Neuroscience

In 2008, researchers at the Perelman School of Medicine at the University of Pennsylvania showed that mutations in two proteins associated with familial Alzheimer’s disease (FAD) disrupt the flow of calcium ions within neurons. The two proteins interact with a calcium release channel in an intracellular compartment. Mutant forms of these proteins that cause FAD, but not the normal proteins, result in exaggerated calcium signaling in the cell.

Now, the same team, led by J. Kevin Foskett, PhD, chair of Physiology, and a graduate student, Dustin Shilling, has found that suppressing the hyperactivity of the calcium channels alleviated FAD-like symptoms in mice models of the disease. Their findings appear this week in the Journal of Neuroscience.

Current therapies for Alzheimer’s include drugs that treat the symptoms of cognitive loss and dementia, and drugs that address the pathology of Alzheimer’s are experimental. These new observations suggest that approaches based on modulating calcium signaling could be explored, says Foskett.

The two proteins, called PS1 and PS2 (presenilin 1 and 2), interact with a calcium release channel, the inositol trisphosphate receptor (IP3R), in the endoplasmic reticulum. Mutant PS1 and PS2 increase the activity of the IP3R, in turn increasing calcium levels in the cell. “We set out to answer the question: Is increased calcium signaling, as a result of the presenilin-IP3R interaction, involved in the development of familial Alzheimer’s disease symptoms, including dementia and cognitive deficits?” says Foskett. “And looking at the findings of these experiments, the answer is a resounding ‘yes.’”

Exaggerated intracellular calcium signaling is a robust phenomenon seen in cells expressing FAD-causing mutant presenilins, in both human cells in culture and in mice. The team used two FAD mouse models to look for these connections. Specifically, they found that reducing the expression of IP3R1, the dominant form of this receptor in the brain, by 50 percent, normalized the exaggerated calcium signaling observed in neurons of the cortex and hippocampus in both mouse models.

(Image caption: Amyloid-beta (antibody 12F4) and hyper-phosphorylated tau (antibody AT180) immunostaining of hippocampus from 18-month-old mice. Amyloid plaques (top row) and intracellular tau tangles (bottom row) in the 3xTg mouse were strongly reduced by genetic deletion of 50% of the IP3R1 in the 3xTg/Opt mouse. Wild-type (WT) and Opt mice expressing 50% of InsP3R exhibited no pathology. Credit: J. Kevin Foskett, PhD & Dustin Shilling, Perelman School of Medicine, University of Pennsylvania)

In addition, using 3xTg mice – animals that contain presenilin 1 with an FAD mutation, as well as expressed mutant human tau protein and APP genes — the team observed that the reduced expression of IP3R1 profoundly decreased amyloid plaque accumulation in brain tissue and the hyperphosphorylation of tau protein, a biochemical hallmark of advanced Alzheimer’s disease. Reduced expression of IP3R1 also rescued defective electrical signaling in the hippocampus, as well and memory deficits in the 3xTg mice, as measured by behavioral tests. 

“Our results indicate that exaggerated calcium signaling, which is associated with presenilin mutations in familial Alzheimer’s disease, is mediated by the IP3R and contributes to disease symptoms in animals,” says Foskett. “Knowing this now, the IP3 signaling pathway could be considered a potential therapeutic target for patients harboring mutations in presenilins linked to AD.”

 “The ‘calcium dysregulation’ hypothesis for inherited, early-onset familial Alzheimer’s disease has been suggested by previous research findings in the Foskett lab. Alzheimer’s disease affects as many as 5 million Americans, 5 percent of whom have the familial form. The hallmark of the disease is the accumulation of tangles and plaques of amyloid beta protein in the brain.

“The ‘amyloid hypothesis’ that postulates that the primary defect is an accumulation of toxic amyloid in the brain has long been used to explain the cause of Alzheimer’s”, says Foskett. In his lab’s 2008 Neuron study, cells that carried the disease-causing mutated form of PS1 showed increased processing of amyloid beta that depended on the interaction of the PS proteins with the IP3R. This observation links dysregulation of calcium inside cells with the production of amyloid, a characteristic feature in the brains of people with Alzheimer’s disease.

Clinical trials for AD have largely been directed at reducing the amyloid burden in the brain. So far, says Foskett, these trials have failed to demonstrate therapeutic benefits. One idea is that the interventions started too late in the disease process. Accordingly, anti-amyloid clinical trials are now underway using asymptomatic FAD patients because it is known that they will eventually develop the disease, whereas predicting who will develop the common form of AD is much less certain.

“There has been an assumption that FAD is simply AD with an earlier, more aggressive onset,” says Foskett. “However, we don’t know if the etiology of FAD pathology is the same as that for common AD. So the relevance of our findings for understanding common AD is not clear. What’s important, in my opinion, is to recognize that AD could be a spectrum of diseases that result in common end-stage pathologies. FAD might therefore be considered an orphan-disease, and it’s important to find effective treatments, specifically for these patients - ones that target the IP3R and calcium signaling.”

Stimulation of a certain population of neurons within the brain can alter the learning process, according to a team of neuroscientists and neurosurgeons at the University of Pennsylvania. A report in the Journal of Neuroscience describes for the first time that human learning can be modified by stimulation of dopamine-containing neurons in a deep brain structure known as the substantia nigra. Researchers suggest that the stimulation may have altered learning by biasing individuals to repeat physical actions that resulted in reward.

"Stimulating the substantia nigra as participants received a reward led them to repeat the action that preceded the reward, suggesting that this brain region plays an important role in modulating action-based associative learning," said co-senior author Michael Kahana, PhD, professor of Psychology in Penn’s School of Arts and Sciences.

Eleven study participants were all undergoing deep brain stimulation (DBS) treatment for Parkinson’s disease. During an awake portion of the procedure, participants played a computer game where they chose between pairs of objects that carried different reward rates (like choosing between rigged slot machines in a casino). The objects were displayed on a computer screen and participants made selections by pressing buttons on hand-held controllers. When they got a reward, they were shown a green screen and heard a sound of a cash register (as they might in a casino). Participants were not told which objects were more likely to yield reward, but that their task was to figure out which ones were “good” options based on trial and error. 

When stimulation was provided in the substantia nigra following reward, participants tended to repeat the button press that resulted in a reward. This was the case even when the rewarded object was no longer associated with that button press, resulting in poorer performance on the game when stimulation was given (48 percent accuracy), compared to when stimulation was not given (67 percent).

"While we’ve suspected, based on previous studies in animal models, that these dopaminergic neurons in the substantia nigra - play an important role in reward learning, this is the first study to demonstrate in humans that electrical stimulation near these neurons can modify the learning process," said the study’s co-senior author Gordon Baltuch, MD, PhD, professor of Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania. “This result also has possible clinical implications through modulating pathological reward-based learning, for conditions such as substance abuse or problem gambling, or enhancing the rehabilitation process in patients with neurological deficits.”

Much like using dimmer switches to brighten or darken rooms, biochemists have identified a protein that can be used to slow down or speed up the growth of brain tumors in mice.

Brain and other nervous system cancers are expected to claim 14,320 lives in the United States this year.

The results of the preclinical study led by Eric J. Wagner, Ph.D., and Ann-Bin Shyu, Ph.D., of The University of Texas Health Science Center at Houston (UTHealth) and Wei Li, Ph.D., of Baylor College of Medicine appear in the Advance Online Publication of the journal Nature.

“Our work could lead to the development of a novel therapeutic target that might slow down tumor progression,” said Wagner, assistant professor in the Department of Biochemistry and Molecular Biology at the UTHealth Medical School.

Shyu, professor and holder of the Jesse H. Jones Chair in Molecular Biology at the UTHealth Medical School, added, “This link to brain tumors wasn’t previously known.”

“Its role in brain tumor progression was first found through big data computational analysis, then followed by animal-based testing. This is an unusual model for biomedical research, but is certainly more powerful, and may lead to the discovery of more drug targets,” said Li, an associate professor in the Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology at Baylor. 

Wagner, Shyu, Li and their colleagues discovered a way to slow tumor growth in a mouse model of brain cancer by altering the process by which genes are converted into proteins.

Appropriately called messenger RNA for short, these molecules take the information inside genes and use it to make body tissues. While it was known that the messenger RNA molecules associated with the cancerous cells were shorter than those with healthy cells, the mechanism by which this occurred was not understood.

The research team discovered that a protein called CFIm25 is critical to keeping messenger RNA long in healthy cells and that its reduction promotes tumor growth. The key research finding in this study was that restoring CFIm25 levels in brain tumors dramatically reduced their growth.

“Understanding how messenger RNA length is regulated will allow researchers to begin to develop new strategies aimed at interfering with the process that causes unusual messenger RNA shortening during the formation of tumors,” Wagner said.

Additional preclinical tests are needed before the strategy can be evaluated in humans.

“The work described in the Nature paper by Drs. Wagner and Shyu stems from a high-risk/high-impact Cancer Prevention & Research Institute of Texas (CPRIT) proposal they submitted together and received several years ago,” said Rod Kellems, Ph.D., professor and chairman of the Department of Biochemistry and Molecular Biology at the UTHealth Medical School.

“Their research is of fundamental biological importance in that it seeks to understand the role of messenger RNA length regulation in gene expression,” Kellems said.  “Using a sophisticated combination of biochemistry, genetics and bioinformatics, their research uncovered an important role for a specific protein that is linked to glioblastoma tumor suppression.”

Bottom Line: Cerebral small-vessel disease (SVD) and Alzheimer disease (AD) pathology appear to be associated.

Author:  Maartje I. Kester, M.D., Ph.D., of the VU University Medical Center, Amsterdam, the Netherlands, and colleagues.

Background: AD is believed to be caused by the buildup of amyloid protein in the brain and tau tangles. Previous studies have suggested that SVD and vascular risk factors increase the risk of developing AD. In both SVD and vascular dementia (VaD), signs of AD pathology have been seen. But it remains unclear how the interaction between SVD and AD pathology leads to dementia.

How the Study Was Conducted: Authors examined the association between SVD and AD pathology by looking at magnetic resonance imaging (MRI)-based microbleeds (MB), white matter hyperintensities (WMH) and lacunes (which are measures for SVD) along with certain protein levels in cerebrospinal fluid (CSF) which reflect AD pathophysiology in patients with AD, VaD and healthy control patients. The authors also examined the relationship of apolipoprotein E (APOE) Ɛ4 genotype, a well-known risk factor for AD.

Results: The presence of both MBs and WMH was associated with lower CSF levels of Aβ42, suggesting a direct relationship between SVD and AD. Amyloid deposits also appear to be abnormal in patients with SVD, especially in (APOE) Ɛ4 carriers.

Discussion: “Our study supports the hypothesis that the pathways of SVD and AD pathology are interconnected. Small-vessel disease could provoke amyloid pathology while AD-associated cerebral amyloid pathology may lead to auxiliary vascular damage.”

People who are exposed to paint, glue or degreaser fumes at work may experience memory and thinking problems in retirement, decades after their exposure, according to a study published in the May 13, 2014, print issue of Neurology®, the medical journal of the American Academy of Neurology.

“Our findings are particularly important because exposure to solvents is very common, even in industrialized countries like the United States.” said study author Erika L. Sabbath, ScD, of Harvard School of Public Health in Boston. “Solvents pose a real risk to the present and future cognitive health of workers, and as retirement ages go up, the length of time that people are exposed is going up, too.”

The study involved 2,143 retirees from the French national utility company. Researchers assessed the workers’ lifetime exposure to chlorinated solvents, petroleum solvents, and benzene, including the timing of last exposure and lifetime dosage. Benzene is used to make plastics, rubber, dye, detergents and other synthetic materials. Chlorinated solvents can be found in dry cleaning solutions, engine cleaners, paint removers and degreasers. Petroleum solvents are used in carpet glue, furniture polishes, paint, paint thinner and varnish. Of the participants, 26 percent were exposed to benzene, 33 percent to chlorinated solvents and 25 percent to petroleum solvents.

Participants took eight tests of their memory and thinking skills an average of 10 years after they had retired, when they were an average age of 66. A total of 59 percent of the participants had impairment on one to three of the eight tests; 23 percent had impairment on four or more tests; 18 percent had no impaired scores.

The average lifetime solvent exposure was determined based on historical company records, and the participants were categorized as having no exposure, moderate exposure if they had less than the average and high exposure if they had higher than the average. They were also divided by when the last exposure occurred, with those last exposed from 12 to 30 years prior to the testing considered as recent exposure and those last exposed 31 to 50 years prior considered as more distant exposure.

The research found that people with high, recent exposure to solvents were at greatest risk for memory and thinking deficits. For example, those with high, recent exposure to chlorinated solvents were 65 percent more likely to have impaired scores on tests of memory and visual attention and task switching than those who were not exposed to solvents. The results remained the same after accounting for factors such as education level, age, smoking and alcohol consumption.

“The people with high exposure within the last 12 to 30 years showed impairment in almost all areas of memory and thinking, including those not usually associated with solvent exposure,” Sabbath said. “But what was really striking was that we also saw some cognitive problems in those who had been highly exposed much longer ago, up to 50 years before testing. This suggests that time may not fully lessen the effect of solvent exposure on some memory and cognitive skills when lifetime exposure is high.”

Sabbath said the results may have implications for policies on workplace solvent exposure limits. “Of course, the first goal is protecting the cognitive health of individual workers. But protecting workers from exposure could also benefit organizations, payers, and society by reducing workers’ post-retirement health care costs and enabling them to work longer,” said Sabbath. “That said, retired workers who have had prolonged exposure to solvents during their career may benefit from regular cognitive screening to catch problems early, screening and treatment for heart problems that can affect cognitive health, or mentally stimulating activities like learning new skills.”

If counting sheep can’t help you sleep, you could try thinking of an elephant, French toast and scuba diving.

Simon Fraser University researcher Luc Beaudoin has created mySleepButton, a first-of-its-kind app that harnesses the power of the imagination to help users nod off.

Distributed by Apple as a free iTunes download, the app incorporates concepts from cognitive science, a multidisciplinary study of the mind and its processes. It works by preventing sleep-interfering thoughts and activating a mechanism that could help trigger sleep.

Based on the “cognitive shuffle” technique developed by Beaudoin, an SFU adjunct education professor, the app works by prompting users to imagine various objects or scenes in rapid succession.

“For example, one moment, users may be directed to think of a baby, then next a football game, then beans, a ball, London and so on,” he says.

The method is based on the uniquely incoherent nature of sleep onset “mentation,” a term used by Beaudoin that refers to all kinds of mental activity.

“As you fall asleep, you tend to entertain various detached thoughts and images. The app gets users to think in a manner that, like sleep onset, is both visual and random,” explains Beaudoin. “In a nutshell, it’s a case of ‘fake it until you make it.’

“Brain areas involved in controlling sleep detect that sense-making has been suspended. This basically gives them an implicit license to continue the transition to sleep,” he says.

Executive functions—brain functions like planning, worrying and problem solving that are vital for helping us make sense of the world during waking hours—can delay sleep when they don’t switch off at bed time.

By prompting users to interpret and visualize words, mySleepButton can help deactivate these executive functions.

“While you’re thinking about random objects or scenes, you can’t think about your mortgage, an important meeting or an impending divorce,” says Beaudoin.

“That’s because, to a certain extent, we all have one track minds. It’s very hard to think about multiple distinct things at the same time.”

Beaudoin, an associate member of SFU’s cognitive science program, says the app could also help increase cognitive productivity.

“Quality of work decreases when people are sleep-deprived and getting adequate sleep is very important for cognitive performance,” he says.

The app has potential applications for industries that employ scientific knowledge workers, such as software and aviation, or for employees on variable schedules who need to be alert, such as transportation workers.

The application is also a valuable research tool for sleep science and cognitive science, says Beaudoin, who authored the book Cognitive Productivity.

Data collected from consenting users could be used in scientific studies or feed directly into further development of the app.

St. Jude Children’s Research Hospital scientists studying two rare, inherited childhood neurodegenerative disorders have identified a new, possibly common source of DNA damage that may play a role in other neurodegenerative diseases, cancer and aging. The findings appear in the current issue of the scientific journal Nature Neuroscience.

Researchers showed for the first time that an enzyme required for normal DNA functioning causes DNA damage in the developing brain. DNA is the molecule found in nearly every cell that carries the instructions needed to assemble and sustain life.

The enzyme is topoisomerase 1 (Top1). Normally, Top1 works by temporarily attaching to and forming a short-lived molecule called a Top1 cleavage complex (Top1cc). Top1ccs cause reversible breaks in one strand of the double-stranded DNA molecule. That prompts DNA to partially unwind, allowing cells to access the DNA molecule in preparation for cell division or to begin production of the proteins that do the work of cells.

Different factors, including the free radicals that are a byproduct of oxygen metabolism, result in Top1ccs becoming trapped on DNA and accumulating in cells. This study, however, is the first to link the buildup to disease. The results also broaden scientific understanding of the mechanisms that maintain brain health.

Investigators made the connection between DNA damage and accumulation of Top1cc while studying DNA repair problems in the rare neurodegenerative disorders ataxia telangiectasia (A-T) and spinocerebellar ataxia with axonal neuropathy 1(SCAN1). The diseases both involve progressive difficulty with walking and other movement. This study showed that A-T and SCAN1 also share the buildup of Top1ccs as a common mechanism of DNA damage. A-T is associated with a range of other health problems, including an increased risk of leukemia, lymphoma and other cancers.

“We are now working to understand how this newly recognized source of DNA damage might contribute to tumor development or the age-related DNA damage in the brain that is associated with neurodegenerative disorders like Alzheimer’s disease,”said co-corresponding author Peter McKinnon, Ph.D., a member of the St. Jude Department of Genetics. The co-corresponding author is Sachin Katyal, Ph.D., of the University of Manitoba Department of Pharmacology and Therapeutics and formerly of St. Jude.

A-T and SCAN1 are caused by mutations in different enzymes involved in DNA repair. Mutations in the ATM protein lead to A-T. Alterations in the Tdp1 protein cause SCAN1.

Working in nerve cells growing in the laboratory and in the nervous system of specially bred mice, researchers showed for the first time that ATM and Tdp1 work cooperatively to repair breaks in DNA. Scientists also demonstrated how the proteins accomplish the task.

The results revealed a new role for ATM in repairing single-strand DNA breaks. Until this study, ATM was linked to double-strand DNA repair. ATM was also known to work exclusively as a protein kinase. Kinases are enzymes that use chemicals called phosphate groups to regulate other proteins.

Scientists reported that when Top1ccs are trapped ATM functions as a protein kinase and alert cells to the DNA damage. But researchers found ATM also serves a more direct role by marking the trapped Top1ccs for degradation by the protein complex cells use to get rid of damaged or unnecessary proteins. ATM accomplishes that task by promoting the addition of certain proteins called ubiquitin and SUMO to the Top1cc surface.

Tdp1 then completes the DNA-repair process by severing the chemical bonds that tether Top1 to DNA.

Mice lacking either Atm or Tdp1 survived with apparently normal neurological function. But compared to normal mice, the animals missing either protein had elevated levels of Top1cc. Those levels rose sharply during periods of rapid brain development and in response to radiation, oxidation and other factors known to cause breaks in DNA.

When researchers knocked out both Atm and Tdp1, Top1cc accumulation rose substantially as did a form of programmed cell death called apoptosis. Investigators reported that apoptosis was concentrated in the developing brain and few mice survived to birth. McKinnon said the results add to evidence that the brain is particularly sensitive to DNA damage.

Researchers then used the anti-cancer drug topotecan to link elevated levels of Top1cc to the cell death and other problems seen in mice lacking Atm and Tdp1. Topotecan works by trapping Top1ccs in tumor cells, resulting in the DNA damage that triggers apoptosis. Investigators showed that the impact of Top1cc accumulation was strikingly similar whether the cause was topotecan or the loss of Atm and Tdp1.

In a paper published in the latest issue of the neuroscience journal Neuron, McLean Hospital investigators report that a gene essential for normal brain development, and previously linked to Autism Spectrum Disorders, also plays a critical role in addiction-related behaviors.

"In our lab, we investigate the brain mechanisms behind drug addiction – a common and devastating disease with limited treatment options," explained Christopher Cowan, PhD, director of the Integrated Neurobiology Laboratory at McLean and an associate professor of Psychiatry at Harvard Medical School. "Chronic exposure to drugs of abuse causes changes in the brain that could underlie the transition from casual drug use to addiction. By discovering the brain molecules that control the development of drug addiction, we hope to identify new treatment approaches."

The Cowan lab team, led by Laura Smith, PhD, an instructor of Psychiatry at Harvard Medical School, used animal models to show that the fragile X mental retardation protein, or FMRP, plays a critical role in the development of addiction-related behaviors. FMRP is also the protein that is missing in Fragile X Syndrome, the leading single-gene cause of autism and intellectual disability. Consistent with its important role in brain function, the team found that cocaine utilizes FMRP to facilitate brain changes involved in addiction-related behaviors.

Cowan, whose work tends to focus on identifying novel genes related to conditions such as autism and drug addiction, explained that FMRP controls the remodeling and strength of connections in the brain during normal development. Their current findings reveal that FMRP plays a critical role in the changes in brain connections that occur following repeated cocaine exposure.

"We know that experiences are able to modify the brain in important ways. Some of these brain changes help us, by allowing us to learn and remember. Other changes are harmful, such as those that occur in individuals struggling with drug abuse," noted Cowan and Smith. "While FMRP allows individuals to learn and remember things in their environment properly, it also controls how the brain responds to cocaine and ends up strengthening drug behaviors. By better understanding FMRP’s role in this process, we may someday be able to suggest effective therapeutic options to prevent or reverse these changes."

An estimated 15-20 percent of U.S. troops returning from Iraq and Afghanistan suffer from some form of traumatic brain injury (TBI) sustained during their deployment, with most injuries caused by blast waves from exploded military ordnance. The obvious cognitive symptoms of minor TBI — including learning and memory problems — can dissipate within just a few days. But blast-exposed veterans may continue to have problems performing simple auditory tasks that require them to focus attention on one sound source and ignore others, an ability known as “selective auditory attention.”

According to a new study by a team of Boston University (BU) neuroscientists, such apparent “hearing” problems actually may be caused by diffuse injury to the brain’s prefrontal lobe — work that will be described at the 167th meeting of the Acoustical Society of America, to be held May 5-9, 2014 in Providence, Rhode Island.

"This kind of injury can make it impossible to converse in everyday social settings, and thus is a truly devastating problem that can contribute to social isolation and depression," explains computational neuroscientist Scott Bressler, a graduate student in BU’s Auditory Neuroscience Laboratory, led by biomedical engineering professor Barbara Shinn-Cunningham.

For the study, Bressler, Shinn-Cunningham and their colleagues — in collaboration with traumatic brain injury and post-traumatic stress disorder expert Yelena Bogdanova of VA Healthcare Boston — presented a selective auditory attention task to 10 vets with mild TBI and to 17 control subjects without brain injuries. Notably, on average, veterans had hearing within a normal range.

In the task, three different melody streams, each comprised of two notes, were simultaneously presented to the subjects from three different perceived directions (this variation in directionality was achieved by differing the timing of the signals that reached the left and right ears). The subjects were then asked to identify the “shape” of the melodies (i.e., “going up,” “going down,” or “zig-zagging”) while their brain activity was measured by electrodes on the scalp.

"Whenever a new sound begins, the auditory cortex responds, encoding the sound onset," Bressler explains. "Attentional focus, however, changes the strength of this response: when a listener is attending to a particular sound source, the neural activity in response to that sound is greater." This change of the neural response occurs because the brain’s "executive control" regions, located in the brain’s prefrontal cortex, send signals to the auditory sensory regions of the brain, modulating their response.

The researchers found that blast-exposed veterans with TBI performed worse on the task — that is, they had difficulty controlling auditory attention — “and in all of the TBI veterans who performed well enough for us to measure their neural activity, 6 out of our 10 initial subjects, the brain response showed weak or no attention-related modulation of auditory responses,” Bressler says.

"Our hope is that some of our findings can be used to develop methods to assess and quantify TBI, identifying specific factors that contribute to difficulties communicating in everyday settings," he says. "By identifying these factors on an individual basis, we may be able to define rehabilitation approaches and coping strategies tailored to the individual."

Some TBI patients also go on to develop chronic traumatic encephalopathy (CTE) — a debilitating progressive degenerative disease with symptoms that include dementia, memory loss and depression — which can now only be definitively diagnosed after death. “With any luck,” Bressler adds, “neurobehavioral research like ours may help identify patients at risk of developing CTE long before their symptoms manifest.”

Scientists have found that pressure from the fluid surrounding the brain plays a role in maintaining proper eye function, opening a new direction for treating glaucoma — the second leading cause of blindness worldwide. The research is being presented at the 2014 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) this week in Orlando, Fla. (Abstract Title: Effect of translaminar pressure modification on the rat optic nerve head).

Using a rat model, researchers found that elevating the pressure of the fluid surrounding the brain can counterbalance elevated pressure in the eye, preventing the optic nerve from bending backward. Rats with higher fluid pressure from the brain maintained their ability to respond to light better than rats with lower pressure.

The brain and eye are connected by the optic nerve. In diseases like glaucoma — where vision loss is associated with elevated pressure within the eye — the optic nerve bows backward, away from the eye and toward the brain. This investigation might explain why some people with normal eye pressure develop glaucoma, and why people with intraocular pressure never develop the condition.

A newly identified difference between the brains of women and men with multiple sclerosis (MS) may help explain why so many more women than men get the disease, researchers at Washington University School of Medicine in St. Louis report.

In recent years, the diagnosis of MS has increased more rapidly among women, who get the disorder nearly four times more than men. The reasons are unclear, but the new study is the first to associate a sex difference in the brain with MS.

(Image caption: An image of tissue from a female brain (left) affected by multiple sclerosis (MS) shows that the brain has much higher levels of a blood vessel receptor (shown in red) than a male brain affected by MS (right). The difference could help explain why so many more women get MS. Credit: Robyn Klein)

The findings appear May 8 in The Journal of Clinical Investigation.

Studying mice and people, the researchers found that females susceptible to MS produce higher levels of a blood vessel receptor protein, S1PR2, than males and that the protein is present at even higher levels in the brain areas that MS typically damages.

“It was a ‘Bingo!’ moment – our genetic studies led us right to this receptor,” said senior author Robyn Klein, MD, PhD. “When we looked at its function in mice, we found that it can determine whether immune cells cross blood vessels into the brain. These cells cause the inflammation that leads to MS.”

An investigational MS drug currently in clinical trials blocks other receptors in the same protein family but does not affect S1PR2. Klein recommended that researchers work to develop a drug that disables S1PR2.

MS is highly unpredictable, flaring and fading at irregular intervals and producing a hodgepodge of symptoms that includes problems with mobility, vision, strength and balance. More than 2 million people worldwide have the condition.

In MS, inflammation caused by misdirected immune cells damages a protective coating that surrounds the branches of nerve cells in the brain and spinal column. This leads the branches to malfunction and sometimes causes them to wither away, disrupting nerve cell communication necessary for normal brain functions such as movement and coordination.

For the new research, Klein studied a mouse model of MS in which the females get the disease more often than the males. The scientists compared levels of gene activity in male and female brains. They also looked at gene activity in the regions of the female brain that MS damages and in other regions the disorder typically does not harm.

They identified 20 genes that were active at different levels in vulnerable female brain regions. Scientists don’t know what 16 of these genes do. Among the remaining genes, the increased activity of S1PR2 stood out because researchers knew from previous studies that the protein regulates how easy it is for cells and molecules to pass through the walls of blood vessels.

Additional experiments showed that S1PR2 opens up the blood-brain barrier, a structure in the brain’s blood vessels that tightly regulates the materials that cross into the brain and spinal fluid. This barrier normally blocks potentially harmful substances from entering the brain. Opening it up likely allows the inflammatory cells that cause MS to get into the central nervous system.

When the researchers tested brain tissue samples obtained from 20 patients after death, they found more S1PR2 in MS patients’ brains than in people without the disorder. Brain tissue from females also had higher levels of S1PR2 than male brain tissue. The highest levels of S1PR2 were found in the brains of two female patients whose symptoms flared and faded irregularly, a pattern scientists call relapsing and remitting MS.

Klein is collaborating with chemists to design a tracer that will allow scientists to monitor S1PR2 levels in the brains of people while they are living. She hopes this will lead to a fuller understanding of how S1PR2 contributes to MS.

“This is an exciting first step in resolving the mystery of why MS rates are dramatically higher in women and in finding better ways to reduce the incidence of this disorder and control symptoms,” said Klein, associate professor of medicine. Klein also is an associate professor of pathology and immunology and of neurobiology and anatomy.

New research suggests that certain types of brain cells may be “picky eaters,” seeming to prefer one specific energy source over others. The finding has implications for understanding the cognitive decline seen in aging and degenerative diseases such as Alzheimer’s and multiple sclerosis.

(Image caption: Neural stem cells differentiate into three different cell types: neurons (purple), oligodendrocytes (red), which produce axon insulation, and astrocytes (green), which also support neurons. Cell nuclei are shown in blue. Credit: Liana Roberts Stein)

Studying mice, investigators from Washington University School of Medicine in St. Louis showed that a specific energy source called NAD is important in cells responsible for maintaining the overall structure of the brain and for performing complex cognitive functions. NAD (nicotinamide adenine dinucleotide) is a molecule that harvests energy from nutrients in food and converts it into a form cells can use.

The work appears in two journal articles — in the May 8 issue of The EMBO Journal, a publication of the European Molecular Biology Organization, and in a recent issue of The Journal of Neuroscience.

“We are interested in understanding how cells make NAD and what implications that has for cellular function, especially in the context of aging and longevity,” said Shin-ichiro Imai, MD, PhD, professor of developmental biology and of medicine and senior author of both papers. “We know, for example, NAD levels decrease with age in tissues such as muscle and fat. We wanted to find out if the same is true in the brain.”

The investigators looked at two types of brain cells: adult neural stem cells, responsible for maintaining supplies of neurons and their supporting cells, and forebrain neurons, vital for performing complex cognitive tasks.

In The EMBO Journal, they reported that NAD levels decreased with age in the mouse hippocampus, a vital region of the brain for cognition. The researchers then used genetic techniques to find out what would happen when NAD manufacturing is turned off in the adult neural stem cells of the mouse brain.

“Neural stem cells are very metabolically expensive, so you might expect them to be particularly vulnerable to loss of an energy source,” said first author Liana Roberts Stein, PhD, postdoctoral researcher in Imai’s lab. “There are other energy sources for brain cells, such as glucose, but no one had ever looked at where NAD is coming from in these cells.”

According to the researchers, there are four pathways of NAD synthesis, and the scientists focused on just one. They wanted to find out whether this particular pathway — a longtime focus of Imai’s lab — is important for these cells or if the other routes could compensate.

The pathway begins with the B vitamin nicotinamide. Cells take dietary nicotinamide and, with a helper protein called Nampt, manufacture a molecule called NMN, which then is processed further to make NAD. When Stein eliminated Nampt from neural stem cells, several significant changes took place.

Levels of NAD dropped, and the neural stem cells stopped dividing; they stopped renewing themselves; and they stopped being able to create important cells that insulate axons, the “wires” that carry electrical signals throughout the brain. With less insulation, these signals slow down, impairing brain function.

Imai and Stein pointed out possible therapeutic implications of this finding, especially in light of what is known about cognitive decline in aging and certain diseases.

“Scientists have shown that with age there actually isn’t a large decrease in the total neuron population,” Stein said. “But there is quite a substantial decrease in white matter, which is primarily composed of cells that function in axon insulation. This pathway also could be relevant in conditions involving loss of cells that make this insulation, like multiple sclerosis.”

Imai and Stein also found they could prevent the loss of the neural stem cells missing Nampt by giving the mice NMN, the next molecule in the chain of events leading to NAD.

“We gave the mice NMN in their drinking water for 12 months,” Stein said. “And at the higher dose, we saw a rescue of the neural stem cell pool in aged mice.”

Imai called this finding exciting because it supports the possibility of a future NMN supplement.

“We think that NMN could convey a similar effect in people,” Imai said. “A future clinical trial for NMN will tell us if it has any efficacy in humans.”

In addition to maintaining stem cell populations and keeping the brain supplied with all its cell types, the investigators showed that NAD also is vital for the process of cognition itself.

Reporting in The Journal of Neuroscience, they showed that neurons of the mouse forebrain depend heavily on NAD in normal cognitive function. Instead of deleting Nampt in stem cells, this time Stein deleted it only in neurons of the forebrain. All other cells were normal, including those that make axon insulation.

Without Nampt and its eventual product, NAD, in forebrain neurons, the behavior of the mice changed dramatically, according to the investigators.

“The mice were really hyperactive, with a twofold increase in activity levels,” Stein said. “They also showed a loss of anxiety-like behaviors. These mice didn’t seem to sense or fear potentially threatening situations and showed fairly drastic memory defects.”

Stein pointed out that these neurons are in a region of the brain known to be particularly vulnerable to neurodegenerative conditions from Alzheimer’s disease to stroke.

“It’s possible that these neurons’ dependence on Nampt is responsible for their extreme susceptibility to these conditions,” she said. “It would be interesting to model some of these diseases in mice and see if supplementing NMN provides any benefit to their behavior or memory.”

“We haven’t done that study yet,” Imai added. “But this is the direction the entire field is going.”

When emotions are processed in a negatively biased manner in the brain, an individual is at risk to develop depression. Psilocybin, the bioactive component of the Mexican magic mushroom, seems to intervene positively in the emotion-processing mechanism. Even a small amount of the natural substance attenuates the processing of negative emotions and brightens mood as shown by UZH researchers using imaging methods.

Emotions like fear, anger, sadness, and joy enable people to adjust to their environment and react flexibly to stress and strain and are vital for cognitive processes, physiological reactions, and social behaviour. The processing of emotions is closely linked to structures in the brain, i.e. to what is known as the limbic system. Within this system the amygdala plays a central role – above all it processes negative emotions like anxiety and fear. If the activity of the amygdala becomes unbalanced, depression and anxiety disorders may develop.

Researchers at the Psychiatric University Hospital of Zurich have now shown that psilocybin, the bioactive component in the Mexican magic mushroom, influences the amygdala, thereby weakening the processing of negative stimuli. These findings could “point the way to novel approaches to treatment” comments the lead author Rainer Krähenmann on the results which have now been published in the renowned medical journal “Biological Psychiatry”.

Psilocybin inhibits the processing of negative emotions in the amygdala

The processing of emotions can be impaired by various causes and elicit mental disorders. Elevated activity of the amygdala in response to stimuli leads to the neurons strengthening negative signals and weakening the processing of positive ones. This mechanism plays an important role in the development of depression and anxiety disorders. Psilocybin intervenes specifically in this mechanism as shown by Dr. Rainer Krähenmann’s research team of the Neuropsychopharmacology and Brain Imaging Unit led by Prof. Dr. Franz Vollenweider.

Psilocybin positively influences mood in healthy individuals. In the brain, this substance stimulates specific docking sites for the messenger serotonin. The scientists therefore assumed that psilocybin exerts its mood-brightening effect via a change in the serotonin system in the limbic brain regions. This could, in fact, be demonstrated using functional magnetic resonance imaging (fMRI). “Even a moderate dose of psilocybin weakens the processing of negative stimuli by modifying amygdala activity in the limbic system as well as in other associated brain regions”, continues Krähenmann. The study clearly shows that the modulation of amygdala activity is directly linked to the experience of heightened mood.

Next study with depressive patients

According to Krähenmann, this observation is of major clinical importance. Depressive patients in particular react more to negative stimuli and their thoughts often revolve around negative contents. Hence, the neuropharmacologists now wish to elucidate in further studies whether psilocybin normalises the exaggerated processing of negative stimuli as seen in neuroimaging studies of depressed patients - and may consequently lead to improved mood in these patients.

Rainer Krähenmann considers research into novel approaches to treatment very important, because current available drugs for the treatment of depression and anxiety disorders are not effective in all patients and are often associated with unwanted side effects.

Premature menopause is associated with long-term negative effects on cognitive function, suggests a new study published today (7 May) in BJOG: An International Journal of Obstetrics and Gynaecology (BJOG).

The average age of menopause is around 50 years in the Western World. Premature menopause refers to menopause at or before 40 years of age, this could be due to a bilateral ovariectomy, (surgically induced menopause)or non-surgical loss of ovarian function (sometimes referred to as ‘natural’ menopause).

The study, based on a sample of 4868 women, used cognitive tests and clinical dementia diagnosis at baseline and after two, four and seven years and aimed to determine whether premature menopause can have an effect on later-life cognitive function. The effects of the type of menopause, whether natural or surgical, and use of hormone treatment were also examined.

Of the 4,868 women in this study, natural menopause was reported by 79% of the women, 10% as a surgical menopause and 11% of women reported menopause due to other causes, such as radiation or chemotherapy. Around 7.6% of the women in the study had a premature menopause and a further 12.8% an early menopause (between the ages of 41 and 45 years). Over a fifth of the women used hormone treatment during the menopause.

Results show that in comparison to women who experienced menopause after the age of 50, those with a premature menopause had a more than 40% increased risk of poor performance on tasks assessing verbal fluency and visual memory and was associated with a 35% increased risk of decline in psychomotor speed (coordination between the brain and the muscles that brings about movement) and overall cognitive function over 7 years. There was no significant association with the risk of dementia.

Furthermore, both premature ovarian failure and premature surgical menopause were associated with a more than two-fold risk of poor verbal fluency. In terms of visual memory, premature ovarian failure was associated with a significantly increased risk of poor performance, and there was a similar trend for premature surgical menopause.

When the potential modifying effect of using hormone treatment at the time of premature menopause was examined, there was some evidence that it may be beneficial for visual memory, but it could increase the risk of poor verbal fluency.

Dr Joanne Ryan, Postdoctoral Research Fellow, Neuropsychiatry: Epidemiological and Clinical Research, Hospital La Colombiere, Montpellier, said:

“Both premature surgical menopause and premature ovarian failure, were associated with long-term negative effects on cognitive function, which are not entirely offset by menopausal hormone treatment.

“In terms of surgical menopause, our results suggest that the potential long-term effects on cognitive function should form part of the decision-making process when considering ovariectomy in younger women.”

Pierre Martin Hirsch, BJOG deputy editor-in-chief added:

“With the ageing population it is important to have a better understanding of the long term effects of a premature menopause on later-life cognitive function and the potential benefit from using menopausal hormone treatment.

“This study adds to the existing evidence base to suggest premature menopause can have a significant impact on cognitive function in later life which healthcare professionals must be aware of.”

Scientists have been linking an increasing range of behaviors and inclinations from monogamy to addiction to animals’, including humans’, underlying biology. To that growing list, they’re adding division of labor — at least in killer bees. A report published in ACS’ Journal of Proteome Research presents new data that link the amounts of certain neuropeptides in these notorious bees’ brains with their jobs inside and outside the hive.

Mario Sergio Palma and colleagues explain that dividing tasks among individuals in a group is a key development in social behavior among Hymenoptera insects, which include bees, ants, sawflies and wasps. One of the starkest examples of this division of labor is the development of “castes,” which, through nutrition and hormones, results in long-lived queens that lay all the thousands of eggs in a colony and barren workers that forage for food and protect the hive. Bee researchers had already observed that honeybees, including Africanized Apis mellifera, better known as “killer” bees, divide tasks by age. As workers get older, their roles change from nursing and cleaning the hive to guarding and foraging. Palma’s team wanted to see whether peptides in the brain were associated with the bees’ shifting duties.

They found that the amounts of two substances varied by time and location in the brains of the honeybees in a way that mirrored the timing of their changing roles. “Thus, these neuropeptides appear to have some functions in the honeybee brain that are specifically related to the age-related division of labor,” the scientists conclude.

Extraordinarily complex networks of circuits that transmit signals from the brain to the spinal cord control voluntary movements. Researchers have been challenged to identify the controlling circuits, but they lacked the tools needed to dissect, at the neural level, the way the brain produces voluntary movements.

Recently, Dr. John Martin, medical professor in City College’s Sophie Davis School of Biomedical Education, postdoctoral fellow Dr. Najet Serradi and other colleagues employed a sensitive genetic technique that eliminated a particular gene in the cerebral cortex and, in the process, changed the circuitry.

The team hypothesized that the corticospinal tract, which stretches from cerebral cortex to the spinal cord, is important for voluntary reaching movements, but not for more routine and stereotypic walking movements. “We reasoned that if we genetically altered the corticospinal tract we would affect voluntary reaching movements, but not walking.” Professor Martin said.

In genetically intact mice, corticospinal tract signals are transmitted from one side of the cerebral cortex to the opposite side of the spinal cord. Such mice reach with one arm, or the other – but not both arms together.

Professor Martin and colleagues used specially bred mice, i.e. knockout mice, with the gene EphA4 removed from the cerebral cortex. These mice reached with both forelimbs together, rather than with one. This happened because the genetic manipulation changed the circuit; it caused the signal to move to be transmitted from one side of the cerebral cortex to both sides of the spinal cord.

However, their stereotypic walking was unaffected. Professor Martin said this shows that while voluntary movements depend on the corticospinal tract walking depends on circuits in other parts of the brain and spinal cord, which are not affected by the gene manipulation.

The findings, he added, “etch away at the vexing problem of achieving a deeper understanding of how the brain functions in voluntary movement.” In addition greater knowledge of how voluntary circuits function could lead to new understanding of cerebral palsy, a condition in which the corticospinal tract is injured around the time of birth and people often make “mirror movements” of both arms when they intend to move only one, he said.

The research, which is funded by the National Institute of Neurological Diseases and Stroke, aims to understand the brain and spinal cord circuits for voluntary movement. Using similar genetic tools, his team hopes to further dissect the connections and functions of the corticospinal tract movement circuits in ways to restore movements after brain or spinal cord injury.

A collaborative discovery involving Kansas State University researchers may lead to the first universal treatment for dystonia, a neurological disorder that affects nearly half a million Americans.

Michal Zolkiewski, associate professor of biochemistry and molecular biophysics at Kansas State University, and Jeffrey Brodsky at the University at Pittsburgh co-led a study that focused on a mutated protein associated with early onset torsion dystonia, or EOTD, the most severe type of dystonia that typically affects adolescents before the age of 20. Dystonia causes involuntary and sustained muscle contractions that can lead to paralysis and abnormal postures.

"It’s a painful and debilitating disease for which there is no cure or treatment that would be effective for all patients," Zolkiewski said. "There are some treatments that are being tested, but nothing is really available to those patients that would cure the symptoms completely."

In addition to Zolkiewski and Brodsky, researchers involved in the study included Hui-Chuan Wu, Kansas State University doctoral student in biochemistry and molecular biophysics, Taiwan, and colleagues at the University of Texas Southwestern Medical Center and the University of Adelaide in Australia.

The Journal of Biological Chemistry recently published the team’s study, "The BiP molecular chaperone plays multiple roles during the biogenesis of TorsinA, a AAA+ ATPase associated with the neurological disease Early-Onset Torsion Dystonia." The study was funded by the Dystonia Medical Research Foundation.

Researchers built the study on a decade-old discovery that patients with early onset torsion dystonia typically have a mutated gene that encodes the protein TorsionA.

"TorsinA is a protein that all people have in their bodies," Zolkiewski said. "It appears to perform an important role in the nervous system, but currently nobody knows what that role is. There also is no understanding of the link between the mutation and dystonia."

In order to study protein expression in a living organism, researchers used yeast — one of the simplest living systems. The yeast was engineered to produce the human protein TorsionA.

Observations revealed that a second protein named BiP — pronounced “dip” — helps process the TorsinA protein and maintain its active form. Additionally, researchers found that BiP also guides TorsinA to being destroyed by cells if the protein is defective. Humans carry the BiP protein as well as the TorsinA protein.

"BiP is a molecular chaperone that assists other proteins in maintaining their function," Zolkiewski said. "In this study we found that BiP really has a dual role. On one hand it’s helping TorsinA and on the other it’s leading to its degradation."

Future studies may focus on BiP as a target for treating dystonia, as modulating BiP in human cells would affect TorsinA, Zolkiewski said.

"Because we don’t know what exactly the function of TorsinA is, we may not be able to design a treatment based on that protein," Zolkiewski said. "We know what BiP does, however. It is a pretty well-studied chaperone, which makes it much easier to work with."

Automation in the cockpit is traditionally believed to free pilots’ attention from mundane flight tasks and allow them to focus on the big picture or prepare for any unexpected events during flight. However, a new study published in Human Factors indicates that pilots may have a hard time concentrating on the automated systems that now carry out many of the tasks once completed by humans.

“The automated systems in today’s cockpits assume many of the tasks formerly performed by human pilots and do it with impressive reliability,” says Stephen Casner, coauthor of “Thoughts in Flight: Automation Use and Pilots’ Task-Related and Task-Unrelated Thought” and research psychologist at NASA’s Ames Research Center. “This leaves pilots to watch over the automation as it does its work, but people can only concentrate on something uneventful for so long. Humans aren’t robots. We can’t stare at a green light for hours at a stretch without getting tired, bored, or going crazy.”

Researchers Casner and coauthor Jonathan Schooler designed a flight simulation study in which they asked pilots to follow a published arrival procedure into New York’s busy John F. Kennedy International Airport. As the pilots navigated the flight, they were asked about what they were thinking during various levels of automation and to assign their thoughts to three categories: the specific task at hand, higher-level thoughts (for example planning ahead), or thoughts unrelated to the flight (e.g., what’s for dinner).

The pilots reported an increase in big-picture flight-related thoughts when using higher levels of automation, but when the flight was progressing according to plan and pilots were not interacting with the automation, their thoughts were more likely to wander.

“The mind is restless,” says Schooler, a professor of psychological and brain sciences at the University of California, Santa Barbara. “When we’re not given something specific to think about, we come up with something else to think about.”

“Pilots limited their off-task thoughts to times in which the automation was doing the flying and all was going according to plan,” adds Casner. “Nevertheless, there seem to be potential costs to situations in which pilots disengage from a highly-automated task. What happens when something suddenly goes amiss after long periods of uneventful flight?”

The study’s authors concluded that although automation frees pilots’ minds from tedious tasks and enables them to focus on the overall flight, it might inadvertently encourage them to devote time to unrelated thoughts. Casner notes that on the basis of these findings, researchers studying cockpit automation might consider rethinking the interaction between humans and machines.

“As technology grows in capability, we seem to be taking the approach of using humans as safety nets for computers,” he says. “We need to sort out the strengths and weaknesses of both humans and computers and think of work environments that combine and exploit the best features of both to keep humans meaningfully engaged in their work.”

George Washington University (GW) researcher David Mendelowitz, Ph.D., was recently published in the Journal of Neuroscience for his research on how heart rate increases in response to alertness in the brain. Specifically, Mendelowitz looked at the interactions between neurons that fire upon increased attention and anxiety and neurons that control heart rate to discover the “why,” “how,” and “where to next” behind this phenomenon.

“This study examines how changes in alertness and focus increase your heart rate,” said Mendelowitz, vice chair and professor of pharmacology and physiology at the GW School of Medicine and Health Sciences. “If you need to focus on a new task at hand, or suddenly need to become more alert, your heart rate increases. We sought to understand the mechanisms of how that happens.”

While the association between vigilance and increased heart rate is long accepted, the neurobiological link had not yet been identified. In this study, Mendelowitz found that locus coeruleus (LC) noradrenergic neurons — neurons critical in generating alertness — directly influence brainstem parasympathetic cardiac vagal neurons (CVNs) — neurons responsible for controlling heart rate. LC noradrenergic neurons were shown to inhibit the brainstem CVNs that generate parasympathetic activity to the heart. The receptors activated within this pathway may be targets for new drug therapies to promote slower heart rates during heightened states.

“Our results have important implications for how we may treat certain conditions in the future, such as post-traumatic stress disorder, chronic anxiety, or even stress,” said Mendelowitz. “Understanding how these events alter the cardiovascular system gives us clues on how we may target these pathways in the future.”