Neuroscience

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.”

When mice are born lacking the master gene Atoh1, none breathe well and all die in the newborn period. Why and how this occurs could provide new answers about sudden infant death syndrome (SIDS), but the solution has remained elusive until now.

Research led by Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital demonstrates that when the gene is lacking in a special population of neurons called RTN (retrotrapezoid nucleus), roughly half the young mice die at birth. Those who survive are less likely to respond to excess levels of carbon dioxide as adults. A report of their work appears online in the journal Neuron.

"The death of mice at birth clued us in that Atoh1 must be needed for the function of some neurons critical for neonatal breathing, so we set out to define these neurons," said Dr. Huda Zoghbi, senior author of the report and director of the Neurological Research Institute and a professor of molecular and human genetics, neuroscience, neurology and pediatrics at BCM. Zoghbi is also a Howard Hughes Medical Institute investigator.

"We took a genetic approach to find the critical neurons," said Wei-Hsiang Huang, a graduate student in the Program in Developmental Biology at BCM who works in Zoghbi’s laboratory. With careful studies to "knockout" the activity of the gene in a narrower and narrower area in the brain, they slowly eliminated possible neurons to determine that loss of Atoh1 in the RTN neurons was the source of the problem.

"Discovering that Atoh1 is indeed critical for the RTN neurons to take their right place in the brainstem and connect with the breathing center helped us uncover why they are important for neonatal breathing," said Zoghbi.

"This population of neurons resides in the ventral brainstem," said Huang. "When there is a change in the makeup of the blood (lack of oxygen or buildup of carbon dioxide), the RTN neurons sense that and tell the body to change the way it breathes." A defect in these neurons can disrupt this response.

"Without Atoh1 the mice have significant breathing problems because they do not automatically adjust their breathing to decrease carbon dioxide and oxygenate the blood," he said.

It turns out the findings from this mouse study are relevant to human studies.

"A paper just published reports that developmental abnormalities in the RTN neurons of children with sudden infant death syndrome or sudden unexplained intrauterine death may be linked to altered ventilatory response to carbon dioxide", said Huang (Lavezzi, A.M., et al., Developmental alterations of the respiratory human retrotrapezoid nucleus in sudden unexplained fetal and infant death, Auton. Neurosci. (2012), doi:10.1016/j.autneu.2012.06.005).

September 5, 2012 by Michael C. Purdy

Sleep disruptions may be among the earliest indicators of Alzheimer’s disease, scientists at Washington University School of Medicine in St. Louis report Sept. 5 in Science Translational Medicine.

Working in a mouse model, the researchers found that when the first signs of Alzheimer’s plaques appear in the brain, the normal sleep-wake cycle is significantly disrupted.

“If sleep abnormalities begin this early in the course of human Alzheimer’s disease, those changes could provide us with an easily detectable sign of pathology,” says senior author David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of Washington University’s Department of Neurology. “As we start to treat Alzheimer’s patients before the onset of dementia, the presence or absence of sleep problems may be a rapid indicator of whether the new treatments are succeeding.”

Holtzman’s laboratory was among the first to link sleep problems and Alzheimer’s through studies of sleep in mice genetically altered to develop Alzheimer’s plaques as they age. In a study published in 2009, he showed that brain levels of a primary ingredient of the plaques naturally rise when healthy young mice are awake and drop after they go to sleep. Depriving the mice of sleep disrupted this cycle and accelerated the development of brain plaques.

A similar rising and falling of the plaque component, a protein called amyloid beta, was later detected in the cerebrospinal fluid of healthy humans studied by co-author Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University.

The new research, led by Jee Hoon Roh, MD, PhD, a neurologist and postdoctoral fellow in Holtzman’s laboratory, shows that when the first indicators of brain plaques appear, the natural fluctuations in amyloid beta levels stop in both mice and humans.

“We suspect that the plaques are pulling in amyloid beta, removing it from the processes that would normally clear it from the brain,” Holtzman says.

Mice are nocturnal animals and normally sleep for 40 minutes during every hour of daylight, but when Alzheimer’s plaques began forming in their brains, their average sleep times dropped to 30 minutes per hour.

To confirm that amyloid beta was directly linked to the changes in sleep, researchers gave a vaccine against amyloid beta to a new group of mice with the same genetic modifications. As these mice grew older, they did not develop brain plaques. Their sleeping patterns remained normal and amyloid beta levels in the brain continued to rise and fall regularly.

Scientists now are evaluating whether sleep problems occur in patients who have markers of Alzheimer’s disease, such as plaques in the brain, but have not yet developed memory or other cognitive problems.

“If these sleep problems exist, we don’t yet know exactly what form they take—reduced sleep overall or trouble staying asleep or something else entirely,” Holtzman says. “But we’re working to find out.”

A North Carolina State University researcher has created a roadmap to areas of the brain associated with affective aggression in mice. This roadmap may be the first step toward finding therapies for humans suffering from affective aggression disorders that lead to impulsive violent acts.

Affective aggression differs from defensive aggression or premeditated aggression used by predators, in that the role of affective aggression isn’t clear and could be considered maladaptive. NC State neurobiologist Dr. Troy Ghashghaei was interested in finding the areas of the brain engaged with this type of aggressive behavior. Using mice that had been specially bred for affective aggression by his research associate Dr. Derrick L Nehrenberg, Ghashghaei and former undergraduate student Atif Sheikh were able to locate the regions in the mouse brain that switched on and those that were off when the mice displayed affective aggression.

“The brain works by using clusters of neurons that cross communicate at extremely rapid rates, much like a computer,” Ghashghaei explains. “One region will process a stimulus, and then that region sends messages to other clusters within the brain, like circuits within a computer. We looked at how the switches flipped in the brains of aggressive mice, and compared that with the brains of completely nonaggressive mice in the same setting, to see how the two processed the situation differently.”

They found that affectively aggressive mice demonstrated a large difference in the way their “executive centers” operated when the mice encountered another mouse. “Sensory inputs come in and are sent to the executive center, the part of the brain that decides how to respond to the input,” Ghashghaei says. “In the meantime, the information about the response you made gets processed back with either a pleasant or unpleasant association.”

According to Ghashghaei, the affectively aggressive mice could react violently because their brains are hardwiredto respond to certain situations aggressively without assessing whether their response to the situation is appropriate or without regard to the behavior’s consequences. In addition, affectively aggressive mice may be forming pleasant associations with their violent displays, which would reinforce their aggressive tendencies.

“We cannot say which of the two possibilities underlie the persistent aggressive displays by our mice,” Ghashghaei says, “but we can see that the patterns of neuronal activity are very different in the executive centers of these mice. Additionally, there are differences in the neuronal clusters involved with creating pleasant or unpleasant associations to the stimulus or their response. That gives us a few starting spots to begin identifying the mechanisms that underlie these profound behavioral differences.”

The regions of the brain that were involved in affective aggression in the mice are similar across all mammalian species. Ghashghaei hopes that his findings in mice will be useful to researchers studying violent behavior in humans, as well as aggression in other animals.

“With the brain, just knowing where to start looking is huge,” Ghashghaei says. “Once you have a few targets, you can tease out the possibilities and get to the heart of the problem.  We are confident that manipulation of some of the identified targets in our study will disrupt displays of affective aggression in our mouse model.”

A new University of Wisconsin-Madison imaging study shows the brains of people with generalized anxiety disorder (GAD) have weaker connections between a brain structure that controls emotional response and the amygdala, which suggests the brain’s “panic button” may stay on due to lack of regulation.

Anxiety disorders are the most common class of mental disorders and GAD, which is characterized by excessive, uncontrollable worry, affects nearly 6 percent of the population.

Lead author Dr. Jack Nitschke, associate professor of psychiatry in the UW School of Medicine and Public Health, says the findings support the theory that reduced communications between parts of the brain explains the intense anxiety felt by people with GAD.

In this case, two types of scans showed the amygdala, which alerts us to threat in our surroundings and initiates the “fight-or-flight” response, seems to have weaker “white matter” connections to the prefrontal and anterior cingulate cortex (ACC), the center of emotional regulation.

The researchers did two types of imaging - diffusion tensor imaging (DTI) and functional magnetic resonance (fMRI) - on the brains of 49 GAD patients and 39 healthy volunteers. Compared with the healthy volunteers, the imaging showed the brains of people with GAD had reduced connections between the prefrontal and anterior cingulate cortex and the amygdala via the uncinate fasciculus, a primary “white matter” tract that connects these brain regions. This reduced connectivity was not found in other white matter tracts elsewhere in their brains.

"We know that in the brain, if you use a circuit you build it up, the way you build muscle by exercise,” says Nitschke, a clinical psychologist who treats patients with anxiety disorders and does research at the UW-Madison’s Waisman Center.

Nitschke says that researchers wonder if this weak connection results in the intense anticipatory anxiety and worry that is the hallmark of GAD, because the ACC is unable to tell the amygdala to “chill out.” It also suggests that behavioral therapy that teaches patients to consciously exercise this emotional regulation works to reduce anxiety by strengthening the connection.

"It’s possible that this is exactly what we’re doing when we teach patients to regulate their reactions to the negative events that come up in everyone’s lives,” Nitschke says. "We can help build people’s tolerance to uncontrollable future events by teaching them to regulate their emotions to the uncertainty that surrounds those events.

3-Sep-2012

Researchers at Emory University have found that a medication that inhibits inflammation may offer new hope for people with difficult-to-treat depression. The study was published Sept. 3 in the online version of Archives of General Psychiatry.

"Inflammation is the body’s natural response to infection or wounding, says Andrew H. Miller, MD, senior author for the study and professor of Psychiatry and Behavioral Sciences at Emory University School of Medicine. "However when prolonged or excessive, inflammation can damage many parts of the body, including the brain."

Prior studies have suggested that depressed people with evidence of high inflammation are less likely to respond to traditional treatments for the disorder, including anti-depressant medications and psychotherapy. This study was designed to see whether blocking inflammation would be a useful treatment for either a wide range of people with difficult-to-treat depression or only those with high levels of inflammation.

The study employed infliximab, one of the new biologic drugs used to treat autoimmune and inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. A biologic drug copies the effects of substances naturally made by the body’s immune system. In this case, the drug was an antibody that blocks tumor necrosis factor (TNF), a key molecule in inflammation that has been shown to be elevated in some depressed individuals.

Study participants all had major depression and were moderately resistant to conventional antidepressant treatment. Each participant was assigned either to infliximab or to a non-active placebo treatment.

When investigators looked at the results for the group as a whole, no significant differences were found in the improvement of depression symptoms between the drug and placebo groups. However, when the subjects with high inflammation were examined separately, they exhibited a much better response to infliximab than to placebo.

Inflammation in this study was measured using a simple blood test that is readily available in most clinics and hospitals and measures C-reactive protein or CRP. The higher the CRP, the higher the inflammation, and the higher the likelihood of responding to the drug.

"The prediction of an antidepressant response using a simple blood test is one of the holy grails in psychiatry," says Miller. "This is especially important because the blood test not only measured what we think is at the root cause of depression in these patients, but also is the target of the drug."

"This is the first successful application of a biologic therapy to depression," adds Charles L. Raison, MD, first author of the study. "The study opens the door to a host of new approaches that target the immune system to treat psychiatric diseases." Raison, formerly at Emory, is now associate professor in the Department of Psychiatry at the University of Arizona College of Medicine – Tucson.