Neuroscience

Researchers at Newcastle University have revealed the mechanism by which neurons, the nerve cells in the brain and other parts of the body, age.

The research, published in Aging Cell, opens up new avenues of understanding for conditions where the ageing of neurons are known to be responsible, such as dementia and Parkinson’s disease.

The ageing process has its roots deep within the cells and molecules that make up our bodies. Experts have previously identified the molecular pathway that react to cell damage and stems the cell’s ability to divide, known as cell senescence.

However, in cells that do not have this ability to divide, such as neurons in the brain and elsewhere, little was understood of the ageing process. Now a team of scientists at Newcastle University, led by Professor Thomas von Zglinicki have shown that these cells follow the same pathway.

This challenges previous assumptions on cell senescence and opens new areas to explore in terms of treatments for conditions such as dementia, motor neuron disease or age-related hearing loss.

Newcastle University’s Professor Thomas von Zglinicki who led the research said: “We want to continue our work looking at the pathways in human brains as this study provides us with a new concept as to how damage can spread from the first affected area to the whole brain.”

Working with the University’s special colony of aged mice, the scientists have discovered that ageing in neurons follows exactly the same rules as in senescing fibroblasts, the cells which divide in the skin to repair wounds.

DNA damage responses essentially re-program senescent fibroblasts to produce and secrete a host of dangerous substances including oxygen free radicals or reactive oxygen species (ROS) and pro-inflammatory signalling molecules. This makes senescent cells the ‘rotten apple in a basket’ that can damage and spoil the intact cells in their neighbourhood.  However, so far it was always thought that ageing in cells that can’t divide - post-mitotic, non-proliferating cells - like neurons would follow a completely different pathway.

Now, this research explains that in fact ageing in neurons follows exactly the same rules as in senescing fibroblasts.

Professor von Zglinicki, professor of Cellular Gerontology at Newcastle University said: “We will now need to find out whether the same mechanisms we detected in mouse brains are also associated with brain ageing and cognitive loss in humans. We might have opened up a short-cut towards understanding brain ageing, should that be the case.”

Dr Diana Jurk, who did most of this work during her PhD in the von Zglinicki group, said: “It was absolutely fascinating to see how ageing processes that we always thought of as completely separate turned out to be identical.  Suddenly so much disparate knowledge came together and made sense.”

Non-smokers who live with or spend time with smokers are damaging their memory, according to new research from Northumbria University. 

The findings, published in the latest online edition of the journal Addiction is the first study to explore the relationship between exposure to other people’s smoke and everyday memory problems.

Dr Tom Heffernan and Dr Terence O’Neil, both researchers at the Collaboration for Drug and Alcohol Research Group at Northumbria University, compared a group of current smokers with two groups of non-smokers – those who were regularly exposed to second-hand smoke and those who were not.

Those exposed to second-hand smoke either lived with smokers or spent time with smokers, for example in a designated “smoking area,” and reported being exposed to second-hand smoke for an average of 25 hours a week for an average of four and a half years.

The three groups were tested on time-based memory (remembering to carry out an activity after some time) and event-based memory (which refers to memory for future intentions and activities).

Researchers found that the non-smokers who had been exposed to second-hand smoke forgot almost 20% more in the memory tests than those non-smokers not exposed. However, both groups out-performed the current smokers who forgot 30% more than those who were not exposed to second-hand smoking.

Dr Heffernan said: “According to recent reports by the World Health Organisation, exposure to second-hand smoke can have serious consequences on the health of people who have never smoked themselves, but who are exposed to other people’s tobacco smoke.

“Our findings suggest that the deficits associated with second-hand smoke exposure extend to everyday cognitive function. We hope our work will stimulate further research in the field in order to gain a better understanding of the links between exposure to second-hand smoke, health problems and everyday cognitive function.”

Researchers from the University of Utah have gained new insight into the regulation of adult nerve cell generation in the hypothalamus, the part of the brain that regulates many aspects of behavior, mood, and metabolism. In the Sept. 10, 2012, issue of Developmental Cell they report that a cell-to-cell communication network known as the Wnt signaling pathway plays an important role in both the production and specialization of nerve cell precursors in the hypothalamus.

The hypothalamus is a highly complex region of the brain that controls hunger, thirst, fatigue, body temperature, and sleep. It also links the central nervous system to the body system that regulates hormone levels. Recent studies have shown that the hypothalamus is one of the parts of the brain in which neurogenesis, the birth of new nerve cells, continues throughout adulthood.

“In our earlier work, we discovered that Wnt signaling was required for neurogenesis in the embryonic zebrafish hypothalamus,” says Richard Dorsky, Ph.D., associate professor of neurobiology and anatomy at the University of Utah School of Medicine and senior author on the study. “We also found that, in zebrafish, both Wnt signaling and hypothalamic neurogenesis continue into adulthood. The goal of this study was to define specific roles for Wnt signaling in neurogenesis.”

The Wnt signaling pathway is a network of proteins that transmits signals from the cell surface to DNA in the cell nucleus to regulate gene expression, and it is known to play a critical role in cell-to-cell communication in both embryos and adults. In this study, Dorsky and his colleagues demonstrated that in zebrafish embryos Wnt signaling is present in progenitor cells that are actively multiplying in the hypothalamus. Progenitor cells have the potential to divide and differentiate into a variety of specialized cell types. Dorsky and his colleagues also found that Wnt signaling continues to be required for hypothalamic neurogenesis throughout life.

Neural progenitor cells arise from neural stem cells, and retain the capacity to develop into more specialized types of nerve cells. After the embryo is formed, some neural stem cells lie dormant in the brain and spinal cord until they are activated to serve as a repair system. When tissue damage or death occurs, chemical substances trigger these neural stem cells to make neural progenitor cells that assist in tissue recovery. Recent research suggests that other neural progenitor cells continue to make new nerve cells in the uninjured brain and contribute to the plasticity of the brain in response to changes in the environment.

“From a functional standpoint, it is not yet clear why the ability to continuously produce hypothalamic nerve cells is important in adult zebrafish,” says Dorsky. “However, in adult mice, hypothalamic neurogenesis seems to be significant in the regulation of feeding behaviors due to environmental changes.”

Dorsky and his colleagues discovered that the role of the Wnt signaling pathway differs between embryos and adults. In zebrafish embryos, activation of Wnt signaling is required for proliferation of progenitor cells contributing to growth of brain structures. However, at later stages of development including adulthood, Wnt signaling must be active for neural progenitor cells to commit to becoming nerve cells, but then must be inhibited for these cells to complete the differentiation process. Significantly, Dorsky and his colleagues also found that mice displayed a similar pattern of Wnt activity.

“Compared to other regions of the brain, the hypothalamus is relatively unstudied as a model of post-embryonic neurogenesis,” says Dorsky. “Our research represents a significant contribution to the field because it establishes the vertebrate hypothalamus as a model of Wnt-regulated neural progenitor differentiation that can be used to shed light on the plasticity of the adult brain.”

A computer is being taught to interpret human emotions based on lip pattern, according to research published in the International Journal of Artificial Intelligence and Soft Computing. The system could improve the way we interact with computers and perhaps allow disabled people to use computer-based communications devices, such as voice synthesizers, more effectively and more efficiently.

Karthigayan Muthukaruppanof Manipal International University in Selangor, Malaysia, and co-workers have developed a system using a genetic algorithm that gets better and better with each iteration to match irregular ellipse fitting equations to the shape of the human mouth displaying different emotions. They have used photos of individuals from South-East Asia and Japan to train a computer to recognize the six commonly accepted human emotions - happiness, sadness, fear, angry, disgust, surprise - and a neutral expression. The upper and lower lip is each analyzed as two separate ellipses by the algorithm.

"In recent years, there has been a growing interest in improving all aspects of interaction between humans and computers especially in the area of human emotion recognition by observing facial expression," the team explains. Earlier researchers have developed an understanding that allows emotion to be recreated by manipulating a representation of the human face on a computer screen. Such research is currently informing the development of more realistic animated actors and even the behavior of robots. However, the inverse process in which a computer recognizes the emotion behind a real human face is still a difficult problem to tackle.

It is well known that many deeper emotions are betrayed by more than movements of the mouth. A genuine smile for instance involves flexing of muscles around the eyes and eyebrow movements are almost universally essential to the subconscious interpretation of a person’s feelings. However, the lips remain a crucial part of the outward expression of emotion. The team’s algorithm can successfully classify the seven emotions and a neutral expression described.

The researchers suggest that initial applications of such an emotion detector might be helping disabled patients lacking speech to interact more effectively with computer-based communication devices, for instance.

Executive function tests key to early detection of Alzheimer’s, Concordia study shows

By the time older adults are diagnosed with Alzheimer’s disease, the brain damage is irreparable. For now, modern medicine is able to slow the progression of the disease but is incapable of reversing it. What if there was a way to detect if someone is on the path to Alzheimer’s before substantial and non-reversible brain damage sets in?

This was the question Erin K. Johns, a doctoral student in Concordia University’s Department of Psychology and member of the Center for Research in Human Development (CRDH), asked when she started her research on older adults with mild cognitive impairment (MCI). These adults show slight impairments in memory, as well as in “executive functions” like attention, planning, and problem solving. While the impairments are mild, adults with MCI have a high risk of developing Alzheimer’s disease.

“We wanted to help provide more reliable tools to identify people who are at increased risk for developing Alzheimer’s so that they can be targeted for preventive strategies that would stop brain damage from progressing,” says Johns.

The new study was published in the Journal of the International Neuropsychological Society and was funded by the Quebec Network for Research on Aging and the Canadian Institutes of Health Research. In it, Johns and her colleagues found that people with MCI are impaired in several aspects of executive functioning, the biggest being inhibitory control. 

This ability is crucial for self-control: everything from resisting buying a candy bar at the checkout aisle to resisting the urge to mention the obvious weight gain in a relative you haven’t seen in a while. Adults with MCI also had trouble with tests that measure the ability to plan and organize.

Johns and her colleagues found that all the adults with MCI they tested were impaired in at least one executive function and almost half performed poorly in all the executive function tests. This is in sharp contrast with standard screening tests and clinical interviews, which detected impairments in only 15 percent of those with MCI.

“The problem is that patients and their families have difficulty reporting executive functioning problems to their physician, because they may not have a good understanding of what these problems look like in their everyday life.” says Johns. “That’s why neuropsychological testing is important.”

Executive function deficits affect a person’s everyday life and their ability to plan and organize their activities. Even something as easy as running errands and figuring out whether to go to the drycleaners or to the supermarket can be difficult for adults with MCI. Detecting these problems early could improve patient care and treatment planning.

“If we miss the deficits, we miss out on an opportunity to intervene with the patient and the family to help them know what to expect and how to cope,” says Johns. She is now conducting a follow-up study funded by the Alzheimer Society of Canada and Canadian Institutes of Health Research, along with her supervisor, Natalie Phillips, associate professor in the Department of Psychology and member of CRDH.

Johns hopes her continued research will lead to a better understanding of why these deficits start at such an early stage of Alzheimer’s and what other tools could be used for earlier detection of the disease.

Washington State University researchers have found a cellular mechanism that contributes to the lack of motivation and negative emotions of a cocaine addict going through withdrawal. Their discovery, published in the latest Proceedings of the National Academy of Sciences, offers a deeper look into the cellular and behavioral implications of addiction.

Bradley Winters, lead author of the PNAS paper and a freshly minted WSU doctor of neuroscience, says he, his major advisor Yan Dong, and colleagues at WSU, the University of Pittsburgh and the European Neuroscience Institute focused on cells that produce a signaling molecule called cannabinoid receptor 1, or CB1. Its main function is regulating the communication between nerve cells related to the functions like memory, motor control, perception, mood and appetite. Those same functions are affected by THC, the cannabinoid in its namesake cannabis, or marijuana.

"These receptors are not here just to make marijuana fun,” says Winters. "Their main function is changes in how nerve cells communicate with each other.”

The researchers studied the CB1 cells by producing a line of mice in which the cells that make CB1 were labeled fluorescently. The researchers could then identify the cells and target them with glass pipettes 1/100th the width of a human hair and record electrical currents they use to communicate with other nerve cells.

The CB1 cells act like brakes, slowing down activity in a brain region called the nucleus accumbens, which governs emotion and motivation.

"Cocaine causes profound cellular changes in the nucleus accumbens, but no one has ever looked at this type of cell, and these cells are important because they help organize the output,” says Winters.

The researchers found that cocaine increases the excitability of the CB1 cells, in effect stepping on the brakes of emotion and motivation. When an addict is high on cocaine, the brakes are struggling to slow things down. The problem is, they stay on even when the cocaine has worn off.

"As you do cocaine, it speeds everything up, pushing you to a highly rewarding emotional state,” says Winters. "It is kind of like going down a steep hill so you have to start riding that brake really hard. But then after the cocaine wears off and the hill levels out, you’re still riding that brake just as hard. Now you’re going down a regular, low-grade hill but you’re going 2 mph because your foot is still jammed on the brake.”

The result is a drag on the emotions and motivation of an addict in withdrawal—a drag that could be linked to sluggish activation of the nucleus accumbens.

"That state is like, ‘I feel terrible and I don’t want to do anything,’” says Winters. "You have the high and the crashing low and this low that you feel is what brings you back to the drug because you want to feel better and the drug is the only thing you feel motivation for.”

Muscles that burn energy without contracting have yielded new clues about how the body retains a constant temperature – and they may provide new targets for combating obesity.

Traditionally, the body’s main thermostat was thought to be brown fat. It raids the body’s white fat stores in cold conditions to burn energy and keep the body warm.

Muscles also play a role in keeping the body warm by contracting and triggering the shiver response – but this is only a short-term fix because prolonged shivering damages muscles. Now it seems that muscles have another way to turn up the heat.

"Our findings demonstrate for the first time that muscle, which accounts for 40 per cent of body weight in humans, can generate heat independent of shivering," says Muthu Periasamy of Ohio State University in Columbus.

Sarcolipin: idle body’s thermostat (Image: David Trood/Stone/Getty)

Surviving the chill

Through experiments on mice that had their usual thermostat – brown fat – surgically removed, Periasamy and his colleagues proved that a protein called sarcolipin helps muscle cells keep the body warm by burning energy, almost like an idling motor car, even if the muscles do not contract.

All of the mice had their brown fat removed, but some of them had been genetically engineered to lack sarcolipin too. These rodents could not survive when held at 4 °C, and died of hypothermia within 10 hours. By contrast, mice that could make sarcolipin were able to survive the chilly temperatures and maintained their core body temperature – despite having no brown fat.

Periasamy also showed that an inability to make sarcolipin made mice 33 per cent heavier than normal when fed a high-fat diet. This suggests that idling muscles might also help combat obesity by burning off excess energy. The search is now on for drugs that perform the same role, triggering idling muscles to burn off excess fat.

"The most interesting finding is that mice unable to make sarcolipin are more susceptible to obesity," says Andy Whittle of the University of Cambridge, who is testing spicy dietary treatments to ramp up the fat-burning activity of brown fat. "The research demonstrates that muscle is an important component even in mice, which have comparatively more brown fat than humans. In humans, burning fat in muscle is likely to be even more important for proper energy balance."

This week, a strategic roadmap to help to the nation’s health care system cope with the impending public health crisis caused Alzheimer’s disease and related dementia will be published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. The plan aims to link the latest scientific findings with clinical care and bring together patients, families, scientists, pharmaceutical companies, regulatory agencies, and advocacy organizations behind a common set of prioritized goals. The consensus document is the outcome of a June meeting of leading Alzheimer’s researchers, advocates and clinicians, who gathered as part of the Marian S. Ware Alzheimer Program at the University of Pennsylvania.

Today, 5.4 million people are living with the disease, and more than 15 million Americans are caring for persons with Alzheimer’s and other dementias, according to the Alzheimer’s Association. Alzheimer’s disease is the sixth-leading cause of death in the United States and the only cause of death among the top 10 in the United States that cannot be prevented, cured, or even slowed.

"Our plan aims to provide good quality care for affected patients and families, advance our understanding of the pathophysiology and natural history of AD and other dementias, develop effective treatments to slow or prevent these diseases, and translate scientific advances successfully into policy and practice," the authors wrote.

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New research offers a possible strategy for treating central nervous system diseases, such as brain and spinal cord injury, brain cancer, epilepsy, and neurological complications of HIV. The experimental treatment method allows small therapeutic agents to safely cross the blood-brain barrier in laboratory rats by turning off P-glycoprotein, one of the main gatekeepers preventing medicinal drugs from reaching their intended targets in the brain.

The findings appeared online Sept. 4 in the Proceedings of the National Academy of Sciences, and is the result of a study from scientists at the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health.

“Many promising drugs fail because they cannot cross the blood-brain barrier sufficiently to provide a therapeutic dose to the brain,” said David Miller, Ph.D., head of the Laboratory of Toxicology and Pharmacology at NIEHS, and leader of the team that performed the study. “We hope our new strategy will have a positive impact on people with brain disorders in the future.”

In a two-pronged approach, the research team first determined that treating rat brain capillaries with the multiple sclerosis drug marketed as Gilenya (fingolimod) stimulated a specific biochemical signaling pathway in the blood-brain barrier that rapidly and reversibly turned off P-glycoprotein. Team members then pretreated rats with fingolimod, and administered three other drugs that P-glycoprotein usually transports away from the brain. They observed a dramatic decline in P-glycoprotein transport activity, which led to a threefold to fivefold increase in brain uptake for each of the three drugs.

Ronald Cannon, Ph.D., is a staff scientist in the Miller lab and first author on the paper. He said one of the burning questions the team wants to tackle next is to understand how the signaling system turns off P-glycoprotein. He equates the mechanism to what happens when a person flips a light switch.

“If you physically turn off a light using the button on the wall, the light will go out because the electrical current to the light bulb has been interrupted,” Cannon explained. “But what happens when the signaling pathway shuts down P-glycoprotein? Does it bring in another protein to bind to the pump, take away its energy source, modify the structure of the pump, or something else?”

Cannon said the paper’s findings open a new way of thinking regarding targets for drug design, a thought that is emotionally gratifying for him and many other researchers whose scientific discoveries generally don’t directly translate into helping people with illnesses.

“Although much more research needs to be done, delivering therapeutics to the central nervous system is one of the final frontiers of pharmacotherapy, Cannon added.”