ScienceDaily (Aug. 27, 2009) — Researchers at MIT’s Picower Institute for Learning and Memory have found that rats use a mental instant replay of their actions to help them decide what to do next, shedding new light on how animals and humans learn and remember.

“By understanding how thoughts and memories are structured, we can gain insight into how they might be disrupted in diseases and disorders of memory and thought such as Alzheimer’s and schizophrenia,” said study author Matthew A. Wilson, the Sherman Fairchild Professor of Neuroscience at the Picower Institute. “This understanding may lead to new methods of diagnosis and treatment.”

Wilson’s laboratory explores how rats form and recall memories by recording — with an unprecedented level of accuracy — the activity of single neurons in the hippocampus while the animal is performing tasks, pausing between actions and sleeping. The hippocampus is the seahorse-shaped brain region researchers believe to be critical for learning and memory.

Wilson’s previous work has shown that after the animals run a maze, their brains “replay” during sleep the sequence of events they experienced while awake. Researchers believe this process is key to sleep-reinforced memory consolidation in both animals and humans.

The latest study shows that these sequences also occur when the animals are awake and may help them decide what to do next.

Not-so-instant replay

When a rat moves through a maze, certain neurons called “place cells,” which respond to the animal’s physical environment, fire in patterns and sequences unique to different locations. By looking at the patterns of firing cells, researchers can tell which part of the maze the animal is running.

While the rat is awake but standing still in the maze, its neurons fire in the same pattern of activity that occurred while it was running. The mental replay of sequences of the animals’ experience occurs in both forward and reverse time order.

“This may be the rat equivalent of ‘thinking,’” Wilson said. “This thinking process looks very much like the reactivation of memory that we see during non-REM dream states, consisting of bursts of time-compressed memory sequences lasting a fraction of a second.

“So, thinking and dreaming may share the same memory reactivation mechanisms,” he said.

Memory’s building blocks

“This study brings together concepts related to thought, memory and dreams that all potentially arise from a unified mechanism rooted in the hippocampus,” said co-author Fabian Kloosterman, senior postdoctoral associate.

The team’s results show that long experiences, which in reality could have taken tens of seconds or minutes, are replayed in only a fraction of a second. To do this, the brain links together smaller pieces to construct the memory of the long experience.

The researchers speculated that this strategy could help different areas of the brain share information — and deal with multiple memories that may share content — in a flexible and efficient way. “These results suggest that extended replay is composed of chains of shorter subsequences, which may reflect a strategy for the storage and flexible expression of memories of prolonged experience,” Wilson said.

Moreover, by comparing the content of the replay with the rat’s physical location on the track and his actual behavior immediately before and after the replay event the researchers could tell the rat was not just thinking about his most recent experience but also about other options, such as: “What if I turned around and went back the way I came?” or “How would I get here if my starting point is at a distant location?”

This suggests that the same brain mechanisms come into play to remember the past and consider future actions, reinforcing recent work by neuroscientists outside of MIT who determined that in humans, cognitive processes related to episodic recall and evaluation of future events overlap to a high degree.

Memory formation and future planning are among the cognitive functions ravaged by diseases such as Alzheimer’s disease, schizophrenia and psychosis.

“A better understanding of how we use memories, not only to learn from past experiences but also to explore our future options, can give us insights into how the system fails under these disease conditions,” Kloosterman said.

The MIT researchers plan to further explore the link between awake replay and cognition in animals engaged in more cognitively demanding tasks such as those involving multiple choices, where the rat has to make a decision (”do I go left or right?”) based on a prior learned rule.

In addition to Wilson, the study was led jointly by Kloosterman and MIT brain and cognitive sciences graduate student Thomas J. Davidson.

This research was supported by National Institutes of Health (NIH).

Original article here.

Researchers at MIT’s Picower Institute for Learning and Memory conducted learning and memory tasks using transgenic mice that were induced to lose a significant number of brain cells. Following Alzheimer’s-like brain atrophy, the mice acted as though they did not remember tasks they had previously learned.  But after taking HDAC inhibitors, the mice regained their long-term memories and ability to learn new tasks. In addition, mice genetically engineered to produce no HDAC2 at all exhibited enhanced memory formation.

The fact that long-term memories can be recovered by elevated histone acetylation supports the idea that apparent memory “loss” is really a reflection of inaccessible memories, Tsai said. “These findings are in line with a phenomenon known as ‘fluctuating memories,’ in which demented patients experience temporary periods of apparent clarity,” she said.

A team led by researchers at MIT’s Picower Institute for Learning and Memory has now pinpointed the exact gene responsible for a 2007 breakthrough in which mice with symptoms of Alzheimer’s disease regained long-term memories and the ability to learn. In the latest development, reported in the May 7 issue of Nature, Li-Huei Tsai, Picower Professor of Neuroscience, and colleagues found that drugs that work on the gene HDAC2 reverse the effects of Alzheimer’s and boost cognitive function in mice.

Original article here

Clinton didn’t inhale, Obama did—and maybe Reagan should have. New research suggests that THC, the chemical that gives marijuana its mind-bending properties, kills developing neurons, yet oddly, the same chemical saves neurons in adults with Alzheimer’s disease.

“Marijuana is not the ‘soft drug’ people like to think it is,” says neuro­pharmacologist Veronica Campbell of Trinity College in Dublin, whose latest study uncovered the harmful effects of THC on young neurons. When Campbell and her co-workers treated brain cells from newborn or adolescent rats with THC, the neurons died, but THC did not have such deadly effects on neurons taken from adult rats. In fact, work from other labs shows that THC benefits adult neurons. “We don’t know why,” Campbell says. Several possi­bilities are being investigated for this “Jekyll and Hyde” effect.

Marijuana, like tobacco and opium, has powerful effects on the brain because certain compounds in the plant happen to have a chemical resemblance to naturally occurring substances in the body. Called endocannabinoids, these natural chemicals regulate important brain functions by controlling synapses in neural circuits that process thought and perception. According to several recent studies, these chemicals have many other functions in the brain and immune system, too—including regulating development and aiding survival of young neurons, as well as controlling the wiring of neurons into circuits for learning and memory. Smoking marijuana during the period of life when the brain is still developing obscures these critical chemical signals, Campbell suspects.

The slaughter of young neurons by THC could explain the developmental cognitive impairment seen in children born to women who smoked marijuana during pregnancy. In addition, some research on adolescent marijuana abusers shows brain damage in neural circuits that are still developing at that age.

In older brains, however, THC seems to have a protective effect. Campbell’s findings indicate that the biochemistry of neurons changes as the cells mature. The role of endocannabi­noids shifts to regulate different functions—most important, assisting in the survival of aged neurons. In patients with Alzheimer’s disease, THC protects neurons from death in several ways. THC boosts depleted levels of the neurotransmitter acetylcholine, which, when diminished, contributes to the weakened mental function in Alzheimer’s patients. THC also suppresses the toxic effects of the so-called a-beta protein that may kill neurons in Alzheimer’s disease. It stimulates secretion of neuron growth by promoting substances such as brain-derived neurotrophic factor, and it dampens release of the excitatory neurotransmitter glutamate, which kills neurons by overstimulation. THC and other cannabinoids also have powerful anti-inflammatory and antioxidant actions that protect neurons from immune system attack.

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Animal studies conducted at the National Institute on Aging Gerontology Research Center and the Johns Hopkins University School of Medicine, for example, have shown that both calorie restriction and intermittent fasting along with vitamin and mineral intake, increase resistance to disease, extend lifespan, and stimulate production of neurons from stem cells.

In addition,
fasting has been shown to enhance synaptic elasticity, possibly increasing the ability for successful re-wiring following brain injury. These benefits appear to result from a cellular stress response, similar in concept to the greater muscular regeneration that results from the stress of regular exercise.

Additional research suggests that increasing time intervals between meals might be a better choice than chronic calorie restriction, because the resultant decline in sex hormones may adversely affect both sexual and brain performance. Sex steroid hormones testosterone and estrogen are positively impacted by an abundant food supply. In other words, you might get smarter that way, but it might adversely affect your fun in the bedroom, among other drawbacks.

But if your not keen on starving yourself, there are other options. Another recent finding, stemming from the Burnham Institute for Medical Research and Iwate University in Japan, reports that the herb rosemary contains an ingredient that fights off free radical damage in the brain. The active ingredient, known as carnosic acid (CA), can protect the brain from stroke and neurodegeneration such as Alzheimer’s and from the effects of normal aging.

Although researchers are patenting more potent forms of isolated compounds in this herb, unlike most new drugs, simply using the rosemary in its natural state may be the most safe and clinically tolerated because it is known to get into the brain and has been consumed by people for over a thousand years. The herb was used in European folk medicine to help the nervous system.

Another brain booster that Bruce N. Ames, Ph.D., a professor of biochemistry and molecular biology at the University of California, Berkeley, swears by his daily 800 mg of alpha-lipoic acid and 2,000 mg of acetyl-L-carnitine, chemicals which boost the energy output of mitochondria that power our cells. Mitochondrial decay is a major factor in aging and diseases such as Alzheimer’s and diabetes. Elderly rats on these supplements had more energy and ran mazes better.

Omega-3s fatty acids DHA and EPA found in walnuts and fatty fish (such as salmon, sardines, and lake trout) are thought to help ward off Alzheimer’s disease. (In addition, they likely help prevent depression and have been shown to help prevent sudden death from heart attack).

Turmeric, typically found in curry, contains curcumin, a chemical with potent antioxidant and anti-inflammatory properties. In India, it is even used as a salve to help heal wounds. East Asians also eat it, which might explain their lower rates (compared to the United States) of Parkinson’s disease and Alzheimer’s disease, in addition to various cancers. If curry isn’t part of your favorite cuisines, you might try a daily curcumin supplement of 500 to 1,000 mg.

Physical exercise may also have beneficial effects on neuron regeneration by stimulating regeneration of brain and muscle cells via activation of stress proteins and the production of growth factors. But again, additional research suggests that not all exercise is equal. Interestingly, some researchers found that exercise considered drudgery was not beneficial in neuronal regeneration, but physical activity that was engaged in purely for fun, even if equal time was spent and equal calories were burned, resulted in neuronal regeneration.

Exercise can also help reduce stress, but any stress-reducing activity, such as meditation and lifestyle changes, can help the brain. There is some evidence that chronic stress shrinks the parts of the brain involved in learning, memory, and mood. (It also delays wound healing, promotes atherosclerosis, and increases blood pressure.)

It should go without saying that short-term cognitive and physical performance is not boosted by
fasting, due to metabolic changes including decrease in body temperature, decreased heart rate and blood pressure and decreased glucose and insulin levels, so you’re better off not planning a marathon or a demanding work session during a
fasting period.

As part of a healthy lifestyle the prescription of moderating food intake, exercising, and eating anti-oxidant rich foods is what we’ve long known will boost longevity, but it’s good to know that we can bring our brains along with us as we make it into those golden years without being the 1 in 7 who suffers from dementia. Keep your fingers crossed and eat some rosemary chicken.

Living with a partner at midlife may lower the risk for Alzheimer’s disease later in life, a new study shows. The findings add to a growing body of evidence that staying socially connected is vital for a healthy and intact brain late in life.

Several studies have shown that lifestyle factors may help to ward off cognitive decline later in life. Education, regular exercise and activity, a mentally challenging job and intellectual activities that might include regularly doing crossword puzzles and word games, have been linked to a sharp memory. Being married and having lots of friends has also been linked to keeping the mind sharp.

In the current study, Scandinavian researchers looked at about 1,500 men and women from Finland at midlife, then again some 20 years later. They found that those who were living with a partner at midlife, around age 50, were least likely to show memory and thinking problems when they were in their late 60s or 70s.

Men and women who were widowed or divorced at midlife and who remained so as seniors were the most likely to have be diagnosed with a condition like Alzheimer’s late in life. The risk was especially high for those who had been widowed and who carried the APOE-E4 gene, a gene that increases the odds of developing Alzheimer’s. Those who were single at midlife were also at increased risk of developing memory problems as seniors compared to those who had been married or partnered in their middle years.

The findings appeared in the British medical journal BMJ. In an editorial that accompanied the findings, a doctor suggests that his colleagues in primary care practice might target unmarried — and especially widowed — people and encourage them “to increase their social engagement” as a means of possible warding off Alzheimer’s disease.

The research is consistent with other evidence showing that staying socially connected with spouses, family and friends helps to preserve memory and keep the brain young. Marriage and partnership is thought to provide social as well as intellectual stimulation that may help to keep the brain working well into old age. The researchers did not look at such factors as the quality of the marriage or the effects of children on outcome. But, they plan to continue their research into this provocative area.

Social interaction may be good for those who care for a loved one with Alzheimer’s, too. Dr. Mary Mittelman and colleagues at New York University have shown that maintaining a close network of family and friends who can be called on for emotional support may be critical for easing the stress of caregiving.

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Alzheimer’s disease (AD) is a neurodegenerative disorder that currently affects nearly 5% of people 65-year old and over 30% of those 85-year old. It is now estimated that there are 18−24 million people suffering from AD worldwide, two-thirds of whom are living in developed or developing countries, and this number is expected to reach 34 million by 2025. AD is characterized by the progressive accumulation of amyloid beta peptide (Aβ), neurofibrillary tangles (NFTs) and hyperphosphorylated microtubule-associated tau protein. Many regions involved in memory and learning processes, such as the hippocampus and frontal cortex, show neuron apoptosis several years before clinical signs appear. Today there is no cure for this devastating disease and therefore it is of great interest for researchers to find new drugs that can hinder the disease process.  Current drugs on the market improve the function of still intact neurons, but do not inhibit the ongoing degenerative process leading to neuronal cell death. Curcumin, a biologically active component of turmeric (Curcuma longa) is used as a curry spice and herbal medicine for the treatment of inflammatory conditions, cancer, AIDS and other diseases. Epidemical studies in India, where turmeric is used routinely, show that the incidence of AD between the ages of 70 and 79 years is 4.4-fold less than in the USA.  Results on mice show that a low dose of curcumin significantly suppressed the inflammation, reduced oxidative damage and plaque burden and decreased the amount of insoluble amyloid. Compared to other antioxidant drugs, such as NSAID or ibuprofen, curcumin had fewer side effects. Evidence suggests that metals are concentrated in the AD brain and curcumin is a chelator which can bind the iron and copper (but not zinc) on beta amyloid, which may be one mechanism potentially contributing to amyloid reduction. In vivo, curcumin may protect cells from the beta amyloid attack and subsequent oxidative stress-induced damage in the antioxidant pathway. The findings of a previous study prove curcumin can induce cognitive improvement by enhancing the cholinergic system and its antioxidant activity. The studies on curcumin are incomplete and there needs to be further investigation of its neuroprotective mechanism.

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Two studies published in this week’s Journal of the American Medical Association add to evidence that long-term lifestyle habits may reduce the risk of mental decline in old age.

The first study, a long-term look at 1,880 elderly people in New York City, found that a Mediterranean-type diet and physical activity each were linked to less risk for Alzheimer’s disease. The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center released the data as part of a larger research project on aging.

The second study, a shorter-term observation of 1,410 patients in France, found some correlation between a Mediterranean-type diet and slower cognitive damage.

Nikolaos Scarmeas, the author of the first study, grew up eating fish and vegetables in Athens, Greece. Now the neurologist suggests more people take up his mother’s cooking. Marked by high consumption of foods such as vegetables, legumes and cereals, served with olive oil, in addition to moderate fish and alcohol intake, the traditional diet has long conferred better cardiovascular health.

Starting in 1992, researchers at Columbia University monitored elderly patients every 18 months for diet, exercise and mental health, in addition to a number of controls including age, sex and education. “This is one of the first studies to tease apart the independent contributions of diet and exercise for dementia prevention,” says Ronald Petersen, director of the Alzheimer’s Disease Research Center at the Mayo Clinic in Rochester, Minn., who was not involved in the research. “It suggests that aging need not be a passive process.”

These studies are observational and not definitive, but they hint at what might reduce the chances of Alzheimer’s or dementia. In the Columbia research, those who adhered most closely to the diet reduced their risk for Alzheimer’s by 40%, while those with the highest physical activity decreased their risk 33%, compared with people who didn’t adhere closely to the diet or were not physically active.

The French study found that subjects who adhered to the Mediterranean-type diet experienced a slower rate of mental decline than those who did not eat the diet, but did not prove a link for dementia, which requires a clinical assessment of a variety of mental and social functions.

Doctors in the field are careful to note that none of these findings demonstrate a causal relationship, but instead reflect the advantages of a continual healthy lifestyle. “The benefits don’t just occur at age 70 when you suddenly stop eating McDonald’s and start eating Brussels sprouts,” says David Knopman, a neurologist at the Mayo Clinic in Rochester, Minn., who wrote the editorial accompanying the studies in JAMA and wasn’t involved in either study. His editorial highlights confounding variables in the studies. “Healthy diet and exercise is part of a package of lifelong healthy living.”

Zaven Khachaturian, a senior science adviser to the Alzheimer’s Association, agrees. “This offers interesting insight but we need to turn it now into clinical trials,” says the former director of the Office of Alzheimer’s Disease Research at the National Institutes of Health.

These findings arrive a few weeks after new research identified a gene that could help predict who will develop Alzheimer’s—the leading cause of dementia—and at what age. The report, given in mid-July at the International Conference on Alzheimer’s Disease, concentrated on DNA surrounding the ApoE gene. Researchers say more studies are needed before the findings can be confirmed.

For now, Dr. Scarmeas says his studies strongly suggest that a Mediterranean diet and exercise both confer independent and positive health benefits. But together, they are even better.

“The relative risk reduction for Alzheimer’s is about 60% when you combine the diet and exercise,” he says.

Original Article by carrie.porter@wsj.com