Neuroscience

Working with human neurons and fruit flies, researchers at Johns Hopkins have identified and then shut down a biological process that appears to trigger a particular form of Parkinson’s disease present in a large number of patients. A report on the study, in the April 10 issue of the journal Cell, could lead to new treatments for this disorder.

“Drugs such as L-dopa can, for a time, manage symptoms of Parkinson’s disease, but as the disease worsens, tremors give way to immobility and, in some cases, to dementia. Even with good treatment, the disease marches on,” says Ted Dawson, M.D., Ph.D., professor of neurology and director of the Johns Hopkins Institute for Cell Engineering, Dawson says the new research builds on a growing body of knowledge about the origins of Parkinson’s disease, whose symptoms appear when dopamine-producing nerve cells in the brain degenerate. Further evidence for a role of genetics in Parkinson’s disease appeared a decade ago when researchers identified key mutations in an enzyme known as leucine-rich repeat kinase 2, or LRRK2 — pronounced “lark2.” When that enzyme was cloned, Dawson, together with his wife and longtime collaborator Valina Dawson, Ph.D., professor of neurology and member of the Institute for Cell Engineering, discovered that LRRK2 was a kinase, a type of enzyme that transfers phosphate groups to proteins and turns proteins on or off to change their activity.

Over the years, it was found that blocking kinase activity in mutated LRRK2 halted degeneration, while enhancing it made things worse. But nobody knew what proteins LRRK2 was acting on.

"For nearly a decade, scientists have been trying to figure out how mutations in LRRK2 cause Parkinson’s disease," said Margaret Sutherland, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke. "This study represents a clear link between LRRK2 and a pathogenic mechanism linked to Parkinson’s disease."

Dawson went fishing for the right proteins using LRRK2 as bait. When his team began to identify those proteins, Dawson says they were surprised to discover that many were linked to the cellular machinery, like ribosomes, that make proteins. Nobody, says Dawson, suspected that LRRK2 might be involved at such a basic level as protein manufacture.

Unsure if they were right, the team then tested the proteins they identified to see which of them, if any, LRRK2 could add phosphate groups to. They came up with three ribosomal protein candidates — s11, s15 and s27. They then altered each ribosomal protein to see what would happen. It turned out that mutating s15 in a manner that blocked LRRK2 phosphorylation protected nerve cells taken from rats, humans and fruit flies from death. In other words, s15 appeared to be the much sought-after target of LRRK2, Dawson says.

"When you go fishing, you want to catch fish. We just happened to catch a big one,” Dawson says.

With the protein now identified, Dawson’s team is tackling further experiments to find out how excess protein production causes dopamine neurons to degenerate. And they want to see what happens when they block LRRK2 from phosphorylating the s15 protein in mice, to build on their findings from fruit flies and nerve cells grown in a dish.

“There’s a big chasm between animal disease models and human treatments,” says Ian Martin, Ph.D., a neuroscientist in Dawson’s lab and the lead author on the paper. “But it’s exciting. I think it definitely could turn into something real, hopefully in my lifetime.”

How nerve cells flexibly adapt to acoustic signals: Depending on the input signal, neurons generate action potentials either near or far away from the cell body. This flexibility improves our ability to localize sound sources.

(Image caption: A neuron in the brain stem, that processes acoustic information. Depending on the situation, the cell generates action potentials in the axon (thin process) either close to or far from the body. Photo: Felix Felmy)

In order to process acoustic information with high temporal fidelity, nerve cells may flexibly adapt their mode of operation according to the situation. At low input frequencies, they generate most outgoing action potentials close to the cell body. Following inhibitory or high frequency excitatory signals, the cells produce many action potentials more distantly. This way, they are highly sensitive to the different types of input signals. These findings have been obtained by a research team headed by Professor Christian Leibold, Professor Benedikt Grothe, and Dr. Felix Felmy from the LMU Munich and the Bernstein Center and the Bernstein Focus Neurotechnology in Munich, who used computer models in their study. The researchers report their results in the latest issue of The Journal of Neuroscience.

Did the bang come from ahead or from the right? In order to localize sound sources, nerve cells in the brain stem evaluate the different arrival times of acoustic signals at the two ears. Being able to detect temporal discrepancies of up to 10 millionths of a second, the neurons have to become excited very quickly. In this process, they change the electrical voltage that prevails on their cell membrane. If a certain threshold is exceeded, the neurons generate a strong electrical signal — a so-called action potential — which can be transmitted efficiently over long axon distances without weakening. In order to reach the threshold, the input signals are summed up. This is achieved easier, the slower the nerve cells alter their electrical membrane potential.

Input signals are optimally processed
These requirements — rapid voltage changes for a high temporal resolution of the input signals, and slow voltage changes for an optimal signal integration that is necessary for the generation of an action potential — represent a paradoxical challenge for the nerve cell. “This problem is solved by nature by spatially separating the two processes. While input signals are processed in the cell body and the dendrites, action potentials are generated in the axon, a cell process,” says Leibold, leader of the study. But how sustainable is the spatial separation?

In their study, the researchers measured the axons’ geometry and the threshold of the corresponding cells and then constructed a computer model that allowed them to investigate the effectiveness of this spatial separation. The researchers’ model predicts that depending on the situation, neurons produce action potentials with more or less proximity to the cell body. For high frequency or inhibitory input signals, the cells will shift the location from the axon’s starting point to more distant regions. In this way, the nerve cells ensure that the various kinds of input signals are optimally processed — and thus allow us to perceive both small and large acoustic arrival time differences well, and thereby localize sounds in space.

A research led by the Research Institute Vall d’Hebron (VHIR), in which the University of Valencia participated, has shown that pathological forms of the α-synuclein protein present in deceased patients with Parkinson’s disease are able to initiate and spread in mice and primates the neurodegenerative process that typifies this disease. The discovery, published in the March cover of Annals of Neurology, opens the door to the development of new treatments that allow to stop the progression of Parkinson’s disease, aimed at blocking the expression, the pathological conversion and the transmission of this protein.

Recent studies have shown that synthetic forms of α-synuclein are toxic for the neurons, both in vitro (cell culture) and in vivo (mice), which can spread from one cell to another. However, until now it was not known if this pathogenic protein synthetic capacity could be extended to the pathological human protein found in patients with Parkinson and, therefore, whether it was relevant for the disease in humans.

In the present study, led by Doctor Miquel Vila, from the group of Neurodegenerative Diseases of the VHIR and CIBERNED member, and in which two other groups of CIBERNED have also participated (the lead by Doctor Isabel Fariñas, University of Valencia, and the led by Doctor José Obeso, CIMA-University of Navarra), as well as a group from the University of Bordeaux in France (Doctor Erwan Bezard), the researchers extracted α-synuclein aggregates of brains of dead patients because of the Parkinson’s disease to inject them into the brains of rodents and primates.

Four months after the injection into mice, and nine months after the injection into monkeys, these animals began to present degeneration of dopaminergic neurons and intracellular cumulus of α-synuclein pathology in these cells, as occurs in the Parkinson’s disease. Months later, the animals also showed cumulus of this protein in other brain remote areas, with a pattern of similar extension to that observed in the brains of patients after years of disease evolution.

According to Doctor Vila, these results indicate that “the pathological aggregates of this protein obtained from patients with the Parkinson’s disease have the ability to initiate and extend the neurodegenerative process that typifies the Parkinson’s disease in mice and primates”. A discovery that, he adds, “provides new insights about the possible mechanisms of initiation and progression of the disease and opens the door to new therapeutic opportunities”. Therefore, the next step is to find out how to stop the progression and spread of the disease, by blocking the transmission of cell to cell of the α-synuclein, as well as regulating the levels of expression and stopping the pathological conversion of this protein.

The Parkinson’s disease

The Parkinson’s disease is the second most common neurodegenerative disease after the Alzheimer’s disease. It is characterized by progressive loss of neurons that produce dopamine in a brain region (the substantia nigra of the ventral midbrain) and the presence in these cells of pathological intracellular aggregates of the α-synuclein protein, called Lewy bodies. The loss of brain dopamine as a consequence of neuronal death results in the typical motor manifestations of the disease, such as muscle stiffness, tremors and slow movement.

The most effective treatment for this disease is the levodopa, a palliative drug that allows to restore the missing dopamine. However, as the disease progresses, the pathological process of neurodegeneration and accumulation of α-synuclein progressively extends beyond the ventral midbrain to other brain areas. As a result, there is a progressive worsening of the patient and the emergence of non-motor clinical manifestations unresponsive to dopaminergic drugs. There is currently no treatment that avoids, delays or halts the progressive evolution of the neurodegenerative process.

Research linked to stress in mice confirms blood-brain comparison is valid

Johns Hopkins researchers say they have confirmed suspicions that DNA modifications found in the blood of mice exposed to high levels of stress hormone — and showing signs of anxiety — are directly related to changes found in their brain tissues.

The proof-of-concept study, reported online ahead of print in the June issue of Psychoneuroendocrinology, offers what the research team calls the first evidence that epigenetic changes that alter the way genes function without changing their underlying DNA sequence — and are detectable in blood — mirror alterations in brain tissue linked to underlying psychiatric diseases.

The new study reports only on so-called epigenetic changes to a single stress response gene called FKBP5, which has been implicated in depression, bipolar disorder and post-traumatic stress disorder. But the researchers say they have discovered the same blood and brain matches in dozens more genes, which regulate many important processes in the brain.

“Many human studies rely on the assumption that disease-relevant epigenetic changes that occur in the brain — which is largely inaccessible and difficult to test — also occur in the blood, which is easily accessible,” says study leader Richard S. Lee, Ph.D., an instructor in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. “This research on mice suggests that the blood can legitimately tell us what is going on in the brain, which is something we were just assuming before, and could lead us to better detection and treatment of mental disorders and for a more empirical way to test whether medications are working.”

For the study, the Johns Hopkins team worked with mice with a rodent version of Cushing’s disease, which is marked by the overproduction and release of cortisol, the primary stress hormone also called glucocorticoid. For four weeks, the mice were given different doses of stress hormones in their drinking water to assess epigenetic changes to FKBP5. The researchers took blood samples weekly to measure the changes and then dissected the brains at the end of the month to study what changes were occurring in the hippocampus as a result of glucocorticoid exposure. The hippocampus, in both mice and humans, is vital to memory formation, information storage and organizational abilities.

The measurements showed that the more stress hormones the mice got, the greater the epigenetic changes in the blood and brain tissue, although the scientists say the brain changes occurred in a different part of the gene than expected. This was what made finding the blood-brain connection very challenging, Lee says.

Also, the more stress hormone, the more RNA from the FKBP5 gene was expressed in the blood and brain, and the greater the association with depression. However, it was the underlying epigenetic changes that proved to be more robust. This is important, because while RNA levels may return to normal after stress hormone levels decrease or change due to small fluctuations in hormone levels, epigenetic changes persist, reflect overall stress hormone exposure and predict how much RNA will be made when stress hormone levels increase.

The team of researchers used an epigenetic assay previously developed in their laboratory that requires just one drop of blood to accurately assess overall exposure to stress hormone over 30 days. Elevated levels of stress hormone exposure are considered a risk factor for mental illness in humans and other mammals.

When you throw a wild pitch or sing a flat note, it could be that your basal ganglia made you do it. This area in the middle of the brain is involved in motor control and learning. And one reason for that errant toss or off-key note may be that your brain prompted you to vary your behavior to help you learn, from trial-and-error, to perform better.

But how does the brain do this, how does it cause you to vary your behavior?

Along with researchers from the University of California, San Francisco, Indian Institute of Science Education and Research and Duke University, Professor Sarah Woolley, Department of Biology, investigated this question in songbirds, which learn their songs during development in a manner similar to how humans learn to speak. In particular, songbirds memorize the song of their father or tutor, then practice that song until they can produce a similar song.

“As adults, they continue to produce this learned song, but what’s interesting is that they keep it just a little bit variable” says Woolley. “The variability isn’t a default, it isn’t that they can’t produce a better version, they can — in particular when they sing to a female. So when they sing alone and their song is variable it’s because they are actively making it that way.”  

The team used this change in the variability of the song to look at how the activity of single cells in different parts of the brain altered their activity depending on the social environment.

“We found that the social modulation of variability emerged within the basal ganglia, a brain area known to be important for learning and producing movements not only in birds but also in mammals, including humans” says Woolley. “This indicates that one way that the basal ganglia may be important in motor learning across species is through its involvement in generating variability.”

The researchers studied song birds because they have a cortical-basal ganglia circuit that is specific for singing. In contrast, for most behaviors in other species, the cortical-basal ganglia cells and circuits that are important for particular behaviors, like learning to walk, may be situated right next to, or even intermingled with cells and circuits important for other behaviors. “The evolution in songbirds of an identifiable circuit for a single complex behavior gives us a tremendous advantage as we try to parse out exactly what these parts of the brain do and how they do it,” says Woolley.  

Useful for Parkinson’s disease

The basal ganglia is dramatically affected in illnesses such as Parkinson’s and Huntington disease. The team’s findings may eventually be relevant to understanding changes to learning and flexibility in movement that occur in those diseases.  

“These are the kind of questions that we are now starting to pursue in the lab: how variability is affected when you radically manipulate the system akin to what happens during disease”, says Woolley.

Procrastination and impulsivity are genetically linked, suggesting that the two traits stem from similar evolutionary origins, according to research published in Psychological Science, a journal of the Association for Psychological Science. The research indicates that the traits are related to our ability to successfully pursue and juggle goals.

“Everyone procrastinates at least sometimes, but we wanted to explore why some people procrastinate more than others and why procrastinators seem more likely to make rash actions and act without thinking,” explains psychological scientist and study author Daniel Gustavson of the University of Colorado Boulder. “Answering why that’s the case would give us some interesting insights into what procrastination is, why it occurs, and how to minimize it.”

From an evolutionary standpoint, impulsivity makes sense: Our ancestors should have been inclined to seek immediate rewards when the next day was uncertain.

Procrastination, on the other hand, may have emerged more recently in human history. In the modern world, we have many distinct goals far in the future that we need to prepare for – when we’re impulsive and easily distracted from those long-term goals, we often procrastinate.

Thinking about the two traits in that context, it seems logical that people who are perpetual procrastinators would also be highly impulsive. Many studies have observed this positive relationship, but it is unclear what cognitive, biological, and environmental influences are responsible for it.

The most effective way to understand why these traits are correlated is to study human twins. Identical twins — who share 100% of their genes — tend to show greater similarities in behavior than fraternal twins, who only share 50% of their genes (just like any other siblings). Researchers take advantage of this genetic discrepancy to figure out the relative importance of genetic and environmental influences on particular behaviors, like procrastination and impulsivity.

Gustavson and colleagues had 181 identical-twin pairs and 166 fraternal-twin pairs complete several surveys intended to probe their tendencies toward impulsivity and procrastination, as well as their ability to set and maintain goals.

They found that procrastination is indeed heritable, just like impulsivity. Not only that, there seems to be a complete genetic overlap between procrastination and impulsivity — that is, there are no genetic influences that are unique to either trait alone.

That finding suggests that, genetically speaking, procrastination is an evolutionary byproduct of impulsivity — one that likely manifests itself more in the modern world than in the world of our ancestors.

In addition, the link between procrastination and impulsivity also overlapped genetically with the ability to manage goals, lending support to the idea that delaying, making rash decisions, and failing to achieve goals all stem from a shared genetic foundation.

Gustavson and colleagues are now investigating how procrastination and impulsivity are related to higher-level cognitive abilities, such as executive functions, and whether these same genetic influences are related to other aspects of self-regulation in our day-to-day lives.

“Learning more about the underpinnings of procrastination may help develop interventions to prevent it, and help us overcome our ingrained tendencies to get distracted and lose track of work,” Gustavson concludes.

Whether at the office, dorm, PTA meeting, or any other social setting, we all know intuitively who the popular people are – who is most liked – even if we can’t always put our finger on why. That information is often critical to professional or social success as you navigate your social networks. Yet until now, scientists have not understood how our brains recognize these popular people. In new work, researchers say that we track people’s popularity largely through the brain region involved in anticipating rewards.

“Being able to track other people’s status in your group is incredibly important in survival terms,” says Kevin Ochsner of Columbia University. “Knowing who is popular or likeable is critically important in times of need or distress, when you seek an alliance, or need help – whether physical or political – etc.” While sociologists, psychologists, and anthropologists have long studied these group dynamics, neuroscientists have only begun to scratch the surface of how we think about people’s social status.

That is all changing, though, Ochsner says with many areas of work bringing together social psychology and sociology with cognitive neuroscience to better understand how individual brain processes connect to group membership. As will be presented today at the annual meeting of the Cognitive Neuroscience Society (CNS) in Boston, researchers are now studying at the neural level everything from social popularity to how ideas successfully spread in groups.

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