Exercise key to warding off dementia

EXERCISE is one of the best ways to protect against dementia in later life and the earlier you start, the greater the effect, research suggests.

Participating in intellectually stimulating leisure activities, paid work, volunteer work or study can also help protect against memory loss and reduce the risk of developing Alzheimer’s disease.

UWA adjunct clinical professor Nicola Lautenschlager, who led a review of strategies to delay cognitive decline, says there is a growing body of evidence that suggests exercise is beneficial for brain health.

"The knowledge we have so far basically makes it very clear that regular physical activity, even at an older age, can be very beneficial for protecting cognition," she says.

"Beyond that it’s also very effective for protecting or maintaining mental health, especially in relation to symptoms of depression or anxiety."

Prof Lautenschlager, who is based at the University of Melbourne, says older people who are well enough are advised to do 150 minutes of physical activity a week, such as going for walks.

"When it comes [to] brain health…it would be good if the walking speed isn’t very slow, so it shouldn’t be a stroll but rather what we call moderate pace," she says.

"Research has shown that the level of physical activity has to have a certain intensity so that the brain benefits."

Enjoyable hobbies key to brain health

Hobbies that keep the brain active, such as playing an instrument, going to concerts or joining a book club, can also be very helpful as long as it is an activity a person enjoys, Prof Lautenschlager says.

"The minute you prescribe an activity they hate doing…most likely the effect in terms of being beneficial for brain health is lost," she says.

"It produces so much stress in the body not wanting to do it that the stress is more harmful than the benefit of keeping the brain active."

Prof Lautenschlager says middle age is a crucial time for making lifestyle decisions that will determine a person’s health in later life.

"Usually we are talking about when you move into your 30s, definitely the 40s and also still the 50s," she says.

"Things like a high blood pressure or carrying too much weight, if you do that in these decades, it seems to harm the brain long-term in terms of how healthy a person is in their 70s or 80s."

Ideally people should aim for a healthy lifestyle from childhood but luckily research shows lifestyle changes still have an effect on brain health if a person is already old, Prof Lautenschlager says.

"Even programs…with seniors in their 70s and 80s can still make a difference," she says.

The research was published this month in the journal Maturitas.

MagLab MRI machine provides in-depth analysis of strokes

New research conducted at the Florida State University-based National High Magnetic Field Laboratory has revealed a new, innovative way to classify the severity of a stroke, aid in diagnosis and evaluate potential treatments.

“Stroke affects millions of adults and children worldwide,” said Sam Grant, MagLab researcher and associate professor of chemical and biomedical engineering at the FAMU-FSU College of Engineering. “This research offers a new technique for the chemical analysis of metabolites during stroke and a means of evaluating dynamic changes in cell processes and size in living tissue.”

The research is detailed in two papers, “Metabolic properties in stroked rats revealed by relaxation-enhanced magnetic resonance spectroscopy at ultrahigh fields,” in Nature Communications and “Metabolic T1 dynamics and longitudinal relaxation enhancement in vivo at ultrahigh magnetic fields on ischemia” in the Journal of Cerebral Blood Flow and Metabolism.

The new technique is a way of narrowly applying energy to the metabolites of a specimen exposed to a very high magnetic field. Metabolites are the biological compounds used in the chemical process of breaking down food or other chemicals into energy and producing new materials.

By selectively “exciting” these metabolites and analyzing their distribution and confinement in brain tissue, the research team can investigate the metabolic microenvironment and tell whether cells were shrinking or expanding, a critical tool to understanding the severity of stroke, Grant said.

That information could help medical professionals better treat patients.

“Strokes cause an interruption of blood and oxygen to flow to the brain,” explained Jens Rosenberg, another MagLab researcher and one of Grant’s co-authors. “Through this research, we can see how neurons and other neural cells respond to the disruption of blood flow after stroke and use that information to better understand the full impacts of stroke.”   

The MagLab’s flagship 900 MHz Ultra Widebore NMR magnet system was a critical component to the research. Utilizing this powerful magnet, the research team, which included scientists from the Champaulimod Center in Portugal and the Weizmann Institute of Science in Israel, were able to acquire localized chemical signatures of metabolites from 125-microliter volumes within the brain with high sensitivity and fidelity in six seconds.

Typical MRIs at hospitals or doctor’s offices measure around 1.5 – 3 tesla (the unit of magnetic field strength), while the 900 MHz measures a whopping 21.1 tesla, providing at least seven times the sensitivity.

“This very high field coupled with the RF pulse sequence design by our collaborators and homebuilt RF probes offer a unique non-invasive way of evaluating stroke evolution and potential treatments,” Rosenberg said.

The team also sees exciting possibilities to use this technique to further investigate debilitating diseases.

“By evaluating spectral regions previously undetectable, we hope to fingerprint certain diseases, like ischemic stroke, so that we can identify new characteristics that are specific to pathological conditions at the metabolic level in vivo,” Grant said. “There is a lot of work to be done to identify these dynamic changes and decide when and how our treatments can be most effective.”

Further research on metabolites using this technique could also be used for analysis of neurological disorders such as dementia, schizophrenia, Lou Gehrig’s, Parkinson’s, Alzheimer’s and Huntington’s diseases.

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Mechanism that repairs brain after stroke discovered

A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems.

The researchers have shown that following an induced stroke in mice, support cells, so-called astrocytes, start to form nerve cells in the injured part of the brain. Using genetic methods to map the fate of the cells, the scientists could demonstrate that astrocytes in this area formed immature nerve cells, which then developed into mature nerve cells.

”This is the first time that astrocytes have been shown to have the capacity to start a process that leads to the generation of new nerve cells after a stroke”, says Zaal Kokaia, Professor of Experimental Medical Research at Lund University.

The scientists could also identify the signalling mechanism that regulates the conversion of the astrocytes to nerve cells. In a healthy brain, this signalling mechanism is active and inhibits the conversion, and, consequently, the astrocytes do not generate nerve cells. Following a stroke, the signalling mechanism is suppressed and astrocytes can start the process of generating new cells.

”Interestingly, even when we blocked the signalling mechanism in mice not subjected to a stroke, the astrocytes formed new nerve cells”, says Zaal Kokaia.

“This indicates that it is not only a stroke that can activate the latent process in astrocytes. Therefore, the mechanism is a potentially useful target for the production of new nerve cells, when replacing dead cells following other brain diseases or damage.”

The new nerve cells were found to form specialized contacts with other cells. It remains to be shown whether the nerve cells are functional and to what extent they contribute to the spontaneous recovery that is observed in a majority of experimental animals and patients after a stroke.

A decade ago, Kokaia’s and Lindvall’s research group was the first to show that stroke leads to the formation of new nerve cells from the adult brain’s own neural stem cells. The new findings further underscore that when the adult brain suffers a major blow such as a stroke, it makes a strong effort to repair itself using a variety of mechanisms.

The major advancement with the new study is that it demonstrates for the first time that self-repair in the adult brain involves astrocytes entering a process by which they change their identity to nerve cells.

”One of the major tasks now is to explore whether astrocytes are also converted to neurons in the human brain following damage or disease. Interestingly, it is known that in the healthy human brain, new nerve cells are formed in the striatum. The new data raise the possibility that some of these nerve cells derive from local astrocytes. If the new mechanism also operates in the human brain and can be potentiated, this could become of clinical importance not only for stroke patients, but also for replacing neurons which have died, thus restoring function in patients with other disorders such as Parkinson’s disease and Huntington’s disease”, says Olle Lindvall, Senior Professor of Neurology.

A developmental study of the effect of music training on timed movements

When people clap to music, sing, play a musical instrument, or dance, they engage in temporal entrainment. We examined the effect of music training on the precision of temporal entrainment in 57 children aged 10–14 years (31 musicians, 26 non-musicians). Performance was examined for two tasks: self-paced finger tapping (discrete movements) and circle drawing (continuous movements). For each task, participants synchronized their movements with a steady pacing signal and then continued the movement at the same rate in the absence of the pacing signal. Analysis of movements during the continuation phase revealed that musicians were more accurate than non-musicians at finger tapping and, to a lesser extent, circle drawing. Performance on the finger-tapping task was positively associated with the number of years of formal music training, whereas performance on the circle-drawing task was positively associated with the age of participants. These results indicate that music training and maturation of the motor system reinforce distinct skills of timed movement.

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(Image caption: Neurons of love: A newly discovered type of brain cell responds to oxytocin and so regulates female mice’s interest in males, but only when the females are in heat. These star-shaped neurons (above) are shown within a brain region called the medial prefrontal cortex.)

Newly discovered brain cells explain a prosocial effect of oxytocin

Oxytocin, the body’s natural love potion, helps couples fall in love, makes mothers bond with their babies, and encourages teams to work together. Now new research at Rockefeller University reveals a mechanism by which this prosocial hormone has its effect on interactions between the sexes, at least in certain situations. The key, it turns out, is a newly discovered class of brain cells.

“By identifying a new population of neurons activated by oxytocin, we have uncovered one way this chemical signal influences interactions between male and female mice,” says Nathaniel Heintz, James and Marilyn Simons Professor and head of the Laboratory of Molecular Biology.

The findings, published today in Cell (October 9), had their beginnings in a search for a new type of interneuron, a specialized neuron that relays messages to other neurons across relatively short distances. As part of her doctoral thesis, Miho Nakajima began creating profiles of the genes expressed in interneurons using a technique known as translating ribosome affinity purification (TRAP) previously developed by the Heintz lab and Paul Greengard’s Laboratory of Molecular and Cellular Neuroscience at Rockefeller. Within some profiles from the outer layer of the brain known as the cortex, she saw an intriguing protein: a receptor that responds to oxytocin.

“This raised the question: What is this small, scattered population of interneurons doing in response to this important signal, oxytocin?” Nakajima says. “Because oxytocin is most involved in social behaviors of females, we decided to focus our experiments on females.”

To determine how these neurons, dubbed oxytocin receptor interneurons or OxtrINs, affected behavior when activated by oxytocin, she silenced only this class of interneurons and, in separate experiments, blocked the receptor’s ability to detect oxytocin in some females. She then gave them a commonly used social behavior test: Given the choice between exploring a room with a male mouse or a room with an inanimate object – in this case a plastic Lego block – what would they do? Generally, a female mouse will go for the non-stackable choice. Legos just aren’t that interesting to rodents. But Nakajima’s results were confusing: Sometimes the mice with the silenced OxtrINs showed an abnormally high interest in the Lego, and sometimes they responded normally.

This led her to suspect the influence of the female reproductive cycle. In another round of experiments, she recorded whether the female mice were in estrus, the sexually receptive phase, or diestrus, a period of sexual inactivity. Estrus, it turned out, was key. Female mice in this phase showed an unusual lack of interest in the males when their receptors were inactivated. They mostly just sniffed at the Lego. There was no effect on mice is diestrus, and there was no effect if the male love interest was replaced with a female. When Nakajima tried the same alteration in males, there was also no effect.

“In general, OxtrINs appear to sit silently when not exposed to oxytocin,” says Andreas Görlich, a postdoc in the lab who recorded the electrical activity of these neurons with and without the hormone. “The interesting part is that when exposed to oxytocin these neurons fire more frequently in female mice than they do in male mice, possibly reflecting the differences that showed up in the behavioral tests.”

“We don’t yet understand how, but we think oxytocin prompts mice in estrus to become interested in investigating their potential mates,” Nakajima says. “This suggests that the social computation going on in a female mouse’s brain differs depending on the stage of her reproductive cycle.”

Oxytocin has similar effects for humans as for mice, however, it is not yet clear if the hormone influences the human version of this mouse interaction, or if it works through a similar population of interneurons. The results do, however, help explain how humans, mice and other mammals respond to changing social situations, Heintz says.

“Oxytocin responses have been studied in many parts of the brain, and it is clear that it, or other hormones like it, can impact behavior in different ways, in different contexts and in response to different physiological cues,” he says. “In a general sense, this new research helps explain why social behavior depends on context as well as physiology.”

Manipulating memory with light

Just look into the light: not quite, but researchers at the UC Davis Center for Neuroscience and Department of Psychology have used light to erase specific memories in mice, and proved a basic theory of how different parts of the brain work together to retrieve episodic memories.

Optogenetics, pioneered by Karl Diesseroth at Stanford University, is a new technique for manipulating and studying nerve cells using light. The techniques of optogenetics are rapidly becoming the standard method for investigating brain function.

Kazumasa Tanaka, Brian Wiltgen and colleagues at UC Davis applied the technique to test a long-standing idea about memory retrieval. For about 40 years, Wiltgen said, neuroscientists have theorized that retrieving episodic memories — memories about specific places and events — involves coordinated activity between the cerebral cortex and the hippocampus, a small structure deep in the brain.

"The theory is that learning involves processing in the cortex, and the hippocampus reproduces this pattern of activity during retrieval, allowing you to re-experience the event," Wiltgen said. If the hippocampus is damaged, patients can lose decades of memories.

But this model has been difficult to test directly, until the arrival of optogenetics.

Wiltgen and Tanaka used mice genetically modified so that when nerve cells are activated, they both fluoresce green and express a protein that allows the cells to be switched off by light. They were therefore able both to follow exactly which nerve cells in the cortex and hippocampus were activated in learning and memory retrieval, and switch them off with light directed through a fiber-optic cable.

They trained the mice by placing them in a cage where they got a mild electric shock. Normally, mice placed in a new environment will nose around and explore. But when placed in a cage where they have previously received a shock, they freeze in place in a “fear response.”

Tanaka and Wiltgen first showed that they could label the cells involved in learning and demonstrate that they were reactivated during memory recall. Then they were able to switch off the specific nerve cells in the hippocampus, and show that the mice lost their memories of the unpleasant event. They were also able to show that turning off other cells in the hippocampus did not affect retrieval of that memory, and to follow fibers from the hippocampus to specific cells in the cortex.

"The cortex can’t do it alone, it needs input from the hippocampus," Wiltgen said. "This has been a fundamental assumption in our field for a long time and Kazu’s data provides the first direct evidence that it is true."

They could also see how the specific cells in the cortex were connected to the amygdala, a structure in the brain that is involved in emotion and in generating the freezing response.

Multiple neurodevelopmental disorders have a common molecular cause

Neurodevelopmental disorders such as Down syndrome and autism-spectrum disorder can have profound, lifelong effects on learning and memory, but relatively little is known about the molecular pathways affected by these diseases. A study published by Cell Press October 9th in the American Journal of Human Genetics shows that neurodevelopmental disorders caused by distinct genetic mutations produce similar molecular effects in cells, suggesting that a one-size-fits-all therapeutic approach could be effective for conditions ranging from seizures to attention-deficit hyperactivity disorder.

"Neurodevelopmental disorders are rare, meaning trying to treat them is not efficient," says senior study author Carl Ernst of McGill University. "Once we fully define the major common pathways involved, targeting these pathways for treatment becomes a viable option that can affect the largest number of people."

A large fraction of neurodevelopmental disorders are associated with variation in specific genes, but the genetic factors responsible for these diseases are very complex. For example, whereas common variants in the same gene have been associated with two or more different disorders, mutations in many different genes can lead to similar diseases. As a result, it has not been clear whether genetic mutations that cause neurodevelopmental disorders affect distinct molecular pathways or converge on similar cellular functions.

To address this question, Ernst and his team used human fetal brain cells to study the molecular effects of reducing the activity of genes that are mutated in two distinct autism-spectrum disorders. Changes in transcription factor 4 (TCF4) cause 18q21 deletion syndrome, which is characterized by intellectual disability and psychiatric problems, and mutations in euchromatic histone methyltransferase 1 (EHMT1) cause similar symptoms in a disease known as 9q34 deletion syndrome.

Interfering with the activity of TCF4 or EHMT1 produced similar molecular effects in the cells. Strikingly, both of these genetic modifications resulted in molecular patterns that resemble those of cells that are differentiating, or converting from immature cells to more specialized cells. “Our study suggests that one fundamental cause of disease is that neural stem cells choose to become full brain cells too early,” Ernst says. “This could affect how they incorporate into cellular networks, for example, leading to the clinical symptoms that we see in kids with these diseases.”

(Image: Wellcome Images)

Hunger Games: How the brain ‘browns’ fat to aid weight loss

Researchers at Yale School of Medicine have uncovered a molecular process in the brain known to control eating that transforms white fat into brown fat. This process impacts how much energy we burn and how much weight we can lose. The results are published in the Oct. 9 issue of the journal Cell.

Obesity is a rising global epidemic. Excess fatty tissue is a major risk factor for type 2 diabetes, cardiovascular disease, hypertension, neurological disorders, and cancer. People become overweight and obese when energy intake exceeds energy expenditure, and excess calories are stored in the adipose tissues. The adipose organ is made up of both white and brown fat. While white fat primarily stores energy as triglycerides, brown fat dissipates chemical energy as heat. The more brown fat you have, the more weight you can lose.

It has previously been shown that energy-storing white fat has the capacity to transform into energy-burning “brown-like” fat. In this new study, researchers from the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, demonstrate that neurons controlling hunger and appetite in the brain control the “browning” of white fat.

Lead author Xiaoyong Yang, associate professor of comparative medicine and physiology at Yale School of Medicine, conducted the study with Tamas Horvath, professor and chair of comparative medicine, and professor of neurobiology and Obstetrics/gynecology at Yale School of Medicine, and their co-authors.

The team stimulated this browning process from the brain in mice and found that it protected the animals from becoming obese on a high-fat diet. The team then studied the molecular changes in hunger-promoting neurons in the hypothalamus and found that the attachment of a unique sugar called “O-GlcNAc” to potassium ion channels acts as a switch to control brain activity to burn fat.

“Our studies reveal white fat “browning” as a highly dynamic physiological process that the brain controls,” said Yang. “This work indicates that behavioral modifications promoted by the brain could influence how the amount of food we eat and store in fat is burned.”

Yang said hunger and cold exposure are two life-history variables during the development and evolution of mammals. “We observed that food deprivation dominates over cold exposure in neural control of white fat browning. This regulatory system may be evolutionarily important as it can reduce heat production to maintain energy balance when we are hungry. Modulating this brain-to-fat connection represents a potential novel strategy to combat obesity and associated illnesses.”