells of patients. This study shows how mutations in VCP might contribute to that process and neurodegenerative disease.
“The results go a long way to explaining the process that links a variety of neurodegenerative diseases, including ALS, frontotemporal dementia and related diseases of the brain, muscle and bone known as multisystem proteinopathies,” said the study’s co-corresponding author, J. Paul Taylor, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. Roy Parker, Ph.D., of the University of Colorado’s Department of Chemistry and Biochemistry and the Howard Hughes Medical Institute (HHMI), is the other corresponding author.
ALS, also known as Lou Gehrig’s disease, is diagnosed in about 5,600 Americans annually and is associated with progressive deterioration of nerve cells in the brain and spine that govern movement, including breathing. There is no effective treatment, and death usually occurs within five years.
“A strength of this study is that it provides a unifying hypothesis about how different genetic mutations all affect stress granules, which suggests that understanding stress granule dynamics and how they can be manipulated might be beneficial for treatment of these diseases,” Parker said.
Earlier work from Taylor’s laboratory identified mutations in VCP as a cause of ALS and related multisystem proteinopathies. Until now, however, little was known about how those mistakes caused disease. The latest findings appeared in the June 20 issue and are highlighted in a review article published in the August 15 issue of Cell.
The research also ties VCP mutations to disruption of RNA regulation, which prior studies have connected to the progression of neurodegenerative diseases, said Regina-Maria Kolaitis, Ph.D., a postdoctoral fellow in Taylor’s laboratory. She and Ross Buchan, Ph.D., a postdoctoral fellow in Parker’s laboratory, are co-first authors.
The work focused on a class of RNA granules called stress granules. They are formed by proteins and an RNA molecule called mRNA that accumulates in the cell cytoplasm in response to stress. Stressed cells do not want to waste energy producing unnecessary proteins. Stress granules are one mechanism cells use to halt production until the cellular environment normalizes, which is when stress granules typically dissolve.
Proteins found in stress granules include RNA-binding proteins like TDP-43, FUS, hnRNPA1 and hnRNPA2B1 that regulate gene activity. Mutations in those proteins can also cause ALS and related disorders.
“VCP has many functions in cells, but it is not an RNA-binding protein and until now it was not connected to stress granules or RNA processing,” Kolaitis said. “This study provides a new window into the disease process, highlighting VCP’s role in keeping cells healthy.”
For this study, researchers used yeast to identify a network of 125 genes that affect the formation and behavior of stress granules. One of the genes that appeared to play a central role in the network was CDC48, which functions like VCP in yeast. In addition, many of the genes identified are involved in a process called autophagy that cells use to break down and recycle unneeded molecules, including proteins.
Working in yeast and mammalian cells, researchers showed that stress granules are cleared by autophagy, which stalled when VCP was mutated. Researchers also reported that stress granules accumulated following mutation of either CDC48 or VCP.
“This work suggests that activating autophagy to help rid cells of stress granules offers a new approach to neurodegenerative disease treatment,” Taylor said.
(Source: stjude.org)
UC Davis team “spikes” stem cells to generate myelin
Findings hold promise for developing regenerative therapies for spinal cord injuries and diseases such as multiple sclerosis
Stem cell technology has long offered the hope of regenerating tissue to repair broken or damaged neural tissue. Findings from a team of UC Davis investigators have brought this dream a step closer by developing a method to generate functioning brain cells that produce myelin — a fatty, insulating sheath essential to normal neural conduction.
“Our findings represent an important conceptual advance in stem cell research,” said Wenbin Deng, principal investigator of the study and associate professor at the UC Davis Department of Biochemistry and Molecular Medicine. “We have bioengineered the first generation of myelin-producing cells with superior regenerative capacity.”
The brain is made up predominantly of two cell types: neurons and glial cells. Neurons are regarded as responsible for thought and sensation. Glial cells surround, support and communicate with neurons, helping neurons process and transmit information using electrical and chemical signals. One type of glial cell — the oligodendrocyte — produces a sheath called myelin that provides support and insulation to neurons. Myelin, which has been compared to insulation around electrical wires that helps to prevent short circuits, is essential for normal neural conduction and brain function; well-recognized conditions involving defective myelin development or myelin loss include multiple sclerosis and leukodystrophies.
In this study, the UC Davis team first developed a novel protocol to efficiently induce embryonic stem cells (ESCs) to differentiate into oligodendroglial progenitor cells (OPCs), early cells that normally develop into oligodendrocytes. Although this has been successfully done by other researchers, the UC Davis method results in a purer population of OPCs, according to Deng, with fewer other cell types arising from their technique.
They next compared electrophysiological properties of the derived OPCs to naturally occurring OPCs. They found that unlike natural OPCs, the ESC-derived OPCs lacked sodium ion channels in their cell membranes, making them unable to generate spikes when electrically stimulated. Using a technique called viral transduction, they then introduced DNA that codes for sodium channels into the ESC-derived OPCs. These OPCs then expressed ion channels in their cells and developed the ability to generate spikes.
According to Deng, this is the first time that scientists have successfully generated OPCs with so-called spiking properties. This achievement allowed them to compare the capabilities of spiking cells to non-spiking cells.
In cell culture, they found that only spiking OPCs received electrical input from neurons, and they showed superior capability to mature into oligodendrocytes.
They also transplanted spiking and non-spiking OPCs into the spinal cord and brains of mice that are genetically unable to produce myelin. Both types of OPCs had the capability to mature into oligo-dendrocytes and produce myelin, but those from spiking OPCs produced longer and thicker myelin sheaths around axons.
“We actually developed ‘super cells’ with an even greater capacity to spike than natural cells,” Deng said. “This appears to give them an edge for maturing into oligodendrocytes and producing better myelin.”
It is well known that adult human neural tissue has a poor capacity to regenerate naturally. Although early cells such as OPCs are present, they do not regenerate tissue very effectively when disease or injury strikes.
Deng believes that replacing glial cells with the enhanced spiking OPCs to treat neural injuries and diseases has the potential to be a better strategy than replacing neurons, which tend to be more problematic to work with. Providing the proper structure and environment for neurons to live may be the best approach to regenerate healthy neural tissue. He also notes that many diverse conditions that have not traditionally been considered to be myelin-related diseases – including schizophrenia, epilepsy and amyotrophic lateral sclerosis (ALS) – actually are now recognized to involve defective myelin.
Researchers discover a potential cause of autism
Key enzymes are found to have a ‘profound effect’ across dozens of genes linked to autism. The insight could help illuminate environmental factors behind autism spectrum disorder and contribute to a unified theory of how the disorder develops.
Problems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research announced today in the journal Nature. Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder’s genetic causes.
“Our study shows the magnitude of what can happen if topoisomerases are impaired,” said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC. “Inhibiting these enzymes has the potential to profoundly affect neurodevelopment — perhaps even more so than having a mutation in any one of the genes that have been linked to autism.”
The study could have important implications for ASD detection and prevention.
“This could point to an environmental component to autism,” said Zylka. “A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. ”
This study could also explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders.
Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.
Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells. “If there are additional compounds like this in the environment, then it becomes important to identify them,” said Zylka. “That’s really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects — so that pregnant women can avoid being exposed to these compounds.”
Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy. Investigating the drug’s effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long — composed of many DNA base pairs. The group then made the serendipitous connection that many autism-linked genes are extremely long.
“That’s when we had the ‘Eureka moment,’” said Zylka. “We realized that a lot of the genes that were suppressed were incredibly long autism genes.”
Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board — even to a small extent — means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.
The study’s findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses — the connections between brain cells. Another 20 percent are related to gene transcription — the process of translating genetic information into biological functions. Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person’s ability to construct synapses.
“Our discovery has the potential to unite these two classes of genes — synaptic genes and transcriptional regulators,” said Zylka. “It could ultimately explain the biological mechanisms behind a large number of autism cases.”
A Major Cause of Age-Related Memory Loss Identified
Study points to possible treatments and confirms distinction between memory loss due to aging and that of Alzheimer’s
A team of Columbia University Medical Center (CUMC) researchers, led by Nobel laureate Eric R. Kandel, MD, has found that deficiency of a protein called RbAp48 in the hippocampus is a significant contributor to age-related memory loss and that this form of memory loss is reversible. The study, conducted in postmortem human brain cells and in mice, also offers the strongest causal evidence that age-related memory loss and Alzheimer’s disease are distinct conditions. The findings were published today in the online edition of Science Translational Medicine.
“Our study provides compelling evidence that age-related memory loss is a syndrome in its own right, apart from Alzheimer’s. In addition to the implications for the study, diagnosis, and treatment of memory disorders, these results have public health consequences,” said Dr. Kandel, who is University Professor & Kavli Professor of Brain Science, co-director of Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, director of the Kavli Institute for Brain Science, and senior investigator, Howard Hughes Medical Institute, at CUMC. Dr. Kandel received a share of the 2000 Nobel Prize in Physiology or Medicine for his discoveries related to the molecular basis of memory.
The hippocampus, a brain region that consists of several interconnected subregions, each with a distinct neuron population, plays a vital role in memory. Studies have shown that Alzheimer’s disease hampers memory by first acting on the entorhinal cortex (EC), a brain region that provides the major input pathways to the hippocampus. It was initially thought that age-related memory loss is an early manifestation of Alzheimer’s, but mounting evidence suggests that it is a distinct process that affects the dentate gyrus (DG), a subregion of the hippocampus that receives direct input from the EC.
“Until now, however, no one has been able to identify specific molecular defects involved in age-related memory loss in humans,” said co-senior author Scott A. Small, MD, the Boris and Rose Katz Professor of Neurology and director of the Alzheimer’s Research Center at CUMC.
The current study was designed to look for more direct evidence that age-related memory loss differs from Alzheimer’s disease. The researchers began by performing microarray (gene expression) analyses of postmortem brain cells from the DG of eight people, ages 33 to 88, all of whom were free of brain disease. The team also analyzed cells from their EC, which served as controls since that brain structure is unaffected by aging. The analyses identified 17 candidate genes that might be related to aging in the DG. The most significant changes occurred in a gene called RbAp48, whoseexpressiondeclined steadily with aging across the study subjects.
To determine whether RbAp48plays an active role in age-related memory loss, the researchers turned to mouse studies. “The first question was whether RbAp48is downregulated in aged mice,” said lead author Elias Pavlopoulos, PhD, associate research scientist in neuroscience at CUMC. “And indeed, that turned out to be the case—there was a reduction of RbAp48 protein in the DG.”
When the researchers genetically inhibited RbAp48inthe brains ofhealthy young mice, they found the same memory loss as in aged mice, as measured by novel object recognition and water maze memory tests. When RbAp48inhibition was turned off, the mice’s memory returned to normal.
The researchers also did functional MRI (fMRI) studies of the mice with inhibited RbAp48 and found a selective effect in the DG, similar to that seen in fMRI studies of aged mice, monkeys, and humans. This effect of RbAp48 inhibition on the DG was accompanied by defects in molecular mechanisms similar to those found in aged mice. The fMRI profile and mechanistic defects of the mice with inhibited RbAp48 returned to normal when the inhibition was turned off.
In another experiment, the researchers used viral gene transfer and increased RbAp48expression inthe DG of aged mice. “We were astonished that not only did this improve the mice’s performance on the memory tests, but their performance was comparable to that of young mice,” said Dr. Pavlopoulos.
“The fact that we were able to reverse age-related memory loss in mice is very encouraging,” said Dr. Kandel. “Of course, it’s possible that other changes in the DG contribute to this form of memory loss. But at the very least, it shows that this protein is a major factor, and it speaks to the fact that age-related memory loss is due to a functional change in neurons of some sort. Unlike with Alzheimer’s, there is no significant loss of neurons.”
Finally, the study data suggest that RbAp48 protein mediates its effects, at least in part, through the PKA-CREB1-CBP pathway, which the team had found in earlier studies to be important for age-related memory loss in the mouse. According to the researchers, RbAp48 and the PKA-CREB1-CBP pathway are valid targets for therapeutic intervention. Agents that enhance this pathway have already been shown to improve age-related hippocampal dysfunction in rodents.
“Whether these compounds will work in humans is not known,” said Dr. Small. “But the broader point is that to develop effective interventions, you first have to find the right target. Now we have a good target, and with the mouse we’ve developed, we have a way to screen therapies that might be effective, be they pharmaceuticals, nutraceuticals, or physical and cognitive exercises.”
“There’s been a lot of handwringing over the failures of drug trials based on findings from mouse models of Alzheimer’s,” Dr. Small said. “But this is different. Alzheimer’s does not occur naturally in the mouse. Here, we’ve caused age-related memory loss in the mouse, and we’ve shown it to be relevant to human aging.”
Migraine May Permanently Change Brain Structure
Migraine may have long-lasting effects on the brain’s structure, according to a study published in the August 28, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“Traditionally, migraine has been considered a benign disorder without long-term consequences for the brain,” said study author Messoud Ashina, MD, PhD, with the University of Copenhagen in Denmark. “Our review and meta-analysis study suggests that the disorder may permanently alter brain structure in multiple ways.”
The study found that migraine raised the risk of brain lesions, white matter abnormalities and altered brain volume compared to people without the disorder. The association was even stronger in those with migraine with aura.
For the meta-analysis, researchers reviewed six population-based studies and 13 clinic-based studies to see whether people who experienced migraine or migraine with aura had an increased risk of brain lesions, silent abnormalities or brain volume changes on MRI brain scans compared to those without the conditions.
The results showed that migraine with aura increased the risk of white matter brain lesions by 68 percent and migraine with no aura increased the risk by 34 percent, compared to those without migraine. The risk for infarct-like abnormalities increased by 44 percent for those with migraine with aura compared to those without aura. Brain volume changes were more common in people with migraine and migraine with aura than those with no migraines.
“Migraine affects about 10 to 15 percent of the general population and can cause a substantial personal, occupational and social burden,” said Ashina. “We hope that through more study, we can clarify the association of brain structure changes to attack frequency and length of the disease. We also want to find out how these lesions may influence brain function.”
(Image: Getty images)
Size of personal space is affected by anxiety
The space surrounding the body (known by scientists as ‘peripersonal space’), which has previously been thought of as having a gradual boundary, has been given physical limits by new research into the relationship between anxiety and personal space.
New findings have allowed scientists to define the limit of the ‘peripersonal space’ surrounding the face as 20-40cm away. The study is published today in The Journal of Neuroscience.
As well as having numerical limits the specific distance was found to vary between individuals. Those with anxiety traits were found to have larger peripersonal space.
In an experiment, Dr Chiara Sambo and Dr Giandomenico Iannetti from UCL recorded the blink reflex - a defensive response to potentially dangerous stimuli at varying distances from subject’s face. They then compared the reflex data to the results of an anxiety test where subjects rated their levels of anxiety in various situations.
Those who scored highly on the anxiety test tended to react more strongly to stimuli 20cm from their face than subjects who got low scores on the anxiety test. Researchers classified those who reacted more strongly to further away stimuli as having a large ‘defensive peripersonal space’ (DPPS).
A larger DPPS means that those with high anxiety scores perceive threats as closer than non-anxious individuals when the stimulus is the same distance away. The research has led scientists to think that the brain controls the strength of defensive reflexes even though it cannot initiate them.
Dr Giandomenico Iannetti (UCL Neuroscience, Physiology and Pharmacology), lead author of the study, said: “This finding is the first objective measure of the size of the area surrounding the face that each individual considers at high-risk, and thus wants to protect through the most effective defensive motor responses.”
In the experiment, a group of 15 people aged 20 to 37 were chosen for study. Researchers applied an intense electrical stimulus to a specific nerve in the hand which causes the subject to blink. This is called the hand-blink reflex (HBR) which is not under conscious control of the brain.
This reflex was monitored with the subject holding their own hand at 4, 20, 40 and 60 cm away from the face. The magnitude of the reflex was used to determine how dangerous each stimulus was considered, and a larger response for stimuli further from the body indicated a larger DPPS.
Subjects also completed an anxiety test in which they self-scored their predicted level of anxiety in different situations. The results of this test were used to classify individuals as more or less anxious, and were compared to the data from the reflex experiment to determine if there was a link between the two tests.
Scientists hope that the findings can be used as a test to link defensive behaviours to levels of anxiety. This could be particularly useful determining risk assessment ability in those with jobs that encounter dangerous situations such as fire, police and military officers.
Perception of Marijuana as a “Safe Drug” Is Scientifically Inaccurate
The nature of the teenage brain makes users of cannabis amongst this population particularly at risk of developing addictive behaviors and suffering other long-term negative effects, according to researchers at the University of Montreal and New York’s Icahn School of Medicine at Mount Sinai.
“Of the illicit drugs, cannabis is most used by teenagers since it is perceived by many to be of little harm. This perception has led to a growing number of states approving its legalization and increased accessibility. Most of the debates and ensuing policies regarding cannabis were done without consideration of its impact on one of the most vulnerable population, namely teens, or without consideration of scientific data,” wrote Professor Didier Jutras-Aswad of the University of Montreal and Yasmin Hurd, MD, PhD, of Mount Sinai. “While it is clear that more systematic scientific studies are needed to understand the long-term impact of adolescent cannabis exposure on brain and behavior, the current evidence suggests that it has a far-reaching influence on adult addictive behaviors particularly for certain subsets of vulnerable individuals.”
The researchers reviewed over 120 studies that looked at different aspects of the relationship between cannabis and the adolescent brain, including the biology of the brain, chemical reaction that occurs in the brain when the drug is used, the influence of genetics and environmental factors, in addition to studies into the “gateway drug” phenomenon. “Data from epidemiological studies have repeatedly shown an association between cannabis use and subsequent addiction to heavy drugs and psychosis (i.e. schizophrenia). Interestingly, the risk to develop such disorders after cannabis exposure is not the same for all individuals and is correlated with genetic factors, the intensity of cannabis use and the age at which it occurs. When the first exposure occurs in younger versus older adolescents, the impact of cannabis seems to be worse in regard to many outcomes such as mental health, education attainment, delinquency and ability to conform to adult role,” Dr Jutras-Aswad said.
Although it is difficult to confirm in all certainty a causal link between drug consumption and the resulting behavior, the researchers note that rat models enable scientists to explore and directly observe the same chemical reactions that happen in human brains. Cannabis interacts with our brain through chemical receptors (namely cannabinoid receptors such as CB1 and CB2.) These receptors are situated in the areas of our brain that govern our learning and management of rewards, motivated behavior, decision-making, habit formation and motor function. As the structure of the brain changes rapidly during adolescence (before settling in adulthood), scientists believe that the cannabis consumption at this time greatly influences the way these parts of the user’s personality develop. In adolescent rat models, scientists have been able to observe differences in the chemical pathways that govern addiction and vulnerability – a receptor in the brain known as the dopamine D2 receptor is well known to be less present in cases of substance abuse.
Only a minority (approximately one in four) of teenage users of cannabis will develop an abusive or dependant relationship with the drug. This suggests to the researchers that specific genetic and behavioral factors influence the likelihood that the drug use will continue. Studies have also shown that cannabis dependence can be inherited through the genes that produce the cannabinoid receptors and an enzyme involved in the processing of THC. Other psychological factors are also likely involved. “Individuals who will develop cannabis dependence generally report a temperament characterized by negative affect, aggressivity and impulsivity, from an early age. Some of these traits are often exacerbated with years of cannabis use, which suggests that users become trapped in a vicious cycle of self-medication, which in turn becomes a dependence” Jutras-Aswad said.
The researchers stress that while a lot remains unknown about the mechanics of cannabis abuse, the body of existing research has clear implications for society. “It is now clear from the scientific data that cannabis is not harmless to the adolescent brain, specifically those who are most vulnerable from a genetic or psychological standpoint. Identifying these vulnerable adolescents, including through genetic or psychological screening, may be critical for prevention and early intervention of addiction and psychiatric disorders related to cannabis use. The objective is not to fuel the debate about whether cannabis is good or bad, but instead to identify those individuals who might most suffer from its deleterious effects and provide adequate measures to prevent this risk” Jutras-Aswad said. “Continuing research should be performed to inform public policy in this area. Without such systematic, evidenced-based research to understand the long-term effects of cannabis on the developing brain, not only the legal status of cannabis will be determined on uncertain ground, but we will not be able to innovate effective treatments such as the medicinal use of cannabis plant components that might be beneficial for treating specific disorders,” Dr Hurd said.
(Image: AP)