Neuroscience

Symmetry is an inherent part of development. As an embryo, an organism’s brain and spinal cord, like the rest of its body, organize themselves into left and right halves as they grow. But a certain set of nerve cells do something unusual: they cross from one side to the other. New research in mice delves into the details of the molecular interactions that help guide these neurons toward this anatomical boundary.

In an embryo, a neuron’s branches, or axons, have special structures on their tips that sense chemical cues telling them where to grow. The new findings, by researchers at Memorial Sloan Kettering Cancer Center and The Rockefeller University, reveal the structural details of how one such cue, Netrin-1, interacts with two sensing molecules on the axons, DCC and a previously less well characterized player known as neogenin, as a part of this process.

“Our work provides the first high-resolution view of the molecular complexes that form on the surface of a developing axon and tell it to move in one direction or another,” says Dimitar Nikolov, a structural biologist at Memorial Sloan Kettering. “This detailed understanding of these assemblies helps us better understand neural wiring, and may one day be useful in the development of drugs to treat spinal cord or brain injuries.”

In a developing nervous system, the signaling molecule, Netrin-1, identified by Rockefeller University Professor Marc Tessier-Lavigne and colleagues, can guide neurons by attracting or repulsing them. In the case of axons that cross from one side to the other, extended by so-called commissural neurons, Netrin-1 attracts them toward the middle.

With a technique that uses X-rays to visualize the structure of crystalized proteins, research scientist Kai Xu and colleagues in Nikolov’s laboratory revealed that Netrin-1 has two separate binding sites on opposite ends, enabling it to simultaneously bind to different receptors. This may explain how Netrin-1, which is an important axon-guiding molecule, can affect in different ways neurons that express different combinations of receptors, Nikolov says.

For some time, scientists have known commissural neurons used the receptor molecule DCC to detect Netrin-1. Neogenin has a structure similar to DCC, and this research, described today in Science, confirms neogenin too acts as a sensing molecule for commissural neurons in mammals.

In experiments that complemented the structural work, conducted by Nicolas Renier and Zhuhao Wu in Tessier-Lavigne’s lab, the researchers confirmed that, like DCC, neogenin senses Netrin-1 for the growing commissural neurons in mice.

These neurons are part of the system by which one side of the brain controls movement on the opposite side of the body. As a result, a mutation in the gene responsible for DCC interferes with this coordination, causing congenital mirror movement disorder. People with this disorder cannot move one side of the body in isolation; for example, a right-handed wave is mirrored by a similar gesture by the left hand.

The work also has implications for understanding why DCC, neogenin and other cell-surface receptors come in slightly different forms, called splice isoforms. The structural research revealed these isoforms bind differently to Netrin-1. However, it is not yet clear what this means for neuron wiring, Nikolov says.

“With this structural knowledge, and with the identification of an additional receptor involved in axon guidance in the spinal cord, we are gaining deeper insight into the mechanisms through which neurons make connections that produce a functioning nervous system, as well as the dysfunction that arises from miswiring of connections” says Tessier-Lavigne.

New research from the Monell Chemical Senses Center reveals that women’s faces are rated as more attractive in the presence of pleasant odors. In contrast, odor pleasantness had less effect on the evaluation of age. The findings suggest that the use of scented products such as perfumes may, to some extent, alter how people perceive one another.

“Odor pleasantness and facial attractiveness integrate into one joint emotional evaluation,” said lead author Janina Seubert, PhD, a cognitive neuroscientist who was a postdoctoral fellow at Monell at the time the research was conducted. “This may indicate a common site of neural processing in the brain.”

Perfumes and scented products have been used for centuries as a way to enhance overall personal appearance. Previous studies had shown perception of facial attractiveness could be influenced when using unpleasant vs. pleasant odors. However, it was not known whether odors influence the actual visual perception of facial features or alternatively, how faces are emotionally evaluated by the brain.

The current study design centered on the principle that judging attractiveness and age involve two distinct perceptual processing methods: attractiveness is regarded as an emotional process while judgments of age are believed to be cognitive, or rationally-based.

In the study, published in open access journal PLOS ONE, 18 young adults, two thirds of whom were female, were asked to rate the attractiveness and age of eight female faces, presented as photographs. The images varied in terms of natural aging features.

While evaluating the images, one of five odors was simultaneously released. These were a blend of fish oil (unpleasant) and rose oil (pleasant) that ranged from predominantly fish oil to predominantly rose oil. The subjects were asked to rate the age of the face in the photograph, the attractiveness of the face and the pleasantness of the odor.

Across the range of odors, odor pleasantness directly influenced ratings of facial attractiveness. This suggests that olfactory and visual cues independently influence judgments of facial attractiveness.

With regard to the cognitive task of age evaluation, visual age cues (more wrinkles and blemishes) were linked to older age perception. However, odor pleasantness had a mixed effect. Visual age cues strongly influenced age perception during pleasant odor stimulation, making older faces look older and younger faces look younger. This effect was weakened in the presence of unpleasant odors, so that younger and older faces were perceived to be more similar in age.

Jean-Marc Dessirier, Lead Scientist at Unilever and a co-author on the study said, “These findings have fascinating implications in terms of how pleasant smells may help enhance natural appearance within social settings. The next step will be to see if the findings extend to evaluation of male facial attractiveness.”

A new treatment for drug-resistant epilepsy with the potential to suppress seizures ‘on demand’ with a pill, similar to how you might take painkillers when you feel a headache coming on, has been developed by UCL researchers funded by the Wellcome Trust.

The treatment, described in Nature Communications, combines genetic and chemical approaches to suppress seizures without disrupting normal brain function. The technique was demonstrated in rodents but in future we could see people controlling seizures on-demand with a simple pill.

Epilepsy affects around 50 million people worldwide including 600,000 in the UK and around a quarter of cases are resistant to conventional treatments. Many of these cases could be addressed by the new treatment method, which relies on genetic modification of brain cells to make them sensitive to a normally inactive compound.

“First, we inject a modified virus into the area of the brain where seizures arise,” explains Professor Dimitri Kullmann of the UCL Institute of Neurology, senior author of the research. “This virus instructs the brain cells to make a protein that is activated by CNO (clozapine-N-oxide), a compound that can be taken as a pill. The activated protein then suppresses the over-excitable brain cells that trigger seizures, but only in the presence of CNO.

“At the moment, severe seizures are treated with drugs that suppress the excitability of all brain cells, and patients therefore experience side effects. Sometimes the dose required to stop seizures is so high that patients need to be sedated and taken to intensive care. If we can take our new method into the clinic, which we hope to do within the next decade, we could treat patients who are susceptible to severe seizures with a one-off injection of the modified virus, and then use CNO only when needed.

“CNO would be given as a pill in the event that patients could predict when seizures were likely to occur. For example, many people with treatment-resistant epilepsy experience clusters of seizures, where severe seizures are preceded by smaller ones. Seizure risk is also high when people are ill, sleep deprived, or at certain times of the menstrual cycle, so these would all be good times to take the pill as a preventative measure. In urgent situations, the compound could be given as an injection. We could even consider a fully automatic delivery system, where CNO was given by a pump, as is done for insulin in some people with diabetes.”

As CNO has a half-life of about a few hours and only affects the pre-treated epileptic parts of the brain, the new method avoids the need to permanently alter the brain or treat the whole brain with seizure-suppressing drugs. It builds on similar work by Professor Kullmann’s group using gene therapy to ‘calm down’ brain cells, or using light pulses to activate seizure-suppressing receptors in the brain. The new technique works in a similar way but is reversible and avoids the need for invasive devices to deliver light to the brain.

“After the one-off injection into affected areas of the brain, our new technique would require nothing beyond CNO, administered as an injection or a pill, to suppress seizures when required,” says Professor Kullmann. “This makes it more attractive than alternative forms of targeted therapy such as surgery to remove the brain region where seizures arise, or gene therapy that permanently alters the excitability of brain cells.

“Although there is currently no evidence that permanently suppressing excitability in a small area affects brain function, we cannot be sure that it would have no impact long-term. Our new method is completely reversible, so if there were any side-effects then people could simply stop taking the CNO pill.”

Virginia Commonwealth University School of Medicine researchers have uncovered a new mechanism of action of fingolimod, a drug widely used to treat multiple sclerosis: elimination of adverse or traumatic memories.

The findings shed light on how the drug works on the molecular level – something that has not been well understood until now.

Fingolimod, or FTY720, which is the first orally available drug for treatment of multiple sclerosis, works by suppressing the immune system. Fingolimod is a prodrug that is phosphorylated in the body to its active form, FTY720-phosphate.

In a study published by the Nature Neuroscience journal on May 25 as an Advanced Online Publication, researchers used a mouse model to show that fingolimod accumulates in the brain and inhibits histone deacetylases, which are enzymes important to regulate gene expression. The team observed an increased expression of a limited number of genes important for certain memory processes. Fingolimod acted similarly to the natural signaling lipid, sphingosine-1-phosphate, which it closely resembles.

“Our work suggests that some of the beneficial effects of FTY720/fingolimod that are not well understood might be mediated by this new activity that we have discovered,” said first author Sarah Spiegel, Ph.D., an internationally renowned researcher and professor and chair of the Department of Biochemistry and Molecular Biology in the VCU School of Medicine.

“It will be important in the future to determine whether this prodrug can reduce loss of cognitive functions and can erase adverse memories,” she said.

Spiegel added that other histone deacetylase inhibitors have long been used for treatment of psychiatric and neurological disorders, yet the mechanism of their effectiveness is not fully understood.

“FTY720/fingolimod may be a useful adjuvant therapy to help stop aversive memories such as in post-traumatic stress disorder and other anxiety disorders,” Spiegel said.

“The work has not been extended to show effectiveness in humans at this time. We are still working to fully understand the molecular underpinnings of the drug and its link to memory,” she said.

The work is based on previous findings by Spiegel’s group that were published in Science in 2009. They had reported that sphingosine-1-phosphate formed in the nucleus of cells is a natural inhibitor of histone deacetylases and a regulator of gene expression.

Puberty is the defining process of adolescent development, beginning a cascade of changes throughout the body, including the brain. Penn Medicine researchers have discovered that cerebral blood flow (CBF) levels decreased similarly in males and females before puberty, but saw them diverge sharply in puberty, with levels increasing in females while decreasing further in males, which could give hints as to developing differences in behavior in men and women and sex-specific pre-dispositions to certain psychiatric disorders. Their findings are available in Proceedings of the National Academy of Science (PNAS).

"These findings help us understand normal neurodevelopment and could be a step towards creating normal ‘growth charts’ for brain development in kids. These results also show what every parent knows: boys and girls grow differently. This applies to the brain as well," says Theodore D. Satterthwaite, MD, MA, assistant professor in the Department of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania. "Hopefully, one day such growth charts might allow us to identify abnormal brain development much earlier before it leads to major mental illness."

Studies on structural brain development have shown that puberty is an important source of sex differences. Previous work has shown that CBF declines throughout childhood, but the effects of puberty on properties of brain physiology such as CBF, also known as cerebral perfusion, are not well known. “We know that adult women have higher blood flow than men, but it was not clear when that difference began, so we hypothesized that the gap between women and men would begin in adolescence and coincide with puberty,” Satterthwaite says.

The Penn team imaged the brains of 922 youth ages 8 through 22 using arterial spin labeled (ASL) MRI. The youth were all members of the Philadelphia Neurodevelopmental Cohort, a National Institute of Mental Health-funded collaboration between the University of Pennsylvania Brain Behavior Laboratory and the Center for Applied Genomics at the Children’s Hospital of Philadelphia.

They found support for their hypothesis.

Age related differences were observed in the amount and location of blood flow in males versus females, with blood flow declining at a similar rate before puberty and diverging markedly in mid-puberty. At around age 16, while male CBF values continue to decline with advanced age, females CBF values actually increased. This resulted in females having notably higher CBF than males by the end of adolescence. The difference between males and females was most notable in parts of the brain that are critical for social behaviors and emotion regulation such as the orbitofrontal cortex. The researchers speculate that such differences could be related to females’ well-established superior performance on social cognition tasks. Potentially, these effects could also be related to the higher risk in women for depression and anxiety disorders, and higher risk of flat affect and schizophrenia in men.

Researchers reveal that neurons can utilize a supremely localized internal store of calcium to initiate the secretion of neuropeptides, one class of signaling molecules through which neurons communicate with each other and with other cells. The study appears in The Journal of General Physiology.

(Image caption: Localization of ryanodine receptors (red) in an isolated nerve terminal from the posterior pituitary gland. Image credit: McNally et al., 2014)

Neuropeptides are released from neurons through a process that—like other secretory events—is triggered primarily by the influx of calcium into the neuron through voltage-gated channels. Although neuropeptides are stored in large dense core vesicles (LDCVs) that also contain large amounts of calcium, it has been unclear whether these locally based calcium supplies can also be used to modulate secretion.

A team of researchers led by José Lemos from the University of Massachusetts Medical School examined the mechanisms at play during secretion of vasopressin from nerve terminals in the posterior pituitary gland, which releases the neuropeptide into the blood so that it can make its way to the kidney and regulate water retention. The researchers found that certain intracellular calcium channels known as ryanodine receptors are likely responsible for mobilizing calcium from LDCVs to facilitate vasopressin release. The findings indicate that neurons have a greater capacity than previously appreciated to fine-tune the release of neuropeptides and thereby their communications with other cells.

Research presented by Dr. Lynn Raymond, from the University of British Columbia, shows that blocking a specific class of glutamate receptors, called extrasynaptic NMDA receptors, can improve motor learning and coordination, and prevent cell death in animal models of Huntington disease. As Huntington disease is an inherited condition that can be detected decades before any clinical symptoms are seen in humans, a better understanding of the earliest changes in brain cell (neuronal) function, and the molecular pathways underlying those changes, could lead to preventive treatments that delay the onset of symptoms and neurodegeneration. “After more than a decade of research on the pre-symptomatic phase of Huntington disease, markers are being developed to facilitate assessment of interventional therapy in individuals carrying the genetic mutation for Huntington disease, before they become ill. This will make it possible to delay onset of disease,” says Dr. Raymond. These results were presented at the 2014 Canadian Neuroscience Meeting, the 8th annual meeting of the Canadian Association for Neuroscience - Association Canadienne des Neurosciences (CAN-ACN), held in Montreal, May 25-28.

The neurotransmitter glutamate has long been known to promote cell death, and its toxic effects occur through the action of a family of receptors known as the NMDARs (N-methyl-D-Aspartate ionotropic glutamate receptors). Unfortunately, treating disorders of the nervous system by blocking NMDARs has not been successful because such treatments have numerous side effects. A recent hypothesis based on work from many scientists suggests that NMDARs located in different regions at the surface of neurons may have opposite effects, which would explain why blocking all NMDARs is not a good treatment option. A synapse is a structure that allows one neuron to connect to another neuron and pass an electrical or chemical signal between them. Many receptors for neurotransmitters are located in synapses, as these are the main area where these chemical signals are transmitted. However, receptors can also be found outside the synapse, and in this case are called extra-synaptic receptors. Many recent studies have revealed that NMDARs located at synapses act to increase survival signaling and promote learning and memory, whereas extra-synaptic NMDARs shut off survival signaling, interfere with learning mechanisms, and increase cell death pathways.

Dr. Raymond and her team were able, by using a drug that selectively blocks extra-synaptic NMDARs early, before the appearance of any symptoms, to delay the onset of Huntington-like symptoms in a mouse model of the disease. These promising results could lead to new treatment avenues for Huntington patients, and delay the appearance of symptoms. “The drug we used, memantine, is currently being used to treat moderate-stage Alzheimer disease patients. Our results suggest that clinical studies of memantine and similarly-acting drugs in Huntington disease, particularly in the pre-symptomatic stage, are warranted,”says Dr. Raymond.

Extra-synaptic NMDARs have also been shown to be involved in other neurodegenerative diseases, such as Alzheimer disease, and in damage caused by traumatic brain injury and some forms of stroke. These results therefore suggest novel treatment avenues for many conditions in which neurons degenerate and die, a new way to protect neurons before the appearance of symptoms of neurodegeneration.

‘Seeing is believing’, so the idiom goes, but new research suggests vision also involves a bit of hearing.

Scientists studying brain process involved in sight have found the visual cortex also uses information gleaned from the ears as well as the eyes when viewing the world.

They suggest this auditory input enables the visual system to predict incoming information and could confer a survival advantage.

Professor Lars Muckli, of the Institute of Neuroscience and Psychology at the University of Glasgow, who led the research, said: “Sounds create visual imagery, mental images, and automatic projections.

“So, for example, if you are in a street and you hear the sound of an approaching motorbike, you expect to see a motorbike coming around the corner. If it turned out to be a horse, you’d be very surprised.”

The study, published in the journal Current Biology, involved conducting five different experiments using functional Magnetic Resonance Imaging (fMRI) to examine the activity in the early visual cortex in 10 volunteer subjects.

In one experiment they asked the blindfolded volunteers to listen to three different sounds – birdsong, traffic noise and a talking crowd.

Using a special algorithm that can identify unique patterns in brain activity, the researchers were able to discriminate between the different sounds being processed in early visual cortex activity.

A second experiment revealed even imagined images, in the absence of both sight and sound, evoked activity in the early visual cortex.

Lars Muckli said: “This research enhances our basic understanding of how interconnected different regions of the brain are. The early visual cortex hasn’t previously been known to process auditory information, and while there is some anatomical evidence of interconnectedness in monkeys, our study is the first to clearly show a relationship in humans.

“In future we will test how this auditory information supports visual processing, but the assumption is it provides predictions to help the visual system to focus on surprising events which would confer a survival advantage.

“This might provide insights into mental health conditions such as schizophrenia or autism and help us understand how sensory perceptions differ in these individuals.”

Children with profound deafness who receive a cochlear implant had as much as five times the risk of having delays in areas of working memory, controlled attention, planning and conceptual learning as children with normal hearing, according to Indiana University research published May 22 in the Journal of the American Medical Association Otolaryngology—Head and Neck Surgery.

The authors evaluated 73 children implanted before age 7 and 78 children with normal hearing to determine the risk of deficits in executive functioning behaviors in everyday life.

Executive functioning, a set of mental processes involved in regulating and directing thinking and behavior, is important for focusing and attaining goals in daily life. All children in the study had average to above-average IQ scores. The results, reported in “Neurocognitive Risk in Children With Cochlear Implants,” are the first from a large-scale study to compare real-world executive functioning behavior in children with cochlear implants and those with normal hearing.

A cochlear implant device consists of an external component that processes sound into electrical signals that are sent to an internal receiver and electrodes that stimulate the auditory nerve. Although the device restores the ability to perceive many sounds to children who are born deaf, some details and nuances of hearing are lost in the process.

First author William Kronenberger, Ph.D., professor of clinical psychology in psychiatry at the IU School of Medicine and a specialist in neurocognitive and executive function testing, said that delays in executive functioning have been commonly reported by parents and others who work with children with cochlear implants. Based on these observations, his group sought to evaluate whether elevated risks of delays in executive functioning in children with cochlear implants exist, and what components of executive functioning were affected.

"In this study, about one-third to one-half of children with cochlear implants were found to be at-risk for delays in areas of parent-rated executive functioning such as concept formation, memory, controlled attention and planning. This rate was 2 to 5 times greater than that seen in normal-hearing children," reported Dr. Kronenberger, who also is co-chief of the ADHD-Disruptive Behavior Disorders Clinic and directs the psychology testing clinic at Riley Hospital for Children at IU Health.

"This is really innovative work," said co-author David B. Pisoni, Ph.D., director of the Speech Research Laboratory in the IU Department of Psychological and Brain Sciences. "Almost no one has looked at these issues in these children. Most audiologists, neuro-otologists, surgeons and speech-language pathologists — the people who work in this field — focus on the hearing deficit as a medical condition and have been less focused on the important discoveries in developmental science and cognitive neuroscience." Dr. Pisoni also is a Chancellors’ Professor of Psychological and Brain Sciences at IU Bloomington.

Richard Miyamoto, M.D., chair of the IU School of Medicine Department of Otolaryngology-Head and Neck Surgery and a pioneer in the field of cochlear implantation in children and adults, said this finding augments other research on interventions to help children with cochlear implants perform at a level similar to children without hearing deficits.

"The ultimate goal of our department’s research with cochlear implants has always been to influence higher-level neurocognitive functioning," Dr. Miyamoto said. "Much of the success we have seen to date clearly relates to the brain’s ability to process an incomplete signal. The current research will further assist in identifying gaps in our knowledge."

One possible answer may lie in earlier implantation, Dr. Miyamoto said. The age at which children are implanted has been steadily decreasing, which has produced significant improvement in spoken language outcomes. Research shows the early implantation is related to better outcomes in speech and understanding, and it is reasonable to believe that there may be less of a deficit in executive functioning with earlier implantation, said Dr. Miyamoto, who is the Arilla Spence DeVault Professor of Otolaryngology-Head and Neck Surgery and medical director of audiology and speech language pathology at the IU School of Medicine.

Preschoolers in the IU study were implanted at an average age of 18 months, and they had fewer executive function delays than school-age children who were implanted 10 months later, at an average age of 28 months. 

Children in the study were divided into two age groups: preschool (3 to 5 years) and school-age (7 to17 years). Using an established rating scale, parents rated executive function in everyday life for children with cochlear implants and for the control group with normal hearing.

"We compared parent ratings and looked at the percentage of children in each group who scored above a cut-off value that indicates at least a mild delay in executive functioning," Dr. Kronenberger said. "In the critical areas of controlled attention, working memory, planning and solving new problems, about 30 to 45 percent of the children with cochlear implants scored above the cut-off value, compared to about 15 percent or less of the children in the normal-hearing sample."

Dr. Kronenberger said the research also shows that many children develop average or better executive functioning skills after cochlear implantation.

"These results show that half or more of our group with cochlear implants did not have significant delays in executive functioning," Dr. Kronenberger said. "Cochlear implants produce remarkable gains in spoken language and other neurocognitive skills, but there is a certain amount of learning and catch-up that needs to take place with children who have experienced a hearing loss prior to cochlear implantation. So far, most of the interventions to help with this learning have focused on speech and language. Our findings show a need to identify and help some children in certain domains of executive functioning as well."

"We are now looking for early markers in children who are at risk before they get implants," Dr. Pisoni said. "It will be beneficial to identify as early as possible which children might be at risk for poor outcomes, and we need to understand the variability in the outcome and what can be done about it."

Approximately one third of all brain aneurysms rupture during a patient’s lifetime, resulting in a brain haemorrhage. A recent Finnish study demonstrates that, unlike what was previously assumed, the size of the aneurysm does not significantly impact the risk of rupture.

(Image credit: Miikka Korja)

The new Finnish study established that approximately one third of all aneurysms and up to one fourth of small aneurysms will rupture during a patient’s lifetime. The lifetime risk for rupture of a brain aneurysm depends heavily on the patient’s overall load of risk factors.

The risk of rupture is particularly high for female smokers with brain aneurysms of seven millimetres or more in diameter.

What surprised the researchers most was that the size of an aneurysm had little impact on its risk for rupture, particularly for men, despite a previously presumed correlation. In addition, the risk of rupture among non-smoking men was exceptionally low.

This is not to say that aneurysms in non-smoking men never rupture, but that the risk is much lower than we previously thought. This means treating every unruptured aneurysm may be unnecessary if one is discovered in a non-smoking man with low blood pressure, says Docent Seppo Juvela, University of Helsinki.

The study, published in Stroke 22nd May, is unique in that it monitored aneurysm patients over their entire lifetimes, whereas typical follow-up studies last only between one and five years in duration. The study is also exceptionally broad in scope.

It is unlikely that another similar, non-selected lifetime follow-up study on aneurysm patients will ever be conducted again, Juvela states.

Current care practices are based largely on the results of previous, shorter studies. Such studies have shown that the size of the aneurysm is the most significant factor predicting its risk for rupture. Consequently, small aneurysms have often been left untreated.

It is difficult to conduct reliable epidemiological research in brain aneurysms. The past 10–15 years have seen a distortion in the field due to a very limited group of researchers determining the direction for research. Now the situation is clearly changing, and clinically reasonable, population-based studies using non-selected data are on the rise again, states Docent Miikka Korja of the HUCS neurosurgery clinic.

Blocking a pain receptor in mice not only extends their lifespan, it also gives them a more youthful metabolism, including an improved insulin response that allows them to deal better with high blood sugar.

"We think that blocking this pain receptor and pathway could be very, very useful not only for relieving pain, but for improving lifespan and metabolic health, and in particular for treating diabetes and obesity in humans," said Andrew Dillin, a professor of molecular and cell biology at the University of California, Berkeley, and senior author of a new paper describing these results. "As humans age they report a higher incidence of pain, suggesting that pain might drive the aging process."

The “hot” compound in chili peppers, capsaicin, is already known to activate this pain receptor, called TRPV1 (transient receptor potential cation channel subfamily V member 1). In fact, TRPV1 is often called the capsaicin receptor. Constant activation of the receptor on a nerve cell results in death of the neuron, mimicking loss of TRPV1, which could explain why diets rich in capsaicin have been linked to a lower incidence of diabetes and metabolic problems in humans.

More relevant therapeutically, however, is an anti-migraine drug already on the market that inhibits a protein called CGRP that is triggered by TRPV1, producing an effect similar to that caused by blocking TRPV1. Dillin showed that giving this drug to older mice restored their metabolic health to that of younger mice.

"Our findings suggest that pharmacological manipulation of TRPV1 and CGRP may improve metabolic health and longevity," said Dillin, who is a Howard Hughes Medical Institute investigator and the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research. "Alternatively, chronic ingestion of compounds that affect TRPV1 might help prevent metabolic decline with age and lead to increased longevity in humans."

Dillin and his colleagues at UC Berkeley and The Salk Institute for Biological Studies in La Jolla, Calif., will publish their results in the May 22 issue of the journal Cell.

Pain and obesity

TRPV1 is a receptor found in the skin, nerves and joints that reacts to extremely high temperatures and other painful stimuli. The receptor is also found in nerve fibers that contact the pancreas, where it stimulates the release of substances that cause inflammation or, like CGRP (calcitonin gene-related peptide), prevent insulin release. Insulin promotes the uptake of sugar from the blood and storage in the body’s tissue, including fat.

Past research has shown that mice lacking TRPV1 are protected against diet-induced obesity, suggesting that this receptor plays a role in metabolism. Disrupting sensory perception also increases longevity in worms and flies. But until now, it was not known whether sensory perception also affects aging in mammals.

Dillin and his team have now found that mice genetically manipulated to lack TRPV1 receptors lived, on average, nearly four months – or about 14 percent – longer than normal mice. The TRPV1-deficient mice also showed signs of a youthful metabolism late in life, due to low levels of CGRP — a molecule that blocks insulin release resulting in increased blood glucose levels and thus could contribute to the development of type 2 diabetes. Throughout aging, these mice showed improved ability to quickly clear sugar from the blood as well as signs that they could burn more calories without increasing exercise levels.

Moreover, old mice treated with the anti-migraine drug, which inhibits the activity of CGRP receptors, showed a more youthful metabolic profile than untreated old mice.

UC Berkeley and The Salk Institute filed a patent May 16 on the technology described in the Cell paper. Dillin plans to continue his studies of the effects of TRPV1 and CGRP blockers on mice and, if possible, humans.

Learning can only occur if certain neuronal “brakes” are released. As the group led by Andreas Lüthi at the Friedrich Miescher Institute for Biomedical Research has now discovered, learning processes in the brain are dynamically regulated by various types of interneurons. The new connections essential for learning can only be established if inhibitory inputs from interneurons are reduced at the right moment. These findings have now been published in Nature.

Image caption: Example of a dendrite of a principal neuron (white) and synaptic contacts (yellow arrowheads) from SOM1 interneurons.

For some years, most neurobiologists studying learning processes have assumed that the new connections required for learning can only be established and ultimately reinforced if certain neuronal “brakes” are released – a process known as disinhibition. It has also been supposed for some time that various types of interneurons could be involved in disinhibition. Interneurons are nerve cells that surround and – via their connections – inhibit the activity of principal neurons. It has not been clear, however, whether these cell types actually play a role in disinhibition and how they control learning.

Andreas Lüthi and his group at the Friedrich Miescher Institute for Biomedical Research have now demonstrated for the first time how a learning process is dynamically regulated by specific types of interneurons.

In Lüthi’s experiments, mice were trained to associate a sound with an unpleasant stimulus, so that the animals subsequently knew what would happen when they heard the auditory cue. The researchers showed that, during the learning process, the sound stimulus released a brake in some of the principal neurons. More precisely, it induced the activation of parvalbumin-positive (PV+) interneurons, leading indirectly – via somatostatin-positive (SOM+) interneurons – to disinhibition of the principal neurons. The latter thus became receptive to further sensory inputs. If this was immediately followed by the unpleasant stimulus, then another brake was released. Once again, PV+ interneurons were involved, but this time the principal neurons were directly disinhibited. Steffen Wolff, a postdoc in Lüthi’s group and first author of the publication, explains: “The principal neurons temporarily reached a level of activation enabling neuronal connections to be reinforced in such a way that the animal could learn the association between the sound and the unpleasant stimulus.”

Lüthi comments: “This is the first time we’ve been able to identify so clearly the function of defined interneurons in a learning process, and to show how successive disinhibition can enable this process. We assume that interneurons disinhibit the principal neurons in a highly dynamic manner. They integrate, as it were, the state of numerous different neural networks, activated for example by sensory input, earlier experiences or emotional states, and thus permit or prevent learning. I think these findings are also of interest in the context of conditions where learning processes are impaired or dysfunctional, as in the case of anxiety disorders.”

Duke University researchers have found an antibody that simultaneously blocks the sensations of pain and itching in studies with mice.

The new antibody works by targeting the voltage-sensitive sodium channels in the cell membrane of neurons. The results appear online on May 22 in Cell.

Voltage-sensitive sodium channels control the flow of sodium ions through the neuron’s membrane. These channels open and close by responding to the electric current or action potential of the cells. One particular type of sodium channel, called the Nav1.7 subtype, is responsible for sensing pain.

Mutations in the human gene encoding the Nav1.7 sodium channel can lead to either the inability to sense pain or pain hypersensitivity. Interestingly, these mutations do not affect other sensations such as touch or temperature. Hence, the Nav1.7 sodium channel might be a very specific target for treating pain disorders without perturbing the patients’ ability to feel other sensations.

"Originally, I was interested in isolating these sodium channels from cells to study their structure," said Seok-Yong Lee, assistant professor of biochemistry in the Duke University Medical School and principal investigator of the study. He designed antibodies that would capture the sodium channels so that he could study them. "But then I thought, what if I could make an antibody that interferes with the channel function?"

The team first tested the antibody in cultured cells engineered to express the Nav1.7 sodium channel. They found that the antibody can bind to the channel and stabilize its closed state.

"The channel is off when it is closed," Lee explained. "Since the antibody stabilizes the closed state, the channel becomes less sensitive to pain." If this held true in live animals, then the animals would also be less sensitive to pain.

To test this idea, Lee sought the help of Ru-Rong Ji, professor of anesthesiology and neurobiology, who is an expert in the study of pain and itch sensation. Using laboratory mouse models of inflammatory and neuropathic pain, they showed that the antibody can target the Nav1.7 channel and reduce the pain sensation in these mice. More importantly, mice receiving the treatment did not show signs of physical dependence or enhanced tolerance toward the antibody.

"Pain and itch are distinct sensations, and pain is often known to suppress itch", said Ji.
The team found that the antibody can also relieve acute and chronic itch in mouse models, making them the first to discover the role of Nav1.7 in transmitting the itch sensation.

"Now we have a compound that can potentially treat both pain and itch at the same time," said Lee. Both of these symptoms are common in allergic contact dermatitis, which affects more than 10 million patients a year in the United States alone.

The team is pursuing a patent for the antibody.

"We hope our discovery will garner interest from pharmaceutical companies that can help us expand our studies into clinical trials," Lee said. Their goal is to develop a safer treatment for pain and itch as an alternative to opioids, which often cause addiction and other detrimental side effects.

Vivid hallucinations experienced by people with sight loss last far longer and have more serious consequences than previously thought, according to new research from King’s College London and the Macular Society. 

The study is the largest survey of the phenomenon, known as Charles Bonnet Syndrome, and documented the experiences of 492 visually impaired people who had experienced visual hallucinations. The findings, published in the British Journal of Ophthalmology, show there is a serious discrepancy between medical opinion and the realities of the condition.

Charles Bonnet Syndrome is widely considered by the medical profession to be benign and short-lived. However, the new research shows that 80% of respondents had hallucinations for five years or more and 32% found them predominantly unpleasant, distressing and negative. 

The study described this group of people as having “negative outcome Charles Bonnet Syndrome”. The group was more likely to have frequent, fear inducing, longer duration hallucinations, which affected daily activities. They were more likely to attribute hallucinations to serious mental illness and were less likely to have been warned about the possibility of hallucinations before they started. 

Of respondents, 38% regarded their hallucinations as startling, terrifying or frightening when they first occurred and 46% said hallucinations had an effect on their ability to complete daily tasks. 36% of people who discussed the issue with a medical professional said the professional was “unsure or did not know” about the diagnosis.

Dr Dominic ffytche, who led the research at the Institute of Psychiatry at King’s, says:  “Charles Bonnet Syndrome has been traditionally thought of as benign. Indeed, it has been questioned whether it should even be considered a medical condition given it does not cause problems and goes away by itself. The results of our survey paint a very different picture.

“With no specific treatments for Charles Bonnet Syndrome, the survey highlights the importance of raising awareness to reduce the distress it causes, particularly before symptoms start. All people with Charles Bonnet Syndrome are relieved or reassured to find out about the cause of their hallucinations and our evidence shows the knowledge may help reduce negative outcome.”

People with macular disease are particularly prone to Charles Bonnet hallucinations. They are thought to be a reaction of the brain to the loss of visual stimulation. More than half of people with severe sight loss experience them but many do not tell others for fear they will be thought to have a serious mental illness. 

Age-related macular (AMD) degeneration affects the central vision and is the most common cause of sight loss in the UK. Nearly 600,000 people have late-stage AMD today and more people will become affected as our population ages. Around half will have hallucinations at some stage. 

Tony Rucinski, Chief Executive, the Macular Society, said: “It is essential that people affected by sight loss are given information about Charles Bonnet Syndrome at diagnosis or as soon after as possible. 

“Losing your sight is bad enough without the fear that you have something like dementia as well. We need medical professionals to recognise the seriousness of Charles Bonnet Syndrome and ensure that people don’t suffer unnecessarily. More research is also needed to investigate Charles Bonnet Syndrome and possible ways of reducing its impact.”

Dr ffytche is also leading a large NIHR funded research programme on visual hallucinations to develop a much-needed evidence base to inform NHS practice in managing and treating the symptoms.