Neuroscience

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Untangling Alzheimer’s Disease

TAU researchers identify specific molecules that could be targeted to treat the disorder

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Plaques and tangles made of proteins are believed to contribute to the debilitating progression of Alzheimer’s disease. But proteins also play a positive role in important brain functions, like cell-to-cell communication and immunological response. Molecules called microRNAs regulate both good and bad protein levels in the brain, binding to messenger RNAs to prevent them from developing into proteins.

Now, Dr. Boaz Barak and a team of researchers in the lab of Prof. Uri Ashery of Tel Aviv University’s Department of Neurobiology at the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience have identified a specific set of microRNAs that detrimentally regulate protein levels in the brains of mice with Alzheimer’s disease and beneficially regulate protein levels in the brains of other mice living in a stimulating environment.

"We were able to create two lists of microRNAs — those that contribute to brain performance and those that detract — depending on their levels in the brain," says Dr. Barak. "By targeting these molecules, we hope to move closer toward earlier detection and better treatment of Alzheimer’s disease."

Prof. Daniel Michaelson of TAU’s Department of Neurobiology in the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience, Dr. Noam Shomron of TAU’s Department of Cell and Developmental Biology and Sagol School of Neuroscience, Dr. Eitan Okun of Bar-Ilan University, and Dr. Mark Mattson of the National Institute on Aging collaborated on the study, published in Translational Psychiatry.

A double-edged sword

Alzheimer’s disease is the most common form of dementia. Currently incurable, it increasingly impairs brain function over time, ultimately leading to death. The TAU researchers became interested in the disease while studying the brains of mice living in an “enriched environment” — an enlarged cage with running wheels, bedding and nesting material, a house, and frequently changing toys. Such environments have been shown to improve and maintain brain function in animals much as intellectual activity and physical fitness do in people.

The researchers ran a series of tests on a part of the mice’s brains called the hippocampus, which plays a major role in memory and spatial navigation and is one of the earliest targets of Alzheimer’s disease in humans. They found that, compared to mice in normal cages, the mice from the enriched environment developed higher levels of good proteins and lower levels of bad proteins. Then, for the first time, they identified the microRNAs responsible for regulating the expression of both good and bad proteins.

Armed with this new information, the researchers analyzed changes in the levels of microRNAs in the hippocampi of young, middle-aged, and old mice with an Alzheimer’s-disease-like condition. They found that some of the microRNAs were expressed in exactly inverse amounts in mice with Alzheimer’s disease as they were in mice from the enriched environment. The results were higher levels of bad proteins and lower levels of good proteins in the hippocampi of old mice with Alzheimer’s disease. The microRNAs the researchers identified had already been shown or predicted to regulate the expression of proteins in ways that contributed to Alzheimer’s disease. Their finding that the microRNAs are inversely regulated in mice from the enriched environment is important, because it suggests the molecules can be targeted by activities or drugs to preserve brain function.

Brain-busting potential

Two findings appear to have particular potential for treating people with Alzheimer’s disease. In the brains of old mice with the disease, microRNA-325 was diminished, leading to higher levels of tomosyn, a protein that is well known to inhibit cellular communication in the brain. The researchers hope that eventually microRNA-325 can be used to create a drug to help Alzheimer’s patients maintain low levels of tomosyn and preserve brain function. Additionally, the researchers found several important microRNAs at low levels starting in the brains of young mice. If the same can be found in humans, these microRNAs could be used as biomarker to detect Alzheimer’s disease at a much earlier age than is now possible — at 30 years of age, for example, instead of 60.

"Our biggest hope is to be able to one day use microRNAs to detect Alzheimer’s disease in people at a young age and begin a tailor-made treatment based on our findings, right away," says Dr. Barak.

(Source: aftau.org)

Filed under alzheimer's disease hippocampus microRNA tomosyn synaptic plasticity neuroscience science

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Nurturing may protect kids from brain changes linked to poverty Growing up in poverty can have long-lasting, negative consequences for a child. But for poor children raised by parents who lack nurturing skills, the effects may be particularly worrisome, according to a new study at Washington University School of Medicine in St. Louis. Among children living in poverty, the researchers identified changes in the brain that can lead to lifelong problems like depression, learning difficulties and limitations in the ability to cope with stress. The study showed that the extent of those changes was influenced strongly by whether parents were nurturing. The good news, according to the researchers, is that a nurturing home life may offset some of the negative changes in brain anatomy among poor children. And the findings suggest that teaching nurturing skills to parents — particularly those living in poverty — may provide a lifetime benefit for their children. The study is published online Oct. 28 and will appear in the November issue of JAMA Pediatrics. Using magnetic resonance imaging (MRI), the researchers found that poor children with parents who were not very nurturing were likely to have less gray and white matter in the brain. Gray matter is closely linked to intelligence, while white matter often is linked to the brain’s ability to transmit signals between various cells and structures. The MRI scans also revealed that two key brain structures were smaller in children who were living in poverty: the amygdala, a key structure in emotional health, and the hippocampus, an area of the brain that is critical to learning and memory. “We’ve known for many years from behavioral studies that exposure to poverty is one of the most powerful predictors of poor developmental outcomes for children,” said principal investigator Joan L. Luby, MD, a Washington University child psychiatrist at St. Louis Children’s Hospital. “A growing number of neuroscience and brain-imaging studies recently have shown that poverty also has a negative effect on brain development.  “What’s new is that our research shows the effects of poverty on the developing brain, particularly in the hippocampus, are strongly influenced by parenting and life stresses that the children experience.” Luby, a professor of psychiatry and director of the university’s Early Emotional Development Program, is in the midst of a long-term study of childhood depression. As part of the Preschool Depression Study, she has been following 305 healthy and depressed kids since they were in preschool. As the children have grown, they also have received MRI scans that track brain development. “We actually stumbled upon this finding,” she said. “Initially, we thought we would have to control for the effects of poverty, but as we attempted to control for it, we realized that poverty was really driving some of the outcomes of interest, and that caused us to change our focus to poverty, which was not the initial aim of this study.” In the new study, Luby’s team looked at scans from 145 children enrolled in the depression study. Some were depressed, others healthy, and others had been diagnosed with different psychiatric disorders such as ADHD (attention-deficit hyperactivity disorder). As she studied these children, Luby said it became clear that poverty and stressful life events, which often go hand in hand, were affecting brain development. The researchers measured poverty using what’s called an income-to-needs ratio, which takes a family’s size and annual income into account. The current federal poverty level is $23,550 for a family of four. Although the investigators found that poverty had a powerful impact on gray matter, white matter, hippocampal and amygdala volumes, they found that the main driver of changes among poor children in the volume of the hippocampus was not lack of money but the extent to which poor parents nurture their children. The hippocampus is a key brain region of interest in studying the risk for impairments. Luby’s team rated nurturing using observations made by the researchers — who were unaware of characteristics such as income level or whether a child had a psychiatric diagnosis — when the children came to the clinic for an appointment. And on one of the clinic visits, the researchers rated parental nurturing using a test of the child’s impatience and of a parent’s patience with that child. While waiting to see a health professional, a child was given a gift-wrapped package, and that child’s parent or caregiver was given paperwork to fill out. The child, meanwhile, was told that s/he could not open the package until the caregiver completed the paperwork, a task that researchers estimated would take about 10 minutes. Luby’s team found that parents living in poverty appeared more stressed and less able to nurture their children during that exercise. In cases where poor parents were rated as good nurturers, the children were less likely to exhibit the same anatomical changes in the brain as poor children with less nurturing parents. “Parents can be less emotionally responsive for a whole host of reasons,” Luby said. “They may work two jobs or regularly find themselves trying to scrounge together money for food. Perhaps they live in an unsafe environment. They may be facing many stresses, and some don’t have the capacity to invest in supportive parenting as much as parents who don’t have to live in the midst of those adverse circumstances.” The researchers also found that poorer children were more likely to experience stressful life events, which can influence brain development. Anything from moving to a new house to changing schools to having parents who fight regularly to the death of a loved one is considered a stressful life event. Luby believes this study could provide policymakers with at least a partial answer to the question of what it is about poverty that can be so detrimental to a child’s long-term developmental outcome. Because it appears that a nurturing parent or caregiver may prevent some of the changes in brain anatomy that this study identified, Luby said it is vital that society invest in public health prevention programs that target parental nurturing skills. She suggested that a key next step would be to determine if there are sensitive developmental periods when interventions with parents might have the most powerful impact. “Children who experience positive caregiver support don’t necessarily experience the developmental, cognitive and emotional problems that can affect children who don’t receive as much nurturing, and that is tremendously important,” Luby said. “This study gives us a feasible, tangible target with the suggestion that early interventions that focus on parenting may provide a tremendous payoff.”

Nurturing may protect kids from brain changes linked to poverty

Growing up in poverty can have long-lasting, negative consequences for a child. But for poor children raised by parents who lack nurturing skills, the effects may be particularly worrisome, according to a new study at Washington University School of Medicine in St. Louis.

Among children living in poverty, the researchers identified changes in the brain that can lead to lifelong problems like depression, learning difficulties and limitations in the ability to cope with stress. The study showed that the extent of those changes was influenced strongly by whether parents were nurturing.

The good news, according to the researchers, is that a nurturing home life may offset some of the negative changes in brain anatomy among poor children. And the findings suggest that teaching nurturing skills to parents — particularly those living in poverty — may provide a lifetime benefit for their children.

The study is published online Oct. 28 and will appear in the November issue of JAMA Pediatrics.

Using magnetic resonance imaging (MRI), the researchers found that poor children with parents who were not very nurturing were likely to have less gray and white matter in the brain. Gray matter is closely linked to intelligence, while white matter often is linked to the brain’s ability to transmit signals between various cells and structures.

The MRI scans also revealed that two key brain structures were smaller in children who were living in poverty: the amygdala, a key structure in emotional health, and the hippocampus, an area of the brain that is critical to learning and memory.

“We’ve known for many years from behavioral studies that exposure to poverty is one of the most powerful predictors of poor developmental outcomes for children,” said principal investigator Joan L. Luby, MD, a Washington University child psychiatrist at St. Louis Children’s Hospital. “A growing number of neuroscience and brain-imaging studies recently have shown that poverty also has a negative effect on brain development. 

“What’s new is that our research shows the effects of poverty on the developing brain, particularly in the hippocampus, are strongly influenced by parenting and life stresses that the children experience.”

Luby, a professor of psychiatry and director of the university’s Early Emotional Development Program, is in the midst of a long-term study of childhood depression. As part of the Preschool Depression Study, she has been following 305 healthy and depressed kids since they were in preschool. As the children have grown, they also have received MRI scans that track brain development.

“We actually stumbled upon this finding,” she said. “Initially, we thought we would have to control for the effects of poverty, but as we attempted to control for it, we realized that poverty was really driving some of the outcomes of interest, and that caused us to change our focus to poverty, which was not the initial aim of this study.”

In the new study, Luby’s team looked at scans from 145 children enrolled in the depression study. Some were depressed, others healthy, and others had been diagnosed with different psychiatric disorders such as ADHD (attention-deficit hyperactivity disorder). As she studied these children, Luby said it became clear that poverty and stressful life events, which often go hand in hand, were affecting brain development.

The researchers measured poverty using what’s called an income-to-needs ratio, which takes a family’s size and annual income into account. The current federal poverty level is $23,550 for a family of four.

Although the investigators found that poverty had a powerful impact on gray matter, white matter, hippocampal and amygdala volumes, they found that the main driver of changes among poor children in the volume of the hippocampus was not lack of money but the extent to which poor parents nurture their children. The hippocampus is a key brain region of interest in studying the risk for impairments.

Luby’s team rated nurturing using observations made by the researchers — who were unaware of characteristics such as income level or whether a child had a psychiatric diagnosis — when the children came to the clinic for an appointment. And on one of the clinic visits, the researchers rated parental nurturing using a test of the child’s impatience and of a parent’s patience with that child.

While waiting to see a health professional, a child was given a gift-wrapped package, and that child’s parent or caregiver was given paperwork to fill out. The child, meanwhile, was told that s/he could not open the package until the caregiver completed the paperwork, a task that researchers estimated would take about 10 minutes.

Luby’s team found that parents living in poverty appeared more stressed and less able to nurture their children during that exercise. In cases where poor parents were rated as good nurturers, the children were less likely to exhibit the same anatomical changes in the brain as poor children with less nurturing parents.

“Parents can be less emotionally responsive for a whole host of reasons,” Luby said. “They may work two jobs or regularly find themselves trying to scrounge together money for food. Perhaps they live in an unsafe environment. They may be facing many stresses, and some don’t have the capacity to invest in supportive parenting as much as parents who don’t have to live in the midst of those adverse circumstances.”

The researchers also found that poorer children were more likely to experience stressful life events, which can influence brain development. Anything from moving to a new house to changing schools to having parents who fight regularly to the death of a loved one is considered a stressful life event.

Luby believes this study could provide policymakers with at least a partial answer to the question of what it is about poverty that can be so detrimental to a child’s long-term developmental outcome. Because it appears that a nurturing parent or caregiver may prevent some of the changes in brain anatomy that this study identified, Luby said it is vital that society invest in public health prevention programs that target parental nurturing skills. She suggested that a key next step would be to determine if there are sensitive developmental periods when interventions with parents might have the most powerful impact.

“Children who experience positive caregiver support don’t necessarily experience the developmental, cognitive and emotional problems that can affect children who don’t receive as much nurturing, and that is tremendously important,” Luby said. “This study gives us a feasible, tangible target with the suggestion that early interventions that focus on parenting may provide a tremendous payoff.”

Filed under poverty brain development nurture amygdala hippocampus childhood psychology neuroscience science

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Lower Blood Sugars May Be Good for the Brain

Even for people who don’t have diabetes or high blood sugar, those with higher blood sugar levels are more likely to have memory problems, according to a new study published in the October 23, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

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The study involved 141 people with an average age of 63 who did not have diabetes or pre-diabetes, which is also called impaired glucose tolerance. People who were overweight, drank more than three-and-a-half servings of alcohol per day, and those who had memory and thinking impairment were not included in the study.

The participants’ memory skills were tested, along with their blood glucose, or sugar, levels. Participants also had brain scans to measure the size of the hippocampus area of the brain, which plays an important role in memory.

People with lower blood sugar levels were more likely to have better scores on the memory tests. On a test where participants needed to recall a list of 15 words 30 minutes after hearing them, recalling fewer words was associated with higher blood sugar levels. For example, an increase of about 7 mmol/mol of a long-term marker of glucose control called HbA1c went along with recalling 2 fewer words. People with higher blood sugar levels also had smaller volumes in the hippocampus.

“These results suggest that even for people within the normal range of blood sugar, lowering their blood sugar levels could be a promising strategy for preventing memory problems and cognitive decline as they age,” said study author Agnes Flöel, MD, of Charité University Medicine in Berlin, Germany. “Strategies such as lowering calorie intake and increasing physical activity should be tested.”

Filed under glucose diabetes hippocampus neuroimaging neuroscience science

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Schizophrenia linked to abnormal brain waves Neuroscientists discover neurological hyperactivity that produces disordered thinking Schizophrenia patients usually suffer from a breakdown of organized thought, often accompanied by delusions or hallucinations. For the first time, MIT neuroscientists have observed the neural activity that appears to produce this disordered thinking. The researchers found that mice lacking the brain protein calcineurin have hyperactive brain-wave oscillations in the hippocampus while resting, and are unable to mentally replay a route they have just run, as normal mice do. Mutations in the gene for calcineurin have previously been found in some schizophrenia patients. Ten years ago, MIT researchers led by Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, created mice lacking the gene for calcineurin in the forebrain; these mice displayed several behavioral symptoms of schizophrenia, including impaired short-term memory, attention deficits, and abnormal social behavior. In the new study, which appears in the Oct. 16 issue of the journal Neuron, Tonegawa and colleagues at the RIKEN-MIT Center for Neural Circuit Genetics at MIT’s Picower Institute for Learning and Memory recorded the electrical activity of individual neurons in the hippocampus of these knockout mice as they ran along a track. Previous studies have shown that in normal mice, “place cells” in the hippocampus, which are linked to specific locations along the track, fire in sequence when the mice take breaks from running the course. This mental replay also occurs when the mice are sleeping. These replays occur in association with very high frequency brain-wave oscillations known as ripple events. In mice lacking calcineurin, the researchers found that brain activity was normal as the mice ran the course, but when they paused, their ripple events were much stronger and more frequent. Furthermore, the firing of the place cells was abnormally augmented and in no particular order, indicating that the mice were not replaying the route they had just run. This pattern helps to explain some of the symptoms seen in schizophrenia, the researchers say. “We think that in this mouse model, we may have some kind of indication that there’s a disorganized thinking process going on,” says Junghyup Suh, a research scientist at the Picower Institute and one of the paper’s lead authors. “During ripple events in normal mice we know there is a sequential replay event. This mutant mouse doesn’t seem to have that kind of replay of a previous experience.” The paper’s other lead author is David Foster, a former MIT postdoc. Other authors are Heydar Davoudi and Matthew Wilson, the Sherman Fairchild Professor of Neuroscience at MIT and a member of the Picower Institute. The researchers speculate that in normal mice, the role of calcineurin is to suppress the connections between neurons, known as synapses, in the hippocampus. In mice without calcineurin, a phenomenon known as long-term potentiation (LTP) becomes more prevalent, making synapses stronger. Also, the opposite effect, known as long-term depression (LTD), is suppressed. “It looks like this abnormally high LTP has an impact on activity of these cells specifically during resting periods, or post exploration periods. That’s a very interesting specificity,” Tonegawa says. “We don’t know why it’s so specific.” The researchers believe the abnormal hyperactivity they found in the hippocampus may represent a disruption of the brain’s “default mode network” — a communication network that connects the hippocampus, prefrontal cortex (where most thought and planning occurs), and other parts of the cortex. This network is more active when a person (or mouse) is resting between goal-oriented tasks. When the brain is focusing on a specific goal or activity, the default mode network gets turned down. However, this network is hyperactive in schizophrenic patients before and during tasks that require the brain to focus, and patients do not perform well in these tasks. Further studies of these mice could help reveal more about the role of the default mode network in schizophrenia, Tonegawa says.

Schizophrenia linked to abnormal brain waves

Neuroscientists discover neurological hyperactivity that produces disordered thinking

Schizophrenia patients usually suffer from a breakdown of organized thought, often accompanied by delusions or hallucinations. For the first time, MIT neuroscientists have observed the neural activity that appears to produce this disordered thinking.

The researchers found that mice lacking the brain protein calcineurin have hyperactive brain-wave oscillations in the hippocampus while resting, and are unable to mentally replay a route they have just run, as normal mice do.

Mutations in the gene for calcineurin have previously been found in some schizophrenia patients. Ten years ago, MIT researchers led by Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, created mice lacking the gene for calcineurin in the forebrain; these mice displayed several behavioral symptoms of schizophrenia, including impaired short-term memory, attention deficits, and abnormal social behavior.

In the new study, which appears in the Oct. 16 issue of the journal Neuron, Tonegawa and colleagues at the RIKEN-MIT Center for Neural Circuit Genetics at MIT’s Picower Institute for Learning and Memory recorded the electrical activity of individual neurons in the hippocampus of these knockout mice as they ran along a track.

Previous studies have shown that in normal mice, “place cells” in the hippocampus, which are linked to specific locations along the track, fire in sequence when the mice take breaks from running the course. This mental replay also occurs when the mice are sleeping. These replays occur in association with very high frequency brain-wave oscillations known as ripple events.

In mice lacking calcineurin, the researchers found that brain activity was normal as the mice ran the course, but when they paused, their ripple events were much stronger and more frequent. Furthermore, the firing of the place cells was abnormally augmented and in no particular order, indicating that the mice were not replaying the route they had just run.

This pattern helps to explain some of the symptoms seen in schizophrenia, the researchers say.

“We think that in this mouse model, we may have some kind of indication that there’s a disorganized thinking process going on,” says Junghyup Suh, a research scientist at the Picower Institute and one of the paper’s lead authors. “During ripple events in normal mice we know there is a sequential replay event. This mutant mouse doesn’t seem to have that kind of replay of a previous experience.”

The paper’s other lead author is David Foster, a former MIT postdoc. Other authors are Heydar Davoudi and Matthew Wilson, the Sherman Fairchild Professor of Neuroscience at MIT and a member of the Picower Institute.

The researchers speculate that in normal mice, the role of calcineurin is to suppress the connections between neurons, known as synapses, in the hippocampus. In mice without calcineurin, a phenomenon known as long-term potentiation (LTP) becomes more prevalent, making synapses stronger. Also, the opposite effect, known as long-term depression (LTD), is suppressed.

“It looks like this abnormally high LTP has an impact on activity of these cells specifically during resting periods, or post exploration periods. That’s a very interesting specificity,” Tonegawa says. “We don’t know why it’s so specific.”

The researchers believe the abnormal hyperactivity they found in the hippocampus may represent a disruption of the brain’s “default mode network” — a communication network that connects the hippocampus, prefrontal cortex (where most thought and planning occurs), and other parts of the cortex.

This network is more active when a person (or mouse) is resting between goal-oriented tasks. When the brain is focusing on a specific goal or activity, the default mode network gets turned down. However, this network is hyperactive in schizophrenic patients before and during tasks that require the brain to focus, and patients do not perform well in these tasks.

Further studies of these mice could help reveal more about the role of the default mode network in schizophrenia, Tonegawa says.

Filed under prefrontal cortex neural activity LTP hippocampus depression schizophrenia calcineurin psychology neuroscience science

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Scientists identify protein linking exercise to brain health

A protein that is increased by endurance exercise has been isolated and given to non-exercising mice, in which it turned on genes that promote brain health and encourage the growth of new nerves involved in learning and memory, report scientists from Dana-Farber Cancer Institute and Harvard Medical School.

The findings, reported in the journal Cell Metabolism, help explain the well-known capacity of endurance exercise to improve cognitive function, particularly in older people. If the protein can be made in a stable form and developed into a drug, it might lead to improved therapies for cognitive decline in older people and slow the toll of neurodegenerative diseases such Alzheimer’s and Parkinson’s, according to the investigators.

“What is exciting is that a natural substance can be given in the bloodstream that can mimic some of the effects of endurance exercise on the brain,” said Bruce Spiegelman, PhD, of Dana-Farber and HMS. He is co-senior author of the publication with Michael E. Greenberg, PhD, chair of neurobiology at HMS.

The Spiegelman group previously reported that the protein, called FNDC5, is produced by muscular exertion and is released into the bloodstream as a variant called irisin. In the new research, endurance exercise – mice voluntarily running on a wheel for 30 days – increased the activity of a metabolic regulatory molecule, PGC-1α, in muscles, which spurred a rise in FNDC5 protein. The increase of FNDC5 in turn boosted the expression of a brain-health protein, BDNF (brain-derived neurotrophic protein) in the dentate gyrus of the hippocampus, a part of the brain involved in learning and memory.

It has been found that exercise stimulates BDNF in the hippocampus, one of only two areas of the adult brain that can generate new nerve cells. BDNF promotes development of new nerves and synapses – connections between nerves that allow learning and memory to be stored – and helps preserve the survival of brain cells.

How exercise raises BDNF activity in the brain wasn’t known; the new findings linking exercise, PGC-1α, FNDC5 and BDNF provide a molecular pathway for the effect, although Spiegelman and his colleagues suggest there are probably others.

Having shown that FNDC5 is a molecular link between exercise and increased BDNF in the brain, the scientists asked whether artificially increasing FNDC5 in the absence of exercise would have the same effect. They used a harmless virus to deliver the protein to mice through the bloodstream, in hopes the FNDC5 could reach the brain and raise BDNF activity. Seven days later, they examined the mouse brains and observed a significant increase in BDNF in the hippocampus.

“Perhaps the most exciting result overall is that peripheral deliver of FNDC5 with adenoviral vectors is sufficient to induce central expression of Bdnf and other genes with potential neuroprotective functions or those involved in learning and memory,” the authors said. Spiegelman cautioned that further research is needed to determine whether giving FNDC5 actually improves cognitive function in the animals. The scientists also aren’t sure whether the protein that got into the brain is FNDC5 itself, or irisin, or perhaps another variant of the protein.

Spiegelman said that development of irisin as a drug will require creating a more stable form of the protein.

(Source: dana-farber.org)

Filed under memory dementia hippocampus neurodegenerative diseases cognitive function neuroscience science

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Neurological Researchers Find Fat May Be Linked to Memory Loss

Although problems with memory become increasingly common as people age, in some persons, memories last long time, even a life time. On the other hand, some people experience milder to substantial memory problems even at an earlier age.

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Although there are several risk factors of dementia, abnormal fat metabolism has been known to pose a risk for memory and learning. People with high amounts of abdominal fat in their middle age are 3.6 times as likely to develop memory loss and dementia later in their life.

Neurological scientists at the Rush University Medical Center in collaboration with the National Institutes of Health have discovered that same protein that controls fat metabolism in the liver resides in the memory center of the brain (hippocampus) and controls memory and learning.

Results from the study funded by the Alzheimer’s Association and the National Institutes of Health were recently published in Cell Reports.

“We need to better understand how fat is connected to memory and learning so that we can develop effective approach to protect memory and learning,” said Kalipada Pahan, PhD, the Floyd A. Davis professor of neurology at Rush University Medical Center.

The liver is the body’s major fat metabolizing organ. Peroxisome proliferator-activated receptor alpha (PPARalpha) is known to control fat metabolism in the liver. Accordingly, PPARalpha is highly expressed in the liver.

“We are surprised to find high level of PPARalpha in the hippocampus of animal models,” said Pahan.

“While PPARalpha deficient mice are poor in learning and memory, injection of PPARα to the hippocampus of PPARalpha deficient mice improves learning and memory,” said Pahan.

Since PPARalpha directly controls fat metabolism, people with abdominal fat levels have depleted PPARalpha in the liver and abnormal lipid metabolism. At first, these individuals lose PPARalpha from the liver and then eventually from the whole body including the brain. Therefore, abdominal fat is an early indication of some kind of dementia later in life, according to Pahan.

By bone marrow chimera technique, researchers were able to create some mice having normal PPARalpha in the liver and depleted PPARalpha in the brain. These mice were poor in memory and learning. On the other hand, mice that have normal PPARalpha in the brain and depleted PPARalpha in the liver showed normal memory.

“Our study indicates that people may suffer from memory-related problems only when they lose PPARalpha in the hippocampus”, said Pahan.

CREB (cyclic AMP response element-binding protein) is called the master regulator of memory as it controls different memory-related proteins. “Our study shows that PPARalpha directly stimulates CREB and thereby increases memory-related proteins”, said Pahan.

“Further research must be conducted to see how we could potentially maintain normal PPARalpha in the brain in order to be resistant to memory loss”, said Pahan.

(Source: rush.edu)

Filed under alzheimer's disease dementia hippocampus memory metabolism learning neuroscience science

9,692 notes

How depression blurs memories To pinpoint why depression messes with memory, researchers took a page from Sesame Street’s book. The show’s popular game “One of these things is not like the others” helps young viewers learn to differentiate things that are similar – a process known as “pattern separation.” A new Brigham Young University study concludes that this same skill fades in adults in proportion to the severity of their symptoms of depression. The more depressed someone feels, the harder it is for them to distinguish similar experiences they’ve had. If you’ve ever forgotten where you parked the car, you know the feeling (though it doesn’t mean you have depression). “That’s really the novel aspect of this study – that we are looking at a very specific aspect of memory,” said Brock Kirwan, a psychology and neuroscience professor at BYU. Depression has been generally linked to poor memory for a long time. To find out why, Kirwan and his former grad student D.J. Shelton put people through a computer-aided memory test. The participants viewed a series of objects on the screen. For each one, they responded whether they had seen the object before on the test (old), seen something like it (similar), or not seen anything like it (new). With old and new items, participants with depression did just fine. They often got it wrong, however, when looking at objects that were similar to something they had seen previously. The most common incorrect answer was that they had seen the object before. “They don’t have amnesia,” Kirwan said. “They are just missing the details.” This can be a challenge in a number of everyday situations, such as trying to remember which friends and family members you’ve told about something personal – and which ones are still in the dark. The findings also give an important clue about what is happening in the brain that might explain this. “There are two areas in your brain where you grow new brain cells,” Kirwan said. “One is the hippocampus, which is involved in memory. It turns out that this growth is decreased in cases of depression.” Because of this study, we know a little more about what these new brain cells are for: helping us see and remember new experiences. The study appears in the journal Behavioral Brain Research.

How depression blurs memories

To pinpoint why depression messes with memory, researchers took a page from Sesame Street’s book.

The show’s popular game “One of these things is not like the others” helps young viewers learn to differentiate things that are similar – a process known as “pattern separation.”

A new Brigham Young University study concludes that this same skill fades in adults in proportion to the severity of their symptoms of depression. The more depressed someone feels, the harder it is for them to distinguish similar experiences they’ve had.

If you’ve ever forgotten where you parked the car, you know the feeling (though it doesn’t mean you have depression).

“That’s really the novel aspect of this study – that we are looking at a very specific aspect of memory,” said Brock Kirwan, a psychology and neuroscience professor at BYU.

Depression has been generally linked to poor memory for a long time. To find out why, Kirwan and his former grad student D.J. Shelton put people through a computer-aided memory test. The participants viewed a series of objects on the screen. For each one, they responded whether they had seen the object before on the test (old), seen something like it (similar), or not seen anything like it (new).

With old and new items, participants with depression did just fine. They often got it wrong, however, when looking at objects that were similar to something they had seen previously. The most common incorrect answer was that they had seen the object before.

“They don’t have amnesia,” Kirwan said. “They are just missing the details.”

This can be a challenge in a number of everyday situations, such as trying to remember which friends and family members you’ve told about something personal – and which ones are still in the dark.

The findings also give an important clue about what is happening in the brain that might explain this.

“There are two areas in your brain where you grow new brain cells,” Kirwan said. “One is the hippocampus, which is involved in memory. It turns out that this growth is decreased in cases of depression.”

Because of this study, we know a little more about what these new brain cells are for: helping us see and remember new experiences. The study appears in the journal Behavioral Brain Research.

Filed under depression memory hippocampus psychology neuroscience science

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Made to Order at the Synapse: Dynamics of Protein Synthesis at Neuron Tip is Basis for Memory and Learning

Understanding RNA biology in dendrites may inform neurological and psychiatric illness therapeutics

Protein synthesis in the extensions of nerve cells, called dendrites, underlies long-term memory formation in the brain, among other functions. “Thousands of messenger RNAs reside in dendrites, yet the dynamics of how multiple dendrite messenger RNAs translate into their final proteins remain elusive,” says James Eberwine, PhD, professor of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, and co-director of the Penn Genome Frontiers Institute.

image

Dendrites, which branch from the cell body of the neuron, play a key role in the communication between cells of the nervous system, allowing for many neurons to connect with each other. Dendrites detect the electrical and chemical signals transmitted to the neuron by the axons of other neurons. The synapse is the neuronal structure where this chemical connection is formed, and investigators surmise that it is here where learning and memory occur.

These structural and chemical changes – called synaptic plasticity — require rapid, new synthesis of proteins. Cells may use different rates of translation in different types of mRNA to produce the right amounts and ratios of required proteins.

Knowing how proteins are made to order – as it were - at the synapse can help researchers better understand how memories are made. Nevertheless, the role of this “local” environment in regulating which messenger RNAs are translated into proteins in a neuron’s periphery is still a mystery.

Eberwine, first author Tae Kyung Kim, PhD, a postdoc in the Eberwine lab, and colleagues including Jai Yoon Sul, PhD, assistant professor in Pharmacology, showed that protein translation of two dendrite mRNAs is complex in space and time, as reported online in Cell Reports this week. 

“We needed to look at more than one RNA at the same time to get a better handle on real- world processes, and this is the first study to do that in a live neuron,” Eberwine explains.

At Home in the Hippocampus

“It’s not always one particular RNA that dominates at a translation hotspot versus another type of RNA,” says Eberwine. “Since there are 1,000 to 3,000 different mRNA types present in the dendrite overall, but not 1,000 to 3,000 different translational hot spots, do the mRNAs ‘take turns’ being translated in space and time at the ribosomes at the hotspots?”

The researchers engineered the glutamate receptor RNAs to contain different fluorescent proteins that are independently detectable, as well as a photo-switchable protein to determine when new proteins were being made. In the case of the photo-switchable protein studies, when an mRNA for the glutamate receptor protein is marked green, it means it has already been translated.

When a laser is passed over the green protein, it changes to red as a way of tagging when it has been been translated, and new proteins synthesized at that hotspot would be green, which is visible by the appearance of yellow fluorescence (green + red, as measured by light on the visible spectrum). These tricks of the light allow the team to keep track of newly made proteins over time and space.

“This is the first time this method of protein labeling has been used to measure the act of translation of multiple proteins over space and time in a quantitative way,” says Eberwine. “We call it quantitative functional genomics of live cell translation.”

“Our results suggest that the location of the translational hotspot is a regulator of the simultaneous translation of multiple messenger RNAs in nerve cell dendrites and therefore synaptic plasticity,” says Sul.

Laying the Groundwork

Almost 10 years ago, the Eberwine lab discovered that nerve-cell dendrites have the capacity to splice messenger RNA, a process once believed to take place only in the nucleus of cells. Here, a gene is copied into mRNA, which possesses both exons (mature mRNA regions that code for proteins) and introns (non-coding regions). mRNA splicing works by cutting out introns and merging the remaining exon pieces, resulting in an mRNA capable of being translated into a specific protein.

The vast array of proteins within the human body arises in part from the many ways that mRNAs can be spliced and reconnected. Specifically, splicing removes pieces of intron and exon regions from the RNA. The resulting spliced RNA is made into protein.

If the RNA has different exons spliced in and out of it, then different proteins can be made from this RNA. The Eberwine lab was successful in showing that splicing can occur in dendrites because they used sensitive technologies developed in their lab, which permits them to detect and quantify RNA splicing, as well as the translated protein in single isolated dendrites.

Understanding the dynamics of RNA biology and protein translation in dendrites promises to provide insight into regulatory mechanisms that may be modulated for therapeutic purposes in neurological and psychiatric illnesses. The directed development of therapeutics requires this detailed knowledge, says Eberwine.

Filed under synaptic plasticity learning neurons synapses hippocampus LTM neuroscience science

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During pregnancy, the bone hormone osteocalcin is produced by the mother; it crosses the placenta, to reach the fetus, where it promotes the formation of the hippocampus and the development of spatial learning and memory. Postnatally, osteocalcin crosses the blood-brain barrier (BBB), to act in various regions of the brain, including the hippocampus, where it causes changes in brain chemistry that help prevent anxiety and depression and improve spatial learning and memory.Image credit: Gerard Karsenty, MD, PhD and Franck Oury, PhD/Columbia University Medical Center Bone Hormone Influences Brain Development and Cognition Findings could lead to new treatments for memory loss, anxiety, and depression Researchers from Columbia University Medical Center (CUMC) have found that the skeleton, acting through the bone-derived hormone osteocalcin, exerts a powerful influence on prenatal brain development and cognitive functions such as learning, memory, anxiety, and depression in adult mice. Findings from the mouse study could lead to new approaches to the prevention and treatment of neurologic disorders. The study was published today in the online edition of Cell. “The brain is commonly viewed as an organ that influences other organs and parts of the body, but less often as the recipient of signals coming from elsewhere, least of all, the bones,” said study leader Gerard Karsenty, MD, PhD, Paul A. Marks Professor of Genetics and Development, professor  of medicine, and chair of the Department of Genetics and Development. “In an earlier study, we showed that the brain is a powerful inhibitor of bone mass accrual,” he said. “This effect was so powerful that it immediately raised the question, ‘Does the bone signal back to the brain to limit this negative influence?’ ‘If so, what signals does it use and how do they work?’” Dr. Karsenty suspected that osteocalcin, a hormone recently identified by his lab and secreted by osteoblasts, might be involved in such bone-to-brain signaling. Earlier studies had shown that osteocalcin affects a variety of processes, such as energy expenditure, glucose balance, and male fertility. “Since most hormones influence a range of physiological processes, it was reasonable to assume that the endocrine functions of osteocalcin were even broader than what was already known,” he said. To determine whether osteocalcin did indeed play a role in the brain, Dr. Karsenty and his team studied “osteocalcin-null” mice (mice that have been genetically engineered to not produce any osteocalcin). Using these mice, they were able to show unambiguously that osteocalcin can cross the blood-brain barrier; binds to neurons in the brainstem, midbrain, and hippocampus (which is responsible for learning and memory); promotes the birth of neurons; and increases the synthesis of several neurotransmitters, including serotonin, dopamine, and catecholamine. They also found that osteocalcin-null mice had abnormally small hippocampi, a part of the brain involved in memory. The researchers then hypothesized that the changes in neurotransmitter synthesis should alter the animals’ behavior. In a series of behavioral tests, they confirmed that osteocalcin-null mice exhibit increased anxiety and depression-like behaviors, as well as impaired learning and memory, compared with normal mice. These changes are similar to those seen in the aging population. “As we age, bone mass decreases, and the production of osteocalcin probably does, too,” said Dr. Karsenty. “We’re currently looking into this. It is not inconceivable that treatments that boost osteocalcin levels or stimulate osteocalcin receptors could help counter the cognitive effects of aging and aging-related diseases such as Alzheimer’s.” When adult osteocalcin-null mice were infused with osteocalcin, their anxiety and depression did decrease, “but the infusions didn’t affect learning and memory or the size of the hippocampus,” said Dr. Karsenty. “This was perplexing, so we did another experiment—a postnatal knockout of osteocalcin (a genetically engineered model in which the synthesis of osteocalcin is blocked after birth). These mice were anxious and depressed but had normal memory and hippocampus structure. The unavoidable conclusion of the two experiments was that osteocalcin must act during development.” This led to the second part of their study. In subsequent experiments, the researchers showed that osteocalcin crosses the placenta from mother to fetus and that this maternal pool of osteocalcin is necessary for formation of the hippocampus and the establishment of memory. Lastly, they showed that once-a-day injections of osteocalcin in osteocalcin-null mothers during pregnancy could prevent the development of behavioral abnormalities in their offspring. “This finding could explain some of the effects observed in children born from undernourished mothers who develop, with an unusually high frequency, metabolic and psychiatric disorders just as osteocalcin-null mice do,” said Dr. Karsenty. “Malnutrition decreases the activity of bone cells; as a result, undernourished mothers have low bone mass, which affects osteocalcin production. This has clinical relevance even today, in developing countries, where maternal malnutrition is still common.” Any therapies related to osteocalcin are still years away, however, he added.

During pregnancy, the bone hormone osteocalcin is produced by the mother; it crosses the placenta, to reach the fetus, where it promotes the formation of the hippocampus and the development of spatial learning and memory. Postnatally, osteocalcin crosses the blood-brain barrier (BBB), to act in various regions of the brain, including the hippocampus, where it causes changes in brain chemistry that help prevent anxiety and depression and improve spatial learning and memory.
Image credit: Gerard Karsenty, MD, PhD and Franck Oury, PhD/Columbia University Medical Center

Bone Hormone Influences Brain Development and Cognition

Findings could lead to new treatments for memory loss, anxiety, and depression

Researchers from Columbia University Medical Center (CUMC) have found that the skeleton, acting through the bone-derived hormone osteocalcin, exerts a powerful influence on prenatal brain development and cognitive functions such as learning, memory, anxiety, and depression in adult mice. Findings from the mouse study could lead to new approaches to the prevention and treatment of neurologic disorders. The study was published today in the online edition of Cell.

“The brain is commonly viewed as an organ that influences other organs and parts of the body, but less often as the recipient of signals coming from elsewhere, least of all, the bones,” said study leader Gerard Karsenty, MD, PhD, Paul A. Marks Professor of Genetics and Development, professor  of medicine, and chair of the Department of Genetics and Development.

“In an earlier study, we showed that the brain is a powerful inhibitor of bone mass accrual,” he said. “This effect was so powerful that it immediately raised the question, ‘Does the bone signal back to the brain to limit this negative influence?’ ‘If so, what signals does it use and how do they work?’”

Dr. Karsenty suspected that osteocalcin, a hormone recently identified by his lab and secreted by osteoblasts, might be involved in such bone-to-brain signaling. Earlier studies had shown that osteocalcin affects a variety of processes, such as energy expenditure, glucose balance, and male fertility. “Since most hormones influence a range of physiological processes, it was reasonable to assume that the endocrine functions of osteocalcin were even broader than what was already known,” he said.

To determine whether osteocalcin did indeed play a role in the brain, Dr. Karsenty and his team studied “osteocalcin-null” mice (mice that have been genetically engineered to not produce any osteocalcin). Using these mice, they were able to show unambiguously that osteocalcin can cross the blood-brain barrier; binds to neurons in the brainstem, midbrain, and hippocampus (which is responsible for learning and memory); promotes the birth of neurons; and increases the synthesis of several neurotransmitters, including serotonin, dopamine, and catecholamine. They also found that osteocalcin-null mice had abnormally small hippocampi, a part of the brain involved in memory.

The researchers then hypothesized that the changes in neurotransmitter synthesis should alter the animals’ behavior. In a series of behavioral tests, they confirmed that osteocalcin-null mice exhibit increased anxiety and depression-like behaviors, as well as impaired learning and memory, compared with normal mice.

These changes are similar to those seen in the aging population. “As we age, bone mass decreases, and the production of osteocalcin probably does, too,” said Dr. Karsenty. “We’re currently looking into this. It is not inconceivable that treatments that boost osteocalcin levels or stimulate osteocalcin receptors could help counter the cognitive effects of aging and aging-related diseases such as Alzheimer’s.”

When adult osteocalcin-null mice were infused with osteocalcin, their anxiety and depression did decrease, “but the infusions didn’t affect learning and memory or the size of the hippocampus,” said Dr. Karsenty. “This was perplexing, so we did another experiment—a postnatal knockout of osteocalcin (a genetically engineered model in which the synthesis of osteocalcin is blocked after birth). These mice were anxious and depressed but had normal memory and hippocampus structure. The unavoidable conclusion of the two experiments was that osteocalcin must act during development.” This led to the second part of their study.

In subsequent experiments, the researchers showed that osteocalcin crosses the placenta from mother to fetus and that this maternal pool of osteocalcin is necessary for formation of the hippocampus and the establishment of memory. Lastly, they showed that once-a-day injections of osteocalcin in osteocalcin-null mothers during pregnancy could prevent the development of behavioral abnormalities in their offspring.

“This finding could explain some of the effects observed in children born from undernourished mothers who develop, with an unusually high frequency, metabolic and psychiatric disorders just as osteocalcin-null mice do,” said Dr. Karsenty. “Malnutrition decreases the activity of bone cells; as a result, undernourished mothers have low bone mass, which affects osteocalcin production. This has clinical relevance even today, in developing countries, where maternal malnutrition is still common.”

Any therapies related to osteocalcin are still years away, however, he added.

Filed under brain development osteocalcin hippocampus memory learning cognition neuroscience science

254 notes

Maths experts are “made, not born” A new study of the brain of a maths supremo supports Darwin’s belief that intellectual excellence is largely due to “zeal and hard work” rather than inherent ability. University of Sussex neuroscientists took fMRI scans of  champion ‘mental calculator’ Yusnier Viera during arithmetical tasks that were either familiar or unfamiliar to him and found that his brain did not behave in an extraordinary or unusual way. The paper, published this week (23 September 2013) in PLOS ONE, provides scientific evidence that some calculation abilities are a matter of practice. Co-author Dr Natasha Sigala says: “This is a message of hope for all of us. Experts are made, not born.” Cuban-born Yusnier holds world records for being able to name the days of the week for any dates of the past 400 years, giving his answer in less than a second.  This is the kind of ability sometimes found in those with autism, although Yusnier is not on the autistic spectrum. Unlike those with autism or the related condition  Asperger’s, he is able to explain exactly how he calculates his answers – and even teaches his system and has written books on the subject.   The study, carried out at the Clinical Imaging Sciences Centre on the University of Sussex campus, suggests that Yusnier has honed his ability to create short cuts to his answers by storing information in the middle part of the brain specialised for long-term working memory (the hippocampus and surrounding cortex). This type of memory helps us carry out tasks in our area of expertise with speed  and efficiency. Although the left side of his brain was activated during mathematical problems – which is normal for all brains – the scientists observed that something slightly different happened when Yusnier was presented with unfamiliar problems. The scans showed marked connectivity of the anterior parts of the brain (prefrontal cortex), which are  involved  in decision making, during the unfamiliar calculations. This supports Yusnier’s report that he was building in an extra step to his mental processes to turn an unfamiliar problem into a familiar one. His answers to the unfamiliar questions had an 80 per cent degree of accuracy (compared with more than 90 per cent for familiar questions) and his responses were slightly slower. Dr Sigala explains: “Although this kind of ability is seen among some people with autism, it is much rarer in those not on that spectrum. Brain scans of those with autism tend to show a variety of activity patterns, and autistic people are not able to explain how they reach their answer. “With Yusnier, however, it is clear that his expertise is a result of long-term practice – and motivation.” She adds: “It was beyond the scope of our paper to discuss the debate on deliberate practice vs. innate ability.  But our study does not provide evidence for specific innate ability for mental calculations. As put by Charles Darwin to Francis Galton: ‘ […] I have always maintained that, excepting fools, men did not differ much in intellect, only in zeal and hard work; I still think this an eminently important difference.’”

Maths experts are “made, not born”

A new study of the brain of a maths supremo supports Darwin’s belief that intellectual excellence is largely due to “zeal and hard work” rather than inherent ability.

University of Sussex neuroscientists took fMRI scans of  champion ‘mental calculator’ Yusnier Viera during arithmetical tasks that were either familiar or unfamiliar to him and found that his brain did not behave in an extraordinary or unusual way.

The paper, published this week (23 September 2013) in PLOS ONE, provides scientific evidence that some calculation abilities are a matter of practice. Co-author Dr Natasha Sigala says: “This is a message of hope for all of us. Experts are made, not born.”

Cuban-born Yusnier holds world records for being able to name the days of the week for any dates of the past 400 years, giving his answer in less than a second.  This is the kind of ability sometimes found in those with autism, although Yusnier is not on the autistic spectrum. Unlike those with autism or the related condition  Asperger’s, he is able to explain exactly how he calculates his answers – and even teaches his system and has written books on the subject.  

The study, carried out at the Clinical Imaging Sciences Centre on the University of Sussex campus, suggests that Yusnier has honed his ability to create short cuts to his answers by storing information in the middle part of the brain specialised for long-term working memory (the hippocampus and surrounding cortex). This type of memory helps us carry out tasks in our area of expertise with speed  and efficiency.

Although the left side of his brain was activated during mathematical problems – which is normal for all brains – the scientists observed that something slightly different happened when Yusnier was presented with unfamiliar problems.

The scans showed marked connectivity of the anterior parts of the brain (prefrontal cortex), which are  involved  in decision making, during the unfamiliar calculations. This supports Yusnier’s report that he was building in an extra step to his mental processes to turn an unfamiliar problem into a familiar one. His answers to the unfamiliar questions had an 80 per cent degree of accuracy (compared with more than 90 per cent for familiar questions) and his responses were slightly slower.

Dr Sigala explains: “Although this kind of ability is seen among some people with autism, it is much rarer in those not on that spectrum. Brain scans of those with autism tend to show a variety of activity patterns, and autistic people are not able to explain how they reach their answer.

“With Yusnier, however, it is clear that his expertise is a result of long-term practice – and motivation.”

She adds: “It was beyond the scope of our paper to discuss the debate on deliberate practice vs. innate ability.  But our study does not provide evidence for specific innate ability for mental calculations. As put by Charles Darwin to Francis Galton: ‘ […] I have always maintained that, excepting fools, men did not differ much in intellect, only in zeal and hard work; I still think this an eminently important difference.’”

Filed under autism asperger's syndrome ASD hippocampus prefrontal cortex neuroimaging memory neuroscience science

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