Increased neurogenesis from exercise does not cause forgetting of previously learned task

From Vital Record News from Texas A & M University Health Science Center:

Forget old memories

Study shows exercise won’t cause you to forget things

Contradicting earlier work, researchers confirm exercise is good for you—and your brain
August 2, 2016

Research has found that exercise causes more new neurons to be formed in a critical brain region, and contrary to an earlier study, these new neurons do not cause the individual to forget old memories, according to research by Texas A&M College of Medicine scientists, in the Journal of Neuroscience.

Exercise is well known for its cognitive benefits, thought to occur because it causes neurogenesis, or the creation of new neurons, in the hippocampus, which is a key brain region for learning, memory and mood regulation. Therefore, it was a surprise in 2014 when a research study, published in the journal Science, found that exercise caused mice to forget what they’d already learned.

“It stunned the field of hippocampal neurogenesis,” said Ashok K. Shetty, PhD, a professor in the Texas A&M College of Medicine Department of Molecular and Cellular Medicine, associate director of the Institute for Regenerative Medicine, and research career scientist at the Central Texas Veterans Health Care System. “It was a very well-done study, so it caused some concern that exercise might in some way be detrimental for memory.”

The animal models in the exercise group—in the previous study—showed far more neurogenesis than the control group, but contrary to what one might think, these additional neurons seemed to erase memories that were formed before they started the exercise regimen. To test this, the researchers removed the extra neurons, and the mice suddenly were able to remember again.

“The mice who exercised had a large number of new neurons,” Shetty said, “but somehow that seemed to break down the old connections, making them forget what they knew.”

Shetty and his team decided to replicate this earlier research, using rats instead of mice. Rats are thought to be more like humans physiologically, with more-similar neuronal workings. They found that—luckily for runners everywhere—these animal models showed no such degradation in memories.

“We had completely contradictory findings from the 2014 study,” said Maheedhar Kodali, PhD, a postdoctoral fellow at the Institute for Regenerative Medicine and the first author of this study. “Now we need to study other species to fully understand this phenomenon.”

Shetty and his team trained their animal models to complete a task over the course of four days, followed by several days of memory consolidation by performing the task over and over again. Then, half the trained animal models were put into cages with running wheels for several weeks, while the control group remained sedentary.

The rats who ran further over the course of that time had much greater neurogenesis in their hippocampus, and all rats who had access to a wheel (and therefore ran at least some), had greater neurogenesis than the sedentary group. On an average, they ran about 48 miles in four weeks, and neuron formation doubled in the hippocampus of these animals.

“This is pretty clear evidence that exercise greatly increases neurogenesis in the hippocampus, which has functional implications,” Kodali said. “Neurogenesis is important for maintaining normal mood function, as well as for learning and creating new memories.” This connection may help explain why exercise is an effective antidepressant.

Importantly, despite differing levels of increased neurogenesis, both moderate runners and brisk runners (those who ran further than average) in Shetty’s study showed the same ability as the sedentary runners to recall the task they learned before they began to exercise. This means even a large amount of running (akin to people who perform significant amount of exercise on a daily basis) doesn’t interfere with the recall of memory.

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Role of Hippocampal Sleep Spindles in Memory Consolidation

From The Scientist:

Minding the Pulse of Memory Consolidation

Studying sleep spindles could help neuroscientists better understand certain cognitive impairments.

By Richard Kemeny | July 28, 2016

Thalamus (red) WIKIMEDIA, LIFE SCIENCE DATABASES

Sleep is essential for memory. Mounting evidence continues to support the notion that the nocturnal brain replays, stabilizes, reorganizes, and strengthens memories while the body is at rest. Recently, one particular facet of this process has piqued the interest of a growing group of neuroscientists: sleep spindles. For years these brief bursts of brain activity have been largely ignored. Now it seems that examining these neuronal pulses could help researchers better understand—perhaps even treat—cognitive impairments.

Sleep spindles are a defining characteristic of stage 2 non-rapid eye movement (NREM) sleep. These electrical bursts between 10-16 Hz last only around a second, and are known to occur in the human brain thousands of times per night. Generated by a thin net of neurons enveloping the thalamus, spindles appear across several regions of the brain, and are thought to perform various functions, including maintaining sleep in the face of disturbances in the environment.

It appears they are also a fundamental part of the process by which the human brain consolidates memories during sleep.

A memory formed during the day is stored temporarily in the hippocampus, before being spontaneously replayed during the night. Information about the memory is distributed out and integrated into the neocortex through an orchestra of slow-waves, spindles, and rapid hippocampal ripples. Spindles, it seems, could be a guiding force—providing the plasticity and coordination needed for this delicate, interregional transfer of information.

“Spindles appear to play a central role whenever memories during sleep are undergoing transformation that might be necessary to integrate them into neocortical long-term storage networks,” Jan Born, a professor of behavioral neurobiology of the University of Tübingen, told The Scientist during a conference dedicated to sleep spindles held in Budapest in May.

Fewer spindles, therefore, would be expected to coincide with a breakdown in memory consolidation.

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High dose of resveratrol helps reduce neuronal inflammation in Alzheimer’s

From EurekAlert!:

Public Release: 27-Jul-2016

Resveratrol appears to restore blood-brain barrier integrity in Alzheimer’s disease

Georgetown University Medical Center

WASHINGTON — Resveratrol, given to Alzheimer’s patients, appears to restore the integrity of the blood-brain barrier, reducing the ability of harmful immune molecules secreted by immune cells to infiltrate from the body into brain tissues, say researchers at Georgetown University Medical Center. The reduction in neuronal inflammation slowed the cognitive decline of patients, compared to a matching group of placebo-treated patients with the disorder.

The laboratory data provide a more complete picture of results from a clinical trial studying resveratrol in Alzheimer’s disease that was first reported in 2015. The new findings will be presented at the Alzheimer’s Association International Conference 2016 in Toronto on July 27th.

The Alzheimer’s disease brain is damaged by inflammation, thought to be due to a reaction to the buildup of abnormal proteins, including Abeta40 and Abeta42, linked to destruction of neurons. Researchers believe that heightened inflammation — which was historically thought to come only from “resident” brain immune cells — worsens the disease. According to the researchers, this study suggests that some of the immune molecules that can cause inflammation in the blood can enter the brain through a leaky blood-brain barrier.

“These findings suggest that resveratrol imposes a kind of crowd control at the border of the brain. The agent seems to shut out unwanted immune molecules that can exacerbate brain inflammation and kill neurons,” says neurologist Charbel Moussa, MD, PhD, scientific and clinical research director of the GUMC Translational Neurotherapeutics Program. “These are very exciting findings because it shows that resveratrol engages the brain in a measurable way, and that the immune response to Alzheimer’s disease comes, in part, from outside the brain.”

Resveratrol is a naturally occurring compound found in foods such as red grapes, red wine, raspberries and dark chocolate. GUMC researchers, led by R. Scott Turner, MD, PhD, tested the substance in 119 patients, the largest nationwide phase II clinical trial to study high-dose pure synthetic (pharmaceutical-grade) resveratrol in individuals with mild to moderate Alzheimer’s. The study was published Sept. 11, 2015 in Neurology.

The new part of the resveratrol study examines specific molecules in the cerebrospinal fluid (CSF) taken from participants with biomarker-confirmed Alzheimer’s disease — 19 were given a placebo, and 19 treated daily for a year with resveratrol, equivalent to the amount found in about 1,000 bottles of red wine.

Previous studies with animals found that age-related diseases–including Alzheimer’s — can be prevented or delayed by long-term caloric restriction (consuming two-thirds the normal caloric intake). The researchers studied resveratrol because it mimics the effects of caloric restriction by also activating proteins called sirtuins.

In this new study, Moussa and Turner found that treated patients had a 50 percent reduction in matrix metalloproteinase-9 (MMP-9) levels in the cerebrospinal fluid. MMP-9 is decreased when sirtuin1 (SIRT1) is activated. High levels of MMP-9 cause a breakdown in the blood-brain barrier, allowing proteins and molecules from the body to enter the brain. Normally low MMP-9 levels maintain the barrier, say the researchers.

“These new findings are exciting because they increase our understanding of how resveratrol may be clinically beneficial to individuals with Alzheimer’s disease. In particular, they point to the important role of inflammation in the disease, and the potent anti-inflammatory effects of resveratrol,” says Turner, director of GUMC’s Memory Disorders Program and co-director of the Translational Neurotherapeutics Program.

They also found that resveratrol increased the level of molecules linked to a long-term beneficial or “adaptive” immune reaction, suggesting involvement of inflammatory cells that are resident in the brain, says Moussa. “This is the kind of immune response you want — it is there to remove and degrade neurotoxic proteins.”

“A puzzling finding from the resveratrol study (as well as immunotherapy strategies for Alzheimer’s under investigation) is the greater shrinkage of the brain found with treatment. These new findings support the notion that resveratrol decreases swelling that results from inflammation in Alzheimer’s brain,” says Turner. “This seemingly paradoxical effect is also found with many of the drugs that are beneficial for patients with multiple sclerosis — another brain disease characterized by excessive inflammation.”

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Scientists activate and distinguish glutamate receptor subtypes

From Kyoto University research news:

Flipping a protein switch to illuminate brain functions

28 Jun 2016

Pacman-shaped receptor’s “bite” sheds light on learning and memory processes

Japan — What goes on inside the brain when we learn new things? Much still remains wrapped in mystery, but scientists have found a way to examine this at the molecular level.

Researchers in Japan have engineered an artificial switch that could let scientists turn individual neurotransmitter receptors on and off. Shedding light on these receptors’ role in memory formation could contribute to the development of new drugs for neurological diseases, including Alzheimer’s, Parkinson’s, and ALS.

Neurotransmitter receptors help relay information from neuron to neuron. “Investigating the functions of various neurotransmitter receptors could be immensely useful, because a majority of drugs on the market target them,” says lead author Ryou Kubota of Kyoto University. “But with so many similarly-structured proteins in the membrane, it’s been extremely difficult to determine which receptors do what.

“Discovering the functions of each neurotransmitter receptor in the brain could help us understand how we learn and acquire memory; to do that, it’s crucial to be able to activate them selectively.”

In the study, published in Nature Chemistry, the team succeeded in selectively activating glutamate receptors, which are pacman-shaped neutrotransmitter receptors known to be involved in memory formation.

Membrane proteins change in shape when they become active. For pacman-shaped glutamate receptors, activation happens when they “bite”. The team genetically engineered glutamate receptors to include switches forcing activation and deactivation. “The switch comes in the shape of two ‘clips’ on what would be the upper and lower lips of pacman,” explains Kubota. “When we tell the clips to bind together, we force the glutamate receptor to activate.”

The current study only reports outcomes with glutamate receptors, but the authors say that their method also shows promise with other kinds of membrane receptors. “Even within glutamate receptors there are subtypes, and within those subtypes there are further distinctions. This time we were able to distinguish and selectively activate each subtype,” remarks Kubota.

[…]

 

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N-Acetylcysteine (NAC) treatment may improve Parkinson’s

From Newswise:

Natural Molecule Could Improve Parkinson’s

A natural molecule shows benefit in a preliminary clinical trial for Parkinson’s Disease

Released: 16-Jun-2016 2:00 PM EDT
Brain scans of a representative patient showing Dopamine transporter binding (red) before and after 3-month NAC treatment.

Thomas Jefferson University Brain scans of a representative patient showing Dopamine transporter binding (red) before and after 3-month NAC treatment.

Newswise — (PHILADELPHIA) — The natural molecule, n-acetylcysteine (NAC), with strong antioxidant effects, shows potential benefit as part of the management for patients with Parkinson’s disease, according to a study published today in the journal PLOS ONE. Combining clinical evaluations of a patient’s mental and physical abilities with brain imaging studies that tracked the levels of dopamine, the lack of which is thought to cause Parkinson’s, doctors from the Departments of Integrative Medicine, Neurology, and Radiology, at Thomas Jefferson University showed that patients receiving NAC improved on both measures.

Current treatments for Parkinson’s disease are generally limited to temporarily replacing dopamine in the brain as well as some medications designed to slow the progression of the disease process. Recently, researchers have shown that oxidative stress in the brain may play a critical role in the Parkinson’s disease process, and that this stress also lowers levels of glutathione, a chemical produced by the brain to counteract oxidative stress. Studies in brain cells showed that NAC helps reduce oxidative damage to neurons by helping restore the levels of the antioxidant glutathione. NAC is an oral supplement that can be obtained at most nutrition stores, and interestingly also comes in an intravenous form which is used to protect the liver in acetaminophen overdose.

“This study reveals a potentially new avenue for managing Parkinson’s patients and shows that n-acetylcysteine may have a unique physiological effect that alters the disease process and enables dopamine neurons to recover some function,” said senior author on the paper Daniel Monti, M.D., M.B.A., Director of the Myrna Brind Center of Integrative Medicine, and the Brind-Marcus Center of Integrative Medicine at Thomas Jefferson University.

In this study, Parkinson’s patients who continued their current standard of care treatment, were placed into two groups. The first group received a combination of oral and intravenous (IV) NAC for three months. These patients received 50mg/kg NAC intravenously once per week and 600mg NAC orally 2x per day on the non IV days. The second group, the control patients, received only their standard of care for Parkinson’s treatment. Patients were evaluated initially, before starting the NAC and then after three months of receiving the NAC while the control patients were simply evaluated initially and three months later. The evaluation consisted of standard clinical measures such as the Unified Parkinson’s Disease Rating Scale (UPDRS), a survey administered by doctors to help determine the stage of disease, and a brain scan via DaTscan SPECT imaging, which measures the amount of dopamine transporter in the basal ganglia, the area most affected by the Parkinson’s disease process. Compared to controls, the patients receiving NAC had improvements of 4-9 percent in dopamine transporter binding and also had improvements in their UPDRS score of about 13 percent.

“We have not previously seen an intervention for Parkinson’s disease have this kind of effect on the brain,” said first author and neuro-imaging expert Andrew Newberg, M.D., Professor at the Sidney Kimmel Medical College at Jefferson and Director of Research at the Myrna Brind Center of Integrative Medicine. The investigators hope that this research will open up new avenues of treatment for Parkinson’s disease patients.

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DHA can reverse effects of fructose on brain genes

Funny how researchers always spin research findings toward drug development – I assume to attract pharmaceutical dollars.

From UCLA Newsroom:

Fructose alters hundreds of brain genes, which can lead to a wide range of diseases

UCLA scientists report that diet rich in omega-3 fatty acids can reverse the damage

Stuart Wolpert | April 21, 2016

Syrup contains fructose, which alters brain genes linked to many diseases, UCLA life scientists report.

 

A range of diseases — from diabetes to cardiovascular disease, and from Alzheimer’s disease to attention deficit hyperactivity disorder — are linked to changes to genes in the brain. A new study by UCLA life scientists has found that hundreds of those genes can be damaged by fructose, a sugar that’s common in the Western diet, in a way that could lead to those diseases.

However, the researchers discovered good news as well: An omega-3 fatty acid known as docosahexaenoic acid, or DHA, seems to reverse the harmful changes produced by fructose.

“DHA changes not just one or two genes; it seems to push the entire gene pattern back to normal, which is remarkable,” said Xia Yang, a senior author of the study and a UCLA assistant professor of integrative biology and physiology. “And we can see why it has such a powerful effect.”

DHA occurs naturally in the membranes of our brain cells, but not in a large enough quantity to help fight diseases.

“The brain and the body are deficient in the machinery to make DHA; it has to come through our diet,” said Fernando Gomez-Pinilla, a UCLA professor of neurosurgery and of integrative biology and physiology, and co-senior author of the paper.

Reed Hutchinson/UCLA Xia Yang and Fernando Gomez-Pinilla

DHA strengthens synapses in the brain and enhances learning and memory. It is abundant in wild salmon (but not in farmed salmon) and, to a lesser extent, in other fish and fish oil, as well as walnuts, flaxseed, and fruits and vegetables, said Gomez-Pinilla, who also is a member of UCLA’s Brain Injury Research Center.

Americans get most of their fructose in foods that are sweetened with high-fructose corn syrup, an inexpensive liquid sweetener made from corn starch, and from sweetened drinks, syrups, honey and desserts. The Department of Agriculture estimates that Americans consumed an average of about 27 pounds of high-fructose corn syrup in 2014. Fructose is also found is in most baby food and in fruit, although the fiber in fruit substantially slows the body’s absorption of the sugar — and fruit contains other healthy components that protect the brain and body, Yang said.

To test the effects of fructose and DHA, the researchers trained rats to escape from a maze, and then randomly divided the animals into three groups. For the next six weeks, one group of rats drank water with an amount of fructose that would be roughly equivalent to a person drinking a liter of soda per day. The second group was given fructose water and a diet rich in DHA. The third received water without fructose and no DHA.

After the six weeks, the rats were put through the maze again. The animals that had been given only the fructose navigated the maze about half as fast than the rats that drank only water — indicating that the fructose diet had impaired their memory. The rats that had been given fructose and DHA, however, showed very similar results to those that only drank water — which strongly suggests that the DHA eliminated fructose’s harmful effects.

Other tests on the rats revealed more major differences: The rats receiving a high-fructose diet had much higher blood glucose, triglycerides and insulin levels than the other two groups. Those results are significant because in humans, elevated glucose, triglycerides and insulin are linked to obesity, diabetes and many other diseases.

The research team sequenced more than 20,000 genes in the rats’ brains, and identified more than 700 genes in the hypothalamus (the brain’s major metabolic control center) and more than 200 genes in the hippocampus (which helps regulate learning and memory) that were altered by the fructose. The altered genes they identified, the vast majority of which are comparable to genes in humans, are among those that interact to regulate metabolism, cell communication and inflammation. Among the conditions that can be caused by alterations to those genes are Parkinson’s disease, depression, bipolar disorder, and other brain diseases, said Yang, who also is a member of UCLA’s Institute for Quantitative and Computational Biosciences.

Of the 900 genes they identified, the researchers found that two in particular, called Bgn and Fmod, appear to be among the first genes in the brain that are affected by fructose. Once those genes are altered, they can set off a cascade effect that eventually alters hundreds of others, Yang said.

That could mean that Bgn and Fmod would be potential targets for new drugs to treat diseases that are caused by altered genes in the brain, she added.

The research also uncovered new details about the mechanism fructose uses to disrupt genes. The scientists found that fructose removes or adds a biochemical group to cytosine, one of the four nucleotides that make up DNA. (The others are adenine, thymine and guanine.) This type of modification plays a critical role in turning genes “on” or “off.”

The research is published online in EBioMedicine, a journal published jointly by Cell and The Lancet. It is the first genomics study of all the genes, pathways and gene networks affected by fructose consumption in the regions of the brain that control metabolism and brain function.

Previous research led by Gomez-Pinilla found that fructose damages communication between brain cells and increases toxic molecules in the brain; and that a long-term high-fructose diet diminishes the brain’s ability to learn and remember information.

“Food is like a pharmaceutical compound that affects the brain,” said Gomez-Pinilla. He recommends avoiding sugary soft drinks, cutting down on desserts and generally consuming less sugar and saturated fat.

Although DHA appears to be quite beneficial, Yang said it is not a magic bullet for curing diseases. Additional research will be needed to determine the extent of its ability to reverse damage to human genes.

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Drawing words has a recall advantage over writing them

From Waterloo News:

Need to remember something? Better draw it, study finds

Thursday, April 21, 2016
Researchers at the University of Waterloo have found that drawing pictures of information that needs to be remembered is a strong and reliable strategy to enhance memory.

Watch video on YouTube

“We pitted drawing against a number of other known encoding strategies, but drawing always came out on top,” said the study’s lead author, Jeffrey Wammes, PhD candidate in the Department of Psychology. “We believe that the benefit arises because drawing helps to create a more cohesive memory trace that better integrates visual, motor and semantic information.”

The study, by Wammes, along with fellow PhD candidate Melissa Meade and Professor Myra Fernandes, presented student participants with a list of simple, easily drawn words, such as “apple.” The students were given 40 seconds to either draw the word, or write it out repeatedly. They were then given a filler task of classifying musical tones to facilitate the retention process. Finally, the researchers asked students to freely recall as many words as possible from the initial list in just 60 seconds.

The study appeared in the the Quarterly Journal of Experimental Psychology.

“We discovered a significant recall advantage for words that were drawn as compared to those that were written,” said Wammes. “Participants often recalled more than twice as many drawn than written words. We labelled this benefit ‘the drawing effect,’ which refers to this distinct advantage of drawing words relative to writing them out.”

In variations of the experiment in which students drew the words repeatedly, or added visual details to the written letters, such as shading or other doodles, the results remained unchanged. Memory for drawn words was superior to all other alternatives. Drawing led to better later memory performance than listing physical characteristics, creating mental images, and viewing pictures of the objects depicted by the words.

“Importantly, the quality of the drawings people made did not seem to matter, suggesting that everyone could benefit from this memory strategy, regardless of their artistic talent. In line with this, we showed that people still gained a huge advantage in later memory, even when they had just 4 seconds to draw their picture,” said Wammes.

While the drawing effect proved reliable in testing, the experiments were conducted with single words only. Wammes and his team are currently trying to determine why this memory benefit is so potent, and how widely it can be applied to other types of information.

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