Posts tagged striatum
Articles and news from the latest research reports.
Inner-Ear Disorders May Cause Hyperactivity
Behavioral abnormalities are traditionally thought to originate in the brain. But a new study by researchers at Albert Einstein College of Medicine of Yeshiva University has found that inner-ear dysfunction can directly cause neurological changes that increase hyperactivity. The study, conducted in mice, also implicated two brain proteins in this process, providing potential targets for intervention. The findings were published today in the online edition of Science.
For years, scientists have observed that many children and adolescents with severe inner-ear disorders – particularly disorders affecting both hearing and balance – also have behavioral problems, such as hyperactivity. Until now, no one has been able to determine whether the ear disorders and behavioral problems are actually linked.
"Our study provides the first evidence that a sensory impairment, such as inner-ear dysfunction, can induce specific molecular changes in the brain that cause maladaptive behaviors traditionally considered to originate exclusively in the brain," said study leader Jean M. Hébert, Ph.D., professor in the Dominick P. Purpura Department of Neuroscience and of genetics at Einstein.
The inner ear consists of two structures, the cochlea (responsible for hearing) and the vestibular system (responsible for balance). Inner-ear disorders are typically caused by genetic defects but can also result from infection or injury.
The idea for the study arose when Michelle W. Antoine, a Ph.D. student at Einstein at the time, noticed that some mice in Dr. Hébert’s laboratory were unusually active – in a state of near-continual movement, chasing their tails in a circular pattern. Further investigation revealed that the mice had severe cochlear and vestibular defects and were profoundly deaf. “We then realized that these mice provided a good opportunity to study the relationship between inner-ear dysfunction and behavior,” said Dr. Hébert.
The researchers established that the animals’ inner-ear problems were due to a mutation in a gene called Slc12a2, which mediates the transport of sodium, potassium, and chloride molecules in various tissues, including the inner ear and central nervous system (CNS). The gene is also found in humans.
To determine whether the gene mutation was linked to the animals’ hyperactivity, the researchers took healthy mice and selectively deleted Slc12a2 from either the inner ear, various parts of the brain that control movement or the entire CNS. “To our surprise, it was only when we deleted the gene from the inner ear that we observed increased locomotor activity,” said Dr. Hébert.
The researchers hypothesized that inner-ear defects cause abnormal functioning of the striatum, a central brain area that controls movement. Tests revealed increased levels of two proteins involved in a signaling pathway that controls the action of neurotransmitters: pERK (phosphorylated extracellular signal-regulated kinase) and pCREB (phospho-cAMP response-element binding protein), which is further down the signaling pathway from pERK. Increases in levels of the two proteins were seen only in the striatum and not in other forebrain regions.
To discover whether increased pERK levels caused the abnormal increase in locomotor activity, Slc12a2-deficient mice were given injections of SL327, a pERK inhibitor. Administering SL327 restored locomotor activity to normal, without affecting activity levels in controls. The SL327 injections did not affect grooming, suggesting that increased pERK in the striatum selectively elevates locomotor activity and not general activity. According to the researchers, the findings suggest that hyperactivity in children with inner-ear disorders might be controllable with medications that directly or indirectly inhibit the pERK pathway in the striatum.
"Our study also raises the intriguing possibility that other sensory impairments not associated with inner-ear defects could cause or contribute to psychiatric or motor disorders that are now considered exclusively of cerebral origin," said Dr. Hébert. "This is an area that has not been well studied."
New Findings Could Help Improve Development of Drugs for Addiction
Scientists from the Florida campus of The Scripps Research Institute have described findings that could enable the development of more effective drugs for addiction with fewer side effects.
The study, published in the August 2, 2013 issue of the Journal of Biological Chemistry, showed in a combination of cell and animal studies that one active compound maintains a strong bias towards a single biological pathway, providing insight into what future drugs could look like.
The compound examined in the study, known as 6’- guanidinonaltrindole (6’-GNTI), targets the kappa opioid receptor (KOR). Located on nerve cells, KOR plays a role in the release of dopamine, a neurotransmitter that plays a key role in drug addiction. Drugs of abuse often cause the brain to release large amounts of dopamine, flooding the brain’s reward system and reinforcing the addictive cycle.
“There are a number of drug discovery efforts ongoing for KOR,” said Laura Bohn, a TSRI associate professor, who led the study. “The ultimate question is how this receptor should be acted upon to achieve the best therapeutic effects. Our study identifies a marker that shows how things normally happen in live neurons—a critically important secondary test to evaluate potential compounds.”
While KOR has become the focus for drug discovery efforts aimed at treating addiction and mood disorders, KOR can react to signals that originate independently from multiple biological pathways, so current drug candidates targeting KOR often produce unwanted side effects. Compounds that activate KOR can decrease the rewarding effects of abused drugs, but also induce sedation and depression.
The new findings, from studies of nerve cells in the striatum (an area of the brain involved in motor activity and higher brain function), reveal a point on the KOR signaling pathway that may prove to be an important indicator of whether drug candidates can produce effects similar to the natural biological effects.
“Standard screening assays can catch differences but those differences may not play out in live tissue,” Bohn noted. “Essentially, we have shown an important link between cell-based screening assays and what occurs naturally in animal models.”
(Source: scripps.edu)
Mice Give New Clues to Origins of OCD
Columbia Psychiatry researchers have identified what they think may be a mechanism underlying the development of compulsive behaviors. The finding suggests possible approaches to treating or preventing certain characteristics of OCD.
OCD consists of obsessions, which are recurrent intrusive thoughts, and compulsions, which are repetitive behaviors that patients perform to reduce the severe anxiety associated with the obsessions. The disorder affects 2–3 percent of people worldwide and is an important cause of illness-related disability, according to the World Health Organization.
Using a new technology in a mouse model, the researchers found that repeated stimulation of specific circuits linking the brain’s cortex and striatum produces progressive repetitive behavior. By targeting this region, it may be possible to stop abnormal circuit changes before they become pathological behaviors in people at risk for obsessive-compulsive disorder (OCD). The study, which was led by Susanne Ahmari, MD, PhD, assistant professor of clinical psychiatry at Columbia Psychiatry and the New York State Psychiatric Institute, was published in the June 7 issue of Science.
While the obsessions and compulsions that are the hallmarks of OCD are thought to be centered in the cortex, which controls thoughts, and the striatum, which controls movements, little is known about how abnormalities in these brain regions lead to compulsive behaviors in patients.
To simulate the increased activity that takes place in the brains of OCD patients, Dr. Ahmari and her colleagues used a new technology called optogenetics, in which light-activated ion channels are expressed in subsets of neurons in mice, and neural circuits are then selectively activated using light delivered through fiberoptic probes.
“What we found was really surprising,” said Dr. Ahmari. “That activation of cortico-striatal circuits did not lead directly to repetitive behaviors in the mice. But if we repeatedly stimulated for multiple days in a row for only five minutes a day, we saw a progressive development of repetitive behaviors—in this case, repetitive grooming behavior—that persisted up to two weeks after the stimulation was stopped.”
She added, “And not only that, when we treated the mice with fluoxetine, one of the most common medications used for OCD, their behavior went back to normal.” The current study, as well as others currently being performed by Dr. Ahmari and her team, may ultimately provide clues for new treatment targets in terms of both novel drug development and direct stimulation techniques, including deep brain stimulation (DBS).
Scientists discover how brain’s auditory center transmits information for decisions and actions
When a pedestrian hears the screech of a car’s brakes, she has to decide whether, and if so, how, to move in response. Is the action taking place blocks away, or 20 feet to the left?
One of the truly primal mechanisms that we depend on every day of our lives — acting on the basis of information gathered by our sense of hearing — is yielding its secrets to modern neuroscience. A team of researchers from Cold Spring Harbor Laboratory (CSHL) today publishes experimental results in the journal Nature which they describe as surprising. The results fill in a key piece of the puzzle about how mammals act on the basis of sound cues.
It’s well known that sounds detected by the ears wind up in a part of the brain called the auditory cortex, where they are translated – transduced – into information that scientists call representations. These representations, in turn, form the informational basis upon which other parts of the brain can make decisions and issue commands for specific actions. What scientists have not understood is what happens between the auditory cortex and portions of the brain that ultimately issue commands, say, for muscles to move in response to the sound of that car’s screeching brakes.
To find out, CSHL Professor Anthony Zador and Dr. Petr Znamenskiy trained rats to listen to sounds and to make decisions based on those sounds. When a high-frequency sound is played, the animals are rewarded if they move to the left. When the sound is low-pitched, the reward is given if the animal moves right.
To the striatum
On the simplest level, says Zador, “we know that sound is coming into the ear; and we know what’s coming out in the end – a decision,” in the form of a muscle movement. The surprise, he says, is the destination of the information used by the animal to perform this task of discriminating between sounds of high and low frequency, as revealed in his team’s experiments.
“It turns out the information passes through a particular subset of neurons in the auditory cortex whose axons wind up in another part of the brain, called the striatum,” says Zador. The classic series of experiments that provided inspiration and a model for this work, performed at Stanford University by William Newsome and colleagues, involved the visual system of primates, and had led Zador to expect by analogy that representations formed in the auditory cortex would lead to other locations within the cortex.
These experiments in rats have implications for how neural circuits make decisions, according to Zador. Even though many neurons in auditory cortex are “tuned” to low or high frequencies, most do not transmit their information directly to the striatum. Rather, their information is transmitted by a much smaller number of neurons in their vicinity, which convey their “votes” directly to the striatum.
“This is like the difference between a direct democracy and a representative democracy, of the type we have in the United States,” Zador explains. “In a direct democracy model of how the auditory cortex conveys information to the rest of the brain, every neuron activated by a low- or high-pitched sound would have a ‘vote.’ Since there is noise in every perception, some minority of neurons will indicate ‘low’ when the sound is in fact ‘high,’ and vice-versa. In the direct democracy model, the information sent to the striatum for further action would be the equivalent of a simple sum of all these votes.
“In contrast – and this is what we found to be the case – the neurons registering ‘high’ and ‘low’ are represented by a specialized subset of neurons in their local area, which we might liken to members of Congress or the Electoral College: these in turn transmit the votes of the larger population to the place — in this case the auditory striatum — in which decisions are made and actions are taken.”
(Source: cshl.edu)
Psychopaths are not neurally equipped to have concern for others
Prisoners who are psychopaths lack the basic neurophysiological “hardwiring” that enables them to care for others, according to a new study by neuroscientists at the University of Chicago and the University of New Mexico.
“A marked lack of empathy is a hallmark characteristic of individuals with psychopathy,” said the lead author of the study, Jean Decety, the Irving B. Harris Professor in Psychology and Psychiatry at UChicago. Psychopathy affects approximately 1 percent of the United States general population and 20 percent to 30 percent of the male and female U.S. prison population. Relative to non-psychopathic criminals, psychopaths are responsible for a disproportionate amount of repetitive crime and violence in society.
“This is the first time that neural processes associated with empathic processing have been directly examined in individuals with psychopathy, especially in response to the perception of other people in pain or distress,” he added.
The results of the study, which could help clinical psychologists design better treatment programs for psychopaths, are published in the article, “Brain Responses to Empathy-Eliciting Scenarios Involving Pain in Incarcerated Individuals with Psychopathy,” which appears online April 24 in the journal JAMA Psychiatry.
Joining Decety in the study were Laurie Skelly, a graduate student at UChicago; and Kent Kiehl, professor of psychology at the University of New Mexico.
For the study, the research team tested 80 prisoners between ages 18 and 50 at a correctional facility. The men volunteered for the test and were tested for levels of psychopathy using standard measures.
They were then studied with functional MRI technology, to determine their responses to a series of scenarios depicting people being intentionally hurt. They were also tested on their responses to seeing short videos of facial expressions showing pain.
The participants in the high psychopathy group exhibited significantly less activation in the ventromedial prefrontal cortex, lateral orbitofrontal cortex, amygdala and periaqueductal gray parts of the brain, but more activity in the striatum and the insula when compared to control participants, the study found.
The high response in the insula in psychopaths was an unexpected finding, as this region is critically involved in emotion and somatic resonance. Conversely, the diminished response in the ventromedial prefrontal cortex and amygdala is consistent with the affective neuroscience literature on psychopathy. This latter region is important for monitoring ongoing behavior, estimating consequences and incorporating emotional learning into moral decision-making, and plays a fundamental role in empathic concern and valuing the well-being of others.
“The neural response to distress of others such as pain is thought to reflect an aversive response in the observer that may act as a trigger to inhibit aggression or prompt motivation to help,” the authors write in the paper.
“Hence, examining the neural response of individuals with psychopathy as they view others being harmed or expressing pain is an effective probe into the neural processes underlying affective and empathy deficits in psychopathy,” the authors wrote.
Decety is one of the world’s leading experts on the biological underpinnings of empathy. His work also focuses on the development of empathy and morality in children.
The motivation to move: Study finds rats calculate ‘average’ of reward across several tests
Suppose you had $1,000 to invest in the stock market. How would you decide to pick one stock over another? Scientists have made great progress in understanding the neuroscience behind how people choose between similar options.
But what happens when neither choice is right?
During an economic downturn, for instance, your best option might be not to invest at all, but to wait for market conditions to improve.
Using an unusual decision-making study, Harvard researchers exploring the question of motivation found that rats will perform a task faster or slower depending on the size of the benefit they receive, suggesting that they maintain a long-term estimate of whether it’s worth it to them to invest energy in a task.
As described in an April 14 paper in Nature Neuroscience, a research team led by Naoshige Uchida, associate professor of molecular and cellular biology, found that rats averaged how much benefit they received over as many as five trials. When their brains were impaired in one region, however, the rats based their actions solely on the prior trial.
“This is a new framework to think about decision-making,” Uchida said. “There have been many studies that focused on action selection or choices, but the question of the overall pace or rate of performance has been largely ignored.”
To get at those decision-making questions, Uchida and his team designed the experiment.
In each trial, rats were presented with an apparatus that had three holes. Based on whether a sweet or sour odor was delivered through the middle hole, rats went either left or right to receive a water reward. On one side they received a large reward; the other side delivered a smaller reward.
“What we measured was, after getting the reward, how quickly they went back to initiate the next trial,” Uchida said.
What researchers found, Uchida said, was surprising. When rats received, on average, a larger reward, they were more likely to quickly initiate the next trial, which suggested that they weren’t reacting merely to the prior result, but were “averaging the size of the reward from several previous trials.”
“They essentially calculate the average over the previous five or six trials, and adjust their performance accordingly,” Uchida said. “They’re making a calculation to determine whether they’re getting something out of the task or not. If it’s worth it for them, they go faster. If not, they go slower.”
When researchers impaired part of the striatum, a brain structure that is part of the basal ganglia and is thought to be involved with associative thinking, in the rats’ brains, however, that calculation changed. Rather than considering the average of multiple trials, the rats chose whether to go slower or faster based solely on the prior result.
“They still go faster or slower depending on the size of the reward, but they base that decision only on the size of the reward they just got,” Uchida said. “So the rat becomes very myopic. They only care about what just happened, and they don’t take other trials into account.”
In addition to shedding new light on how decision-making happens, the study may also offer some hope for people suffering from Parkinson’s disease.
“This part of the striatum receives a great deal of inputs from dopamine neurons, so it may be related to Parkinson’s disease,” Uchida said. “Some people now think Parkinson’s may actually be related to the motivation, or ‘vigor’ to perform some movement. So if we can identify brain regions that are involved in the regulation of general motivation, it’s possible that it could be contributing to the symptoms of Parkinson’s disease.”
Going forward, Uchida said, he hopes to study the role dopamine plays in regulating motivation and decision making, as well as working to understand what role other areas of the striatum might play in the process.
“There are some interesting similarities between this part of the striatum in rats and in humans,” he said. “One is that this area receives very heavy inputs from the prefrontal cortex. That’s an area that may be important in integrating information over a longer period of time. Deconstructing this process is a critical step to understanding our behavior, and this could go a long way toward that.”
Exploring the Brain’s Relationship to Habits
The basal ganglia, structures deep in the forebrain already known to control voluntary movements, also may play a critical role in how people form habits, both bad and good, and in influencing mood and feelings.
"This system is not just a motor system," says Ann Graybiel. "We think it also strongly affects the emotional part of the brain."
Graybiel, an investigator at the McGovern Institute of the Massachusetts Institute of Technology and professor in MIT’s department of brain and cognitive sciences, believes that a core function of the basal ganglia is to help humans develop habits that eventually become automatic, including habits of thought and emotion.
"Many everyday movements become habitual through repetition, but we also develop habits of thought and emotion," she says."If cognitive and emotional habits are also controlled by the basal ganglia, this may explain why damage to these structures can lead not only to movement disorders, but also to repetitive and intrusive thoughts, emotions and desires."
Graybiel’s research focuses on the brain’s relationship to habits—how we make or break them—and the neurobiology of the habit system. She and her team have identified and traced neural loops that run from the outer layer of the brain—“the thinking cap,” as she calls it—to a region called the striatum, which is part of the basal ganglia, and back again. These loops, in fact, connect sensory signals to habitual behaviors.
Her work ultimately could have an impact not just on such classic movement disorders as Parkinson’s and Huntington’s diseases, but in other conditions where repetitive movements commonly occur, such as Tourette Syndrome, autism, or obsessive-compulsive disorder, the latter when sufferers experience unwanted and repeated thoughts, feelings, ideas, sensations or behaviors that make them feel driven to do something, for example, repeatedly washing their hands.
Moreover, the research could have an immediate value for trying to understand “what happens in the brain as addiction occurs, as bad habits form, not just good habits,” she says. “There are many psychiatric and neurologic conditions in which these same brain regions are disordered.
"These conditions may in part be influenced by the very system we are working on," Graybiel adds. "We are working with models of anxiety and depression, stress and some of these movement disorders."
It turns out that the emotional circuits of the brain have strong ties to the striatum, she says. Graybiel’s research suggests that activity in the striatum strongly affects the emotional decisions that people make: whether to accept a good outcome or a potentially bad one, for example, and that there are circuits favoring good outcomes, and, surprisingly, other circuits that favor bad ones.
"This work ties into new research suggesting that there are brain systems for ‘good’ and brain systems for ‘bad,’" she says. "What is intriguing is that we may have identified the circuits that decide between the two."
A scientific explanation to why people perform better after receiving a compliment
A team of Japanese scientists have found scientific proof that people doing exercises appear to perform better when another person compliments them. The research was carried out by a group lead by National Institute for Physiological Sciences Professor Norihiro Sadato, Graduate University for Advanced Studies graduate student Sho Sugawara, Nagoya Institute of Technology Tenure-Track Associate Professor Satoshi Tanaka, and in collaboration with Research Center for Advanced Science and Technology Associate Professor Katsumi Watanabe. The team had previously discovered that the same area of the brain, the striatum, is activated when a person is rewarded a compliment or cash. Their latest research could suggest that when the striatum is activated, it seems to encourage the person to perform better during exercises. The paper is published online in PLOS ONE
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According to Professor Sadato, “To the brain, receiving a compliment is as much a social reward as being rewarded money. We’ve been able to find scientific proof that a person performs better when they receive a social reward after completing an exercise. There seems to be scientific validity behind the message ‘praise to encourage improvement’. Complimenting someone could become an easy and effective strategy to use in the classroom and during rehabilitation.”