Neuroscience

The day of the big barbecue arrives and it’s time to fire up the grill. But rather than toss the hamburgers and hotdogs haphazardly onto the grate, you wait for the heat to reach an optimal temperature, and then neatly lay them out in their apportioned areas according to size and cooking times. Meanwhile, your friend is preparing the beverages. Cups are grabbed face down from the stack, turned over, and – using the other hand – filled with ice.

While these tasks – like countless, everyday actions – may seem trivial at first glance, they are actually fairly complex, according to Robrecht van der Wel, an assistant professor of psychology at Rutgers–Camden. “For instance, the observation that you grab a glass differently when you are filling a beverage than when you are stacking glasses suggests that you are thinking about the goal that you want to achieve,” he says. “How do you manipulate the glass? How do you coordinate your actions so that the liquid goes into the cup?  These kinds of actions are not just our only way to accomplish our intentions, but they reveal our intentions and mental states as well.”

van der Wel and his research partners, Marlene Meyer and Sabine Hunnius, turned their attention to how action planning generalizes to collaborative actions performed with others in a study, titled Higher-order planning for individual and joint object manipulations, published recently in Experimental Brain Research.

According to van der Wel, the researchers were especially interested in determining whether people’s actions exhibit certain social capabilities when performing multiple-action sequences in concert with a partner. “It is a pretty astonishing ability that we, as people, are able to plan and coordinate our actions with others,” says van der Wel. “If people plan ahead for themselves, what happens if they are now in a task where their action might influence another person’s comfort? Do they actually take that into account or not, even though, for their personal action, it makes no difference?”

In the research study, participants first completed a series of individual tasks requiring them to pick up a cylindrical object with one hand, pass it to their other hand, and then place it on a shelf. In the collaborative tasks, individuals picked up the object and handed it to their partner, who placed it on the shelf. The researchers varied the height of the shelf, to test whether people altered their grasps to avoid uncomfortable end postures. The object could only be grasped at one of two positions, implying that the first grasp would determine the postures – and comfort – of the remaining actions.

According to the researchers, the results from both the individual and joint performances show that participants altered their grasp location relative to the height of the shelf.  The participants in both scenarios were thus more likely to use a low-grasp location when the shelf was low, and vice versa. Doing so implied that the participants ended the sequences in comfortable postures. The researchers conclude that, in both individual and collaborative scenarios, participants engaged in extended planning to finish the object-transport sequences in a relatively comfortable posture. Given that participants did plan ahead for the sake of their action partner, it indicates an implicit social awareness that supports collaboration across individuals.

van der Wel notes that, while such basic actions may seem insignificant, it is important to understand how people perform basic tasks such as manipulating objects when considering those populations that aren’t able to complete them so efficiently. “How to pick up an object seems like a really trivial problem when you look at healthy adults, but as soon as you look at children, or people suffering from a stroke, it takes some time to develop that skill properly,” says van der Wel. “When someone has a stroke, it is not that they have damage to the musculature involved in doing the task; rather, damage to action planning areas in the brain results in an inability to perform simple actions. A better understanding of the mechanisms involved in action planning may guide rehabilitation strategies in such cases.”

According to van der Wel, the researchers are currently working on modifying the task to determine the age at which children begin planning their actions with respect to other peoples’ comfort. In particular, they want to understand how the development of social action planning links with the development of other cognitive and social abilities.

New work at the University of California, Davis, shows for the first time how visual attention affects activity in specific brain cells. The paper, published June 26 in the journal Nature, shows that attention increases the efficiency of signaling into the brain’s cerebral cortex and boosts the ratio of signal over noise.

It’s the first time neuroscientists have been able to look at the behavior of synaptic circuits at such a fine-grained level of resolution while measuring the effects of attention, said Professor Ron Mangun, dean of social sciences at UC Davis and a researcher at the UC Davis Center for Mind and Brain.

Our brains recreate an internal map of the world we see through our eyes, mapping our visual field onto specific brain cells. Humans and our primate relatives have the ability to pay attention to objects in the visual scene without looking at them directly, Mangun said.

"Essentially, we ‘see out of the corner of our eyes,’ as the old saying goes. This ability helps us detect threats, and react quickly to avoid them, as when a car running a red light at high speed is approach from our side," he said.

Postdoctoral scholar Farran Briggs worked with Mangun and Professor Martin Usrey at the UC Davis Center for Neuroscience to measure signaling through single nerve connections, or synapses, in monkeys while they performed a standard cognitive test for attention: pressing a joystick in response to seeing a stimulus appear in their field of view.

By taking measurements on each side of a synapse leading into the cerebral cortex, the team could measure when neurons were firing, the strength of the signal and the signal-to-noise ratio.

The researchers found that when the animals were paying attention to an area within their field of view, the signal strength through corresponding synapses leading into the cortex became more effective, and the signal was boosted relative to background noise.

Combining established cognitive psychology with advanced neuroscience, the technique opens up new possibilities for research.

"There are a lot of questions about attention that we can now investigate, such as which brain mechanisms are disordered in diseases that affect attention," Usrey said.

The method could be used, for example, to probe the cholinergic nervous system, which is impacted by Alzheimer’s disease. It could also help to better understand developmental disorders that involve defects in attention, such as attention deficit hyperactivity disorder and autism.

"It’s going to turn out to be important for understanding and treating all kinds of diseases," Mangun predicted.

Vision and Hearing Work Together in the Brain to Help Us Catch a Moving Target

A new study has found that chasing down a moving object is not only a matter of sight or of sound, but of mind.

The study found that people who are blindfolded employ the same strategy to intercept a running ball carrier as people who can see, which suggests that multiple areas of the brain cooperate to accomplish the task.

Regardless of whether they could see or not, the study participants seemed to aim ahead of the ball carrier’s trajectory and then run to the spot where they expected him or her to be in the near future. Researchers call this a “constant target-heading angle” strategy, similar to strategies used by dogs catching Frisbees and baseball players catching fly balls.

It’s also the best way to catch an object that is trying to evade capture, explained Dennis Shaffer, assistant professor of psychology at The Ohio State University at Mansfield.

“The constant-angle strategy geometrically guarantees that you’ll reach your target, if your speed and the target’s speed stay constant, and you’re both moving in a straight line. It also gives you leeway to adjust if the target abruptly changes direction to evade you,” Shaffer said.

“The fact that people run after targets at a constant angle regardless of whether they can see or not suggests that there are brain mechanisms in place that we would call ‘polymodal’—areas of the brain that serve more than one form of sensory modality. Sight and hearing may be different senses, but within the brain the results of the sensory input for this task may be the same.”

The study appears in the journal Psychonomic Bulletin and Review.

Nine people participated in the study—mainly students at Ohio State and Arizona State University, where the study took place. Some had experience playing football, either at a high school or collegiate intramural level, while others had limited or no experience with football.

The nine of them donned motion-capture equipment and took turns in pairs, one running a football across a 20-meter field (nearly 22 yards), and one chasing. They randomly assigned participants to sighted and blindfolded conditions. In the blindfolded condition, participants wore a sleep mask and the runner carried a foam football with a beeping device inside, so that the chaser had a chance to locate them by sound. The runners ran in the general direction of the chasers at different angles, and sometimes the runner would cut right or left halfway through the run.

The study was designed so that the pursuer wouldn’t have time to consciously think about how to catch the runner.

“We were just focused on trying to touch the runner as soon as possible and before they exited the field,” Shaffer said. “The idea was to have the strategy emerge by instinct.”

About 97 percent of the time, the person doing the chasing used the constant-angle strategy—even when they were blindfolded and only able to hear the beeping football.

The results were surprising, even to Shaffer.

“I knew that this seemed to be a universal strategy across species, but I expected that people’s strategies would vary more when they were blindfolded, just because we aren’t used to running around blindfolded. I didn’t expect that the blindfolded strategies would so closely match the sighted ones.”

The findings suggest that there’s some common area in the brain that processes sight and sound together when we’re chasing something.

There is another strategy for catching moving targets. Researchers call it the pursuit or aiming strategy, because it involves speeding directly at the target’s current location. It’s how apex predators such as sharks catch prey.

“As long as you are much faster than your prey, the pursuit strategy is great. You just overtake them,” Shaffer said.

In a situation where the competition is more equal, the constant-angle strategy works better—the pursuer doesn’t have to be faster than the target, and if the target switches direction, the pursuer has time to adjust.

The study builds on Shaffer’s previous work with how collegiate-level football players chase ball carriers. He’s also studied how people catch baseballs and dogs catch Frisbees. All appear to use strategies similar to the constant target-heading angle strategy, which suggests that a common neural mechanism could be at work.

UC Berkeley researchers have found that a lack of sleep, which is common in anxiety disorders, may play a key role in ramping up the brain regions that contribute to excessive worrying.

Neuroscientists have found that sleep deprivation amplifies anticipatory anxiety by firing up the brain’s amygdala and insular cortex, regions associated with emotional processing. The resulting pattern mimics the abnormal neural activity seen in anxiety disorders. Furthermore, their research suggests that innate worriers – those who are naturally more anxious and therefore more likely to develop a full-blown anxiety disorder – are acutely vulnerable to the impact of insufficient sleep.

“These findings help us realize that those people who are anxious by nature are the same people who will suffer the greatest harm from sleep deprivation,” said Matthew Walker, a professor of psychology and neuroscience at UC Berkeley and senior author of the paper, which was published in the Journal of Neuroscience.

The results suggest that people suffering from such maladies as generalized anxiety disorder, panic attacks and post-traumatic stress disorder, may benefit substantially from sleep therapy. At UC Berkeley, psychologists such as Allison Harvey, a co-author on the Journal of Neuroscience paper, have been garnering encouraging results in studies that use sleep therapy on patients with depression, bipolar disorder and other mental illnesses.

“If sleep disruption is a key factor in anxiety disorders, as this study suggests, then it’s a potentially treatable target,” Walker said. “By restoring good quality sleep in people suffering from anxiety, we may be able to help ameliorate their excessive worry and disabling fearful expectations.”

While previous research has indicated that sleep disruption and psychiatric disorders often occur together, this latest study is the first to causally demonstrate that sleep loss triggers excessive anticipatory brain activity associated with anxiety, researchers said.

“It’s been hard to tease out whether sleep loss is simply a byproduct of anxiety, or whether sleep disruption causes anxiety,” said Andrea Goldstein, a UC Berkeley doctoral student in neuroscience and lead author of the study. “This study helps us understand that causal relationship more clearly.”

In their experiments, performed at UC Berkeley’s Sleep and Neuroimaging Laboratory, Walker and his research team scanned the brains of 18 healthy young adults as they viewed dozens of images, first after a good night’s rest, and again after a sleepless night. The images were either neutral, disturbing or alternated between both.

Participants in the experiments reported a wide range of baseline anxiety levels, but none fit the criteria for a clinical anxiety disorder. After getting a full night’s rest at the lab, which researchers monitored by measuring neural electrical activity, their brains were scanned via functional MRI as they waited to be shown, and then viewed 90 images during a 45-minute session.

To trigger anticipatory anxiety, researchers primed the participants using one of three visual cues prior to each series of images. A large red minus sign signaled to participants that they were about to see a highly unpleasant image, such as a death scene. A yellow circle portended a neutral image, such as a basket on a table. Perhaps most stressful was a white question mark, which indicated that either a grisly image or a bland, innocuous one was coming, and kept participants in a heightened state of suspense.

When sleep-deprived and waiting in suspenseful anticipation for a neutral or disturbing image to appear, activity in the emotional brain centers of all the participants soared, especially in the amygdala and the insular cortex. Notably, the amplifying impact of sleep deprivation was most dramatic for those people who were innately anxious to begin with.

“This discovery illustrates how important sleep is to our mental health,” said Walker. “It also emphasizes the intimate relationship between sleep and psychiatric disorders, both from a cause and a treatment perspective.”

Researchers with the UC Davis MIND Institute and Agilent Laboratories have found that Prader-Willi syndrome — a genetic disorder best known for causing an insatiable appetite that can lead to morbid obesity — is associated with the loss of non-coding RNAs, resulting in the dysregulation of circadian and metabolic genes, accelerated energy expenditure and metabolic differences during sleep.

The research was led by Janine LaSalle, a professor in the UC Davis Department of Medical Microbiology and Immunology who is affiliated with the MIND Institute. It is published online in Human Molecular Genetics.

“Prader-Willi syndrome children do not sleep as well at night and have daytime sleepiness,” LaSalle said. “Parents have to lock up their pantries because the kids are rummaging for food in the middle of the night, even breaking into their neighbors’ houses to eat.”

The study found that these behaviors are rooted in the loss of a long non-coding RNA that functions to balance energy expenditure in the brain during sleep. The finding could have a profound effect on how clinicians treat children with Prader-Willi, as well as point the way to new, innovative therapies, LaSalle said.

The leading cause of morbid obesity among children in the United States, Prader-Willi involves a complex, and sometimes contradictory, array of symptoms. Shortly after birth children with Prader-Willi experience failure to thrive. Yet after they begin to feed themselves, they have difficulty sleeping and insatiable appetites that lead to obesity if their diets are not carefully monitored.

The current study was conducted in a mouse model of Prader-Willi syndrome. It found that mice engineered with the loss of a long non-coding RNA showed altered energy use and metabolic differences during sleep.

Prader-Willi has been traced to a specific region on chromosome 15 (SNORD116), which produces RNAs that regulate gene expression, rather than coding for proteins. When functioning normally, SNORD116 produces small nucleolar (sno) RNAs and a long non-coding RNA (116HG), as well as a third non-coding RNA implicated in a related disorder, Angelman syndrome. The 116HG long non-coding RNA forms a cloud inside neuronal nuclei that associates with proteins and genes regulating diurnal metabolism in the brain, LaSalle said.

“We thought the cloud would be activating transcription, but in fact it was doing the opposite,” she said. “Most of the genes were dampened by the cloud. This long non-coding RNA was acting as a decoy, pulling the active transcription factors away from genes and keeping them from being expressed.”

As a result, losing snoRNAs and 116HG causes a chain reaction, eliminating the RNA cloud and allowing circadian and metabolic genes to get turned on during sleep periods, when they should be dampened down. This underlies a complex cycle in which the RNA cloud grew during sleep periods (daytime for nocturnal mice), turning down genes associated with energy use, and receded during waking periods, allowing these genes to be expressed. Mice without the 116HG gene lacked the benefit of this neuronal cloud, causing greater energy expenditure during sleep.

The researchers said that the work provides a clearer picture of why children with Prader-Willi syndrome can’t sleep or feel satiated and may change therapeutic approaches. For example, many such children have been treated with growth hormone because of short stature, but this actually may boost other aspects of the disease.

“People had thought the kids weren’t sleeping at night because of the sleep apnea caused by obesity,” said LaSalle. “What this study shows is that the diurnal metabolism is central to the disorder, and that the obesity may be as a result of that. If you can work with that, you could improve therapies, for example figuring out the best times to administer medications.”

Myelin, the fatty coating that protects neurons in the brain and spinal cord, is destroyed in diseases such as multiple sclerosis. Researchers have been striving to determine whether oligodendrocytes, the cells that produce myelin, can be stimulated to make new myelin. Using live imaging in zebrafish to track oligodendrocytes in real time, researchers reporting in the June 24 issue of the Cell Press journal Developmental Cell discovered that individual oligodendrocytes coat neurons with myelin for only five hours after they are born. If the findings hold true in humans, they could lead to new treatment strategies for multiple sclerosis.

"The study could help improve our understanding of the triggers needed to encourage cells to produce myelin," says senior author Dr. David Lyons, of the University of Edinburgh, UK. For example, if scientists could determine what is blocking the cells from making myelin after five hours, they might be able to remove that blockage. Alternatively, treatments could focus on creating more new oligodendrocytes rather than trying to stimulate existing oligodendrocytes.

Dr. Lyons and his team used zebrafish to study the formation of myelin sheaths by oligodendrocytes because this laboratory animal is transparent at early stages of its development, which allows investigators to directly observe cells within the organism. It is also known that zebrafish and humans have very similar genes, and these similarities extend to more than 80% of the genes associated with human disease. Zebrafish therefore respond in very similar ways to most drugs used for therapeutic purposes in humans.

"In the future, zebrafish will be used to identify new genes and drugs that can influence myelin formation and myelin repair," says Dr. Lyons.

A UC San Francisco-led research team has identified the likely genetic mechanism that causes some patients with multiple sclerosis (MS) to progress more quickly than others to a debilitating stage of the disease. This finding could lead to the development of a test to help physicians tailor treatments for MS patients.

Researchers found that the absence of the gene Tob1 in CD4+ T cells, a type of immune cell, was the key to early onset of more serious disease in an animal model of MS.

Senior author Sergio Baranzini, PhD, a UCSF associate professor of neurology, said the potential development of a test for the gene could predict the course of MS in individual patients.

The study, done in collaboration with UCSF neurology researchers Scott Zamvil, MD, and Jorge Oksenberg, PhD, was published on June 24 in the Journal of Experimental Medicine.

MS is an inflammatory disease in which the protective myelin sheathing that coats nerve fibers in the brain and spinal cord is damaged and ultimately stripped away – a process known as demyelination. During the highly variable course of the disease, a wide range of cognitive, debilitating and painful neurological symptoms can result.

In previously published work, Baranzini and his research team found that patients at an early stage of MS, known as clinically isolated syndrome, who expressed low amounts of Tob1 were more likely to exhibit further signs of disease activity – a condition known as relapsing-remitting multiple sclerosis – earlier than those who expressed normal levels of the gene.

The current study, according to Baranzini, had two goals: to recapitulate in an animal model what the researchers had observed in humans, and uncover the potential mechanism by which it occurs.

The authors were successful on both counts. They found that when an MS-like disease was induced in mice genetically engineered to be deficient in Tob1, the mice had significantly earlier onset compared with wild-type mice, and developed a more aggressive form of the disease.

Subsequent experiments revealed the probable cause: the absence of Tob1 in just CD4+ T cells. The scientists demonstrated this by transferring T cells lacking the Tob1 gene into mice that had no immune systems but had normal Tob1 in all other cells. They found that the mice developed earlier and more severe disease than mice that had normal Tob1 expression in all cells including CD4+.

“This shows that Tob1 only needs to be absent in this one type of immune cell in order to reproduce our initial observations in mice lacking Tob1 in all of their cells,” said Baranzini.

Personalized Treatments for MS Patients

The researchers also found the likely mechanism of disease progression in the Tob1-deficient mice: higher levels of Th1 and Th17 cells, which cause an inflammatory response against myelin, and lower levels of Treg cells, which normally regulate inflammatory responses. The inflammation results in demyelination.

The research is significant for humans, said Baranzini, because the presence or absence of Tob1 in CD4+ cells could eventually serve as a prognostic biomarker that could help clinicians predict the course and severity of MS in individual patients. “This would be useful and important,” he said, “because physicians could decide to switch or modify therapies if they know whether the patient is likely to have an aggressive course of disease, or a more benign course.”

Ultimately, predicted Baranzini, “This may become an example of personalized medicine. When the patient comes to the clinic, we will be able to tailor the therapy based on what the tests tell us. We’re now laying the groundwork for this to happen.”

A rare, inherited form of mental retardation has led scientists at Washington University School of Medicine in St. Louis to three important “travel agents” at work in the developing brain.

The agents — two individual proteins and a tightly bound cluster of four additional proteins — make it possible for brain neurons to travel from the area where they are born to other brain regions where they will reside permanently and integrate into neuronal circuits. Inhibiting any of these proteins in embryonic mice reduces the ability of neurons, which process and transmit information, to reach their final destinations and, presumably, to hardwire the brain.

“That kind of misplacement of brain cells is likely to seriously disrupt mental functions,” said Azad Bonni, MD, PhD, the Edison Professor and chairman of the Department of Anatomy and Neurobiology. “This is just one of many ways that brain development can go awry. To understand intellectual disability and develop treatments, we need to understand the many problems that can arise as the brain develops and its circuitry is established.”

The results appeared June 19 in Neuron.

The new work began as an inquiry into PHF6, a gene that is mutated in patients with Börjeson-Forssman-Lehmann syndrome. This disorder causes mental retardation, developmental delays and skeletal abnormalities. More than a decade ago, scientists identified a link between the condition and PHF6, but they did not know what the gene did in the brain.

Bonni’s laboratory added green fluorescent protein to brain cells to track their development and movement in embryonic mice. Then the researchers inhibited PHF6 in some mice.

In normal mice, as expected, brain neurons migrated from the ventricular zone, where they were born, to the cortical plate, the precursor site of the cerebral cortex. In the mature brain, the cerebral cortex is responsible for higher brain functions such as processing of sensory data, attention and decision-making. In mice whose brain cells lacked PHF6, many brain cells either stayed in the ventricular zone or only completed part of their journey.

In a series of additional experiments, Bonni’s research group showed that the PHF6 protein operates in the nucleus of brain neurons, the command center of the cell. The scientists found that the PHF6 protein interacts with the PAF1 complex, a tightly bound cluster of four proteins that regulates programs of gene expression. This cluster then turns on a cell surface protein called neuroglycan C in brain neurons.

If any of these factors were inhibited, mouse brain neurons were unable to complete their normal migration. The researchers could “rescue” the neurons by restoring the missing protein, allowing the cells to complete their journey.

Disrupting proper brain structure and organization may not be the only problem caused by the PHF6 mutation. A portion of patients with Börjeson-Forssman-Lehmann syndrome also have epilepsy.

In tests in mice, Bonni’s group found that the misplaced brain neurons were more excitable. This might result from changes in the activity of other proteins regulated by PHF6 and could make the brain more susceptible to seizures.

The researchers also learned that increasing the production of neuroglycan C in brain neurons overcomes the harmful effects of PHF6 loss on the migration of neurons.

“Cell surface proteins such as neuroglycan C are in good position to help cells move through their environment,” Bonni said. “The protein’s position on the cell surface of neurons also one day might make it an accessible target for drug treatments for developmental cognitive disorders.”

Bonni suspects there might be additional problems in brain cells that develop without normal PHF6 and that errors in the gene might even impair function in neurons that make it to their final destinations. Further studies are underway.

In a new study, post-menopausal women on testosterone therapy showed a significant improvement in verbal learning and memory, offering a promising avenue for research into memory and ageing.

Led by Director of the Women’s Health Research Program at Monash University, Professor Susan Davis, and presented at ENDO 2103, the research is the first large, randomised, placebo-controlled investigation into the effects of testosterone on cognitive function in postmenopausal women.

Testosterone has been implicated as being important for brain function in men and these results indicate that it has a role in optimising learning and memory in women.

Dementia, which was estimated to affect more than 35 million people worldwide in 2010, is more common in women than men. There are no effective treatments to prevent memory decline.

In the study, 96 postmenopausal women recruited from the community were randomly allocated to receive a testosterone gel or a visually identical placebo gel to be applied to the skin. Participants underwent a comprehensive series of cognitive tests at the beginning of the study and 26 weeks later.

All women performed in the normal range for their age at the beginning of the trial. There was a statistically significant and clinically meaningful improvement in verbal learning and memory amongst the women using the testosterone gel after 26 weeks.

Professor Davis said the results indicated that testosterone played an important role in women’s health. 

"Much of the research on testosterone in women to date has focused on sexual function. But testosterone has widespread effects in women, including, it appears, significant favourable effects on verbal learning and memory," Professor Davis said. 

"Our findings provide compelling evidence for the conduct of larger clinical studies to further investigate the role of testosterone in cognitive function in women.

Androgen levels did increase in the cohort on testosterone therapy, but on average, remained in the normal female range. No negative side-effects of the therapy were observed.

A synthetic compound is able to turn off “secondary” vacuum cleaners in the brain that take up serotonin, resulting in the “happy” chemical being more plentiful, scientists from the School of Medicine at The University of Texas Health Science Center San Antonio have discovered. Their study, released June 18 by The Journal of Neuroscience, points to novel targets to treat depression.

Serotonin, a neurotransmitter that carries chemical signals, is associated with feelings of wellness. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants that block a specific “vacuum cleaner” for serotonin (the serotonin transporter, or SERT) from taking up serotonin, resulting in more supply of the neurotransmitter in circulation in the extracellular fluid of the brain.

Delicate balance

"Serotonin is released by neurons in the brain," said Lyn Daws, Ph.D., professor of physiology and pharmacology in the School of Medicine. "Too much or too little may be a bad thing. It is thought that having too little serotonin is linked to depression. That’s why we think Prozac-type drugs (SSRIs) work, by stopping the serotonin transporter from taking up serotonin from extracellular fluid in the brain."

A problem with SSRIs is that many depressed patients experience modest or no therapeutic benefit. It turns out that, while SSRIs block the activity of the serotonin transporter, they don’t block other “vacuum cleaners.” “Until now we did not appreciate the presence of backup cleaners for serotonin,” Dr. Daws said. “We were not the first to show their presence in the brain, but we were among the first show that they were limiting the ability of the SSRIs to increase serotonin signaling in the brain. The study described in this new paper is the first demonstration of enhancing the antidepressant-like effect of an SSRI by concurrently blocking these backup vacuum cleaners.”

Serotonin ceiling

Even if SERT activity is blocked, the backup vacuum cleaners (called organic cation transporters) keep a ceiling on how high the serotonin levels can rise, which likely limits the optimal therapeutic benefit to the patient, Dr. Daws said.

"Right now, the compound we have, decynium-22, is not an agent that we want to give to people in clinical trials," she said. "We are not there yet. Where we are is being able to use this compound to identify new targets in the brain for antidepressant activity and to turn to medicinal chemists to design molecules to block these secondary vacuum cleaners."

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have found a compound that could counter Parkinson’s disease in two ways at once.

In a new study published recently online ahead of print by the journal ACS Chemical Biology, the scientists describe a “dual inhibitor”—two compounds in a single molecule—that attacks a pair of proteins closely associated with development of Parkinson’s disease.

“In general, these two enzymes amplify the effect of each other,” said team leader Phil LoGrasso, a TSRI professor who has been a pioneer in the development of JNK inhibitors for the treatment of neurodegenerative diseases. “What we were looking for is a high-affinity, high-selectivity treatment that is additive or synergistic in its effect—a one-two punch.”

That could be what they found.

This new dual inhibitor attacks two enzymes—the leucine-rich repeat kinase 2 (LRRK2) and the c-jun-N-terminal kinase (JNK)—pronounced “junk.” Genetic testing of several thousand Parkinson’s patients has shown that mutations in the LRRK2 gene increase the risk of Parkinson’s disease, while JNK has been shown to play an important role in neuron (nerve cell) survival in a range of neurodegenerative diseases. As such, they have become highly viable targets for drugs to treat disorders such as Parkinson’s disease.

A dual inhibitor ultimately would be preferred over separate individual JNK and LRRK2 inhibitors because a combination molecule would eliminate complications of drug-drug interactions and the need to optimize individual inhibitor doses for efficacy, the study noted.

Now the team’s new dual inhibitor will need to be optimized for potency, high selectivity (which reduces off-target side effects) and bioavailability so it can be tested in animal models of Parkinson’s disease.

No matter how we jump, roll, sit, or lie down, our brain manages to maintain a visual representation of the world that stays upright relative to the pull of gravity. But a new study of rider experiences on the Hong Kong Peak Tram, a popular tourist attraction, shows that specific features of the environment can dominate our perception of verticality, making skyscrapers appear to fall.

The study is published in Psychological Science, a journal of the Association for Psychological Science.

The Hong Kong Peak Tram to Victoria Peak is a popular way to survey the Hong Kong skyline and millions of people ride the tram every year.

“On one trip, I noticed that the city’s skyscrapers next to the tram started to appear very tilted, as if they were falling, which anyone with common sense knows is impossible,” says lead researcher Chia-huei Tseng of the University of Hong Kong. “The gasps of the other passengers told me I wasn’t the only one seeing it.”

The illusion was perplexing because, in contrast with most illusions studied in the laboratory, observers have complete access to visual cues from the outside world through the tram’s open windows.

Exploring the illusion under various conditions, Tseng and colleagues found that the perceived, or illusory, tilt was greatest on night-time rides, perhaps a result of the relative absence of visual-orientation cues or a heightened sense of enclosure at night. Enhancing the tilted frame of reference within the tram car — indicated by features like oblique window frames, beams, floor, and lighting fixtures — makes the true vertical of the high rises seem to tilt in the opposite direction.

The illusion was significantly reduced by obscuring the window frame and other reference cues inside the tram car, by using wedges to adjust observers’ position, and by having them stand during the tram ride.

But no single modification was sufficient to eliminate the illusion.

“Our findings demonstrate that signals from all the senses must be consonant with each other to abolish the tilt illusion,” the researchers write. “On the tram, it seems that vision dominates verticality perception over other sensory modalities that also mediate earth gravity, such as the vestibular and tactile systems.”

The robustness of the tram illusion took the researchers by surprise:

“We took the same tram up and down for hundreds of trips, and the illusion did not reduce a bit,” says Tseng. “This suggests that our experiences and our learned knowledge about the world — that buildings should be vertical — are not enough to cancel our brain’s wrong conclusion.”

People can plan strategic movements to several different targets at the same time, even when they see far fewer targets than are actually present, according to a new study published in Psychological Science, a journal of the Association for Psychological Science.

A team of researchers at the Brain and Mind Institute at the University of Western Ontario took advantage of a pictorial illusion — known as the “connectedness illusion” — that causes people to underestimate the number of targets they see.

When people act on these targets, however, they can rapidly plan accurate and strategic reaches that reflect the actual number of targets.

Using sophisticated statistical techniques to analyze participants’ responses to multiple potential targets, the researchers found that participants’ reaches to the targets were unaffected by the presence of the connecting lines.

Thus, the “connectedness illusion” seemed to influence the number of targets they perceived but did not impact their ability to plan actions related to the targets.

These findings indicate that the processes in the brain that plan visually guided actions are distinct from those that allow us to perceive the world.

“The design of the experiments allowed us to separate these two processes, even though they normally unfold at the same time,” explained lead researcher Jennifer Milne, a PhD student at the University of Western Ontario.

“It’s as though we have a semi-autonomous robot in our brain that plans and executes actions on our behalf with only the broadest of instructions from us!”

According to Mel Goodale, professor at the University of Western Ontario and senior author on the paper, these findings “not only reveal just how sophisticated the visuomotor systems in the brain are, but could also have important implications for the design and implementation of robotic systems and efficient human-machine interfaces.”

One in four people who survive a stroke or transient ischemic attack (TIA) suffer from symptoms of post-traumatic stress disorder (PTSD) within the first year post-event, and one in nine experience chronic PTSD more than a year later. The data suggest that each year nearly 300,000 stroke/TIA survivors will develop PTSD symptoms as a result of their health scare. The study, led by Columbia University Medical Center researchers, was published today in the online edition of PLOS ONE.

“This work builds on recent findings of ours that PTSD is common among heart attack survivors and that it contributes to a doubled risk of a future cardiac event or of dying within one to three years. Our current results show that PTSD in stroke and TIA survivors may increase their risk for recurrent stroke and other cardiovascular events,” said first author Donald Edmondson, PhD, MPH, assistant professor of behavioral medicine (Center for Behavioral Cardiovascular Health) at CUMC. “Given that each event is life-threatening and that strokes/TIAs add hundreds of millions of dollars to annual health expenditures, these findings are important to both the long-term survival and health costs of these patient populations.”

“PTSD is not just a disorder of combat veterans and sexual assault survivors, but strongly affects survivors of stroke and other potentially traumatic acute cardiovascular events as well,” said Ian M. Kronish, MD, MPH, assistant professor of medicine (Center for Behavioral Cardiovascular Health) and the study’s senior author. “Surviving a life-threatening health scare can have a debilitating psychological impact, and health care providers should make it a priority to screen for symptoms of depression, anxiety, and PTSD among these patient populations.”

Stroke is the fourth-leading cause of death and the top cause of disability in the United States. According to data from the American Stroke Association, nearly 795,000 Americans each year suffer a new or recurrent stroke, and up to an additional 500,000 suffer a TIA.

PTSD is an anxiety disorder initiated by exposure to a traumatic event. Common symptoms include nightmares, avoidance of reminders of the event, and elevated heart rate and blood pressure. Chronic PTSD is a duration of these symptoms for three months or longer (as defined by the DSM-IV).

Since only a few studies have assessed PTSD due to stroke, Drs. Edmondson and Kronish and their colleagues performed the first meta-analysis of clinical studies of stroke- or TIA-induced PTSD. The nine studies in the meta-analysis included a total of 1,138 stroke or TIA survivors.

The study found that 23 percent, or roughly one in four, of the patients developed PTSD symptoms within the first year after their stroke or TIA, with 11 percent, or roughly one in nine, experiencing chronic PTSD more than a year later.

“PTSD and other psychological disorders in stroke and TIA patients appear to be an under-recognized and undertreated problem,” said Dr. Kronish.

“Fortunately, there are good treatments for PTSD,” said Dr. Edmondson. “But first, physicians and patients have to be aware that this is a problem. Family members can also help. We know that social support is a good protective factor against PTSD due to any type of traumatic event.”

“The next step is further research to assess whether mental health treatment can reduce stroke- and TIA-induced PTSD symptoms and help these patients regain a feeling of normalcy and calm as soon as possible after their health scare,” said Dr. Edmondson.

A line of genetically modified mice that Western University scientists call “Forrest Gump” because, like the movie character, they can run far but they aren’t smart, is furthering the understanding of a key neurotransmitter called acetylcholine (ACh). Marco Prado, PhD, and his team at Robarts Research Institute say the mice show what happens when too much of this neurotransmitter becomes available in the brain. Boosting ACh is a therapeutic target for Alzheimer’s disease because it’s found in reduced amounts when there’s cognitive failure. Prado’s research is published in the Journal of Neuroscience.

“We wanted to know what happens if you have more of the gene which controls how much acetylcholine is secreted by neurons,” says Prado, a Robarts scientist and professor in the Departments of Physiology and Pharmacology and Anatomy and Cell Biology at Western’s Schulich School of Medicine & Dentistry. “The response was the complete opposite of what we expected. It’s not a good thing. Acetylcholine release was increased threefold in these mice, which seemed to disturb cognitive function. But put them on a treadmill and they can run twice as far as normal mice before tiring. They’re super-athletes.” In addition to its function in modulating cognitive abilities, ACh drives muscle contraction which allowed for the marked improvement in motor endurance.

One of the tests the scientists, including first author Benjamin Kolisnyk, used is called the touch screen test for mice which uses technology similar to a tablet. After initiating the test, the mice have to scan five different spots on the touch screen to see a light flash, and then run and touch that area. If they get it right they get a reward.  Compared to the control mice, the “Forrest Gump” mice failed miserably at the task.  The researchers found the mice, which have the scientific name ChAT-ChR2-EYFP, had terrible attention spans, as well as dysfunction in working memory and spatial memory.

Prado interprets the research as showing ACh is very important for differentiating cues. So if your brain is presented with a lot of simultaneous information, it helps to pick what’s important. But when you flood the brain with ACh, your brain loses the ability to discern what’s relevant. This study was funded mainly by the Canadian Institutes of Health Research.

The protein mSYD1 has a key function in transmitting information between neurons. This was recently discovered by the research group of Prof Peter Scheiffele at the Biozentrum, University of Basel. The findings of the investigations have been published in the scientific journal “Neuron”.

Synapses are the most important sites of information transfer between neurons. The functioning of our brain is based on the ability of the synapses to release neurotransmitter substances in a fraction of a second, so that neuronal signals can be rapidly propagated and integrated. Peter Scheiffele’s team has now identified a new mechanism, which ensures that synaptic vesicles, the carrier of the transmitter substances, are concentrated at their designated place, thereby contributing to rapid signal transmission.

mSYD1 as organizer of synaptic structures
The speed and precision of synaptic transmission is based on a highly complex protein apparatus in the synapse. A concentration of synaptic vesicles is found at the synaptic contact sites between neurons. When a nerve cell is activated, vesicles fuse with the edge of the synapse, the so-called active zone, and send neurotransmitters to the neighboring cells.

Peter Scheiffele’s research group has now identified a previously unknown protein called mSYD1, which regulates the deposition of the vesicles at the active zone. In nerve cells, in which no mSYD1 protein is present, synaptic contacts continue to be formed but the accumulation of the synaptic vesicles at the active zone is disrupted. This results in a significant reduction of synaptic transmission.

Inactive mSYD1 in autistic disorders
These findings provide important new insights into the mechanisms underlying the formation of functional neuronal networks. In patients with a developmental disorder belonging the autism spectrum, mSYD1 is one of a group of genes that are inactivated. In further investigations, the research group is now looking at how the inactivation of mSYD1 affects the behavior of mice, in order to gain insights into the fundamental neuronal defects associated with autism.

A chemical hormone released in the body as a reaction to stress could be a key trigger of the mechanism for the late onset of Alzheimer’s disease, according to a study by researchers at Temple University.

Previous studies have shown that the chemical hormone corticosteroid, which is released into the body’s blood as a stress response, is found at levels two to three times higher in Alzheimer’s patients than non-Alzheimer’s patients.

“Stress is an environmental factor that looks like it may play a very important role in the onset of Alzheimer’s disease,” said Domenico Praticò, professor of pharmacology and microbiology and immunology in Temple’s School of Medicine, who led the study. “When the levels of corticosteroid are too high for too long, they can damage or cause the death of neuronal cells, which are very important for learning and memory.”

In their study, “Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathology in 3xTg mice,” published in the journal Aging Cell, the Temple researchers set up a series of experiments to examine the mechanisms by which stress can be responsible for the Alzheimer’s pathology in the brain.

Using triple transgenic mice, which develop amyloid beta and the tau protein, two major brain lesion signatures for Alzheimer’s, the Temple researchers injected one group with high levels of corticosteroid each day for a week in order to mimic stress.

While they found no significant difference in the mice’s memory ability at the end of the week, they did find that the tau protein was significantly increased in the group that received the corticosteroid. In addition, they found that the synapses, which allow neuronal cells to communicate and play a key role in learning and memory, were either damaged or destroyed.

“This was surprising because we didn’t see any significant memory impairment, but the pathology for memory and learning impairment was definitely visible,” said Pratico. “So we believe we have identified the earliest type of damage that precedes memory deficit in Alzheimer’s patients.”
Pratico said another surprising outcome was that a third group of mice that were genetically altered to be devoid of the brain enzyme 5-lipoxygenase appeared to be immune and showed no neuronal damage from the corticosteroid.

In previous studies, Pratico and his team have shown that elevated levels of 5-lipoxygenase cause an increase in tau protein levels in regions of the brain controlling memory and cognition, disrupting neuronal communications and contributing to Alzheimer’s disease. It also increases the levels of amyloid beta, which is thought to be the cause for neuronal death and forms plaques in the brain.

Pratico said the corticosteroid causes the 5-lipoxygenase to over-express and increase its levels, which in turn increases the levels of the tau protein and amyloid beta.

“The question has always been what up-regulates or increases 5-lipoxygenase, and now we have evidence that it is the stress hormone,” he said. “We have identified a mechanism by which the risk factor — having high levels of corticosteroid — could put you at risk for the disease.

“Corticosteroid uses the 5-lipoxygenase as a mechanism to damage the synapse, which results in memory and learning impairment, both key symptoms for Alzheimer’s,” said Pratico. “So that is strong support for the hypothesis that if you block 5-lipoxygenase, you can probably block the negative effects of corticosteroid in the brain.”