Posts tagged dopamine neurons
Articles and news from the latest research reports.
Researchers debunk myth about Parkinson’s disease
Using advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease. The findings have recently been published in the prestigious Journal of Neuroscience.
The defining symptoms of Parkinson’s disease are slow movements, muscular stiffness and shaking. There is currently no cure for the condition, so it is essential to conduct innovative research with the potential to shed some light on this terrible disruption to the central nervous system that affects one person in a thousand in Denmark.
Dopamine is an important neurotransmitter which affects physical and psychological functions such as motor control, learning and memory. Levels of this substance are regulated by special dopamine cells. When the level of dopamine drops, nerve cells that constitute part of the brain’s ‘stop signal’ are activated.
“This stop signal is rather like the safety lever on a motorised lawn mower: if you take your hand off the lever, the mower’s motor stops. Similarly, dopamine must always be present in the system to block the stop signal. Parkinson’s disease arises because for some reason the dopamine cells in the brain are lost, and it is known that the stop signal is being over-activated somehow or other. Many researchers have therefore considered it obvious that long-term lack of dopamine must be the cause of the distinctive symptoms that accompanies the disease. However, we can now use advanced computer simulations to challenge the existing paradigm and put forward a different theory about what actually takes place in the brain when the dopamine cells gradually die,” explains Jakob Kisbye Dreyer, Postdoc at the Department of Neuroscience and Pharmacology, University of Copenhagen.
A thorn in the side
Scanning the brain of a patient suffering from Parkinson’s disease reveals that in spite of dopamine cell death, there are no signs of a lack of dopamine – even at a comparatively late stage in the process.
“The inability to establish a lack of dopamine until advanced cases of Parkinson’s disease has been a thorn in the side of researchers for many years. On the one hand, the symptoms indicate that the stop signal is over-activated, and patients are treated accordingly with a fair degree of success. On the other hand, data prove that they are not lacking dopamine,” says Postdoc Jakob Kisbye Dreyer.
Computer models predict the progress of the disease
“Our calculations indicate that cell death only affects the level of dopamine very late in the process, but that symptoms can arise long before the level of the neurotransmitter starts to decline. The reason for this is that the fluctuations that normally make up a signal become weaker. In the computer model, the brain compensates for the shortage of signals by creating additional dopamine receptors. This has a positive effect initially, but as cell death progresses further, the correct signal may almost disappear. At this stage, the compensation becomes so overwhelming that even small variations in the level of dopamine trigger the stop signal – which can therefore cause the patient to develop the disease.”
The new research findings may pave the way for earlier diagnosis of Parkinson’s disease.
(Source: healthsciences.ku.dk)
Researchers See Promise in Transplanted Fetal Stem Cells for Parkinson’s
Researchers at Harvard-affiliated McLean Hospital have found that fetal dopamine cells transplanted into the brains of patients with Parkinson’s disease were able to remain healthy and functional for up to 14 years, a finding that could lead to new and better therapies for the illness.
The discovery, reported in the June 5, 2014 issue of the journal Cell Reports, could pave the way for researchers to begin transplanting dopamine neurons taken from stem cells grown in laboratories, a way to get treatments to many more patients in an easier fashion.
"We have shown in this paper that the transplanted cells connect and live well and do all the required functions of nerve cells for a very long time," said Ole Isacson, MD (DR MED SCI), director of the Neuroregeneration Research Institute at McLean and a professor of neurology and neuroscience at Harvard Medical School.
The researchers looked at the brains of five patients who got fetal cell transplants over a period of 14 years and found that their dopamine transporters (DAT), proteins that pump the neurotransmitter dopamine, and mitochondria, the power plants of cells, were still healthy at the time the patients died, in each case of causes other than Parkinson’s.
The fact that these cells had remained healthy indicated that the transplants had been successful and that the transplanted cells had not been corrupted as some researchers had suggested they likely had been in other studies, said Dr. Isacson, lead author of the paper.
"These findings are critically important for the rational development of stem cell-based dopamine neuronal replacement therapies for Parkinson’s," the paper concluded.
So far, about 25 patients worldwide have been treated with this particular method of transplanting fetal dopamine cells over a period of two decades and most saw their symptoms improve markedly, he said.
Fetal cell transplants can reduce both Parkinson’s symptoms for many years and can reduce the need for dopamine replacement drugs, even though they can take months or years to start working, the paper said.
However, Dr. Isacson said proof had been lacking that the transplanted cells were able to remain healthy — until this study. This is important for research in the transplant field to move ahead, he said.
All of the patients were in the late stages of Parkinson’s disease at the time of their transplants. Parkinson’s is a disease characterized by tremors, rigidity, slowness of movement and poor balance. It is a chronic, progressive disease that results when dopamine-producing nerve cells in a part of the brain die or are impaired.
Dr. Isacson said there was a need to understand how transplanted neurons could survive despite ongoing disease process in the patients’ brains. He said there has been controversy among scientists, some of whom believe that the transplanted cells could be corrupted by toxic proteins associated with the disease process, even at the same time patients seemed to be doing better.
"Everything we saw looked very healthy," he said, referring to the dopamine transporters and mitochondria cells.
He said the method used to transplant the cells into these patients’ brains was different than another method used on about 60 other patients worldwide. In some of those other trials, scientists said the cells might have been damaged as a result of the disease process.
It may have been that the method used on the patients in this study, which injected tiny bits of liquefied dopamine nerve cells into the brain via a thin needle, was superior to the method used in other studies, which transplanted larger chunks of nerve cells using a larger needle, he said. The transplants on the patients in this study were done in Canada.
In this study, the researchers led by Dr. Isacson compared the patients’ own dopamine producing cells with the transplanted ones. “We found very different patterns,” he said.
The difference was seen in the DAT and mitochondria, which were unhealthy around the patients’ own dopamine neurons and healthy around the transplanted ones. “The transplanted cells don’t have the disease,” he said.
"This is very important in the quest for new therapies," he added.
It is very difficult to obtain dopamine nerve cells from fetal tissue, he said. It would be far easier to grow the cells in a laboratory from stem cells, he noted. There have been no stem cell transplants as of yet for Parkinson’s patients.
Researchers Show Human Learning Altered by Electrical Stimulation of Dopamine Neurons
Stimulation of a certain population of neurons within the brain can alter the learning process, according to a team of neuroscientists and neurosurgeons at the University of Pennsylvania. A report in the Journal of Neuroscience describes for the first time that human learning can be modified by stimulation of dopamine-containing neurons in a deep brain structure known as the substantia nigra. Researchers suggest that the stimulation may have altered learning by biasing individuals to repeat physical actions that resulted in reward.
"Stimulating the substantia nigra as participants received a reward led them to repeat the action that preceded the reward, suggesting that this brain region plays an important role in modulating action-based associative learning," said co-senior author Michael Kahana, PhD, professor of Psychology in Penn’s School of Arts and Sciences.
Eleven study participants were all undergoing deep brain stimulation (DBS) treatment for Parkinson’s disease. During an awake portion of the procedure, participants played a computer game where they chose between pairs of objects that carried different reward rates (like choosing between rigged slot machines in a casino). The objects were displayed on a computer screen and participants made selections by pressing buttons on hand-held controllers. When they got a reward, they were shown a green screen and heard a sound of a cash register (as they might in a casino). Participants were not told which objects were more likely to yield reward, but that their task was to figure out which ones were “good” options based on trial and error.
When stimulation was provided in the substantia nigra following reward, participants tended to repeat the button press that resulted in a reward. This was the case even when the rewarded object was no longer associated with that button press, resulting in poorer performance on the game when stimulation was given (48 percent accuracy), compared to when stimulation was not given (67 percent).
"While we’ve suspected, based on previous studies in animal models, that these dopaminergic neurons in the substantia nigra - play an important role in reward learning, this is the first study to demonstrate in humans that electrical stimulation near these neurons can modify the learning process," said the study’s co-senior author Gordon Baltuch, MD, PhD, professor of Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania. “This result also has possible clinical implications through modulating pathological reward-based learning, for conditions such as substance abuse or problem gambling, or enhancing the rehabilitation process in patients with neurological deficits.”
(Source: uphs.upenn.edu)
Scientists Find Connection Between Gene Mutation, Key Symptoms of Autism
Scientists have known that abnormal brain growth is associated with autism spectrum disorder. However, the relationship between the two has not been well understood.
(Image: Thinkstock)
Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that mutations in a specific gene that is disrupted in some individuals with autism results in too much growth throughout the brain, and yet surprisingly specific problems in social interactions, at least in mouse models that mimic this risk factor in humans.
“What was striking is that these were basically normal animals in terms of behavior, but there were consistent deficits in tests of social interaction and recognition—which approximate a major symptom of autism,” said Damon Page, a TSRI biologist who led the study. “This suggests that when most parts of the brain are overgrown, the brain somehow adapts to it with minimal effects on behavior in general. However, brain circuits relevant to social behavior are more vulnerable or less able to tolerate this overgrowth.”
The study, which focuses on the gene phosphatase and tensin homolog (PTEN), was recently published online ahead of print by the journal Human Molecular Genetics.
Autism spectrum disorder is a neurodevelopmental disorder involving a range of symptoms and disabilities involving social deficits and communication difficulties, repetitive behaviors and interests, and sometimes cognitive delays. The disorder affects in approximately one percent of the population; some 80 percent of those diagnosed are male.
In a previous study, Page and colleagues found that mutations in Pten causes increased brain size and social deficits, with both symptoms being exacerbated by a second “hit” to a gene that regulates levels of the neurotransmitter serotonin in the brain. In the new study, the TSRI team set out to explore whether mutations in Pten result in widespread or localized overgrowth within the brain, and whether changes in brain growth are associated with broad or selective deficits in tests of autism-relevant behaviors in genetically altered mice. The team tested mice for autism spectrum disorder-related behaviors including mood, anxiety, intellectual, and circadian rhythm and/or sleep abnormalities.
The researchers found that Pten mutant mice showed altered social behavior, but few other changes—a more subtle change than would have been predicted given broad expression and critical cellular function of the gene.
Intriguingly, some of the more subtle impairments were sex-specific. In addition to social impairments, males with the mutated gene showed abnormalities related to repetitive behavior and mood/anxiety, while females exhibited additional circadian activity and emotional learning problems.
The results raise the question of how mutations in PTEN, a general regulator of growth, can have relatively selective effects on behavior and cognitive development. One idea is that PTEN mutations may desynchronize the normal pattern of growth in key cell types—the study points to dopamine neurons—that are relevant for social behavior.
“Timing is everything,” Page said. “Connections have to form in the right place at the right time for circuits to develop normally. Circuitry involved in social behavior may turn out to be particularly vulnerable to the effects of poorly coordinated growth.”
(Source: scripps.edu)
A noninvasive avenue for Parkinson’s disease gene therapy
Researchers at Northeastern University in Boston have developed a gene therapy approach that may one day stop Parkinson’s disease (PD) in it tracks, preventing disease progression and reversing its symptoms. The novelty of the approach lies in the nasal route of administration and nanoparticles containing a gene capable of rescuing dying neurons in the brain. Parkinson’s is a devastating neurodegenerative disorder caused by the death of dopamine neurons in a key motor area of the brain, the substantia nigra (SN). Loss of these neurons leads to the characteristic tremor and slowed movements of PD, which get increasingly worse with time. Currently, more than 1% of the population over age 60 has PD and approximately 60,000 Americans are newly diagnosed every year. The available drugs on the market for PD mimic or replace the lost dopamine but do not get to the heart of the problem, which is the progressive loss of the dopamine neurons.
The focus of Dr. Barbara Waszczak’s lab at Northeastern University in Boston is to find a way to harvest the potential of glial cell line-derived neurotrophic factor (GDNF) as a treatment for PD. GDNF is a protein known to nourish dopamine neurons by activating survival and growth-promoting pathways inside the cells. Not surprisingly, GDNF is able to protect dopamine neurons from injury and restore the function of damaged and dying neurons in many animal models of PD. However, the action of GDNF is limited by its inability to cross the blood-brain barrier (BBB), thus requiring direct surgical injection into the brain. To circumvent this problem, Waszczak’s lab is investigating intranasal delivery as a way to bypass the BBB. Their previous work showed that intranasal delivery of GDNF protects dopamine neurons from damage by the neurotoxin, 6-hydroxydopamine (6-OHDA), a standard rat model of PD.
Taking this work a step further, Brendan Harmon, working in Waszczak’s lab, has adapted the intranasal approach so that cells in the brain can continuously produce GDNF. His work utilized nanoparticles, developed by Copernicus Therapeutics, Inc., which are able to transfect brain cells with an expression plasmid carrying the gene for GDNF (pGDNF). When given intranasally to rats, these pGDNF nanoparticles increase GDNF production throughout the brain for long periods, avoiding the need for frequent re-dosing. Now, in new research presented on April 20 at 12:30 pm during Experimental Biology 2013 in Boston, MA, Harmon reports that intranasal administration of Copernicus’ pGDNF nanoparticles results in GDNF expression sufficient to protect SN dopamine neurons in the 6-OHDA model of PD.
Waszczak and Harmon believe that intranasal delivery of Copernicus’ nanoparticles may provide an effective and non-invasive means of GDNF gene therapy for PD, and an avenue for transporting other gene therapy vectors to the brain. This work, which was funded in part by the Michael J. Fox Foundation for Parkinson’s Research and Northeastern University, has the potential to greatly expand treatment options for PD and many other central nervous system disorders.
(Source: eurekalert.org)