How to Erase a Memory – And Restore It

Researchers at the University of California, San Diego School of Medicine have erased and reactivated memories in rats, profoundly altering the animals’ reaction to past events.

The study, published in the June 1 advanced online issue of the journal Nature, is the first to show the ability to selectively remove a memory and predictably reactivate it by stimulating nerves in the brain at frequencies that are known to weaken and strengthen the connections between nerve cells, called synapses.

“We can form a memory, erase that memory and we can reactivate it, at will, by applying a stimulus that selectively strengthens or weakens synaptic connections,” said Roberto Malinow, MD, PhD, professor of neurosciences and senior author of the study.

Scientists optically stimulated a group of nerves in a rat’s brain that had been genetically modified to make them sensitive to light, and simultaneously delivered an electrical shock to the animal’s foot. The rats soon learned to associate the optical nerve stimulation with pain and displayed fear behaviors when these nerves were stimulated.

Analyses showed chemical changes within the optically stimulated nerve synapses, indicative of synaptic strengthening.

In the next stage of the experiment, the research team demonstrated the ability to weaken this circuitry by stimulating the same nerves with a memory-erasing, low-frequency train of optical pulses. These rats subsequently no longer responded to the original nerve stimulation with fear, suggesting the pain-association memory had been erased.

In what may be the study’s most startlingly discovery, scientists found they could re-activate the lost memory by re-stimulating the same nerves with a memory-forming, high-frequency train of optical pulses. These re-conditioned rats once again responded to the original stimulation with fear, even though they had not had their feet re-shocked.

“We can cause an animal to have fear and then not have fear and then to have fear again by stimulating the nerves at frequencies that strengthen or weaken the synapses,” said Sadegh Nabavi, a postdoctoral researcher in the Malinow lab and the study’s lead author.

In terms of potential clinical applications, Malinow, who holds the Shiley Endowed Chair in Alzheimer’s Disease Research in Honor of Dr. Leon Thal, noted that the beta amyloid peptide that accumulates in the brains of people with Alzheimer’s disease weakens synaptic connections in much the same way that low-frequency stimulation erased memories in the rats. “Since our work shows we can reverse the processes that weaken synapses, we could potentially counteract some of the beta amyloid’s effects in Alzheimer’s patients,” he said.

Cynical? You May Be Hurting Your Brain Health

People with high levels of cynical distrust may be more likely to develop dementia, according to a study published in the May 28, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology.

Cynical distrust, which is defined as the belief that others are mainly motivated by selfish concerns, has been associated with other health problems, such as heart disease. This is the first study to look at the relationship between cynicism and dementia.

“These results add to the evidence that people’s view on life and personality may have an impact on their health,” said study author Anna-Maija Tolppanen, PhD, of the University of Eastern Finland in Kuopio. “Understanding how a personality trait like cynicism affects risk for dementia might provide us with important insights on how to reduce risks for dementia.”

For the study, 1,449 people with an average age of 71 were given tests for dementia and a questionnaire to measure their level of cynicism. The questionnaire has been shown to be reliable, and people’s scores tend to remain stable over periods of several years. People are asked how much they agree with statements such as “I think most people would lie to get ahead,” “It is safer to trust nobody” and “Most people will use somewhat unfair reasons to gain profit or an advantage rather than lose it.” Based on their scores, participants were grouped in low, moderate and high levels of cynical distrust.

A total of 622 people completed two tests for dementia, with the last one an average of eight years after the study started. During that time, 46 people were diagnosed with dementia. Once researchers adjusted for other factors that could affect dementia risk, such as high blood pressure, high cholesterol and smoking, people with high levels of cynical distrust were three times more likely to develop dementia than people with low levels of cynicism. Of the 164 people with high levels of cynicism, 14 people developed dementia, compared to nine of the 212 people with low levels of cynicism.

The study also looked at whether people with high levels of cynicism were more likely to die sooner than people with low levels of cynicism. A total of 1,146 people were included in this part of the analysis, and 361 people died during the average of 10 years of follow-up. High cynicism was initially associated with earlier death, but after researchers accounted for factors such as socioeconomic status, behaviors such as smoking and health status, there was no longer any link between cynicism and earlier death.

(Image: Shutterstock)

What Our Ancestors Can Teach Us About Exercise, Alzheimer’s and Human Longevity

Our ancient ancestors’ exercise routines could provide important clues about how best to prevent and treat Alzheimer’s disease and other modern age-related diseases, according to a new paper by two University of Arizona researchers.

The article, featured on the cover of the May issue of the journal Trends in Neurosciences, explores the evolutionary links between physical activity, brain aging and the lifespan of humans, who outlive all other primates.

"This is an effort to try to understand the relationship between exercise and an important genetic risk factor for Alzheimer’s disease and vascular disease, and how the human lifespan evolved, which is a fundamental question that’s been considered in the scientific literature for many years," said UA psychology professor Gene Alexander, who co-authored the paper with David Raichlen, a UA associate professor of anthropology.

While many studies today tout the health benefits of exercise, Alexander and Raichlen consider the link between physical activity and health from an evolutionary perspective, beginning about 2 million years ago. It was around that time that humans made the shift from a more apelike, sedentary lifestyle to a highly active hunter-gatherer lifestyle and began living longer.

During that period, humans likely carried two copies of a genotype known as ApoE4, which is directly linked to higher risk for Alzheimer’s disease and cardiovascular disease. Yet, despite the presence of the problematic gene variation, longer lifespans began to evolve.

"Having this risk allele (ApoE4) is our ancestral condition," Raichlen said. "The lower risk alleles evolved relatively recently, so our question was: How do you evolve a long lifespan when you have this ApoE4 risk allele?"

The answer, Raichlen and Alexander believe, lies in humans’ high level of physical activity 2 million years ago.

"To engage in this hunter-gatherer lifestyle you have to be an aerobically active organism. There’s no way around it. You have to go long distances to find your food," Raichlen said.

"We developed a hypothesis that suggests that exercise may be an important modulating factor that helps to compensate for the negative impact of the (genetic) risk factor for Alzheimer’s and vascular disease, and ultimately might help us to understand why humans are able to live much longer than other primate species," said Alexander, who also teaches in the UA Graduate Interdisciplinary Programs in Neuroscience and Physiological Sciences.

As the human lifestyle today has become increasingly sedentary, this evolutionary link may be important in the development of new prevention therapies and treatments for Alzheimer’s and other age-related diseases, Alexander said.

"We are fundamentally endurance athletes, based on our ancestry. Our recent change, to a more sedentary lifestyle, may have led to a situation where this (ApoE4) genotype has become a problem for us, where it might not have been before," he said.

"With our current tendencies towards less active lifestyles, we need to be thinking about exercise as a potentially important intervention. Considering the evolutionary significance of ApoE4 also gives us some clues about why exercise might be especially important for us."

Today, it has been estimated that about 25 percent of the general U.S. population carries the ApoE4 genotype, and only about 2 percent have two copies of it, putting them at even greater risk for Alzheimer’s or vascular disease. However, the prevalence of the genotype in subgroups of the U.S. population and in some other parts of the world is much higher. 

"There are parts of equatorial Africa where the frequency of the ApoE4 allele is something like 40 percent of the population," Raichlen said, "so thinking about how to use exercise to alter risk around the world is important."

Raichlen has studied in-depth the evolution and effects of physical activity in humans. His research covers a range of topics, including the effects of exercise on happiness, the link between aerobic activity and brain size, the walking patterns of human hunter-gatherers and the role of the runners’ high in human evolution.

Alexander, a member of the UA’s Evelyn F. McKnight Brain Institute and the Arizona Alzheimer’s Consortium, has done extensive research on aging and age-related diseases.

The two came together to explore the connection between their two areas of study by considering research literature in anthropology, brain imaging and neuroscience.

"We’ve generated a new hypothesis from these different scientific literatures that typically don’t cross over," Alexander said. "We are drawing on these different disciplines to look at this question in a new way, and I think it really has important implications for how we understand health issues today. Using what we know about ancestral genotypes, their risks, and how our behaviors evolved over time may help us to gain a better understanding of the underlying mechanisms of Alzheimer’s and age-related cognitive decline."

New tests in UK Biobank trial

Study finds modified stem cells offer potential pathway to treat Alzheimer’s disease

UC Irvine neurobiologists have found that genetically modified neural stem cells show positive results when transplanted into the brains of mice with the symptoms and pathology of Alzheimer’s disease. The pre-clinical trial is published in the journal Stem Cells Research and Therapy, and the approach has been shown to work in two different mouse models.

Alzheimer’s disease, one of the most common forms of dementia, is associated with accumulation of the protein amyloid-beta in the brain in the form of plaques. While the search continues for a viable treatment, scientists are now looking into non-pharmaceutical ways to slow onset of this disease.

One option being considered is increasing the production of the enzyme neprilysin, which breaks down amyloid-beta, and shows lower activity in the brains of people with Alzheimer’s disease. Researchers from UC Irvine investigated the potential of decreasing amyloid-beta by delivering neprilysin to mice brains.

“Studies suggest that neprilysin decreases with age and may therefore influence the risk of Alzheimer’s disease,” said Mathew Blurton-Jones, an assistant professor of neurobiology & behavior. “If amyloid accumulation is the driving cause of Alzheimer’s disease, then therapies that either decrease amyloid-beta production or increase its degradation could be beneficial, especially if they are started early enough.”

The brain is protected by a system called the blood-brain-barrier that restricts access of cells, proteins, and drugs to the brain. While the blood-brain-barrier is important for brain health, it also makes it challenging to deliver therapeutic proteins or drugs to the brain. To overcome this, the researchers hypothesized that stem cells could act as an effective delivery vehicle. To test this hypothesis the brains of two different mouse models (3xTg-AD and Thy1-APP) were injected with genetically modified neural stem cells that over-expressed neprilysin.

These genetically modified stem cells were found to produce 25-times more neprilysin than control neural stem cells, but were otherwise equivalent to the control cells. The genetically modified and control stem cells were then transplanted into the hippocampus or subiculum of the mice brains – two areas of the brain that are greatly affected by Alzheimer’s disease. The mice transplanted with genetically modified stem cells were found to have a significant reduction in amyloid-beta plaques within their brains compared to the controls. The effect remained even one month after stem cell transplantation. This new approach could provide a significant advantage over unmodified neural stem cells because neprilysin-expressing cells could not only promote the growth of brain connections but could also target and reduce amyloid-beta pathology.

Before this can be investigated in humans, more work needs to be done to see if this affects the accumulation of soluble forms of amyloid-beta. Further investigation is also needed to determine whether this new approach improves cognition more than the transplantation of un-modified neural stem cells.

“Every mouse model of Alzheimer’s disease is different and develops varying amounts, distribution, and types of amyloid-beta pathology,” Blurton-Jones said. “By studying the same question in two independent transgenic models, we can increase our confidence that these results are meaningful and applicable to Alzheimer’s disease. But there is clearly a great deal more research needed to determine whether this kind of approach could eventually be translated to the clinic.”