February 7, 2012

ScienceDaily (Feb. 7, 2012) — Parkinson’s disease researchers at the University at Buffalo have discovered how mutations in the parkin gene cause the disease, which afflicts at least 500,000 Americans and for which there is no cure.

The results are published in the current issue of Nature Communications. The UB findings reveal potential new drug targets for the disease as well as a screening platform for discovering new treatments that might mimic the protective functions of parkin. UB has applied for patent protection on the screening platform.

"This is the first time that human dopamine neurons have ever been generated from Parkinson’s disease patients with parkin mutations," says Jian Feng, PhD, professor of physiology and biophysics in the UB School of Medicine and Biomedical Sciences and the study’s lead author.

As the first study of human neurons affected by parkin, the UB research overcomes a major roadblock in research on Parkinson’s disease and on neurological diseases in general. The problem has been that human neurons live in a complex network in the brain and thus are off-limits to invasive studies, Feng explains.

"Before this, we didn’t even think about being able to study the disease in human neurons," he says. "The brain is so fully integrated. It’s impossible to obtain live human neurons to study."

But studying human neurons is critical in Parkinson’s disease, Feng explains, because animal models that lack the parkin gene do not develop the disease; thus, human neurons are thought to have “unique vulnerabilities.”

"Our large brains may use more dopamine to support the neural computation needed for bipedal movement, compared to quadrupedal movement of almost all other animals," he says. Since in 2007, when Japanese researchers announced they had converted human cells to induced pluripotent stem cells (iPSCs) that could then be converted to nearly any cells in the body, mimicking embryonic stem cells, Feng and his UB colleagues saw their enormous potential. They have been working on it ever since.

"This new technology was a game-changer for Parkinson’s disease and for other neurological diseases," says Feng. "It finally allowed us to obtain the material we needed to study this disease."

The current paper is the fruition of the UB team’s ability to “reverse engineer” human neurons from human skin cells taken from four subjects: two with a rare type of Parkinson’s disease in which the parkin mutation is the cause of their disease and two healthy subjects who served as controls.

"Once parkin is mutated, it can no longer precisely control the action of dopamine, which supports the neural computation required for our movement," says Feng.

The UB team also found that parkin mutations prevent it from tightly controlling the production of monoamine oxidase (MAO), which catalyzes dopamine oxidation.

"Normally, parkin makes sure that MAO, which can be toxic, is expressed at a very low level so that dopamine oxidation is under control," Feng explains. "But we found that when parkin is mutated, that regulation is gone, so MAO is expressed at a much higher level. The nerve cells from our Parkinson’s patients had much higher levels of MAO expression than those from our controls. We suggest in our study that it might be possible to design a new class of drugs that would dial down the expression level of MAO."

He notes that one of the drugs currently used to treat Parkinson’s disease inhibits the enzymatic activity of MAO and has been shown in clinical trials to slow down the progression of the disease.

Parkinson’s disease is caused by the death of dopamine neurons. In the vast majority of cases, the reason for this is unknown, Feng explains. But in 10 percent of Parkinson’s cases, the disease is caused by mutations of genes, such as parkin: the subjects with Parkinson’s in the UB study had this rare form of the disease.

"We found that a key reason for the death of dopamine neurons is oxidative stress due to the overproduction of MAO," explains Feng. "But before the death of the neurons, the precise action of dopamine in supporting neural computation is disrupted by parkin mutations. This paper provides the first clues about what the parkin gene is doing in healthy controls and what it fails to achieve in Parkinson’s patients."

He noted in this study that these defects are reversed by delivering the normal parkin gene into the patients’ neurons, thus offering hope that these neurons may be used as a screening platform for discovering new drug candidates that could mimic the protective functions of parkin and potentially even lead to a cure for Parkinson’s.

While the parkin mutations are only responsible for a small percentage of Parkinson’s cases, Feng notes that understanding how parkin works is relevant to all Parkinson’s patients. His ongoing research on sporadic Parkinson’s disease, in which the cause is unknown, also points to the same direction.

Source: ScienceDaily

ScienceDaily (Feb. 7, 2012) — Each part of the body has its own nerve cell area in the brain -we therefore have a map of our bodies in our heads. The functional significance of these maps is largely unclear. What effects they can have is now shown by RUB neuroscientists through reaction time measurements combined with learning experiments and “computational modelling.” They have been able to demonstrate that inhibitory influences of neighbouring “finger nerve cells” affect the reaction time of a finger. The fingers on the outside — i.e. the thumb and little finger — therefore react faster than the middle finger, which is exposed to the “cross fire” of two neighbours on each side. Through targeted learning, this speed handicap can be compensated.

The working group led by PD Dr. Hubert Dinse (Neural Plasticity Lab at the Institute for Neuroral Computation) report in the current issue of PNAS.

Thumb and little finger are the quickest

The researchers set subjects a simple task to measure the speed of decision: they showed them an image on a monitor that represented all ten fingers. If one of the fingers was marked, the subjects were to press a corresponding key as quickly as possible with that finger. The thumb and little finger were the fastest. The middle finger brought up the rear. “You might think that this has anatomical reasons or depends on the exercise” said Dr Dinse, “but we were able to rule that out through further tests. In principle, each finger is able to react equally quickly. Only in the selection task, the middle finger is at a distinct disadvantage.”

Computer simulation depicts brain maps

To explain their observations, the researchers used computer simulations based on a so-called mean-field model. It is especially suited for modelling large neuronal networks in the brain. For these simulations, each individual finger is represented by a group of nerve cells, which are arranged in the form of a topographic map of the fingers based on the actual conditions in the somatosensory cortex of the brain. “Adjacent fingers are adjacent in the brain too, and thus also in the simulation,” explained Dr. Dinse. The communication of the nerve cells amongst themselves is organised so that the nerve cells interact through mutual excitation and inhibition.

Inhibitory influences from both sides slow down the middle finger

The computer simulations showed that the longer reaction time of the middle finger in a multiple choice task is a consequence of the fact that the middle finger is within the inhibition range of the two adjacent fingers. The thumb and little finger on the other hand only receive an inhibitory effect of comparable strength from one adjacent finger each. “In other words, the high level of inhibition received by the nerve cells of the middle fingers mean that it takes longer for the excitement to build up — they therefore react more slowly” said Dr. Dinse.

Targeted reduction of the inhibition through learning

From the results of the computer simulation it can be concluded that weaker inhibition from the neighbouring fingers would shorten the reaction time of the middle finger. This would require a so-termed plastic change in the brain — a specialty of the Neural Plasticity Lab, which has been studying the development of learning protocols that induce such changes for years. One such protocol is the repeated stimulation of certain nerve cell groups, which the laboratory has already used in many experiments. “If, for example, you stimulate one finger electrically or by means of vibration for two to three hours, then its representation in the brain changes” explained Dr. Dinse. The result is an improvement in the sense of touch and a measurable reduction of the inhibitory processes in this brain area. This also results in the enlargement of the representation of the finger stimulated.

Second experiment confirms the prediction

The Bochum researchers then conducted a second experiment in which the middle finger of the right hand was subjected to such stimulation. The result was a significant shortening of the reaction time of this finger in the selection task. “This finding confirms our prediction” Dr. Dinse summed up. Thus, for the first time, Bochum’s researchers have established a direct link between the so-called lateral inhibitory processes and decision making processes. They have shown that learning processes that change the cortical maps can have far-reaching implications not only for simple discrimination tasks, but also for decision processes that were previously attributed to the so-called “higher” cortical areas. 

Source: ScienceDaily

February 6th, 2012

This STED image of a nerve cell in the upper brain layer of a living mouse shows in previously impossible detail the very fine dendritic protrusions of a nerve cell, the so-called spines, at which the synapses are located. The inset shows the mushroom-shaped head of such a dendritic spine at which the nerve cells receive information from their peers. © Max Planck Institute for Biophysical Chemistry

Source: Neuroscience News

February 6, 2012

Rock, paper or scissors? Learning while playing a strategic game against others involves a different pattern of brain activity than learning from the consequences of one’s own actions, researchers found. Credit: L. Brian Stauffer

Researchers have found a way to study how our brains assess the behavior – and likely future actions – of others during competitive social interactions. Their study, described in a paper in the Proceedings of the National Academy of Sciences, is the first to use a computational approach to tease out differing patterns of brain activity during these interactions, the researchers report.

"When players compete against each other in a game, they try to make a mental model of the other person’s intentions, what they’re going to do and how they’re going to play, so they can play strategically against them," said University of Illinois postdoctoral researcher Kyle Mathewson, who conducted the study as a doctoral student in the Beckman Institute with graduate student Lusha Zhu and economics professor and Beckman affiliate Ming Hsu, who now is at the University of California, Berkeley. "We were interested in how this process happens in the brain."

Previous studies have tended to consider only how one learns from the consequences of one’s own actions, called reinforcement learning, Mathewson said. These studies have found heightened activity in the basal ganglia, a set of brain structures known to be involved in the control of muscle movements, goals and learning. Many of these structures signal via the neurotransmitter dopamine.

"That’s been pretty well studied and it’s been figured out that dopamine seems to carry the signal for learning about the outcome of our own actions," Mathewson said. "But how we learn from the actions of other people wasn’t very well characterized."

Researchers call this type of learning “belief learning.”

To better understand how the brain processes information in a competitive setting, the researchers used functional magnetic resonance imaging (fMRI) to track activity in the brains of participants while they played a competitive game, called a Patent Race, against other players. The goal of the game was to invest more than one’s opponent in each round to win a prize (a patent worth considerably more than the amount wagered), while minimizing one’s own losses (the amount wagered in each trial was lost). The fMRI tracked activity at the moment the player learned the outcome of the trial and how much his or her opponent had wagered.

A computational model evaluated the players’ strategies and the outcomes of the trials to map the brain regions involved in each type of learning.

"Both types of learning were tracked by activity in the ventral striatum, which is part of the basal ganglia," Mathewson said. "That’s traditionally known to be involved in reinforcement learning, so we were a little bit surprised to see that belief learning also was represented in that area."

Belief learning also spurred activity in the rostral anterior cingulate, a structure deep in the front of the brain. This region is known to be involved in error processing, regret and “learning with a more social and emotional flavor,” Mathewson said.

The findings offer new insight into the workings of the brain as it is engaged in strategic thinking, Hsu said, and may aid the understanding of neuropsychiatric illnesses that undermine those processes.

"There are a number of mental disorders that affect the brain circuits implicated in our study," Hsu said. "These include schizophrenia, depression and Parkinson’s disease. They all affect these dopaminergic regions in the frontal and striatal brain areas. So to the degree that we can better understand these ubiquitous social functions in strategic settings, it may help us understand how to characterize and, eventually, treat the social deficits that are symptoms of these diseases."

Provided by University of Illinois at Urbana-Champaign

Source: medicalxpress.com

February 6, 2012

February 6, 2012

January 30th, 2012

The hippocampus (highlighted in fuchsia) is a key brain structure important to learning, memory and stress response. New research shows that children who were nurtured by their mothers early in life have a larger hippocampus than children who were not nurtured as much. Credit: Washington University Medical School from press release

Source: Neuroscience News

Article Date: 06 Feb 2012 - 0:00 PST

Men and women may be equals, but they often behave differently when it comes to sex and parenting. Now a study of the differences between the brains of male and female mice in the Cell Press journal Cell provides insight into how our own brains might be programmed for these stereotypically different behaviors.

The new evidence shows that the sex hormones - testosterone, estrogen, and progesterone - act in a key region of the brain, switching certain genes on and others off. When the researchers tinkered with each of these genes one by one, animals showed subtle but important shifts in individual sex-specific behaviors, such as how males mate or females care for their pups.

“What this means is that complex behaviors like male mating or maternal care in mice can be deconstructed at the genetic level,” said Nirao Shah of the University of California, San Francisco. The findings present a cellular and molecular representation of gender that is remarkable in its complexity, the researchers say.

Shah’s team made these discoveries after screening mouse brains for genes that show differences in expression in males versus females. The researchers focused specifically on the hypothalamus, a region previously implicated in the control of sex-specific behaviors. Their screen produced a list of 16 genes with clear sex differences in distinct neurons in the hypothalamus. Surprisingly, Shah’s team found that many of these genes also show sex differences in the amygdala, a part of the brain important for emotions.

In further studies, the researchers examined the effects of a subset of these individual genes. Mice missing only one of these 16 genes seemed to behave normally. But upon closer observation, these mice showed significant differences in sex-specific behaviors. For instance, Shah explained, females mutant for one gene took longer to return their pups to the nest and to fight off intruders. “They still take care of their pups, but less effectively,” he said.

In other experiments, deletion of a single gene produced females that were two-fold less receptive to mating with males. Similarly, males mutant for another gene were less interested in females. Together these results mean that sex-specific behaviors can be controlled in modular fashion, such that the loss of any one gene leads to subtle but potentially important changes.

“At the superficial level, the mice appear normal, but this is pretty significant variation in behavior,” Shah said. It suggests that variation in such genes might explain not just differences between the sexes, but also differences in behaviors within one sex or the other - why some male mice are more aggressive than other males or some females more attentive to their offspring than other females.

The researchers don’t yet know exactly how these differences in gene expression lead to those differences in behavior, although Shah says some of the genes are known to be involved in sending or receiving neural messages in the brain. It also remains to be seen how the male and female gene expression programs might be influenced by the animals’ social interactions and experiences.

There is still a lot to learn about what makes males and females tick. “This gene list of sex differences in the brain is probably just a small subset of what we will eventually unearth,” Shah said.  

Source: Medical News Today