Sleep-dependent memory consolidation and accelerated forgetting

Accelerated long-term forgetting (ALF) is a form of memory impairment in which learning and initial retention of information appear normal but subsequent forgetting is excessively rapid. ALF is most commonly associated with epilepsy and, in particular, a form of late-onset epilepsy called transient epileptic amnesia (TEA). ALF provides a novel opportunity to investigate post-encoding memory processes, such as consolidation. Sleep is implicated in the consolidation of memory in healthy people and a deficit in sleep-dependent memory consolidation has been proposed as an explanation for ALF. If this proposal were correct, then sleep would not benefit memory retention in people with ALF as much as in healthy people, and ALF might only be apparent when the retention interval contains sleep. To test this theory, we compared performance on a sleep-sensitive memory task over a night of sleep and a day of wakefulness. We found, contrary to the hypothesis, that sleep benefits memory retention in TEA patients with ALF and that this benefit is no smaller in magnitude than that seen in healthy controls. Indeed, the patients performed significantly more poorly than the controls only in the wake condition and not the sleep condition. Patients were matched to controls on learning rate, initial retention, and the effect of time of day on cognitive performance. These results indicate that ALF is not caused by a disruption of sleep-dependent memory consolidation. Instead, ALF may be due to an encoding abnormality that goes undetected on behavioural assessments of learning, or by a deficit in memory consolidation processes that are not sleep-dependent.

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(Image: Courtney Icenhour)

(Image caption: In this image, marking shows the axons in retinal neurons (in red) that innervate the superior colliculus (in blue) in a “normal” mouse. Credit: © Michael Reber / Institut des Neurosciences Cellulaires et Intégratives)

Confirmation of the neurobiological origin of attention-deficit disorder

A study, carried out on mice, has just confirmed the neurobiological origin of attention-deficit disorder (ADD), a syndrome whose causes are poorly understood. Researchers from CNRS, the University of Strasbourg and INSERM1 have identified a cerebral structure, the superior colliculus, where hyperstimulation causes behavior modifications similar to those of some patients who suffer from ADD. Their work also shows noradrenaline accumulation in the affected area, shedding light on this chemical mediator having a role in attention disorders. These results are published in the journal Brain Structure and Function.

Attention-deficit disorder affects between 4-8% of children. It manifests mainly through disturbed attention and verbal and motor impulsiveness, sometimes accompanied by hyperactivity. About 60% of these children still show symptoms in adulthood. No cure exists at this time. The only effective treatment is to administer psychostimulants, but these have substantial side effects, such as dependence. Persistent controversy surrounding the neurobiological origin of this disorder has hindered the development of new treatments.

The study in Strasbourg investigated the behavior of transgenic mice having developmental defects in the superior colliculus. This structure, located in the midbrain, is a sensory hub involved in controlling attention and visual and spatial orientation. The mice studied were characterized by duplicated neuron projections between the superior colliculus and the retina. This anomaly causes visual hyperstimulation and excess noradrenaline in the superior colliculus. The effects of the neurotransmitter noradrenaline, which vary from species to species, are still poorly understood. However, we do know that this noradrenaline imbalance is associated with significant behavioral changes in mice carrying the genetic mutation. By studying them, researchers have observed a loss of inhibition: for example mice hesitate less to penetrate a hostile environment. They have difficulties in understanding relevant information and demonstrate a form of impulsiveness. These symptoms remind us of adult patients suffering from one of the forms of ADD.

Currently, the fundamental work on ADD uses mainly animal models obtained by mutations that disturb dopamine production and transmission pathways. In mice with a malformed superior colliculus, these pathways are intact. The changes occur elsewhere in the neural networks of the midbrain. By broadening the classic boundary used to research its causes, using these new models would allow a more global approach to ADD to be developed. Characterizing the effects of noradrenaline on the superior colliculus more precisely could open the way to innovative therapeutic strategies.

(Fig. 1: Humans have the ability to accurately estimate the speed of moving objects under good light conditions, such as a bird on a clear day (left). On a cloudy day (right), however, the sensory information may be more ambiguous and invokes a specific cognitive mechanism—perceptual bias—that is hardwired into the visual cortex. Image credit: Justin Gardner, RIKEN Brain Science Institute)

An early link to motion perception

When viewing a scene with low contrast, such as in cloudy or low-light situations, humans tend to perceive objects to be moving slower or flickering faster than in reality. This less-than-faithful interpretation of the sensory environment is known as perceptual bias and is thought to be a mechanism that can help humans interpret vague motion information. Brett Vintch and Justin Gardner from the Laboratory for Human Systems Neuroscience at the RIKEN Brain Science Institute have now shown that perceptual bias is encoded within the visual cortex—the region of the brain where visual stimuli first arrive and begin to be processed.

Although humans have the ability to estimate the speed of easily visible, high-contrast stimuli quite accurately, the speed of less-visible, low-contrast stimuli is harder to judge and is invariably underestimated. Speed perception is thought to be closely associated with the middle temporal zone of the visual cortex, but measurements have so far been unable to confirm this link.

Vintch and Gardner set out to resolve the link between cortical response and perception by conducting functional magnetic resonance imaging experiments on test subjects exposed to a series of low- and high-contrast images either moving across the screen at different speeds or flickering at different rates.

The researchers found that different speeds of motion in visual stimulus evoked different patterns of activity in the visual cortex. So systematic was the observed pattern of activity that Vintch and Gardner were able to predict the motion speed or flicker frequency of what the observer was viewing simply by examining the measured brain responses. Using these predictions, they found that when the test subjects viewed scenes with low contrast, the patterns of activity shifted to match what the observer was perceiving rather than what was actually physically present. 

The findings indicate that human perceptual bias about the movement of low-contrast stimuli originates from a shift in the response of neuronal populations in the parts of the brain that first start to process images. This early visual processing, which is hardwired into the visual cortex, may help humans make sense of ambiguous or vague visual information, such as moving or flickering scenes under low-contrast conditions (Fig. 1).

“Multiple aspects of human thought, such as sensory inference, language, cognition and reasoning, involve cognitive guesswork. We hope that our study of this very simple form of guessing by the nervous system will have implications for other high-level processes in the human brain,” explains Gardner.

Fruit flies, fighter jets use similar nimble tactics when under attack

When startled by predators, tiny fruit flies respond like fighter jets – employing screaming-fast banked turns to evade attacks.

Researchers at the University of Washington used an array of high-speed video cameras operating at 7,500 frames a second to capture the wing and body motion of flies after they encountered a looming image of an approaching predator.

“Although they have been described as swimming through the air, tiny flies actually roll their bodies just like aircraft in a banked turn to maneuver away from impending threats,” said Michael Dickinson, UW professor of biology and co-author of a paper on the findings in the April 11 issue of Science. “We discovered that fruit flies alter course in less than one one-hundredth of a second, 50 times faster than we blink our eyes, and which is faster than we ever imagined.”

In the midst of a banked turn, the flies can roll on their sides 90 degrees or more, almost flying upside down at times, said Florian Muijres, a UW postdoctoral researcher and lead author of the paper.

“These flies normally flap their wings 200 times a second and, in almost a single wing beat, the animal can reorient its body to generate a force away from the threatening stimulus and then continues to accelerate,” he said.

The fruit flies, a species called Drosophila hydei that are about the size of a sesame seed, rely on a fast visual system to detect approaching predators.

“The brain of the fly performs a very sophisticated calculation, in a very short amount of time, to determine where the danger lies and exactly how to bank for the best escape, doing something different if the threat is to the side, straight ahead or behind,” Dickinson said.

“How can such a small brain generate so many remarkable behaviors? A fly with a brain the size of a salt grain has the behavioral repertoire nearly as complex as a much larger animal such as a mouse. That’s a super interesting problem from an engineering perspective,” Dickinson said.

The researchers synchronized three high-speed cameras each able to capture 7,500 frames per second, or 40 frames per wing beat. The cameras were focused on a small region in the middle of a cylindrical flight arena where 40 to 50 fruit flies flitted about. When a fly passed through the intersection of two laser beams at the exact center of the arena, it triggered an expanding shadow that caused the fly to take evasive action to avoid a collision or being eaten.

With the camera shutters opening and closing every one thirty-thousandth of a second, the researchers needed to flood the space with very bright light, Muijres said. Because flies rely on their vision and would be blinded by regular light, the arena was ringed with very bright infrared lights to overcome the problem. Neither humans nor fruit flies register infrared light.

How the fly’s brain and muscles control these remarkably fast and accurate evasive maneuvers is the next thing researchers would like to investigate, Dickinson said.

Researchers examine metabolism in defective cells

UAlberta researchers are taking a closer look at how two metabolic pathways interact to increase the lifespan of cells with mitochondrial defects. Magnus Friis (PhD ’10) is the lead author of the study, which was published online on April 10 and will be published in the April 24 issue of Cell Reports.

Mitochondria produce energy for cells through oxidative metabolism, but the process produces toxic byproducts that can accumulate and cause defects in the cell’s mitochondria. These defects, in turn, affect the cell’s ability to generate energy and can potentially lead to cell death and are associated with aging and various neurological diseases.

Friis, a postdoctoral fellow in Mike Schultz’s biochemistry lab, examined how dietary changes at the cell level can affect cell health. He exposed normal and defective yeast cells to two different energy sources: glucose, the preferred sugar of cells, and raffinose, a natural sugar found in vegetables and whole grains.

“[The dietary intervention] is a general shift in what we’re feeding the cells to get them to do something different with their whole nutrient metabolism,” Friis noted. “There are signaling pathways that allow a cell to sense its environment and co-ordinate events to allow the cell to adapt to what’s going on. In this case, [cells are responding to] which nutrients are available.”

Friis and Schultz examined two nutrient signaling pathways called the AMPK pathway and the retrograde response. AMPK responds to energy deficits in the cell by down-regulating energy consuming processes, which are often associated with cell growth, and up-regulating energy producing processes. The retrograde response pathway is specific to the yeast used in the study and supplies key amino acids to the cell by changing the metabolic process of the mitochondria.  

When activated individually, neither the AMPK pathway nor the retrograde response provided substantial benefits to cells with damaged mitochondria. When activated simultaneously, clear benefits became evident.

“We looked at the effect activating both pathways had on maintenance of cellular viability in what’s called a chronological aging experiment,” Friis said. “Even when they had defective mitochondria, the cells with the retrograde response and AMPK simultaneously activated during growth were able to live as long as cells with normal mitochondrial function.”

Working in collaboration with John Paul Glaves, a postdoctoral fellow in Bryan Sykes’ lab, and Tao Huan, a PhD student in Liang Li’s lab, Friis measured the molecules produced during the metabolic process. They found that the defective cells had higher levels of branched chain amino acids and trahelose, a carbohydrate found in yeast that can serve an energy source, similar to glycogen in human cells.

“By activating AMPK, we’ve removed certain blocks in metabolism. With the retrograde response, we’ve changed the amino acid metabolism in a way that allowed the cells to accumulate storage carbohydrates, which stabilize their function,” Friis said.

Activated AMPK and retrograde response pathways allow the cell to accumulate a storage carbohydrate, which can be metabolize normally despite mitochondrial defects that affect the cell’s metabolism. The additional energy stabilizes cell function and prevents premature cell death often caused by defects in mitochondria.

“No matter how many people are working on the problem in humans, mitochondrial disorders are too complicated to figure out the nuts and bolts without the work that Magnus is doing,” Schultz said. “This research opens the concept, a new concept on how to deal with these metabolic problems.”

Brain cell find points to new therapies

Insights into how brain cells are produced could lead to treatments for brain cancer and other brain-related disorders.

Scientists have gained new understanding of the role played by a key molecule that controls how and when nerve and brain cells are formed - a process that allows the brain to develop and keeps it healthy.

Their findings could help explain what happens when cell production goes out of control, which is a fundamental characteristic of many diseases including cancer.

Regulatory systems

Researchers have focused on a RNA molecule, known as miR-9, which is linked to the development of brain cells, known as neurons and glial cells.

They have shown that a protein called Lin28a regulates the production of miR-9, which in turn controls the genes involved in brain cell development and function.

Scientists carried out lab studies of embryonic cells, which can develop into neurons, to determine how Lin28a controls the amount of miR-9 that is produced.

Complex pathways

They found that in embryonic cells, Lin28a prevents production of miR-9 by triggering the degradation of its precursor molecule.

In developed brain cells, Lin28a is no longer produced, which enables miR-9 to accumulate and function.

In cancer cells, Lin28a production is re-established, and as a result this natural process is disrupted.

Lab experiments

Researchers used a series of lab tests to unravel the complex processes that are directed by the Lin28a protein.

They say further studies could help explain fully the role of Lin28a and miR-9 in brain development, and pave the way to the development of novel therapies.

The study, published in Nature Communications, was supported by the Wellcome Trust and the Medical Research Council.

Understanding more of the complex science behind the fundamental processes of cell development will helps us learn more about what happens when this goes wrong – and what might be done to prevent it. -Dr Gracjan Michlewski (School of Biological Sciences)

(Image: iStock)

Protein researchers closing in on the mystery of schizophrenia

Seven per cent of the adult population suffer from schizophrenia, and although scientists have tried for centuries to understand the disease, they still do not know what causes the disease or which physiological changes it causes in the body. Doctors cannot make the diagnosis by looking for specific physiological changes in the patient’s blood or tissue, but have to diagnose from behavioral symptoms.

In an attempt to find the physiological signature of schizophrenia, researchers from the University of Southern Denmark have conducted tests on rats, and they now believe that the signature lies in some specific, measurable proteins. Knowing these proteins and comparing their behaviour to proteins in the brains of not-schizophrenic people may make it possible to develop more effective drugs.

It is extremely difficult to study brain activity in schizophrenic people, which is why researchers often use animal models in their strive to understand the mysteries of the schizophrenic brain. Rat brains resemble human brains in so many ways that studying them makes sense if one wants to learn more about the human brain.

Schizophrenic symptoms in rats

The strong hallucinogenic drug phenocyclidine (PCP), also known as “angel’s dust”, provides a range of symptoms in people which are very similar to schizophrenia.

“When we give PCP to rats, the rats become valuable study objects for schizophrenia researchers,” explains Ole Nørregaard Jensen, professor and head of the Department of Biochemistry and Molecular Biology.

Along with Pawel Palmowski, Adelina Rogowska-Wrzesinska and others, he is the author of a scientific paper about the discovery, published in the international Journal of Proteome Research.

Among the symptoms and reactions that can be observed in both humans and rats are changes in movement and reduced cognitive functions such as impaired memory, attention and learning ability.

"Scientists have studied PCP rats for decades, but until now no one really knew what was going on in the rat brains at the molecular level. We now present what we believe to be the largest proteomics data set to date," says Ole Nørregaard Jensen.

PCP is absorbed very quickly by the brain, and it only stays in the brain for a few hours. Therefore, it was important for researchers to examine the rats’ brain cells soon after the rats were injected with the hallucinogenic drug.

"We could see changes in the proteins in the brain already after 15 minutes. And after 240 minutes, it was almost over," says Ole Nørregaard Jensen.

The University of Southern Denmark holds some of the world’s most advanced equipment for studying proteins, and Ole Nørregaard Jensen and his colleagues used the university’s so-called mass spectrometres for their protein studies.

352 proteins cause brain changes

"We found 2604 proteins, and in 352 of them, we saw changes that can be associated with the PCP injections. These 352 proteins will be extremely interesting to study in closer detail to see if they also alter in people with schizophrenia - and if that’s the case, it will of course be interesting to try to develop a drug that can prevent the protein changes that lead to schizophrenia," says Ole Nørregaard Jensen about the discovery and the work that now lies ahead.

The 352 proteins in rat brains responded immediately when the animals were exposed to PCP. Roughly speaking, the drug made proteins turn on or off when they should not turn on and off. This started a chain reaction of other disturbances in the molecular network around the proteins, such as changes in metabolism and calcium balance.

"These 352 proteins are what causes the rats to change their behaviour - and the events are probably comparable to the devastating changes in a schizophrenic brain," explains Ole Nørregaard Jensen.

The protocol for studying rat brain proteins with mass spectrometry, developed by Ole Nørregaard Jensen and his colleagues, is not limited to schizophrenia studies - it can also be used to explore other diseases.

The research was a collaboration between the University of Southern Denmark, the Danish Technological Institute and NeuroSearch A/S.

Details about the experiment
Twelve rats were used for the experiment. Six received an injection with the hallucinogenic drug PCP (10 mg/kg body weight), and six were injected with a saline solution to serve as controls. After 15 minutes, the first two animals in each group were killed and within less than two minutes, samples of their brains (temporal lobes) were taken and quickly frozen in liquid nitrogen.

After 30 and 240 minutes, respectively, the same was done to other rats. All experiments were conducted in accordance with Danish and EU guides for the handling of laboratory animals. The collected tissue samples were then subjected to various mass spectrometric protein analyses. The analyses revealed differences in the phosphorylation of proteins indicating which proteins had been affected by the drug PCP.

Interpretation of the complex protein data set suggest that PCP affects a number of processes in brain cells and leads to changes in calcium balance in the brain cells, changes in the transport of substances into and out of cells, changes in cell metabolism and changes in the structure of the cell’s internal skeleton, the cytoskeleton.

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Splice Variants Reveal Connections Among Autism Genes 

A team of researchers from the University of California, San Diego School of Medicine and the Center for Cancer Systems Biology (CCSB) at the Dana-Farber Cancer Institute has uncovered a new aspect of autism, revealing that proteins involved in autism interact with many more partners than previously known. These interactions had not been detected earlier because they involve alternatively spliced forms of autism genes found in the brain. 

In their study, published in the April 11, 2014 online issue of Nature Communications, the scientists isolated hundreds of new variants of autism genes from the human brain, and then screened their protein products against thousands of other proteins to identify interacting partners. Proteins produced by alternatively-spliced autism genes and their many partners formed a biological network that produced an unprecedented view of how autism genes are connected. 

"When the newly discovered splice forms of autism genes were added to the network, the total number of interactions doubled," said principal investigator Lilia Iakoucheva, PhD, assistant professor in the Department of Psychiatry at UC San Diego. In some cases, the splice forms interacted with a completely different set of proteins. "What we see from this network is that different variants of the same protein could alter the wiring of the entire system," Iakoucheva said. 

"This is the first proteome-scale interaction network to incorporate alternative splice forms," noted Marc Vidal, PhD, CCSB director and a co-investigator on the study. "The fact that protein variants produce such diverse patterns of interactions is exciting and quite unexpected."

The new network also illuminated how multiple autism genes connect to one another. The scientists found that one class of mutations involved in autism, known as copy number variants, involve genes that are closely connected to each other directly or indirectly through a common partner. “This suggests that shared biological pathways may be disrupted in patients with different autism mutations,” said co-first author Guan Ning Lin, PhD, a postdoctoral fellow in Iakouchevaís laboratory.

Beyond providing greater breadth and depth around autism proteins, the network represents a new resource for future autism studies, according to Iakoucheva. For example, she said the physical collection of more than 400 splicing variants of autism candidate genes could be used by other researchers interested in studying a specific protein variant. Some of the highly connected network partners may also represent potential drug targets. All interaction data will reside in the publicly available National Database of Autism Research.   

"With this assembled autism network, we can begin to investigate how newly discovered mutations from patients may disrupt this network,î said Iakoucheva. "This is an important task because the mechanism by which mutant proteins contribute to autism in 99.9 percent of cases remains unknown."

Pictured: Splicing variants (red) of autism genes were cloned from the brain and screened for interactions. The image on the right represents the network of interactions. Gray lines are interactions from a single isoform; red lines are interactions from additional isoforms of autism candidate genes (yellow circles).