Posts tagged animal studies

Xanthohumol, a type of flavonoid found in hops and beer, has been shown in a new study to improve cognitive function in young mice, but not in older animals.

The research was just published in Behavioral Brain Research by scientists from the Linus Pauling Institute and College of Veterinary Medicine at Oregon State University. It’s another step toward understanding, and ultimately reducing the degradation of memory that happens with age in many mammalian species, including humans.

Flavonoids are compounds found in plants that often give them their color. The study of them – whether in blueberries, dark chocolate or red wine - has increased in recent years due to their apparent nutritional benefits, on issues ranging from cancer to inflammation or cardiovascular disease. Several have also been shown to be important in cognition.

Xanthohumol has been of particular interest because of possible value in treating metabolic syndrome, a condition associated with obesity, high blood pressure and other concerns, including age-related deficits in memory. The compound has been used successfully to lower body weight and blood sugar in a rat model of obesity.

The new research studied use of xanthohumol in high dosages, far beyond what could be obtained just by diet. At least in young animals, it appeared to enhance their ability to adapt to changes in the environment. This cognitive flexibility was tested with a special type of maze designed for that purpose.

“Our goal was to determine whether xanthohumol could affect a process we call palmitoylation, which is a normal biological process but in older animals may become harmful,” said Daniel Zamzow, a former OSU doctoral student and now a lecturer at the University of Wisconsin/Rock County.

“Xanthohumol can speed the metabolism, reduce fatty acids in the liver and, at least with young mice, appeared to improve their cognitive flexibility, or higher level thinking,” Zamzow said. “Unfortunately it did not reduce palmitoylation in older mice, or improve their learning or cognitive performance, at least in the amounts of the compound we gave them.”

Kathy Magnusson, a professor in the OSU Department of Biomedical Sciences, principal investigator with the Linus Pauling Institute and corresponding author on this study, said that xanthohumol continues to be of significant interest for its biological properties, as are many other flavonoids.

“This flavonoid and others may have a function in the optimal ability to form memories,” Magnusson said. “Part of what this study seems to be suggesting is that it’s important to begin early in life to gain the full benefits of healthy nutrition.”

It’s also important to note, Magnusson said, that the levels of xanthohumol used in this study were only possible with supplements. As a fairly rare micronutrient, the only normal dietary source of it would be through the hops used in making beer, and “a human would have to drink 2000 liters of beer a day to reach the xanthohumol levels we used in this research.”

In this and other research, Magnusson’s research has primarily focused on two subunits of the NMDA receptor, called GluN1 and GluN2B. Their decline with age appears to be related to the decreased ability to form and quickly recall memories.

In humans, many adults start to experience deficits in memory around the age of 50, and some aspects of cognition begin to decline around age 40, the researchers noted in their report.

(Source: oregonstate.edu)

Now, an international team of pain researchers led by scientists at McGill University in Montreal may have uncovered one important factor behind this vexing problem: the gender of the experimenters has a big impact on the stress levels of rodents, which are widely used in preclinical studies.

In research published online April 28 in Nature Methods, the scientists report that the presence of male experimenters produced a stress response in mice and rats equivalent to that caused by restraining the rodents for 15 minutes in a tube or forcing them to swim for three minutes. This stress-induced reaction made mice and rats of both sexes less sensitive to pain.

Female experimenters produced no such effects.

“Scientists whisper to each other at conferences that their rodent research subjects appear to be aware of their presence, and that this might affect the results of experiments, but this has never been directly demonstrated until now,” says Jeffrey Mogil, a psychology professor at McGill and senior author of the paper.

The research team, which included pain experts from Haverford College and the Karolinska Institutet in Sweden and a chemosensory expert from Université de Montreal, found that the effect of male experimenters on the rodents’ stress levels was due to smell. This was shown by placing cotton T shirts, worn the previous night by male or female experimenters, alongside the mice; the effects were identical to those caused by the presence of the experimenters, themselves.

Further experiments proved that the effects were caused by chemosignals, or pheromones, that men secrete from the armpit at higher concentrations than women. These chemosignals signal to rodents the presence of nearby male animals. (All mammals share the same chemosignals).

These effects are not limited to pain. The researchers found that other behavioural assays sensitive to stress were affected by male but not female experimenters or T-shirts.

“Our findings suggest that one major reason for lack of replication of animal studies is the gender of the experimenter – a factor that’s not currently stated in the methods sections of published papers,” says Robert Sorge, a psychology professor at the University of Alabama, Birmingham. Sorge led the study as a postdoctoral fellow at McGill.

The good news, Mogil says, is that “the problem is easily solved by simple changes to experimental procedures. For example, since the effect of males’ presence diminishes over time, the male experimenter can stay in the room with the animals before starting testing.  At the very least, published papers should state the gender of the experimenter who performed the behavioral testing.”

(Source: mcgill.ca)

Research released today reveals a new model for a genetic eye disease, and shows how animal models — from fruit flies to armadillos and monkeys — can yield valuable information about the human brain. The findings were presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.

Animal models have long been central in how we understand the human brain, behavior, and nervous system due to similarities in many brain areas and functions across species. Almost every major medical advance in the last century was made possible by carefully regulated, humane animal research. Today’s findings build on this rich history and demonstrate what animals can teach us about ourselves.

Today’s new findings show that:

• The nine-banded armadillo may serve as a model for certain types of progressive blindness. The animal’s poor eyesight mimics many human disorders and may shed light on new treatment approaches for such diseases (Christopher Emerling, BS, abstract 150.06, see attached summary).
• Analysis of a baboon population reveals particular genes that may be involved in creating the “folds” in the structure of the brain. These findings provide information on how human genes may have evolved to create the brain’s shape and function (Elizabeth Atkinson, BA, abstract 195.13, see attached summary).
• Monkeys and humans use similar brain pathways while processing decisions. Detailed analyses of similarities and differences in brain wiring could provide new insights into decision-making in humans (Franz-Xaver Neubert, abstract 18.03, see attached summary).

Other recent findings discussed show that:

• Use of powerful genetic tools in fruit flies is helping to reveal the basic building blocks of brain circuitry and function. This work is furthering our understanding of the human brain and may be helpful in developing medical diagnostic devices (Rachel Wilson, PhD, presentation 302, see attached speaker summary).
• Research in a tiny worm (C. elegans) has allowed scientists to map all of the connections between neurons in the species, including the pathways for movement, sex, and more. The findings offer new insights into how the human nervous system functions (Scott Emmons, PhD, presentation 009, see attached speaker summary).

“Neuroscience has always relied on responsible animal research to better understand how our brains and bodies develop, function, and break down,” said press conference moderator Leslie Tolbert, of the University of Arizona, whose work in insects provides insights into brain development. “Today’s studies reveal new ways that research on unlikely-seeming animals, such as armadillos, fruit flies, and worms, could have real impact on our understanding of the human brain and what can go wrong in disease.”

New human and animal research released today demonstrates how experiences impact genes that influence behavior and health. Today’s studies, presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health, provide new insights into how experience might produce long-term brain changes in behaviors like drug addiction and memory formation.

The studies focus on an area of research called epigenetics, in which the environment and experiences can turn genes “on” or “off,” while keeping underlying DNA intact. These changes affect normal brain processes, such as development or memory, and abnormal brain processes, such as depression, drug dependence, and other psychiatric disease — and can pass down to subsequent generations.

Today’s new findings show that:

• Long-term heroin abusers show differences in small chemical modifications of their DNA and the histone proteins attached to it, compared to non-abusers. These differences could account for some of the changes in DNA/histone structures that develop during addiction, suggesting a potential biological difference driving long-term abuse versus overdose (Yasmin Hurd, abstract 257.2, see attached summary).
• Male rats exposed to cocaine may pass epigenetic changes on to their male offspring, thereby altering the next generation’s response to the drug. Researchers found that male offspring in particular responded much less to the drug’s influence (Matheiu Wimmer, PhD, abstract 449.19, see attached summary).
• Drug addiction can remodel mouse DNA and chromosomal material in predictable ways, leaving “signatures,” or signs of the remodeling, over time. A better understanding of these signatures could be used to diagnose drug addiction in humans (Eric Nestler, PhD, abstract 59.02, see attached summary).

Other recent findings discussed show that:

• Researchers have identified a potentially new genetic mechanism, called piRNA, underlying long-term memory. Molecules of piRNA were previously thought to be restricted to egg and sperm cells (Eric Kandel, MD, see attached summary).
• Epigenetic DNA remodeling is important for forming memories. Blocking this process causes memory deficits and stunts brain cell structure, suggesting a mechanism for some types of intellectual disability (Marcelo Wood, PhD, see attached summary).

"DNA may shape who we are, but we also shape our own DNA," said press conference moderator Schahram Akbarian, of the Icahn School of Medicine at Mount Sinai, an expert in epigenetics. "These findings show how experiences like learning or drug exposure change the way genes are expressed, and could be incredibly important in developing treatments for addiction and for understanding processes like memory."

(Source: eurekalert.org)

Clinical trials of drug treatments for neurological diseases such as Alzheimer’s and Parkinson’s often fail because the animal studies that preceded them were poorly designed or biased in their interpretation, according to a new study from an international team of researchers. More stringent requirements are needed to assess the significance of animal studies before testing the treatments in human patients, the researchers say.

The team — led by John Ioannidis, MD, DSc, a professor of medicine at the Stanford University School of Medicine and an expert in clinical trial design — assessed the results of more than 4,000 animal studies in 160 meta-analyses of potential treatments for neurological disorders from Alzheimer’s disease, Parkinson’s disease, stroke, spinal-cord injury and a form of multiple sclerosis. (A meta-analysis is a study that compiles and assesses information and conclusions from many independent experiments of a treatment, or intervention, for a particular condition.).

They determined that only eight of the 160 studies of potential treatments yielded the statistically significant, unbiased data necessary to support advancing the treatment to clinical trials. In contrast, 108 of the treatments were deemed at least somewhat effective at the time they were published.

Ioannidis and his collaborators at the University of Edinburgh in Scotland and the University of Ioannina School of Medicine in Greece say that animal studies of potential interventions can be made more efficient and reliable by increasing average sample size, being aware of statistical bias, publishing negative results and making all the results of all experiments on the effectiveness of a particular treatment — regardless of their outcome — freely accessible to scientists.

"Some researchers have postulated that animals may not be good models for human diseases," said Ioannidis. "I don’t agree. I think animal studies can be useful and perfectly fine. The problem is more likely to be related to the selective availability of information about the studies conducted on animals." Although the researchers focused here on neurological disorders, they believe it is likely that similar bias exists in animal studies of other types of disorders.

Ioannidis, who directs the Stanford Prevention Research Center, is the senior author of the research, published online in PLoS Biology on July 16. Lecturer Konstantinos Tsilidis, PhD, and postgraduate fellow Orestis Panagiotou, MD, of the University of Ioannina share lead authorship of the study. Panagiotou is currently a researcher at the National Cancer Institute’s Division of Cancer Epidemiology and Genetics.

Ioannidis is known for his efforts to strengthen the way that research is planned, carried out and reported. He was called “one of the world’s foremost experts on the credibility of medical research” in a profile published in The Atlantic magazine in 2010. He outlined some of the problems he observed in a 2005 essay in PLoS-Medicine titled, “Why most published research findings are false.” The essay is one of the most-downloaded articles in the history of the Public Library of Science, according to the journal’s media relations office.

For the new study, Ioannidis and his colleagues evaluated results in a database of the thousands of animal studies compiled over the years through the CAMARADES initiative (Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies), led by professor Malcolm MacLeod, PhD, from the University of Edinburgh, who is also a co-author of the study.

The team compared the number of experiments in the meta-analyses that would have been expected to yield positive results (based on their predicted statistical power) with the actual number of experiments with published positive results. The difference was striking: 919 expected versus the 1,719 that were published, implying that either negative results were not published, or that the results of the experiments were interpreted too optimistically.

"We saw that it was very common for these interventions to have published evidence that they would work," said Ioannidis. "It was extremely common to have results that suggest they would be effective in humans."

Furthermore, nearly half (46 percent) of the 160 meta-analyses showed evidence of small-study effects — a term used to describe the fact that a small study using fewer numbers of animals is more likely to find the intervention more effective than a larger study with many animals.

Ioannidis speculated that a reluctance to publish negative findings (that is, those that conclude that a particular intervention did not work any better than the control treatment) and a perhaps unconscious desire on the part of researchers to find a promising treatment has colored the field of neurological research. Obscuring access to studies that conclude a particular treatment is ineffective, while also publishing positive results that are likely to be statistically flawed, tilts the perception toward the potential effectiveness of an intervention and encourages unwarranted human clinical trials.

"There are no standard rules that guide a decision to move from animal studies into human clinical trials," said Ioannidis, who also holds C.F. Rehnborg Professorship at Stanford. "Sometimes interventions are tested in humans with very little evidence that they may be effective. Of the 160 analyses we studied, only eight had what we would call strong evidence of potential effectiveness with no hint of bias in the preliminary animal studies. And of these eight, only two have given positive results in humans."

Ioannidis believes the development of consortiums of groups of researchers studying a particular intervention, coupled with the free sharing of all data about its effectiveness, or lack thereof, is a good first step in reducing bias in animal studies.

"Under the current conditions, only a tiny proportion of interventions that have published some promising results in animals have shown to be at all effective in humans. For example, while dozens of treatments on ischemic or hemorrhagic stroke seem to work in the animal literature, almost none of them have worked in humans," said Ioannidis. "It is hard to believe we could not improve upon that translation record. If we raise the bar for moving into human trials, centralize researchers’ efforts and make all results available, it will be much easier for researchers to know whether they have a potential winner, and it would increase the efficiency of human clinical trials enormously."

(Source: med.stanford.edu)

New research has questioned the reliability of neuroscience studies, saying that conclusions could be misleading due to small sample sizes.

A team led by academics from the University of Bristol reviewed 48 articles on neuroscience meta-analysis which were published in 2011 and concluded that most had an average power of around 20 per cent – a finding which means the chance of the average study discovering the effect being investigated is only one in five.

The paper, being published in Nature Reviews Neuroscience, reveals that small, low-powered studies are ‘endemic’ in neuroscience, producing unreliable research which is inefficient and wasteful.

It focuses on how low statistical power – caused by low sample size of studies, small effects being investigated, or both – can be misleading and produce more false scientific claims than high-powered studies.

It also illustrates how low power reduces a study’s ability to detect any effects and shows that when discoveries are claimed, they are more likely to be false or misleading.

The paper claims there is substantial evidence that a large proportion of research published in scientific literature may be unreliable as a consequence.

Another consequence is that the findings are overestimated because smaller studies consistently give more positive results than larger studies. This was found to be the case for studies using a diverse range of methods, including brain imaging, genetics and animal studies.

Kate Button, from the School of Social and Community Medicine, and Marcus Munafò, from the School of Experimental Psychology, led a team of researchers from Stanford University, the University of Virginia and the University of Oxford.

She said: “There’s a lot of interest at the moment in improving the reliability of science. We looked at neuroscience literature and found that, on average, studies had only around a 20 per cent chance of detecting the effects they were investigating, even if the effects are real. This has two important implications - many studies lack the ability to give definitive answers to the questions they are testing, and many claimed findings are likely to be incorrect or unreliable.”

The study concludes that improving the standard of results in neuroscience, and enabling them to be more easily reproduced, is a key priority and requires attention to well-established methodological principles.

It recommends that existing scientific practices can be improved with small changes or additions to methodologies, such as acknowledging any limitations in the interpretation of results; disclosing methods and findings transparently; and working collaboratively to increase the total sample size and power.

(Source: bristol.ac.uk)