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.
(Source: newswire.rockefeller.edu)
Filed under netrin-1 neogenin spinal cord neurons axons nervous system neuroscience science
Unprecedented detail of intact neuronal receptor offers blueprint for drug developers
Biologists at Cold Spring Harbor Laboratory (CSHL) report today that they have succeeded in obtaining an unprecedented view of a type of brain-cell receptor that is implicated in a range of neurological illnesses, including Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia, autism, and ischemic injuries associated with stroke.
The team’s atomic-level picture of the intact NMDA (N-methyl, D-aspartate) receptor should serve as template and guide for the design of therapeutic compounds.
The NMDA receptor is a massive multi-subunit complex that integrates both chemical and electrical signals in the brain to allow neurons to communicate with one another. These conversations form the basis of memory, learning, and thought, and critically mediate brain development. The receptor’s function is tightly regulated: both increased and decreased NMDA activities are associated with neurological diseases.
Despite the importance of NMDA receptor function, scientists have struggled to understand how it is controlled. In work published today in Science, CSHL Associate Professor Hiro Furukawa and Erkan Karakas, Ph.D., a postdoctoral investigator, use a type of molecular photography known as X-ray crystallography to determine the structure of the intact receptor. Their work identifies numerous interactions between the four subunits of the receptor and offers new insight into how the complex is regulated.
“Previously, our group and others have crystallized individual subunits of the receptor – just fragments – but that simply was not enough,” says Furukawa. “To understand how this complex functions you need to see it all together, fully assembled.”
For such a large complex, this was a challenging task. Using an exhaustive array of protein purification methods, Furukawa and Karakas were able to isolate the intact receptor. Their crystal structure reveals that the receptor looks much like a hot air balloon. “The ‘basket’ is what we call the transmembrane domain. It forms an ion channel that allows electrical signals to propagate through the neuron,” explains Furukawa.
An ion channel is like a gate in the neuronal membrane. Ions, small electrically charged atoms, are unable to pass through the cell membrane. When the ion channel “gate” is closed, ions congregate outside the cell, creating an electrical potential across the cell membrane.
When the ion channel “gate” opens, ions flow in and out of the cell through the channel pores. This generates an electrical current that sums up to create pulses that rapidly propagate through the neuron. But the current can’t jump from one neuron to the next. Rather, the electrical pulse triggers the release of chemical messengers, called neurotransmitters. These molecules traverse the distance between the neurons and bind to receptors, such as the NMDA receptor, on the surface of neighboring cells. There, they act much like a key, unlocking ion channels within the receptor and propelling the electrical signal across another neuron and, ultimately, across the brain.
The “balloon” portion of the receptor that Furukawa describes is found outside the cell. This is the region that binds to neurotransmitters. The structure of the assembled multi-subunit receptor complex, including the elusive ion channel, helps to explain some of the existing data about how NMDA receptors function. “We are able to see how one domain on the exterior side of the receptor directly regulates the ion channel within the membrane,” says Furukawa. “Our structure shows why this particular domain, called the amino terminal domain, is important for the activity of the NMDA receptor, but not for other related receptors.”
This information will be critical as scientists work to develop drugs that control the NMDA receptor. “Our structure defines the interfaces where multiple subunits and domains contact one another,” says Furukawa. “In the future, these will guide the design of therapeutic compounds to treat a wide range of devastating neurological diseases.”
Filed under NMDA receptor drug development ion channel neuroscience science
Outgrowing emotional egocentricity
Children are more egocentric than adults. Scientists from the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig have demonstrated for the first time that children are also worse at putting themselves in other people’s emotional shoes. According to the researchers, the supramarginal gyrus region of the brain must be sufficiently developed in children for them to be able to overcome their egocentric take on the world.
When little Philip rejoices at winning the prize in a game, it is almost impossible for him to understand that his best friend Tom, who has just lost, is not as jubilant. The opposite also applies. “Children are simply more egocentric,” says Nikolaus Steinbeis, a researcher at the Leipzig-based Max Planck Institute, summing up the general hypothesis.
Egocentrism refers to the inability to differentiate between one’s own point of view and that of other people. Egocentric people consider themselves to be the centre of all activity and assess all events and circumstances from this perspective. They project their own ideas, fears and desires onto the environment and others.
Up to now, all that the research in this area had to offer was a few theoretical ideas and studies on the development of cognitive perspective-taking. The question concerning egocentrism in connection with people’s emotional states and the development of this phenomenon over the course of childhood had been largely ignored. “We currently know very little about how emotional egocentrism is expressed in childhood and about the neuronal and cognitive processes on which this is based,” explains Steinbeis.
In order to compare the emotional states of different age groups, Steinbeis used an innovative game involving monetary rewards and punishments. “Earlier studies have shown that similarly strong emotional states can be triggered in both children and adults using such rewards and punishments. Children take as much delight as adults in monetary rewards and they are just as frustrated by losses,” he says.
During the game, two people competed against each other without, however, being able to see each other. Equipped with a computer screen and keyboard, the test subjects were asked to demonstrate their reaction speed. The participants were informed by the screen as to whether they or their opponents could rejoice in victory or despair in defeat. They were then asked to estimate the emotions experienced by their opponents. Of principal interest was how strongly the players’ own results influenced their assessments of their opponents’ emotional state. For example, if, due to their own status as a winner, a participant assessed their counterpart as being happy, despite the fact that the latter had just lost the game, this indicated that the winner was egocentrically projecting their own state onto the opponent.
The results of the study reveal that adults found it easy to overcome this tendency, whereas children between the ages of 6 and 13 tended to be guided by their own emotions when assessing those of others. The ability to assess the emotions of our counterparts independently of our own emotional state improves with age. “In general, the older a child is, the better he or she will be able to put itself in the emotional position of another person,” says Steinbeis, explaining the study findings.
In addition, the scientists measured the activity of different regions of the brain in MRI scanners and discovered a region that plays a crucial role in our ability to overcome our own feelings. The right supramarginal gyrus is a region of the temporoparietal junction, which is generally necessary for overcoming one’s own point of view. It is strongly linked with other brain regions like the anterior insula, which is exclusively responsible for enabling us to identify with other people’s emotional states. “This means that, with the right supramarginal gyrus, we have located a region which mainly functions in enabling us to overcome our own feelings,” says Steinbeis. Moreover, the scientists established that, with increasing age, the cortical thickness of the nerve fibres in this area declines. This suggests that the nerve fibres are more active as we get older.
Emotional egocentrism plays a major role in many conflicts, as the inability to overcome egocentric thinking leads to inappropriate social behaviour. People affected by this condition experience rejection, which has been shown to have a negative impact on health and development. Scientists would therefore like to understand the reasons for socially detrimental behaviour and develop options for targeted intervention.
Filed under supramarginal gyrus emotional egocentricity bias prefrontal cortex children brain development psychology neuroscience science
Research shows why ketamine is an effective antidepressant but memantine is not
Ketamine is a fast-acting antidepressant. However, it can create symptoms that mimic psychosis. Therefore, doctors don’t give it to depressed patients. Memantine, a similar drug, does not have psychotomimetic effects, but it also does not appear to alleviate depression. Lisa M. Monteggia of the University of Texas Southwestern Medical Center and her colleagues have determined that these drugs have different effects on neurotransmitter pathways. In particular, ketamine promotes the expression of neurotrophic factors but memantine doesn’t. The research appears in the Proceedings of the National Academy of Sciences.
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Filed under antidepressants ketamine memantine BDNF eeF2 neurotransmission neuroscience science
Creatures of habit: disorders of compulsivity share common pattern and brain structure
In a study published in the journal Molecular Psychiatry and primarily funded by the Wellcome Trust, researchers show that people who are affected by disorders of compulsivity have lower grey matter volumes (in other words, fewer nerve cells) in the brain regions involved in keeping track of goals and rewards.
In our daily lives, we make decisions based either on habit or aimed at achieving a specific goal. For example, when driving home from work, we tend to follow habitual choices – our ‘autopilot’ mode – as we know the route well; however, if we move to a nearby street, we will initially follow a ‘goal-directed’ choice to find our way home – unless we slip into autopilot and revert to driving back to our old home. However, we cannot always control the decision-making process and make repeat choices even when we know they are bad for us – in many cases this will be relatively benign, such as being tempted by a cake whilst slimming, but extreme cases it can lead to disorders of compulsivity.
In order to understand what happens when our decision-making processes malfunction, a team of researchers led by the Department of Psychiatry at the University of Cambridge compared almost 150 individuals with disorders including methamphetamine dependence, obesity with binge eating and obsessive compulsive disorder, comparing them with healthy volunteers of the same age and gender.
Study participants first took part in a computerised task to test their ability to make choices aimed a receiving a reward over and above making compulsive choices. In a second study, the researchers compared brain scans taken using magnetic resonance imaging (MRI) in healthy individuals and a subset of obese individuals with or without binge eating disorder (a subtype of obesity in which the person binge eats large amounts of food rapidly).
The researchers demonstrated that all of the disorders were connected by a shift away from goal-directed behaviours towards automatic habitual choices. The MRI scans showed that obese subjects with binge eating disorder have lower grey matter volumes – a measure of the number of neurons – in the orbitofrontal cortex and striatum of the brain compared to those who do not binge eat; these brain regions are involved in keeping track of goals and rewards. Even in healthy volunteers, lower grey matter volumes were associated with a shift towards more habitual choices.
Dr Valerie Voon, principal investigator of the study, says: “Seemingly diverse choices – drug taking, eating quickly despite weight gain, and compulsive cleaning or checking – have an underlying common thread: rather that a person making a choice based on what they think will happen, their choice is automatic or habitual.
“Compulsive disorders can have a profoundly disabling effect of individuals. Now that we know what is going wrong with their decision making, we can look at developing treatments, for example using psychotherapy focused on forward planning or interventions such as medication which target the shift towards habitual choices.”
Filed under brain structure gray matter compulsive disorders OCD decision making neuroscience science
Does porn affect the brain? Scientists urge more study
Researchers found less grey matter in the brains of men who watched large amounts of sexually explicit material, according to a new study.
The research, which appeared Wednesday in the journal JAMA Psychiatry, could not determine if porn actually caused the brain to shrink however, and the authors called for additional study on the topic.
"Future studies should investigate the effects of pornography longitudinally or expose naive participants to pornography and investigate the causal effects over time," said researchers at the Max Planck Institute for Human Development in Berlin, Germany.
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Filed under pornography gray matter prefrontal cortex striatum reward system neuroscience science
A tool to better screen and treat aneurysm patients
New research by an international consortium, including a researcher from Lawrence Livermore National Laboratory, may help physicians better understand the chronological development of a brain aneurysm.
Using radiocarbon dating to date samples of ruptured and unruptured cerebral aneurysm (CA) tissue, the team, led by neurosurgeon Nima Etminan, found that the main structural constituent and protein — collagen type I — in cerebral aneurysms is distinctly younger than once thought.
The new research helps identify patients more likely to suffer from an aneurysm and embark on a path toward prevention.
Simplified, a CA is a blood-filled bulge formed in response to a weakness in the wall at branching brain arteries. If the bulge bursts, the person can undergo a brain hemorrhage, which is a subtype of stroke and a life-threatening condition.
For decades, doctors have assumed that CAs rarely undergo structural change, and earlier theories speculated that CAs grow at a constant rate. The new findings, which appear in the June print issue of the journal Stroke, challenge the concept that CAs are present for decades and that they undergo only sporadic episodes of structural change. In view of these findings, it seems more likely that they alternate between periods of stability and instability during which they are prone to rupture.
For patients with CAs, who are more likely to undergo an aneurysm rupture due to risk factors such as smoking or hypertension, the international team including LLNL’s Bruce Buchholz found that the age of collagen type I was significantly younger than those samples taken from people with no risk factors.
The ample amount of relatively young collagen type I in CAs suggests that collagen is changing all the time in aneurysms, which is significantly more rapid in patients with risk factors, Buchholz said.
Radiocarbon bomb-pulse dating uses an isotopic signature created by above-ground nuclear testing between 1955 and 1963, which nearly doubled the amount of carbon-14 in the atmosphere.
When the above-ground test-ban treaty took effect in 1963, atmospheric levels of radiocarbon began to decline as carbon-14 migrated into the oceans and biosphere. Living organisms naturally incorporate carbon into their tissues as the element moves through the food chain. As a result, the concentration of carbon-14 leaves a permanent time stamp on every biological molecule.
"This research may help doctors to formulate better screening and identification of those people at increased risk of an aneurysm rupture," Buchholz said.
The prevalence of unruptured CAs in the general population is 2 percent to 3 percent. The rate of death when they rupture is more than 35 percent. The high rate of death has led the medical community to try to understand the formation and natural history of these lesions to define standards for screening, treatment and identification of those CAs that are likely to rupture.
Filed under brain aneurysm cerebral aneurysm collagen neuroscience science
‘Free choice’ in primates can be altered through brain stimulation
When electrical pulses are applied to the ventral tegmental area of their brain, macaques presented with two images change their preference from one image to the other. The study by researchers Wim Vanduffel and John Arsenault (KU Leuven and Massachusetts General Hospital) is the first to confirm a causal link between activity in the ventral tegmental area and choice behaviour in primates.
The ventral tegmental area is located in the midbrain and helps regulate learning and reinforcement in the brain’s reward system. It produces dopamine, a neurotransmitter that plays an important role in positive feelings, such as receiving a reward. “In this way, this small area of the brain provides learning signals,” explains Professor Vanduffel. “If a reward is larger or smaller than expected, behavior is reinforced or discouraged accordingly.”
Causal link
This effect can be artificially induced: “In one experiment, we allowed macaques to choose multiple times between two images – a star or a ball, for example. This told us which of the two visual stimuli they tended to naturally prefer. In a second experiment, we stimulated the ventral tegmental area with mild electrical currents whenever they chose the initially nonpreferred image. This quickly changed their preference. We were also able to manipulate their altered preference back to the original favorite.”
The study, which will be published online in the journal Current Biology on 16 June, is the first to confirm a causal link between activity in the ventral tegmental area and choice behaviour in primates. “In scans we found that electrically stimulating this tiny brain area activated the brain’s entire reward system, just as it does spontaneously when a reward is received. This has important implications for research into disorders relating to the brain’s reward network, such as addiction or learning disabilities.”
Could this method be used in the future to manipulate our choices? “Theoretically, yes. But the ventral tegmental area is very deep in the brain. At this point, stimulating it can only be done invasively, by surgically placing electrodes – just as is currently done for deep brain stimulation to treat Parkinson’s or depression. Once non-invasive methods – light or ultrasound, for example – can be applied with a sufficiently high level of precision, they could potentially be used for correcting defects in the reward system, such as addiction and learning disabilities.”
Filed under primates ventral tegmental area brain stimulation reward system neuroscience science
Neural Transplant Reduces Absence Epilepsy Seizures in Mice
New research from North Carolina State University pinpoints the areas of the cerebral cortex that are affected in mice with absence epilepsy and shows that transplanting embryonic neural cells into these areas can alleviate symptoms of the disease by reducing seizure activity. The work may help identify the areas of the human brain affected in absence epilepsy and lead to new therapies for sufferers.
Absence epilepsy primarily affects children. These seizures differ from “clonic-tonic” seizures in that they don’t cause muscle spasms; rather, patients “zone out” or stare into space for a period of time, with no memory of the episode afterward. Around one-third of patients with absence epilepsy fail to respond to medication, demonstrating the complexity of the disease.
NC State neurobiology professor Troy Ghashghaei and colleagues looked at a genetic mouse model for absence epilepsy to determine what was happening in their brains during these seizures. They found that the seizures were accompanied by hyperactivity in the areas of the brain associated with vision and touch – areas referred to as primary visual and primary somatosensory cortices in the occipital and parietal lobes, respectively.
“There are neurons that excite brain activity, and neurons that inhibit activity,” Ghashghaei says. “The inhibitory neurons work by secreting an inhibitory neurotransmitter called gamma-aminobutyric acid, or GABA. The ‘GABAergic’ interneurons were recently shown by others to be defective in the mice with absence seizures, and we surmised that these malfunctioning neurons might be part of the problem, especially in the visual and somatosensory cortical areas.”
Ghashghaei’s team took embryonic neural stem cells from a part of the developing brain that generates GABAergic interneurons for the cerebral cortex. They harvested these cells from normal mouse embryos and transplanted them into the occipital cortex of the genetic mice with absence seizures. Absence seizure activity in treated animals decreased dramatically, and the mice gained more weight and survived longer than untreated mice.
“This is a profound and remarkably effective first result, and adds to the recent body of evidence that these transplantation treatments can work in mouse models of epilepsy. But we still don’t understand the mechanisms behind what the normal inhibitory cells are doing in areas of the visual cortex of absence epileptic mice,” Ghashghaei says. “We know that you can get positive results even when a small number of transplanted neurons actually integrate into the cortex of affected mice, which is very interesting. But we don’t know how the transplanted cells are connecting with other cells in the cortex and how they alleviate the absence seizures in the mouse model we employed.
“Our next steps will be to explore these questions. In addition, we are very interested in methods being devised by multiple labs around the world to ‘reprogram’ cells from transplantation patients to generate normal GABAergic and other types of neurons. Once established, this would eliminate the need for embryonic stem cells for this type of treatment. The ultimate goal is to develop new therapies for humans suffering from various forms of epilepsies, especially those for whom drugs do not work.”
Filed under epilepsy cerebral cortex visual cortex interneurons epileptic seizures somatosensory cortex neuroscience science
The brain’s reaction to male odor shifts at puberty in children with gender dysphoria
The brains of children with gender dysphoria react to androstadienone, a musky-smelling steroid produced by men, in a way typical of their biological sex, but after puberty according to their experienced gender, finds a study for the first time in the open-access journal Frontiers in Endocrinology.
Around puberty, the testes of men start to produce androstadienone, a breakdown product of testosterone. Men release it in their sweat, especially from the armpits. Its only known function is to work like a pheromone: when women smell androstadienone, their mood tends to improve, their blood pressure, heart rate, and breathing go up, and they may become aroused.
Previous studies have shown that, in heterosexual women, the brain region that responds most to androstadienone is the hypothalamus, which lies just above the brainstem and links the nervous system to the hormonal system. In men with gender dysphoria (formerly called gender identity disorder) – who are born as males, but behave as and identify with women, and want to change sex – the hypothalamus also reacts strongly to its odor. In contrast, the hypothalamus of heterosexual men hardly responds to it.
Girls without gender dysphoria before puberty already show a stronger reaction in the hypothalamus to androstadienone than boys, finds a new study by Sarah Burke and colleagues from the VU University Medical Center of Amsterdam, the Netherlands, and the University of Liège, Belgium.
The researchers used neuroimaging to also show for the first time that in prepubescent children with gender dysphoria, the hypothalamus reacts to the smell of androstadienone in a way typical of their biological sex. Around puberty, its response shifts, and becomes typical of their experienced gender.
The reaction to the smell of androstadienone in the hypothalamus of 154 children and adolescents, including girls and boys, both before (7 to 11-year-old) and after puberty (15 to 16-year-old), of whom 74 had been diagnosed with gender dysphoria.
Results showed that the hypothalamus was more responsive to androstadienone in 7 to 11-year-old girls than in boys, both without gender dysphoria, although not yet as much as in adolescent girls. This means that the greater receptiveness of women to its odor already exists before puberty, either as an inborn difference or one that arises during early childhood.
Before puberty, the hypothalamus of boys with gender dysphoria hardly reacted to the odor, just as in other boys. But this changed in the 15 to 16-year-olds: the hypothalamus of adolescent boys with gender dysphoria now lit up as much as in heterosexual women, while the other adolescent boys still did not show any reaction. Adolescent girls with gender dysphoria showed the same reaction to androstadienone in their hypothalamus as is typical for heterosexual men.
These results suggest that as children with gender dysphoria grow up, their brain naturally undergoes a partial rewiring, to become more similar to the brain of the opposite sex – so corresponding to their experienced gender.
Filed under androstadienone gender dysphoria puberty hypothalamus neuroscience science
