Spinal cord injury: Using cortical targets to improve motor function

Monica A. Perez, P.T., Ph.D., Associate Professor, Department of Neurological Surgery and The Miami Project, and colleagues, recently published A novel cortical target to enhance hand motor output in humans with spinal cord injury in the June issue of Brain that provides the first evidence that cortical targets could represent a novel therapeutic site for improving motor function in humans paralyzed by spinal cord injury (SCI).

A main goal of rehabilitation strategies in humans with SCI is to strengthen transmission in spared neural networks. Although neuromodulatory strategies have targeted different sites within the central nervous system to restore motor function following SCI, the role of cortical targets remains poorly understood.

“I am excited to see that electrophysiology can be successfully used to guide interventions for recovery of function after spinal cord injury,” says Dr. Perez.

In this study, Drs. Perez, Jinyi Long, Ph.D., and Paolo Federico, Ph.D. used 180 pairs of noninvasive transcranial magnetic stimulation for 30 minutes over the hand representation of the primary motor cortex at an interstimulus interval mimicking the rhythmicity of descending late indirect (I) waves in corticospinal neurons (4.3 ms; late I-wave protocol) or at an interstimulus interval in-between I-waves (3.5 ms; control protocol) on separate days in a randomized order.

Late I-waves are thought to arise from trans-synaptic cortical inputs and have a crucial role in the recruitment of spinal motor neurons following SCI. The researchers found that the excitability of corticospinal projections to intrinsic finger muscles increased in SCI and uninjured participants after the late I-wave but not the control protocol for 30 to 60 minutes after the stimulation. Importantly, individuals with SCI were able to exert more force and electromyographic activity with finger muscles after the stimulation showing an enhanced ability to grasp small objects with their hands.

“This study is a major contribution to the realization of a powerful new class of rehabilitation therapies that can target beneficial plasticity to crucial sites in the nervous system. By taking advantage of recent scientific and technical advances, Dr. Perez’s group produced beneficial change in the cortical circuitry and spinal connections underlying voluntary movement,” says Dr. Jonathan R. Wolpaw, M.D. Director of the National Center for Adaptive Neurotechnologies Albany, New York.

“This carefully conducted study provides several pieces of important information in developing strategies to improve function following spinal cord injury. They provide further evidence demonstrating rather clearly, contrary to years of dogma, that positive functional plasticity potential persists within the sensorimotor system for years after a spinal injury,” says Dr. Reggie Edgerton, Ph.D. UCLA Brain Research Institute.

These results emphasize the need to develop new rehabilitation therapies based on mechanistic approaches to improve motor function in humans with paralysis due to spinal cord injury. Currently, Dr. Perez’ group is testing the effect of this intervention when given on consecutive days and in individuals with more severe muscle paralysis.

“What I find appealing about the work is that they exploit a basic characteristic of the human corticospinal neural circuit and designed a way to strengthen connections that does not depend on the person performing a motor task,” said John H. Martin, Ph.D., The City College of New York.

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UV-sensing protein in the brain of a marine annelid zooplankton

Researchers at Institute for Molecular Sciences reported that a photoreceptive protein expressed in the brain a marine annelid zooplankton (Platynereis dumerilii) is UV-sensitive. This work was carried out as a collaborative work of Drs. Hisao Tsukamoto and Yuji Furutani (Institute for Molecular Science) with Drs. Yoshihiro Kubo and I-Shan Chen (National Institute for Physiological Sciences). This study was published online in the Journal of Biological Chemistry on June 16, 2017.

Most animals use external light signals for vision and “non-visual” photoreceptive functions, such as regulation of circadian behaviors. In some cases, photoreceptor cells outside eyes are involved in non-visual photoreception. Previous studies have shown that larvae of the annelid Platynereis dumerilii (marine ragworm), which are studied as a zooplankton model, possess photoreceptor cells in the brain, and the cells regulate circadian swimming behaviors. Interestingly, the brain photoreceptor cells in Platynereis express an opsin that is closely related to visual pigments in our visual photoreceptor (rod and cone) cells. Zooplankton show a synchronized circadian movement known as diel vertical migration (DVM), moving upward in water at night and downward in daytime. DVM is probably the largest daily movement of biomass, comparable to human commuting. Since a major cause of DVM is to avoid damaging UV (ultra-violet) irradiation, light-dependent DVM regulation via the brain photoreceptor cells was suggested.

This study showed that the Platynereis opsin can receive and transmit UV signals. Unlike vertebrate visual opsins, the opsin can directly bind exogenous all-trans-retinal. This suggests that the opsin enables the brain photoreceptor cells to detect UV signals, even without the supply of 11-cis-retinal, which is specifically produced in eyes. Mutagenesis analyses identified that a single amino acid residue is responsible for not only UV sensing but also direct binding of exogenous all-trans-retinal. Thus, the single residue is essential for the opsin to achieve the characteristics suitable for UV reception in the brain. Taken together, the opsin possesses ideal properties enabling the brain photoreceptor cells in Platynereis to sense ambient UV signals.

As summarized above, this study revealed molecular basis of the opsin to function as a UV-sensor in the brain of the zooplankton model. Since detection of ambient UV signals should be necessary for DVM, the molecular properties of the opsin are helpful to understand the physiology, ecology and evolution of zooplankton species.

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Rare cells are ‘window into the gut’ for the nervous system

Specialized cells in the gut sense potentially noxious chemicals and trigger electrical impulses in nearby nerve fibers, according to a new study led by UC San Francisco scientists. “These cells are sensors, like a window looking into the contents of the gut,” said James Bayrer, MD, PhD, an assistant professor of pediatrics at UCSF and one of the lead authors of the paper.

Using gut-mimicking “organoids” grown from mouse stem cells, the researchers showed how cells in the intestinal lining called enterochromaffin (EC) cells alert the nervous system to signs of trouble in the gut, from bacterial products to inflammatory food molecules.

The authors of the new study — published online in Cell on June 22, 2017 — said that understanding the role of EC cells in how the gut reacts, and overreacts, to chemical irritants could provide new approaches for treating gastrointestinal disorders such as irritable bowel syndrome (IBS).

With over 100 times the surface area of our skin, the gut is the body’s largest surface exposed to external substances. Though EC cells make up only one percent of the gut’s lining, they produce 90 percent of the body’s serotonin, a key signaling molecule, so scientists have long been curious about their functions. Serotonin is best known for mediating mood through its actions in the brain, but it has a very different role in the gut, where it is involved in gut contractions and gastric discomfort.

“There are so few of these cells, but they seem so powerful,” said Holly Ingraham, PhD, a UCSF professor of cellular and molecular pharmacology and co-senior author of the new paper. “People are very interested in understanding what these cells do with all that serotonin.”

EC cells are interspersed among other cells that make up the lining of the intestinal tract, on the surface of tiny, fingerlike structures called villi that project into the gut’s inside space. Within the villi, underneath the EC cells and other cells, are nerve fibers which sense the movement and contents of the gut and contribute to intestinal pain and discomfort. But precisely how these nerve fibers communicate with EC cells has been unclear.

In their new study, the researchers showed that EC cells integrate information about chemical irritants, bacterial compounds, and stress hormones in the gut, then use serotonin to pass that information on to the neighboring nerve cells, from which electrical impulses may travel throughout the gut’s nervous system and ultimately to the brain.

“People had suspected such a role for EC cells before, but this study is exciting because for the first time it gives us a rigorous handle on exactly how the gut talks to the nervous system,” said David Julius, PhD, a professor and chair of UCSF’s Department of Physiology and the study’s other senior author.

Cells Are Electrically Excited by Irritants

The collaboration at the heart of the new study was an unusual one for Ingraham and Julius, who are married but usually take different paths in their research.

Julius’s lab, which is focused on learning how the body’s pain sensors work using natural products like chili peppers, horseradish and snake venom, became interested in this new research direction after discovering that cells sensitive to a painful spider toxin were highly prevalent in the gut. Nicholas Bellono, PhD, a postdoctoral researcher in the lab and the other lead author on the paper, became fascinated by the way the gut’s lining, called the epithelium, appears to sense and react to what’s inside it.

“The nervous system, the immune system, the vasculature, everything converges in the epithelium,” said Bellono. He took particular interest in EC cells, wondering if the serotonin they release activated adjacent nerve fibers.

When Julius mentioned Bellono’s new interest to Ingraham, she suggested that Bellono work with Bayrer, a gastroenterologist who was leading efforts in her lab to study gut disorders using intestinal organoids, small clumps of cells grown from stem cells that can serve as models of the gut. For Bellono and Bayrer, organoids made the EC cells much easier to work with. “You can look in the dish and there’s a little intestine in there — it’s totally wild,” said Bellono.

The team tested the cells’ reactions to dozens of different molecules and found that three classes of molecules caused a change in voltage across the cell’s membranes. Intriguingly, the three types of molecules that triggered EC cells — bacterial byproducts called volatile fatty acids; a class of hormones called catecholamines (including dopamine, epinephrine and norepinephrine) that can signal stress in the gut; and a dietary irritant called AITC, which is responsible for garlic’s pungent flavor — have all previously been linked to IBS.

When the EC cells are excited by any of these molecules, they release serotonin into synapses with the nearby nerve fibers, acting much like other sensory organs, from taste buds to odor receptors. In tissue samples taken from mice, the team showed that this serotonin release triggered electrical impulses in nerve fibers, indicating the signal could move quickly throughout the gut.

“They’re actually electrically excitable,” said Julius, who also holds the Morris Herzstein Chair in Molecular Biology and Medicine at UCSF. “They kind of behave like neurons.”

Signals Could Cause Both Pain and Pooping

The intestines are unique among our organs in that many of the nerve signals that control them come not from the brain but from a network of nerves within the gut sometimes called “the second brain,” which helps carry out much of the organ’s routine contractions and digestive activities without the intervention of the brain itself.

The team thinks the nerve signals that originate with the EC cells can affect both networks, causing involuntary gut contractions or, if the signals reach the brain, what Ingraham described as a “gut ache.”

“Just like when we taste something foul and we try to get rid of it” through gagging, the gut may react to the foul “taste” of bacterial or irritating molecules by trying to push them out the other end, said Bayrer. “This could be a way of the gut sensing which populations of bacteria are around.”

The next step, said the researchers, is to study EC cells in organoids grown from human cells. Because mice and humans have different diets, our EC cells could be sensitive to entirely different molecules.

Targeting Cells Could Help Treat Irritable Bowel Syndrome

Though triggering the gut to push out unwanted chemicals and microbes is normally healthy, overreactions by EC cells and the nerve networks they trigger may cause problems like IBS. The team hopes that understanding what leads these cells to react to food and bacteria will aid the search for drugs that will prevent them from overreacting, perhaps by blocking the proteins that sense these molecules in the first place.

Intriguingly, clinicians already use SSRI’s (Selective Serotonin Reuptake Inhibitors), which affect serotonin levels, to treat IBS, suggesting there may be a link between the disease and the serotonin system. Bayrer, a pediatric gastroenterologist who works with children with IBS, hopes understanding EC cells and other gut sensors will help researchers understand and improve such treatments.

 

Neurons that regenerate, neurons that die

Cells, genetically marked with GFP, are viewed on a flat-mounted retina. The axons or fibers lead to the optic nerve head (round structure in the top right corner) and then exit the eyeball into the optic nerve. The alpha RGCs are killed by sox11 despite its pro-regenerative effect on some other still undefined type(s) of RGCs.

Credit: Image courtesy of Fengfeng Bei, Brigham and Women’s Hospital

The optic nerve is vital for vision — damage to this critical structure can lead to severe and irreversible loss of vision. Fengfeng Bei, PhD, a principal investigator in the Department of Neurosurgery at Brigham and Women’s Hospital, and his colleagues want to understand why the optic nerve — as well as other parts of the central nervous system including the brain and spinal cord — cannot be repaired by the body. In particular, Bei’s lab focuses on axons, the long processes of neurons that serve as signaling wires. In a new study published in Neuron, Bei, Michael Norsworthy in Zhigang He’s lab at Boston Children’s Hospital and colleagues report on a transcription factor that they have found that can help certain neurons regenerate, while simultaneously killing others. Unraveling exactly which signals can help or hinder axon regeneration may eventually lead to new and precise treatment strategies for restoring vision or repairing injury.

“Our long term goal is to repair brain, spinal cord or eye injury by regenerating functional connections,” said Bei. “The goal will be to regenerate as many subtypes of neurons as possible. Our results here suggest that different subtypes of neurons may respond differently to the same factors. This may mean that when we reach the point of developing new therapies, we may need to consider combination therapies for optimal recovery.”

Previous studies using the optic nerve as a model for injury have found that manipulating transcription factors — the master control switches of genes — might represent a promising avenue for stimulating axon regeneration. In the current study, researchers focused on transcription factors likely to influence the early development of retinal ganglion cells (RGCs). There are at least 30 types of RGCs in the human eye, which control different aspects of vision, and the researchers were interested in the effects of transcription factors on various types of RGCs. Using a mouse model of optic nerve injury, the research team found that increasing the production of a transcription factor known as Sox11 appeared to help axons grow past the site of injury. However, the team observed that the very same transcription factor also efficiently killed a type of RGCs known as alpha-RGCs which would preferentially survive the injury if untreated.

Bei notes that the heterogeneity of the nervous system — the inclusion of different cells with different properties and functions — will be an important consideration as researchers work to reprogram and, ultimately, restore the optic nerve, brain or spinal cord after injury.


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Journal Reference:

  1. Norsworthy M et al. Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others. Neuron, June 2017 DOI: 10.1016/j.neuron.2017.05.035

Cite This Page:

Brigham and Women’s Hospital. “Neurons that regenerate, neurons that die: Untangling the complex puzzle of optic nerve regeneration.” ScienceDaily. ScienceDaily, 21 June 2017. .

Brigham and Women’s Hospital. (2017, June 21). Neurons that regenerate, neurons that die: Untangling the complex puzzle of optic nerve regeneration. ScienceDaily. Retrieved June 21, 2017 from www.sciencedaily.com/releases/2017/06/170621132913.htm

Brigham and Women’s Hospital. “Neurons that regenerate, neurons that die: Untangling the complex puzzle of optic nerve regeneration.” ScienceDaily. www.sciencedaily.com/releases/2017/06/170621132913.htm (accessed June 21, 2017).

New light shed on key player in brain development

Researchers at The University of Texas Medical Branch at Galveston have shed light on how the developing brain ensures that connections between brain cells reach their intended destination but that they are also maintained during life-span.

The findings have been just published in the journal Science Signaling.

Like other networks, the brain contains regions that serve specific functions such as interpreting sensory information, controlling bodily movement or formation of memory, and so on. In order for regions to interact with one another to perform complex tasks, the brain has a web of interconnecting pathways.

The study from Krishna M. Bhat, UTMB professor in the department of neuroscience and cell biology, and his lab showed that a protein called Slit is required for maintaining the interconnecting pathways in the nervous system. Without continual guidance from Slit, the intended pathways — which are very important for proper communication between brain regions after birth — drift off course.

The study found that Slit keeps brain cells on their paths in partnership with receptor proteins called Robo. The study also revelealed that Slit-Robo signaling is controlled by an enzyme called Mummy. Mummy modifies Slit in such a way that it could be secreted outside the cell where it is made, and also maintains correct amounts and spatial distribution of Robo during early and late nervous system development.

“Although Slit-Robo signaling is intensely studied, the emphasis has always been on understanding the events controlling the beginning of the process of guiding developing brain circuits to their destinations,” said Bhat. “Here, we show that Slit-Robo signaling is required not only at the intial stages of brain circuitry guidance but also later for maintaining those networks of circuits. This has implications for loss of cognition and other brain functions as we age or in many neuro-diseases.”

The study was conducted using the fruitfly Drosophila, as the control of brain circuitry pathfinding mechanisms is remarkably similar to what happens during human development.

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Mathematical modeling uncovers mysteries of HIV infection in the brain

After uncovering the progression of HIV infection in the brain thanks to a new mathematical model developed by a UAlberta research team, clinicians and researchers are developing a nasal spray to administer drugs more effectively.

The group that developed the model — led by PhD student Weston Roda and Michael Li, a professor in the Department of Mathematical and Statistical Sciences — used data from patients who died five to 15 years after they were infected, as well as known biological processes for the HIV virus to build the model that predicts the growth and progression of HIV in the brain, from the moment of infection onward. It is the first model of an infectious disease in the brain.

HIV infection in the brain has been a proverbial black box for scientists since the development of antiretroviral therapy in the 1990s.

“The nature of the HIV virus allows it to travel across the blood-brain barrier in infected macrophage — or white blood cell — as early as two weeks after infection. Antiretroviral drugs, the therapy of choice for HIV, cannot enter the brain so easily,” said Roda.

This creates what is known as a viral reservoir, a place in the body where the virus can lay dormant and is relatively inaccessible to drugs. Prior to this study, scientists could only study brain infection at autopsy. The new model allows scientists to backtrack, seeing the progression and development of HIV infection in the brain. Using this information, researchers can determine what level of effectiveness is needed for antiretroviral therapy in the brain to decrease active infection.

“The more we understand and can target treatment toward viral reservoirs, the closer we get to developing total suppression strategies for HIV infection,” said Roda. In fact, his results are already being put to use in a University of Alberta lab.

A research team led by Chris Power, Roda’s co-supervisor who is a professor in the Division of Neurology, is planning clinical trials for a nasal spray that would get the drugs into the brain faster — with critical information on dosage and improvement rate provided by Roda’s model.

“Our next steps are to understand other viral reservoirs, like the gut, and develop models similar to this one, as well as understand latently infected cell populations in the brain,” said Roda. “With the antiretroviral therapy, infected cells can go into a latent stage. The idea is to determine the size of the latently infected population so that clinicians can develop treatment strategies”

The paper, “Modeling brain lentiviral infections during antiretroviral therapy in AIDS,” was published in the Journal of Neurovirology.

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Poor adolescent diet may influence brain and behavior in adulthood

Adolescent male mice fed a diet lacking omega-3 fatty acids show increased anxiety-like behavior and worse performance on a memory task in adulthood, according to new research published in The Journal of Neuroscience. The study suggests adequate nutrition in adolescence is important for the refinement of the adult brain and behavior.

The structure and function of the brain continue to change throughout adolescence, at the same time that teenagers gain increasing independence and begin to make their own food choices. Since high-calorie, low-quality diets tend to be more affordable than healthy ones, teenagers may opt for foods that lack key nutrients important for brain health such as omega-3 polyunsaturated fatty acids (n-3 PUFAs), which cannot be produced by the human body and must be obtained from foods such as fish and vegetables.

Oliver Manzoni and colleagues fed mice a balanced diet until early adolescence, when some mice were switched to a diet lacking n-3 PUFAs. Mice fed the poor diet during adolescence had reduced levels of n-3 PUFA in the medial prefrontal cortex and the nucleus accumbens in adulthood compared to control mice. The low-quality diet impaired the brain’s ability to fine-tune connections between neurons in these regions.

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Treating autism by targeting the gut

Experts have called for large-scale studies into altering the make-up of bacteria in the gut, after a review showed that this might reduce the symptoms of Autism Spectrum Disorder (ASD). Until now, caregivers have relied on rehabilitation, educational interventions and drugs to reduce ASD symptoms, but now researchers suggest that treating this condition could be as simple as changing their diet.

A review of more than 150 papers on ASD and gut bacteria found that since the 1960s, scientists have been reporting links between the composition of bacteria in the gut and autistic behaviour. The review highlights many studies showing that restoring a healthy balance in gut bacteria can treat ASD symptoms.

“To date there are no effective therapies to treat this range of brain developmental disorders,” explains Dr Qinrui Li of Peking University, China. “The number of people being diagnosed with ASD is on the rise. As well as being an expensive condition to manage, ASD has a huge emotional and social cost on families of sufferers.”

The link between the gut and ASD is well-known among sufferers: problems like diarrhea, constipation and flatulence are commonly reported. The root of gastro-intestinal problems like these is an imbalance of “good” and “bad” bacteria in the gut.

A cheap and effective treatment?

Many of the papers reviewed support the idea of a gut-brain axis — a way in which factors in the gut can affect processes in the brain. So these gastro-intestinal problems may have a more sinister side. The overgrowth of bad bacteria in the gut inevitably leads to an overproduction of by-products — including toxins. These can make the gut lining more permeable. Then toxins, by-products and even undigested food can get into the bloodstream and travel to the brain.

In a child under three years old, whose brain is at the height of development, the presence of these chemicals can impair neuro-development, leading to ASD.

What causes infants to develop an imbalance in the gut microbiota?

“ASD is likely to be a result of both genetic and environmental factors” explains Dr Li. “The environmental factors include the overuse of antibiotics in babies, maternal obesity and diabetes during pregnancy, how a baby is delivered and how long it is breastfed. All of these can affect the balance of bacteria in an infant’s gut, so are risk factors for ASD.”

However, the researchers found a significant body of evidence that reverting the gut microbiota to a healthy state can reduce ASD symptoms.

“Efforts to restore the gut microbiota to that of a healthy person has been shown to be really effective” continues Dr Li. “Our review looked at taking probiotics, prebiotics, changing the diet — for example, to gluten- and casein-free diets, and faecal matter transplants. All had a positive impact on symptoms .”

These include such things as increased sociability, a reduction in repetitive behaviour, and improved social communication: all hugely beneficial to the life of an ASD sufferer.

The message of this review is one of positivity. This could well be a breakthrough in the treatment of this disorder. However, the researchers believe that the studies are too few and too small, and that new clinical trials are needed to take this research to the next level.

“We are encouraged by our findings, but there is no doubt that further work needs to be carried out in this field” says Dr Li. “We need more well-designed and larger-scale studies to support our theory. For now, behavioural therapies remain the best way to treat ASD. We would hope that our review leads to research on the link between the gut microbiota and ASD, and eventually a cheap and effective treatment.”

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Lack of ‘editing’ in brain molecules potential driver of cancer

Scientists in the UK and India have observed a “significant” lack of ‘editing’ in microRNAs in brain tissue of brain cancer patients.

In a paper published in Nature Scientific Reports, the researchers say the finding is a ‘small but important’ step in our understanding of brain cancer progression, and raises possibility of using genome engineering techniques to slow or reverse the march of the disease.

MicroRNAs are a special type of RNA molecules that do not code for proteins but participate in crucial regulatory functions. They can introduce targeted variations in organization of their building blocks (ribo-nucleotides) — a process known as ‘editing’. In turn, editing can enable RNA molecules to expand their functional repertoire, a process which is vital to maintain cell diversity and help our body adapt and evolve dynamically.

Dr Arijit Mukhopadhyay, a researcher in human genetics and genomics in the School of Environment and Life Sciences, and colleagues in Dehli showed that a specific organisation of these building blocks favour such targeted variations to occur, and that certain variations are decreased in patients with brain cancer which can potentially drive the disease.

Dr Mukhopadhyay and the team also examined the normal microRNA editing spectrum in 13 human tissue types and found the healthy brain to have the highest amount of editing — implicating the importance of the observed drop in case of brain cancers.

“What precisely is happening, we can’t say, but with altered levels and positions of these editing events, cellular output can be significantly altered which we see in case of cancers,” he says.

And he says the findings pose the question of whether biochemically we can re-establish the ‘editing’ process using genome engineering techniques like CRISPR targeted to specific cells to revert the biological outcome.

A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypo-edited in Glioblastoma Multiforme — is published in Nature Scientific Reports.

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Distant brain regions selectively recruit stem cells

Stem cells persist in the adult mammalian brain and generate new neurons throughout life. A research group at the Biozentrum of the University of Basel reports in the current issue of “Science” that long-distance brain connections can target discrete pools of stem cells in their niche and stimulate them to divide and produce specific subtypes of olfactory bulb neurons. This allows the “on-demand” generation of particular types of neurons in the adult brain.

Our brain generates new neurons throughout life. A diversity of stimuli promotes stem cells in their niche to form neurons that migrate to their place of action. In an animal model Prof. Fiona Doetsch’s team at the Biozentrum of the University of Basel has now been able to show that feeding-related neurons in the hypothalamus, a brain control center for many physiological functions, stimulate a distinct type of stem cell to proliferate and mature into specific nerve cells in response to feeding.

Stem cells make neurons important for olfaction

Stem cells reside in only a few areas of the brain. The largest reservoir is the subventricular zone, where quiescent stem cells lie closely packed together. Signals from the environment can trigger stem cells to start dividing. The stem cells in the subventricular zone supply the olfactory bulb with neurons. In rodents, almost 100,000 new neurons migrate from the stem cell niche to the olfactory bulb each day. Olfactory stimuli reaching the nose are processed in the olfactory bulb and the information is then sent to other brain regions. The closely interwoven network of diverse olfactory bulb neurons is important for distinguishing odors.

Stem cell activation over long distances

Each stem cell has its own identity, depending on its location in the subventricular zone. While new neurons are continuously generated, whether niche signals act to control different pools of stem cells is unknown. “We have uncovered a novel long-distance and regionalized connection in the brain between the hypothalamus and the subventricular zone, and show that physiological states such as hunger and satiety can regulate the recruitment of specific pools of stem cells and in turn the formation of certain neuron subtypes in the olfactory bulb,” explains Doetsch. When the animals fasted, the activity of the nerve cells in the hypothalamus decreased and with it also the rate of proliferation in the targeted stem cell population. This returns to normal levels when the animals feed again. The division of stem cells can be controlled by changing the activity of feeding-related neurons.

The researchers reported further that the targeted stem cell subpopulation gives rise to deep granule cells in the olfactory bulb, which may provide a substrate for adaptive responses to the environment. The results of the study raise the exciting possibility that neural circuits from diverse brain regions can regulate different pools of stem cells in response to various stimuli and states.

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Why do those with autism avoid eye contact?

Individuals with autism spectrum disorder (ASD) often find it difficult to look others in the eyes. This avoidance has typically been interpreted as a sign of social and personal indifference, but reports from people with autism suggests otherwise. Many say that looking others in the eye is uncomfortable or stressful for them — some will even say that “it burns” — all of which points to a neurological cause. Now, a team of investigators based at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital has shed light on the brain mechanisms involved in this behavior. They reported their findings in a Scientific Reports paper published online this month.

“The findings demonstrate that, contrary to what has been thought, the apparent lack of interpersonal interest among people with autism is not due to a lack of concern,” says Nouchine Hadjikhani, MD, PhD, director of neurolimbic research in the Martinos Center and corresponding author of the new study. “Rather, our results show that this behavior is a way to decrease an unpleasant excessive arousal stemming from overactivation in a particular part of the brain.”

The key to this research lies in the brain’s subcortical system, which is responsible for the natural orientation toward faces seen in newborns and is important later for emotion perception. The subcortical system can be specifically activated by eye contact, and previous work by Hadjikhani and colleagues revealed that, among those with autism, it was oversensitive to effects elicited by direct gaze and emotional expression. In the present study, she took that observation further, asking what happens when those with autism are compelled to look in the eyes of faces conveying different emotions.

Using functional magnetic resonance imaging (fMRI), Hadjikhani and colleagues measured differences in activation within the face-processing components of the subcortical system in people with autism and in control participants as they viewed faces either freely or when constrained to viewing the eye-region. While activation of these structures was similar for both groups exhibited during free viewing, overactivation was observed in participants with autism when concentrating on the eye-region. This was especially true with fearful faces, though similar effects were observed when viewing happy, angry and neutral faces.

The findings of the study support the hypothesis of an imbalance between the brain’s excitatory and inhibitory signaling networks in autism — excitatory refers to neurotransmitters that stimulate the brain, while inhibitory refers to those that calm it and provide equilibrium. Such an imbalance, likely the result of diverse genetic and environmental causes, can strengthen excitatory signaling in the subcortical circuitry involved in face perception. This in turn can result in an abnormal reaction to eye contact, an aversion to direct gaze and consequently abnormal development of the social brain.

In revealing the underlying reasons for eye-avoidance, the study also suggests more effective ways of engaging individuals with autism. “The findings indicate that forcing children with autism to look into someone’s eyes in behavioral therapy may create a lot of anxiety for them,” says Hadjikhani, an associate professor of Radiology at Harvard Medical School. “An approach involving slow habituation to eye contact may help them overcome this overreaction and be able to handle eye contact in the long run, thereby avoiding the cascading effects that this eye-avoidance has on the development of the social brain.”

The researchers are already planning to follow up the research. Hadjikhani is now seeking funding for a study that will use magnetoencephalography (MEG) together with eye-tracking and other behavioral tests to probe more deeply the relationship between the subcortical system and eye contact avoidance in autism.

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Modeling the brain with ‘Lego bricks’

Researchers from the University of Luxembourg, in cooperation with the University of Strasbourg, have developed a computational method that could be used to guide surgeons during brain surgery.

Surgeons often operate in the dark. They have a limited view of the surface of the organ, and can typically not see what lies hidden inside. Quality images can routinely be taken prior to the surgery, but as soon as the operation begins, the position of the surgeon’s target and risky areas he must avoid, continuously change. This forces practitioners to rely on their experience when navigating surgical instruments to, for example, remove a tumor without damaging healthy tissue or cutting through important blood supplies.

Stéphane Bordas, Professor in Computational Mechanics at the Faculty of Science, Technology and Communication of the University of Luxembourg, and his team have developed methods to train surgeons, help them rehearse for such complex operations and guide them during surgery. To do this, the team develops mathematical models and numerical algorithms to predict the deformation of the organ during surgery and provide information on the current position of target and vulnerable areas. With such tools, the practioner could virtually rehearse a particular operation to anticipate potential complications.

As the brain is a composite material, made up of grey matter, white matter and fluids, the researchers use data from medical imaging, such as MRI to decompose the brain into subvolumes, similar to lego blocks. The colour of each lego block depends on which material it represents: white, grey or fluid. This colour-coded “digital lego brain” consists of thousands of these interacting and deforming blocks which are used to compute the deformation of the organ under the action of the surgeon. The more blocks the researchers use to model the brain, the more accurate is the simulation. However, it becomes slower, as it requires more computing power. For the user, it is therefore important to find the right balance between accuracy and speed when he decides how many blocks to use.

The crucial aspect of Prof Bordas’ work is that it allows, for the first time, to control both the accuracy and the computational time of the simulations. “We developed a method that can save time and money to the user by telling them the minimum size these lego blocks should have to guarantee a given accuracy level. For instance, we can say with certainty: if you can accept a ten per cent error range then your lego blocks should be maximum 1mm, if you are ok with twenty percent you could use 5mm elements,” he explains. “The method has two advantages: You have an estimation of the quality and you can focus the computational effort only on areas where it is needed, thus saving precious computational time.”

Over time, the researchers’ goal is to provide surgeons with a solution that can be used during operations, constantly updating the simulation model in real time with data from the patient. But, according to Prof Bordas, it will take a while before this is realized. “We still need to develop robust methods to estimate the mechanical behavior of each lego block representing the brain. We also must develop a user-friendly platform that surgeons can test and tell us if our tool is helpful,” he said.

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Materials provided by University of Luxembourg. Note: Content may be edited for style and length.

 

How brain circuits govern hunger and cravings

The urge to satisfy hunger is a primal one, but — as any dieter knows — choices about when and what to eat can be influenced by cues in the environment, not just how long it’s been since breakfast. The fact that food-associated visual cues in television commercials and on highway signs can contribute to overeating is well-documented. But how exactly do these external signals trigger cravings and influence behavior?

By developing a new approach to imaging and manipulating particular groups of neurons in the mouse brain, scientists at Beth Israel Deaconess Medical Center (BIDMC) have identified a pathway by which neurons that drive hunger influence distant neurons involved in the decision of whether or not to react to food-related cues. Their findings could open the door to targeted therapies that dampen food cue-evoked cravings in people with obesity. The research was published online today in the journal Nature.

“The main question we were asking is: how do evolutionarily ancient hunger-promoting neurons at the base of the brain, in the hypothalamus, influence ‘cognitive’ brain areas to help us find and eat calorie-rich foods in a complex and changing world?” said co-corresponding author Mark Andermann, PhD, an Assistant Professor of Medicine in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Assistant Professor at Harvard Medical School (HMS).

“To put it simply, when you’re hungry, the picture of a cheeseburger may be extremely appealing and effective in influencing your behavior,” explained lead author Yoav Livneh, PhD, postdoctoral fellow at BIDMC. “But if your belly is full after eating a big meal, the same cheeseburger picture will be unappealing. We think that the pathway we discovered from hunger-promoting neurons to a region of the brain called the insular cortex plays an important role here.”

Brain imaging data in humans support the notion that the insular cortex is involved in deciding if a source of food is worth pursuing. In healthy humans, the insular cortex increases its activity in response to food cues during hunger but not following a meal. Studies suggest that this process often goes awry in patients with obesity or other eating disorders that exhibit excessive cravings. Those findings indicate that specific changes in brain activity, including increased sensitivity to food cues, may underlie these disorders — rather than a ‘lack of willpower’.

In their study, Livneh, Andermann and co-corresponding author Bradford B. Lowell, MD, PhD, Professor of Medicine in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Professor of Medicine at HMS, and colleagues focused on the insular cortex, using a mouse model. Because the mouse insular cortex is located at the side of the brain in a hard-to-reach place, Andermann, Lowell, Livneh and colleagues pioneered the use of a tiny periscope that allowed them to see neurons in this previously unobservable part of the brain. The tool allowed the researchers to monitor and track individual neurons in awake mice as they responded to food cues in both sated and hungry physiological states.

Their experiments demonstrated that visual cues associated with food would specifically activate a certain group of neurons in the insular cortex of hungry mice, and that these neurons were necessary for mice to respond behaviorally to food cues. After mice had eaten until they were full, this brain response to food cues in the insular cortex was no longer present. While the mice were still sated, the researchers used genetic techniques to artificially create hunger by ‘turning on’ hunger-promoting neurons in the hypothalamus. These neurons express the gene for Agouti-related protein (AgRP) and were previously shown to restore simple feeding behaviors. By activating these AgRP neurons, Livneh and colleagues caused sated mice to once again react to visual stimuli and seek more food, and it also restored the pattern of food cue visual responses across neurons in insular cortex to that previously seen in hungry mice.

“These AgRP neurons cause hunger — they are the quintessential hunger neuron,” explained Lowell. “It’s a major advance to learn that we can artificially turn them on and cause full mice to work to get food and to eat as if they hadn’t eaten in a long time. These neurons seem capable of causing a diverse set of behaviors associated with hunger and eating.”

Based on their research, it may also be possible to dial down the specific pathway from AgRP neurons to the insular cortex and reduce over-attention to food cues in the environment, ideally without impacting deliberate eating at mealtimes. This hypothesis requires further investigation, the researchers stress, but has exciting implications for the treatment of human obesity and other eating disorders.

With their unprecedented view into the insular cortex, Andermann and Lowell’s team created a road map of the brain circuitry by which hunger-related AgRP neurons ultimately influence insular cortex. Using powerful genetic and optical methods to switch individual cells on and off at will, the team could observe the effects both on downstream neurons and on behavior. The circuitry they revealed includes the amygdala, thought to update the value of food cues, and the paraventricular thalamus, which is also important for motivated behaviors. The researchers suggest the pathway may bias decision-making by increasing the pros and decreasing the cons of seeking out and eating a given food.

“We’re still trying to understand how this process works,” said Lowell. “Huge questions remain, but they are now addressable thanks to these new imaging methods.”

 

Surprising new link between inflammation and mental illness

Up to 75 percent of patients with systemic lupus erythematosus — an incurable autoimmune disease commonly known as lupus — experience neuropsychiatric symptoms. But so far, our understanding of the mechanisms underlying lupus’ effects on the brain has remained murky. Now, new research from Boston Children’s Hospital has shed light on the mystery and points to a potential new drug for protecting the brain from the neuropsychiatric effects of lupus and other central nervous system (CNS) diseases. The team has published its surprising findings in Nature.

“In general, lupus patients commonly have a broad range of neuropsychiatric symptoms, including anxiety, depression, headaches, seizures, even psychosis,” says Allison Bialas, PhD, first author on the study and a research fellow working in the lab of Michael Carroll, PhD, senior author on the study, who are part of the Boston Children’s Program in Cellular and Molecular Medicine. “But their cause has not been clear — for a long time it wasn’t even appreciated that these were symptoms of the disease.

Collectively, lupus’ neuropsychiatric symptoms are known as central nervous system (CNS) lupus. Carroll’s team wondered if changes in the immune system in lupus patients were directly causing these symptoms from a pathological standpoint.

“How does chronic inflammation affect the brain?”

Lupus, which affects at least 1.5 million Americans, causes the immune systems to attack the body’s tissues and organs. This causes the body’s white blood cells to release type 1 interferon-alpha, a small cytokine protein that acts as a systemic alarm, triggering a cascade of additional immune activity as it binds with receptors in different tissues.

Until now, however, these circulating cytokines were not thought to be able to cross the blood brain barrier, the highly-selective membrane that controls the transfer of materials between circulating blood and the central nervous system (CNS) fluids.

“There had not been any indication that type 1 interferon could get into the brain and set off immune responses there,” says Carroll, who is also professor of pediatrics at Harvard Medical School.

So, working with a mouse model of lupus, it was quite unexpected when Carroll’s team discovered that enough interferon-alpha did indeed appear to permeate the blood brain barrier to cause changes in the brain. Once across the barrier, it launched microglia — the immune defense cells of the CNS — into attack mode on the brain’s neuronal synapses. This caused synapses to be lost in the frontal cortex.

“We’ve found a mechanism that directly links inflammation to mental illness,” says Carroll. “This discovery has huge implications for a range of central nervous system diseases.”

Blocking inflammation’s effects on the brain

The team decided to see if they could reduce synapse loss by administering a drug that blocks interferon-alpha’s receptor, called an anti-IFNAR.

Remarkably, they found that anti-IFNAR did seem to have neuro-protective effects in mice with lupus, preventing synapse loss when compared with mice who were not given the drug. What’s more, they noticed that mice treated with anti-IFNAR had a reduction in behavioral signs associated with mental illnesses such as anxiety and cognitive defects.

Although further study is needed to determine exactly how interferon-alpha is crossing the blood brain barrier, the team’s findings establish a basis for future clinical trials to investigate the effects of anti-IFNAR drugs on CNS lupus and other CNS diseases. One such anti-IFNAR, anifrolumab, is currently being evaluated in a phase 3 human clinical trial for treating other aspects of lupus.

“We’ve seen microglia dysfunction in other diseases like schizophrenia, and so now this allows us to connect lupus to other CNS diseases,” says Bialas. “CNS lupus is not just an undefined cluster of neuropsychiatric symptoms, it’s a real disease of the brain — and it’s something that we can potentially treat.”

The implications go beyond lupus because inflammation underpins so many diseases and conditions, ranging from Alzheimer’s to viral infection to chronic stress.

“Are we all losing synapses, to some varying degree?” Carroll suggests. His team plans to find out.

 

Dressmakers found to have needle-sharp 3-D vision

Haute couture can be credited for enhancing more than catwalks and red carpets. New research from the University of California, Berkeley suggests that the 3D or “stereoscopic” vision of dressmakers is as sharp as their needles.

Stereoscopic vision is the brain’s ability to decode the flat 2D optical information received by both eyes to give us the depth of perception needed to thread a needle, catch a ball, park a car and generally navigate a 3D world.

Using computerized perceptual tasks, researchers from UC Berkeley and the University of Geneva, Switzerland, tested the stereoscopic vision of dressmakers and other professionals, and found dressmakers to be the most eagle-eyed.

The results, published in the June 13 issue of the journal Scientific Reports, show dressmakers to be 80 percent more accurate than non-dressmakers at calculating the distance between themselves and the objects they were looking at, and 43 percent better at estimating the distance between objects.

“We found dressmakers have superior stereovision, perhaps because of the direct feedback involved with fine needlework,” said study lead author Adrien Chopin, a postdoctoral researcher in visual neuroscience at UC Berkeley.

What researchers are still determining is whether dressmaking sharpens stereoscopic vision, or whether dressmakers are drawn to the trade because of their visual stereo-acuity, Chopin said.

To experience what it means to have stereoscopic vision, focus on a visual target. Now blink one eye while still staring at your target. Then blink the other eye. The background should appear to shift position. With stereoscopic vision, the brain’s visual cortex merges the 2D viewpoints of each eye into one 3D image.

It has generally been assumed that surgeons, dentists and other medical professionals who perform precise manual procedures would have superior stereovision. But previous studies have shown this not to be the case.

That spurred Chopin to investigate which professions would produce or attract people with superior stereovision, and led him to dressmakers.

A better understanding of dressmakers’ stereoscopic superpowers will inform ongoing efforts to train people with visual impairments such as amblyopia or “lazy eye” to strengthen their stereoscopic vision, Chopin said.

In addition to helping people with sight disorders, improved stereoscopic vision may be key to the success of military fighters, athletes and other occupations that require keen hand-eye coordination. An estimated 10 percent of people suffer from some form of stereoscopic impairment, and 5 percent suffer from full stereo blindness, Chopin said.

For example, the 17th-century Dutch painter Rembrandt, whose self-portraits occasionally showed him with one lazy eye, is thought to have suffered from stereo blindness, rendering him with flat vision. Some vision scientists have posited that painters tend to have poorer stereovision, which gives them an advantage working in 2D.

For the study, participants viewed objects on a computer screen through a stereoscope and judged the distances between objects, and between themselves and the objects. Researchers recorded their visual precision and found that, overall, dressmakers performed markedly better than their non-dressmaker counterparts in visual acuity.

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Materials provided by University of California – Berkeley. Original written by Yasmin Anwar. Note: Content may be edited for style and length.