The brain’s RAM: Rats, like humans, have a “working memory”

Thousands of times a day, the brain stores sensory information for very short periods of time in a working memory, to be able to use it later. A research study carried out with the collaboration of SISSA has shown, for the first time, that this function also exists in the brain of rodents, a finding that sheds light on the evolutionary origins of this cognitive mechanism.

In computers it’s called “RAM”, but the mechanism is conceptually similar to what scientists call a “working memory” in the brain of humans and primates: when we interact with the environment our senses gather information that a temporary memory system keeps fresh and readily accessible for a few minutes, so that the body can carry out operations (for example, an action). For the first time, a research team coordinated by Mathew Diamond of the International School for Advanced Studies (SISSA) in Trieste has shown that this memory system also exists in simpler mammals like rodents.

Working memory has been studied in detail in humans and primates, but little was known about its existence in other animals. “Knowing that a working memory also exists in the brain of evolutionarily simpler organisms helps us to understand the origins of this important cognitive mechanism”, explains Diamond. “Comparative psychology studies have historically helped scientists not only to trace the evolutionary roots of human brain functions but also to gain deeper insight into human cognitive processes themselves”.

The type of sensory memory studied by Diamond and co-workers in rats is tactile memory. The performance of rodents in tasks assessing recognition of vibratory stimuli was compared with that of humans performing similar tasks (rats used their whiskers and humans their fingertips). “Rats exhibited similar behaviour patterns to humans, demonstrating that these animals use a tactile working memory that enables them to recognise and interact with environmental stimuli”. The research paper has been published in The Proceedings of the National Academy of Sciences (PNAS).

More in detail…

“Working memory is an extraordinary cognitive mechanism”, comments Diamond. “It’s like a container where the brain stores little bits of very recent experience, to be able to assess the best course of action. Without this temporary memory, experience would slip away without any chance of being used”.

“Working memory can hold only a limited amount of information for a fairly short period of time. These limits are the result of a cost-benefit balance: the brain’s computational capacity is fixed and decisions as to what action to take often need to be quick and effective as the same time. Our working memory’s capacity is therefore the best we can achieve in terms of accuracy and speed with our brain”.

“The brain regions responsible for working memory have not yet been identified in rats. Some believe that rats don’t have the brain centres known as “prefrontal cortex” which are involved in this function in primates”, continues Diamond. ”Our surprise was to discover that rodents realize memory in a manner similar to humans. Now we are continuing our studies to understand how these mechanisms work in detail”.

Index Detects Early Signs of Deviation from Normal Brain Development

Researchers at Penn Medicine have generated a brain development index from MRI scans that captures the complex patterns of maturation during normal brain development. This index will allow clinicians and researchers for the first time to detect subtle, yet potentially critical early signs of deviation from normal development during late childhood to early adult.

The study, published online in the journal Cerebral Cortex, shows a relationship between cognitive development and physical changes in the developing young brain (aged 8 to 21).

“Our findings suggest that brain imaging via sophisticated MRI scans may be a useful biomarker for the early detection of subtle developmental abnormalities,” said Guray Erus, PhD, a research associate in the department of Radiology at the Perelman School of Medicine at the University of Pennsylvania, and the study’s lead author. “The abnormalities may, in turn, be the first manifestations of subsequent neuropsychiatric problems.”

Among its key findings is the consistency in healthy brain development of young people. The study examined cognitive performance of outliers – adolescents whose brains developed faster or slower than the normal rates. Early maturers performed significantly better than those with delayed brain development in the speed at which they completed certain tasks. The improved speed of performance indicates increased efficiency in neuronal organization and communication. Slower performance in such tests is a precursor to neuropsychiatric disorders, (the research suggests), including adolescent-onset psychosis. 

The 14 tests used in the Penn study evaluate a broad range of cognitive functions including abstraction and mental flexibility, attention, working memory, verbal memory, face memory, spatial memory, language reasoning, nonverbal reasoning, spatial processing, emotion identification, and sensorimotor speed.

Penn’s brain development index consolidates a number of complex visual maps derived from sophisticated analysis of MRI scans into a unified developmental template. By looking at an individual’s brain maps in relation to the consolidated findings, researchers can estimate the age of the subject. Subjects whose brain development index was higher than their chronological age had significantly superior cognitive processing speed as measured by the cognitive tests compared to subjects whose brain indices were lower than their actual age.

“This is analogous to producing growth charts used in pediatrics to screen for gross abnormalities of physical development,” said Christos Davatzikos, PhD, professor of Radiology and Electrical and Systems Engineering at Penn and one of the study’s co-senior authors. “We can assess individuals in terms of where they place in relation to the overall trends. While single image maps can be used for an accurate estimation of the age of the subject, the combination of all maps achieves a higher accuracy in age prediction than the accuracy of each map independently.”

Previous studies have outlined normative trajectories of growth for individual brain regions across the lifespan; the Penn study is the first to present a comprehensive index for the entire brain during late childhood, adolescence, and young adulthood — periods when the healthy human brain maturates in a remarkably consistent way, deviations from which possibly signify later neuropsychiatric problems.

The Penn study used a sample of 621 participants in the Philadelphia Neurodevelopmental Cohort, a Grand Opportunity study funded by the National Institute of Mental Health, designed to understand how brain maturation mediates cognitive development and vulnerability to psychiatric illness and how genetics impacts this process.

“All of our young study participants have received a standardized neuropsychiatric evaluation at intake, and all agreed to be contacted for future studies. Some are followed up longitudinally,” said Ruben C. Gur, PhD, director of the Brain Behavior Laboratory at Penn and the study’s other co-senior author. “We can therefore follow those who score low on our index and examine whether interventions such as cognitive remediation can mitigate potential symptoms.”

Researchers discover an epigenetic lesion in the hippocampus of Alzheimer’s patients

Alzheimer’s disease can reach epidemic range in the coming decades, by the increasing average age of society. There are two key issues for Alzheimer’s disease: there is currently no effective treatment and it has been described very few associated genetic changes (mutations) which reduces the number of targets for future therapies.

Alzheimer’s disease

Pathologically, Alzheimer’s disease is characterized by the accumulation of protein deposits in the brain of patients. These deposits are formed by plates of a protein called amyloid-beta and rolled tangles of tau protein. The root cause of these lesions in most cases is unknown, but specific alterations in regulating genes expression might be involved.

Today, the prestigious international journal in neurology Hippocampus publishes an article led by Manel Esteller, Director of Epigenetics and Cancer Biology, Institute of Biomedical Research of Bellvitge (IDIBEL), ICREA researcher and Professor of Genetics at the University of Barcelona, with the collaboration of  the Institute of Neuropathology IDIBELL led by Isidre Ferrer, demonstrating for the first time the existence of an epigenetic lesion in the hippocampus of the brain of patients with Alzheimer.

Switches in the hippocampus

"We first started studying 30,000 molecular switches that turn on and off genes in the hippocampal region in the brains of Alzheimer patients in different stages of disease and compared with that of healthy patients of the same age. We note that dusp22 gene switches off (methylates) as the disease advances" explained Manel Esteller, director of the study.

"But more importantly" continues "was the discovery that this gene regulates tau protein. Perhaps therefore the accumulation of tau protein produced in the brain of patients with Alzheimer results from dusp22 epigenetic inactivation".

According Esteller “the finding is relevant not only to determine the causes of the disease, but also to test potential treatments in the future to act on these epigenetic molecular switches”.

Forget about forgetting – The elderly know more and use it better

What happens to our cognitive abilities as we age? If your think our brains go into a steady decline, research reported this week in the Journal Topics in Cognitive Science may make you think again. The work, headed by Dr. Michael Ramscar of Tübingen University, takes a critical look at the measures usually thought to show that our cognitive abilities decline across adulthood. Instead of finding evidence of decline, the team discovered that most standard cognitive measures, which date back to the early twentieth century, are flawed. “The human brain works slower in old age,” says Ramscar, “but only because we have stored more information over time.”

Computers were trained, like humans, to read a certain amount each day, and to learn new things. When the researchers let a computer “read” only so much, its performance on cognitive tests resembled that of a young adult. But if the same computer was exposed to the experiences we might encounter over a lifetime – with reading simulated over decades – its performance now looked like that of an older adult. Often it was slower, but not because its processing capacity had declined. Rather, increased “experience” had caused the computer’s database to grow, giving it more data to process – which takes time.

Technology now allows researchers to make quantitative estimates of the number of words an adult can be expected to learn across a lifetime, enabling the Tübingen team to separate the challenge that increasing knowledge poses to memory from the actual performance of memory itself. “Imagine someone who knows two people’s birthdays and can recall them almost perfectly. Would you really want to say that person has a better memory than a person who knows the birthdays of 2000 people, but can ‘only’ match the right person to the right birthday nine times out of ten?” asks Ramscar.

The answer appears to be “no.” When Ramscar’s team trained their computer models on huge linguistic datasets, they found that standardized vocabulary tests, which are used to take account of the growth of knowledge in studies of ageing, massively underestimate the size of adult vocabularies. It takes computers longer to search databases of words as their sizes grow, which is hardly surprising but may have important implications for our understanding of age-related slowdowns. The researchers found that to get their computers to replicate human performance in word recognition tests across adulthood, they had to keep their capacities the same. “Forget about forgetting,” explained Tübingen researcher Peter Hendrix, “if I wanted to get the computer to look like an older adult, I had to keep all the words it learned in memory and let them compete for attention.”

The research shows that studies of the problems older people have with recalling names suffer from a similar blind spot: there is a far greater variety of given names today than there were two generations ago. This cultural shift toward greater name diversity means the number of different names anyone learns over their lifetime has increased dramatically. The work shows how this makes locating a name in memory far harder than it used to be. Even for computers.

Ramscar and his colleagues’ work provides more than an explanation of why, in the light of all the extra information they have to process, we might expect older brains to seem slower and more forgetful than younger brains. Their work also shows how changes in test performance that have been taken as evidence for declining cognitive abilities in fact demonstrates older adults’ greater mastery of the knowledge they have acquired.

Take “paired-associate learning,” a commonly used cognitive test that involves learning to connect words like “up” to “down” or “necktie” to “cracker” in memory. Using Big Data sets to quantify how often different words appear together in English, the Tuebingen team show that younger adults do better when asked to learn to pair “up” with “down” than “necktie” and “cracker” because “up” and “down” appear in close proximity to one another more frequently. However, whereas older adults also understand which words don’t usually go together, young adults notice this less. When the researchers examined performance on this test across a range of word pairs that go together more and less in English, they found older adult’s scores to be far more closely attuned to the actual information in hundreds of millions of words of English than their younger counterparts.

As Prof. Harald Baayen, who heads the Alexander von Humboldt Quantitative Linguistics research group where the work was carried out puts it, “If you think linguistic skill involves something like being able to choose one word given another, younger adults seem to do better in this task. But, of course, proper understanding of language involves more than this. You have also to not put plausible but wrong pairs of words together. The fact that older adults find nonsense pairs – but not connected pairs – harder to learn than young adults simply demonstrates older adults’ much better understanding of language. They have to make more of an effort to learn unrelated word pairs because, unlike the youngsters, they know a lot about which words don’t belong together.”

The Tübingen research conclude that we need different tests for the cognitive abilities of older people – taking into account the nature and amount of information our brains process. “The brains of older people do not get weak,” says Michael Ramscar. “On the contrary, they simply know more.”

Hydrocephalus: sensors monitor cerebral pressure

Urinary incontinence, a shuffling gait, and deteriorating reasoning skills are all indicators pointing to a Parkinsonian or Alzheimer type disease. An equally plausible explanation is hydrocephalus, commonly known as “water on the brain.” With this diagnosis, the brain produces either too much cerebral fluid, or it cannot “drain off” these fluids with adequate sufficiency. The consequence: Pressure in the brain rises sharply, resulting in damage. A shunt system – a kind of silicon tube that physicians implant into the patient’s brain, provides relief. It draws off superfluous fluid from there, for example, into the abdominal cavity. The heart of this shunt system is a valve: If the pressure increases above a threshold value, then the valve opens; if it declines again, then the valve closes.

In rare cases, over-drainage may occur. The cerebral pressure lowers too much, the cerebral ventricles are virtually squeezed out. Until now, physicians could only detect and verify such over-drainage through elaborate and costly computer and magnetic resonance tomography.

Cerebral pressure measurable anytime

With a new kind of sensor, things are different: If it is implanted into the patient’s brain with the shunt system, the physicians could read out brain pressure using a hand-held meter: within seconds, anytime and without complex investigation. Researchers at the Fraunhofer Institute for Microelectronic Circuits and Systems IMS in Duisburg, working jointly with Christoph Miethke GmbH and Aesculap AG, engineered these sensors.

If the patient complains of discomfort, then the physician merely needs to place the hand- held meter outside, on the patient’s head. The device sends magnetic radio waves and supplies the sensor in the shunt with power- the implant is “awakened,” measures tem- perature and pressure in the cerebral fluid, and transmits these data back to the handheld device. If the pressure on the outside of the desired area, the physician can set the valve on the shunt system from the outside as needed, and individually adjusted to the patient. “The sensor is an active implant, which also takes over measurement functions, in contrast to a stent or a tooth implant,” says Michael Görtz, head of pressure sensor technology at IMS.

The implant must be biocompatible; the body cannot reject it. Researchers had to ensure that the body also would not attack the implant. “The defense response behaves just like an aggressive medium, that would even dilute the silicon of the electronics over the course of time,” explains Görtz. Miethke therefore completely encases the implant into a thin metal casing. “We can still supply it with power from the outside through the metal casing, measure cerebral pressure through the housing and transmit the recorded data outside, through the metal to the reader,” Görtz explains. To do so, the correct metal had to be found. The coating may not be thicker than the walls of a soft drink can – in other words, much thinner than one millimeter. The researchers even developed the handheld reading device, together with the electronics, through which it communicates with the sensor.

The sensor is ready for serial production, and was already approved by Miethke. The company has already initiated the market launch of the system. “The sensor sets the basis for the further development through to theranostic implants – a neologism derived from the words “therapy” and “diagnostic.” In a few years, the sensor could then not only record cerebral pressure and develop a diagnosis on the basis of this, but also properly adjust the pressure independently, immediately on its own and thus, take over the therapy process,” says Görtz.

Fighting Flies

When one encounters a group of fruit flies invading their kitchen, it probably appears as if the whole group is vying for a sweet treat. But a closer look would likely reveal the male flies in the group are putting up more of a fight, particularly if ripe fruit or female flies are present. According to the latest studies from the fly laboratory of California Institute of Technology (Caltech) biologist David Anderson, male Drosophilae, commonly known as fruit flies, fight more than their female counterparts because they have special cells in their brains that promote fighting. These cells appear to be absent in the brains of female fruit flies.  

"The sex-specific cells that we identified exert their effects on fighting by releasing a particular type of neuropeptide, or hormone, that has also been implicated in aggression in mammals including mouse and rat," says Anderson, the Seymour Benzer Professor of Biology at Caltech, and corresponding author of the study. "In addition, there are some recent papers implicating increased levels of this hormone in people with personality disorders that lead to higher levels of aggression."

The team’s findings are outlined in the January 16 version of the journal Cell.

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