Posts tagged psychology

ScienceDaily (Mar. 1, 2012) — Down syndrome (DS) is the most common genetic disorder in live born children arising as a consequence of a chromosomal abnormality. It occurs as a result of having three copies of chromosome 21, instead of the usual two. It causes substantial physical and behavioral abnormalities, including life-long cognitive dysfunction that can range from mild to severe but which further deteriorates as individuals with DS age.

It is not currently possible to effectively treat the cognitive impairments associated with DS. However, these deficits are an increasing focus of research. In this issue of Biological Psychiatry, researchers at Stanford University, led by Dr. Ahmad Salehi, have published a review which highlights potential strategies for the treatment of these cognitive deficits.

The authors focus on insights emerging from animal models of Down syndrome and outline the structural abnormalities in the DS brain. They also discuss studies that have linked the over-expression of the amyloid precursor protein gene, called APP, to the degeneration of neurons in mice. These findings have led to the development of therapeutic treatments in mice, which now must be tested in humans.

"For more than a decade, we have been working on identifying a strategy to treat cognitive disabilities in our Down syndrome mouse models," said Dr. Salehi. "Considering the research and results with mouse models as an indication of success of a strategy in humans, we are ever closer to finding ways to at least partially restore cognitive function in children and adults with Down syndrome."

Interestingly, this research is also providing insights into Alzheimer’s disease (AD), the archetypal disorder of late life. All adults with Down syndrome develop AD pathology by age 40, and there are some remarkable similarities in the brain degeneration and cognitive dysfunction of individuals with DS and those with AD.

The leading AD hypothesis posits that it is caused by increasingly elevated levels of amyloid-related proteins, which are toxic to nerve cells in the brain. These same proteins also accumulate in the brains of people with DS because they are made by the APP gene, which is located on chromosome 21. Individuals with AD don’t have the extra chromosome, of course; rather, it is mutations in APP that appear to cause the brain degeneration associated with AD.

Dr. John Krystal, editor of Biological Psychiatry, commented: “The convergence of research on Down syndrome and Alzheimer’s disease highlights a central point that cannot be overstated. When we understand the fundamental biology of the brain, important new conceptual bridges emerge that guide new treatment approaches.”

Salehi added, “In the near future, we may very likely look back with the perspective that Down syndrome represents an example of how families of affected individuals came together and by supporting basic research, changed the course of a disorder that was considered untreatable for more than a century.”

Source: Science Daily

ScienceDaily (Mar. 1, 2012) — Despite the promise associated with the therapeutic use of human stem cells, a complete understanding of the mechanisms that control the fundamental question of whether a stem cell becomes a specific cell type within the body or remains a stem cell has-until now-eluded scientists.

A University of Georgia study published in the March 2 edition of the journal Cell Stem Cell, however, creates the first ever blueprint of how stem cells are wired to respond to the external signaling molecules to which they are constantly exposed. The finding, which reconciles years of conflicting results from labs across the world, gives scientists the ability to precisely control the development, or differentiation, of stem cells into specific cell types.

"We can use the information from this study as an instruction book to control the behavior of stem cells," said lead author Stephen Dalton, Georgia Research Alliance Eminent Scholar of Molecular Biology and professor of cellular biology in the UGA Franklin College of Arts and Sciences. "We’ll be able to allow them to differentiate into therapeutic cell types much more efficiently and in a far more controlled manner."

The previous paradigm held that individual signaling molecules acted alone to set off a linear chain of events that control the fate of cells. Dalton’s study, on the other hand, reveals that a complex interplay of several molecules controls the “switch” that determines whether a stem cell stays in its undifferentiated state or goes on to become a specific cell type, such as a heart, brain or pancreatic cell.

"This work addresses one of the biggest challenges in stem cell research-figuring out how to direct a stem cell toward becoming a specific cell type," said Marion Zatz, who oversees stem cell biology grants at the National Institutes of Health’s National Institute of General Medical Sciences, which partially supported the work.

"In this paper, Dr. Dalton puts together several pieces of the puzzle and offers a model for understanding how multiple signaling pathways coordinate to steer a stem cell toward differentiating into a particular type of cell. This framework ultimately should not only advance a fundamental understanding of embryonic development, but facilitate the use of stem cells in regenerative medicine."

To get a sense of how murky the understanding of stem cell differentiation was, consider that previous studies reached opposite conclusions about the role of a common signaling molecule known as Wnt. About half the published studies found that Wnt kept a molecular switch in an “off” position, which kept the stem cell in its undifferentiated, or pluripotent, state. The other half reached the opposite conclusion.

Could the same Wnt molecule be responsible for both outcomes? As it turns out, the answer is yes. Dalton’s team found that in small amounts, Wnt signaling keeps the stem cell in its pluripotent state. In larger quantities, it does the opposite and encourages the cell to differentiate.

But Wnt doesn’t work alone. Other molecules, such as insulin-like growth factor (Igf), fibroblast growth factor (Fgf2) and Activin A also play a role. To complicate things further, these signaling molecules amplify each other so that a two-fold increase in one can result in a 10-fold increase in another. The timing with which the signals are introduced matters, too.

"One of the things that surprised us was how all of the pathways ‘talk’ to each other," Dalton said. "You can’t do anything to the Igf pathway without affecting the Fgf2 pathway, and you can’t do anything to Fgf2 without affecting Wnt. It’s like a house of cards; everything is totally interconnected."

Dalton and his team spent a painstaking five years creating hypotheses about the how the signaling molecules function, testing those hypotheses, and-when faced with an unexpected result-rebuilding their hypotheses and re-testing. This process continued until the entire system was resolved.

Their finding gives scientists a more complete understanding of the first step that stem cells take as they differentiate, and Dalton is confident that the same approach can be used to understand subsequent developmental steps that occur as the cells in an embryo divide into ever-more specific cell types.

"Hopefully this type of approach will give us a greater understanding of cells and how they can be manipulated so that we can progress much more rapidly toward the routine use of stem cells in therapeutic settings," Dalton said.

The research was funded by the National Institute of Child Health and Human Development and the National Institute of General Medical Sciences.

Source: Science Daily

(Medical Xpress) — Researchers from Western University have utilized their own game-changing technology – previously developed for use with patients in a vegetative state – to assess a more prevalent group of brain-injured patients, those in the minimally conscious state (MCS). Their findings were released today in Neurology, the medical journal of the American Academy of Neurology.

The study, led by Adrian Owen, Canada Excellence Research Chair in Cognitive Neuroscience and Imaging, and Damian Cruse of Western’s Brain and Mind Institute, is a follow-up to the team’s groundbreaking Lancet publication from November 2011 that used electroencephalography (EEG) to show that some vegetative state patients were able to reliably follow commands, even though this ability was entirely undetectable from their external behaviour. 

In the new paper, titled “The relationship between aetiology and covert cognition in the minimally-conscious state,” the MCS patients showed some inconsistent but reproducible external signs of awareness, such as being able to follow their eyes in a mirror.  Cruse says, however, that currently very little is known about their ‘internal’ state of awareness that may be hidden from their external behaviour. 

"Using our EEG approach, we found that 22 per cent of 23 MCS patients were able to complete a complex task which required them to imagine particular types of movement," says Cruse, a Post-Doctoral Fellow at the Brain and Mind Institute and the lead writer of the paper. "This tells us that these patients have a much higher level of cognitive ability than what you could detect from their behaviour."

Cruse adds that the cause of the brain injury was a determining factor in finding these cognitive abilities as 33 per cent of traumatically injured patients (e.g. traffic accident, fall) returned positive EEG results compared to zero per cent of non-traumatically injured patients (e.g. heart attack, stroke).

The research team, in collaboration with Steven Laureys at the University of Liège, Belgium, asked patients approximately 100 times each to imagine moving his or her right-hand and toes. By making recordings of the patients’ EEG, a measure of the electrical activity of the brain, the team showed that 22 per cent of the MCS patients were able to produce patterns of brain activity that were indistinguishable from a healthy individual following the same commands. 

"There are a large number of patients in the MCS worldwide, and our approach highlights the importance of using EEG and other forms of brain imaging when assessing the mental capabilities of patients following brain injury," says Cruse "It reinforces our understanding that the externally observable abilities of a patient are not necessarily a true reflection of their internal state."

Provided by University of Western Ontario

Source: medicalxpress.com

A major downside of the medical use of marijuana is the drug’s ill effects on working memory, the ability to transiently hold and process information for reasoning, comprehension and learning. Researchers reporting in the March 2 print issue of the Cell Press journal Cell provide new insight into the source of those memory lapses. The answer comes as quite a surprise: Marijuana’s major psychoactive ingredient (THC) impairs memory independently of its direct effects on neurons. The side effects stem instead from the drug’s action on astroglia, passive support cells long believed to play second fiddle to active neurons.

The findings offer important new insight into the brain and raise the possibility that marijuana’s benefits for the treatment of pain, seizures and otherailments might some day be attained without hurting memory, the researchers say.

With these experiments in mice, “we have found that the starting point for this phenomenon – the effect of marijuana on working memory – is the astroglialcells,” said Giovanni Marsicano of INSERM in France.

"This is the first direct evidence that astrocytes modulate working memory," added Xia Zhang of the University of Ottawa in Canada.

The new findings aren’t the first to suggest astroglia had been given short shrift. Astroglial cells (also known as astrocytes) have been viewed as cells that support, protect and feed neurons for the last 100 to 150 years, Marsicano explained. Over the last decade, evidence has accumulated that these cells play a more active role in forging the connections from one neuron to another.

The researchers didn’t set out to discover how marijuana causes its cognitive side effects. Rather, they wanted to learn why receptors that respond to both THC and signals naturally produced in the brain are found on astroglial cells. These cannabinoid type-1 (CB1R) receptors are very abundant in the brain, primarily on neurons of various types.

Zhang and Marsicano now show that mice lacking CB1Rs only on astroglial cells of the brain are protected from the impairments to spatial working memory that usually follow a dose of THC. In contrast, animals lacking CB1Rs in neurons still suffer the usual lapses. Given that different cell types express different variants of CB1Rs, there might be a way to therapeutically activate the receptors on neurons while leaving the astroglial cells out, Marsicano said.

"The study shows that one of the most common effects of cannabinoid intoxication is due to activation of astroglial CB1Rs," the researchers wrote.

The findings further suggest that astrocytes might be playing unexpected roles in other forms of memory in addition to spatial working memory, Zhang said.

The researchers hope to explore the activities of endogenous endocannabinoids, which naturally trigger CB1Rs, on astroglial and other cells. The endocannabinoid system is involved in appetite, pain, mood, memory and many other functions. “Just about any physiological function you can think of in the body, it’s likely at some point endocannabinoids are involved,” Marsicano said.

And that means an understanding of how those natural signaling molecules act on astroglial and other cells could have a real impact. For instance, Zhang said, “we may find a way to deal with working memory problems in Alzheimer’s.”

Source: medicalxpress.com

Decreased cerebral blood flow (CBF) after psilocybin imaged by fMRI. Regions where there was significantly decreased CBF after psilocybin versus after placebo are shown in blue. No CBF increases in any region were observed. Image Copyright © PNAS, doi:10.1073/pnas.1119598109

(Medical Xpress) — Psychedelic substances have long been used for healing, ceremonial, or mind-altering subjective experiences due to compounds that, when ingested or inhaled, generate hallucinations, perceptual distortions, or altered states of awareness. Of these, the psychedelic substance psilocybin, the prodrug (a precursor of a drug that must in vivo chemical conversion by metabolic processes before becoming an active pharmacological agent) of psilocin (4-hydroxy-dimethyltryptamine) and the key hallucinogen found in so-called magic mushrooms, is widely used not only in healing ceremonies, but, more recently, in psychotherapy as well – but little has been known about its specific activity in the brain.

Recently, however, scientists in the Neuropsychopharmacology Unit at Imperial College London used complementary blood-oxygen level dependent (BOLD) functional MRI, or fMRI, in conjunction with a technique for imaging the transition from normal waking consciousness to the psychedelic state. The study found decreased blood flow and BOLD in the thalamus, anterior and posterior cingulate cortex, and medial prefrontal cortex. The researchers concluded that the surprising results strongly suggest that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain’s key connector hubs, enabling a state of unconstrained cognition.

Lead researcher Dr. Robin L. Carhart-Harris, working in the Neuropsychopharmacology Unit created by Prof. David J. Nutt, recounts the team’s main challenges in establishing an fMRI methodology that would be specific enough to highly correlate neurophysiological activity with the neuronal presence or absence of psilocybin. “There were a number of considerations,” Carhart-Harris tells Medical Xpress. “In terms of experimental design, we had to determine the precise dose and delivery protocol that would be appropriate for obtaining clear fMRI results. “For example,” he explains, “we had to consider temporal dynamics: If the drug was administered orally, the protracted period of time between ingestion, metabolism, and crossing of the blood-brain barrier would fall outside of the short scanning window needed to capture induced brain activity.” They therefore had to rely on intravenous administration.

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ScienceDaily (Feb. 29, 2012) — A repression of gene activity in the brain appears to be an early event affecting people with Alzheimer’s disease, researchers funded by the National Institutes of Health have found. In mouse models of Alzheimer’s disease, this epigenetic blockade and its effects on memory were treatable.

In a mouse model of Alzheimer’s disease (right), HDAC2 levels in the hippocampus are higher than in the normal mouse hippocampus (left). Credit: (Credit: Dr. Li-Huei Tsai, MIT)

"These findings provide a glimpse of the brain shutting down the ability to form new memories gene by gene in Alzheimer’s disease, and offer hope that we may be able to counteract this process," said Roderick Corriveau, Ph.D., a program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research.

The study was led by Li-Huei Tsai, Ph.D., who is director of The Picower Institute for Learning and Memory at the Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute. It was published online February 29 in Nature.

Dr. Tsai and her team found that a protein called histone deacetylase 2 (HDAC2) accumulates in the brain early in the course of Alzheimer’s disease in mouse models and in people with the disease. HDAC2 is known to tighten up spools of DNA, effectively locking down the genes within and reducing their activity, or expression.

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ScienceDaily (Feb. 29, 2012) — In a mouse model of Alzheimer’s disease, memory problems stem from an overactive enzyme that shuts off genes related to neuron communication, a new study says.

When researchers genetically blocked the enzyme, called HDAC2, they ‘reawakened’ some of the neurons and restored the animals’ cognitive function. The results, published February 29, 2012, in the journal Nature, suggest that drugs that inhibit this particular enzyme would make good treatments for some of the most devastating effects of the incurable neurodegenerative disease.

"It’s going to be very important to develop selective chemical inhibitors against HDAC2," says Howard Hughes Medical Institute investigator Li-Huei Tsai, whose team at the Massachusetts Institute of Technology performed the experiments. "If we could delay the cognitive decline by a certain period of time, even six months or a year, that would be very significant."

In every cell, DNA wraps itself around proteins called histones. Chemical groups such as methyl and acetyl can bind to histones and affect DNA expression. HDAC2 is a histone deacetylase, an enzyme that removes acetyl groups from the histone, effectively turning off nearby genes.

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A DRUG which minimises brain damage when given three hours after stroke has proved successful in monkeys and humans.

A lack of oxygen in the brain during a stroke can cause fatal brain damage. There is only one approved treatment - tissue plasminogen activator - but it is most effective when administered within 90 minutes after the onset of stroke. Immediate treatment isn’t always available, however, so drugs that can be given at a later time have been sought.

In a series of experiments, Michael Tymianski and colleagues at Toronto Western Hospital in Ontario, Canada, replicated the effects of stroke in macaques before intravenously administering a PSD-95 inhibitor, or a placebo. PSD-95 inhibitors interfere with the process that triggers cell death when the brain is deprived of oxygen.

To test its effectiveness the team used MRI to measure the volume of damaged brain for 30 days following the treatment, and conducted behavioural tests at various intervals within this time.

Monkeys treated with the PSD-95 inhibitor one hour after stroke had 55 per cent less damaged tissue in the brain after 24 hours and 70 per cent less after 30 days, compared with those that took a placebo. These animals also did better in behavioural tests. Importantly, the drug was also effective three hours after stroke (Nature, DOI: 10.1038/nature10841).

An early stage clinical trial in humans, run by firm NoNO in Ontario has also seen positive results.

Source: New Scientist

ScienceDaily (Feb. 28, 2012) — Slowing or preventing the development of Alzheimer’s disease, a fatal brain condition expected to hit one in 85 people globally by 2050, may be as simple as ensuring a brain protein’s sugar levels are maintained.

Slowing or preventing the development of Alzheimer’s disease, a fatal brain condition expected to hit one in 85 people globally by 2050, may be as simple as ensuring a brain protein’s sugar levels are maintained. (Credit: © ktsdesign / Fotolia)

That’s the conclusion seven researchers, including David Vocadlo, a Simon Fraser University chemistry professor and Canada Research Chair in Chemical Glycobiology, make in the latest issue of Nature Chemical Biology.

The journal has published the researchers’ latest paper “Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation.”

Vocadlo and his colleagues describe how they’ve used an inhibitor they’ve chemically created — Thiamet-G — to stop O-GlcNAcase, a naturally occurring enzyme, from depleting the protein Tau of sugar molecules.

"The general thinking in science," says Vocadlo, "is that Tau stabilizes structures in the brain called microtubules. They are kind of like highways inside cells that allow cells to move things around."

Previous research has shown that the linkage of these sugar molecules to proteins, like Tau, in cells is essential. In fact, says Vocadlo, researchers have tried but failed to rear mice that don’t have these sugar molecules attached to proteins.

Vocadlo, an accomplished chess player in his spare time, is having great success checkmating troublesome enzymes with inhibitors he and his students are creating in the SFU chemistry department’s Laboratory of Chemical Glycobiology.

Research prior to Vocadlo’s has shown that clumps of Tau from an Alzheimer brain have almost none of this sugar attached to them, and O-GlcNAcase is the enzyme that is robbing them.

Such clumping is an early event in the development of Alzheimer’s and the number of clumps correlate with the disease’s severity.

Scott Yuzwa and Xiaoyang Shan, grad students in Vocadlo’s lab, found that Thiamet-G blocks O-GlcNAcase from removing sugars off Tau in mice that drank water with a daily dose of the inhibitor. Yuzwa and Shan are co-first authors on this paper.

The research team found that mice given the inhibitor had fewer clumps of Tau and maintained healthier brains.

"This work shows targeting the enzyme O-GlcNAcase with inhibitors is a new potential approach to treating Alzheimer’s," says Vocadlo. "This is vital since to date there are no treatments to slow its progression.

"A lot of effort is needed to tackle this disease and different approaches should be pursued to maximize the chance of successfully fighting it. In the short term, we need to develop better inhibitors of the enzyme and test them in mice. Once we have better inhibitors, they can be clinically tested.

Source: Science Daily

Yale University researchers have discovered a key cellular mechanism that may help the brain control how much we eat, what we weigh, and how much energy we have.

The findings, published in the Feb. 28 issue of the Journal of Neuroscience, describe the regulation of a family of cells that project throughout the nervous system and originate in an area of the brain call the hypothalamus, which has been long known to control energy balances.

Scientists and pharmaceutical companies are closely investigating the role of melanin-concentrating hormone (MCH) neurons in controlling food intake and energy. Previous studies have shown that MCH makes lab animals eat more, sleep more, and have less energy. In contrast, other hypothalamic neurons use the thyrotropin-releasing hormone (TRH) as a neurotransmitter, and these neurons reduce food intake and body weight, and increase physical activity.

The Yale study of brains of mice shows that the two systems appear to act in direct opposition, to help the organism keep these crucial functions in balance.

Although TRH is normally an excitatory neurotransmitter, the Yale study shows that in mice TRH inhibits MCH cells by increasing inhibitory synaptic input. In contrast, TRH had little effect on other types of neurons also involved in energy regulation.

“That these two types of neurons interact at the synaptic level gives us clues as to how the brain controls the amount of food we eat, and how much we sleep,” said Anthony van den Pol, senior author and professor of neurosurgery at Yale School of Medicine.

Three MCH neurons in the hypothalamus region of a mouse brain are highlighted in green. In animals, these neurons are associated with high calorie intake and lower energy levels. Yale researchers have shown how the effects of these key cells are reversed. Image adapted from Yale press release image.

Source: Neuroscience News