Posts tagged neurons
Articles and news from the latest research reports.
To live and learn: making memories has to be a speedy business
The brain is plastic - adapting to the hundreds of experiences in our daily lives by reorganizing pathways and making new connections between nerve cells. This plasticity requires that memories of new information and experiences are formed fast. So fast that the body has a special mechanism, unique to nerve cells, that enables memories to be made rapidly. In a new study from The Montreal Neurological Institute and Hospital, The Neuro, McGill University with colleagues at the Université de Montréal, researchers have discovered that nerve cells have a special ‘pre-assembly’ technique to expedite the manufacture of proteins at nerve cell connections (synapses), enabling the brain to rapidly form memories and be plastic.
Making a memory requires the production of proteins at synapses. These proteins then change the strength of the connection or pathway. In nerve cells the production process for memory proteins is already pre-assembled at the synapse but stalled just before completion, awaiting the proper signals to finish, thereby speeding up the entire process. When it comes time to making the memory, the process is switched on and the protein is made in a flash. The mechanism is analogous to a pre-fab home, or pre-made pancake batter that is assembled in advance and then quickly completed in the correct location at the correct time.
“It’s not only important to make proteins in the right place but, it’s also important not to make the protein when it’s the wrong time,” says Dr. Wayne Sossin, neuroscientist at The Neuro and senior investigator on the paper. “This is especially important with nerve cells in the brain, as you only want the brain to make precise connections. If this process is indiscriminate, it leads to neurological disease. This mechanism to control memory protein synthesis solves two problems: 1) how to make proteins only at the right time and 2) how to make proteins as quickly as possible in order to tightly associate the synaptic change with the experience/memory.
Making proteins from genetic material involves two major steps [a Nobel prize was awarded for the identification of the cell’s protein-making process]. In the first step, called transcription, the information in DNA that is stored and protected within the centre of the cell is copied to a messenger RNA (mRNA) – this copy is then moved to where it is needed in the cell. In the second step, called translation, the mRNA is used as a template of genetic information and ‘read’ by little machines called ribosomes, which decode the mRNA sequence and stitch together the correct amino acids to form the protein.
Dr. Sossin’s group at The Neuro has discovered that the mRNA travels to the synapse already attached to the ribosome, with the protein production process stopped just before completion of the product (at the elongation/termination step of translation, where amino acids are being assembled into protein). The ‘pre-assembly’ process then waits for synaptic signals before re-activating to produce a lot of proteins quickly in order to form a memory. “Our results reveal a new mechanism underlying translation-dependent synaptic plasticity, which is dysregulated in neurodevelopmental and psychiatric pathologies”, added Dr. Sossin. “Understanding the pathways involved may provide new therapeutic targets for neurodevelopmental disorders. “
(Source: mcgill.ca)
Birth gets the brain ready to sense the world
Neurons that process sensory information such as touch and vision are arranged in precise, well-characterized maps that are crucial for translating perception into understanding. A study published by Cell Press on October 14 in the journal Developmental Cell reveals that the actual act of birth in mice causes a reduction in a brain chemical called serotonin in the newborn mice, triggering sensory maps to form. The findings shed light on the key role of a dramatic environmental event in the development of neural circuits and reveal that birth itself is one of the triggers that prepares the newborn for survival outside the womb.
"Our results clearly demonstrate that birth has active roles in brain formation and maturation," says senior study author Hiroshi Kawasaki of Kanazawa University in Japan. "We found that birth regulates neuronal circuit formation not only in the somatosensory system but also in the visual system. Therefore, it seems reasonable to speculate that birth actually plays a wider role in various brain regions."
Mammals ranging from mice to humans have brain maps that represent various types of sensory information. In a region of the rodent brain known as the barrel cortex, neurons that process tactile information from whiskers are arranged in a map corresponding to the spatial pattern of whiskers on the snout, with neighboring columns of neurons responding to stimulation of adjacent whiskers. Although previous studies have shown that the neurotransmitter serotonin influences the development of sensory maps, its specific role during normal development has not been clear until now.
In this new study, Kawasaki and his team find that the birth of mouse pups leads to a drop in serotonin levels in the newborn’s brain, triggering the formation of neural circuits in the barrel cortex and in the lateral geniculate nucleus (LGN), a brain region that processes visual information. When mice were treated with drugs that either induced preterm birth or decreased serotonin signaling, neural circuits in the barrel cortex as well as in the LGN formed more quickly. Conversely, neural circuits in the barrel cortex failed to form when the mice were treated with a drug that increased serotonin signaling, suggesting that a reduction in levels of this neurotransmitter is crucial for sensory map formation.
Because serotonin also plays a key role in mental disorders, it is possible that abnormalities in birth processes and the effects on subsequent serotonin signaling and brain development could increase the risk of psychiatric diseases. “Uncovering the entire picture of the downstream signaling pathways of birth may lead to the development of new therapeutic methods to control the risk of psychiatric diseases induced by abnormal birth,” Kawasaki says.
(Source: eurekalert.org)
Human Cortical Neurons with interconnecting dendrites, 4,200X by David Scharf.
Cortical Neurons make up the brain’s cortex which in part makes up the cerebral cortex, responsible for memory, attention, perceptual awareness, thought, language, and consciousness.
(Image Credit: BNPS/RPS/David Scharf)
Nobel Prize winner reports new model for neurotransmitter release
In a Neuron article published online October 10th, recent Nobel Laureate Thomas C. Südhof challenges long-standing ideas on how neurotransmitter gets released at neuronal synapses. On October 7th, Südhof won the Nobel Prize in Physiology or Medicine, alongside James Rothman and Randy Schekman, for related work on how vesicles—such as those in neurons that contain neurotransmitter—are transported within cells.
Neurotransmitter-containing vesicles are found inside neurons very close to the end of the axon. Here, they can quickly fuse with the neuronal membrane surrounding the axon to spill their contents into the synapse. How these vesicles are able to fuse with the membrane has been controversial, however, and understanding this process would give researchers much greater insight how neurons communicate with each other. Previously, it was thought that proteins found on the outside of the vesicles and on the axon membrane (called SNARE proteins) would come together and physically form a pore through which the contents of the vesicle—the neurotransmitter—could be released into the synapse. Now, the new findings from Südhof suggest that these proteins may not form a pore at all. Instead, their main role may be to physically force the vesicle and the axon membrane to get very close to each other; once they are forced into contact, the two appear able to fuse spontaneously.
"The importance of SNARE transmembrane regions has never been tested in a physiological fusion reaction," says Dr. Südhof. "We show that the SNARE transmembrane regions are dispensible for fusion as such but are important for maintaining the normal efficiency of regulated fusion. These findings rule out an essential participation of the SNARE transmembrane regions in fusion and are consistent with the notion that the SNAREs function in fusion as force generators, i.e., that their function is to force the membranes close together." The results are controversial due to years of research supporting the SNARE-protein pore hypothesis. These provocative findings could change long-held models for how neurotransmitters are released from neurons and suggest that there remain many open questions about the role of SNAREs in neurotransmitter release at synapses.
(Image: This is a molecular model of the active zone protein complex and its relation to the synaptic vesicle fusion machinery, Ca2+ channels, and synaptic cell-adhesion molecules. Credit: Neuron, Volume 75, Issue 1, 11-25, 12 July 2012, Sudhof)
Everything in moderation: excessive nerve cell pruning leads to disease
Scientists at the Montreal Neurological Institute and Hospital-The Neuro, McGill University, have made important discoveries about a cellular process that occurs during normal brain development and may play an important role in neurodegenerative diseases. The study’s findings, published in Cell Reports, a leading scientific journal, point to new pathways and targets for novel therapies for Alzheimer’s, Parkinson’s, ALS and other neurodegenerative diseases that affect millions of people world-wide.
Research into neurodegenerative disease has traditionally concentrated on the death of nerve cell bodies. However, it is now certain that in most cases that nerve cell body death represents the final event of an extended disease process. Studies have shown that protecting cell bodies from death has no impact on disease progression whereas blocking preceding axon breakdown has a significant benefit. The new study by researchers at The Neuro shifts the focus to the loss or degeneration of axons, the nerve-cell ‘branches’ that receive and distribute neurochemical signals among neurons.
During early development, axons are pruned to ensure normal growth of the nervous system. Emerging evidence suggests that this pruning process becomes reactivated in neurodegenerative disease, leading to the aberrant loss of axons and dendrites. Axonal pruning in development is significantly influenced by proteins called caspases. “The idea that caspases are even involved in axonal degeneration during development is very recent” said Dr. Philip Barker, a principal investigator at The Neuro and senior author of the study.
Dr. Barker and his colleagues show that the activity of certain ’executioner’ caspases (caspase-3 and caspase-9) induce axonal degeneration and that their action is suppressed by a protein termed XIAP (X-linked inhibitor of apoptosis). “We found that caspase-3- and -9 play crucial roles in axonal degeneration and that their activities are regulated by XIAP. XIAP acts as a brake on caspase activity and must be removed for degeneration to proceed” added Dr. Barker.
This balancing act between caspases and XIAP ensure that caspases do not cause unnecessary or excessive destruction. However, this balance may shift during neurodegenerative disease. “If we understand the pathways that regulate XIAP levels, we may be able to develop therapies that reduce caspase-dependent degeneration during neurodegenerative disease”.
(Source: mcgill.ca)
How Infections in Newborns are Linked to Later Behavior Problems
In animal study, inflammation stops cells from accessing iron needed for brain development
Researchers exploring the link between newborn infections and later behavior and movement problems have found that inflammation in the brain keeps cells from accessing iron that they need to perform a critical role in brain development.
Specific cells in the brain need iron to produce the white matter that ensures efficient communication among cells in the central nervous system. White matter refers to white-colored bundles of myelin, a protective coating on the axons that project from the main body of a brain cell.
The scientists induced a mild E. coli infection in 3-day-old mice. This caused a transient inflammatory response in their brains that was resolved within 72 hours. This brain inflammation, though fleeting, interfered with storage and release of iron, temporarily resulting in reduced iron availability in the brain. When the iron was needed most, it was unavailable, researchers say.
“What’s important is that the timing of the inflammation during brain development switches the brain’s gears from development to trying to deal with inflammation,” said Jonathan Godbout, associate professor of neuroscience at The Ohio State University and senior author of the study. “The consequence of that is this abnormal iron storage by neurons that limits access of iron to the rest of the brain.”
The research is published in the Oct. 9, 2013, issue of The Journal of Neuroscience.
The cells that need iron during this critical period of development are called oligodendrocytes, which produce myelin and wrap it around axons. In the current study, neonatal infection caused neurons to increase their storage of iron, which deprived iron from oligodendrocytes.
In other mice, the scientists confirmed that neonatal E. coli infection was associated with motor coordination problems and hyperactivity two months later – the equivalent to young adulthood in humans. The brains of these same mice contained lower levels of myelin and fewer oligodendrocytes, suggesting that brief reductions in brain-iron availability during early development have long-lasting effects on brain myelination.
The timing of infection in newborn mice generally coincides with the late stages of the third trimester of pregnancy in humans. The myelination process begins during fetal development and continues after birth.
Though other researchers have observed links between newborn infections and effects on myelin and behavior, scientists had not figured out why those associations exist. Godbout’s group focuses on understanding how immune system activation can trigger unexpected interactions between the central nervous system and other parts of the body.
“We’re not the first to show early inflammatory events can change the brain and behavior, but we’re the first to propose a detailed mechanism connecting neonatal inflammation to physiological changes in the central nervous system,” said Daniel McKim, a lead author on the paper and a student in Ohio State’s Neuroscience Graduate Studies Program.
The neonatal infection caused several changes in brain physiology. For example, infected mice had increased inflammatory markers, altered neuronal iron storage, and reduced oligodendrocytes and myelin in their brains. Importantly, the impairments in brain myelination corresponded with behavioral and motor impairments two months after infection.
Though it’s unknown if these movement problems would last a lifetime, McKim noted that “since these impairments lasted into what would be young adulthood in humans, it seems likely to be relatively permanent.”
The reduced myelination linked to movement and behavior issues in this study has also been associated with schizophrenia and autism spectrum disorders in previous work by other scientists, said Godbout, also an investigator in Ohio State’s Institute for Behavioral Medicine Research (IBMR).
“More research in this area could confirm that human behavioral complications can arise from inflammation changing the myelin pattern. Schizophrenia and autism disorders are part of that,” he said.
This current study did not identify potential interventions to prevent these effects of early-life infection. Godbout and colleagues theorize that maternal nutrition – a diet high in antioxidants, for example – might help lower the inflammation in the brain that follows a neonatal infection.
“The prenatal and neonatal period is such an active time of development,” Godbout said. “That’s really the key – these inflammatory challenges during critical points in development seem to have profound effects. We might just want to think more about that clinically.”
How neurons enable us to know smells we like and dislike, whether to approach or retreat
Think of the smell of freshly baking bread. There is something in that smell, without any other cues – visual or tactile – that steers you toward the bakery. On the flip side, there may be a smell, for instance that of fresh fish, that may not appeal to you. If you haven’t eaten a morsel of food in three days, of course, a fishy odor might seem a good deal more attractive.
How, then, does this work? What underlying biological mechanisms account for our seemingly instant, almost unconscious ability to determine how attractive (or repulsive) a particular smell is? It’s a very important question for scientists who are trying to address the increasingly acute problem of obesity: we need to understand much better than we now do the biological processes underlying food selection and preferences.
New research by neuroscientists at Cold Spring Harbor Laboratory (CSHL), published in The Journal of Neuroscience, reveals a set of cells in the fruit fly brain that respond specifically to food odors. Remarkably, the team finds that the degree to which these neurons respond when the fly is presented different food odors – apple, mango, banana – predicts “incredibly well how much the flies will ‘like’ a given odor,” says the lead author of the research paper, Jennifer Beshel, Ph.D., a postdoctoral investigator in the laboratory of CSHL Professor Yi Zhong, Ph.D.
“We all know that we behave differently to different foods – have different preferences. And we also all know that we behave differently to foods when we are hungry,” explains Dr. Beshel. “Dr. Zhong and I wanted to find the part of the brain that might be responsible for these types of behavior. Is there somewhere in the brain that deals with food odors in particular? How does brain activity change when we are hungry? Can we manipulate such a brain area and change behavior?”
When Beshel and Zhong examined the response of neurons expressing a peptide called dNPF to a range of odors, they saw that they only responded to food odors. (dNPF is the fly analog of appetite-inducing Neuropeptide Y, found in people.) Moreover, the neurons responded more to these same food odors when flies were hungry. The amplitude of their response could in fact predict with great accuracy how much the flies would like a given food odor – i.e., move toward it; the scientists needed simply to look at the responses of the dNPF-expressing neurons.
When they “switched off” these neurons, the researchers were able to make flies treat their most favored odor as if it were just air. Conversely, if they remotely turned these neurons “on,” they could make flies suddenly approach odors they previously had tried to avoid.
As Dr. Beshel explains: “The more general idea is that there are areas in the brain that might be specifically involved in saying: ‘This is great, I should really approach this.’ The activity of neurons in other areas in the brain might only take note of what something is – is it apple? fish? — without registering or ascribing to it any particular value, whether about its intrinsic desirability or its attractiveness at a given moment.
Researchers find hormone vasopressin involved in jet lag
A team of researchers from several research centers in Japan has together found what appears to be a connection between the hormone vasopressin and jet-lag. In their paper published in the journal Science, the team describes experiments they conducted with test mice that indicate that repressing neural connections that respond to vasopressin reduced the time it took for them to readjust their circadian clock.
Adjustments to the circadian clock can be more than a nuisance for long distance flyers, research over the years has shown that it can cause stressed induced medical problems for those that work odd hours. For that reason, scientists have been looking for a way to reset the circadian clock much quicker than happens naturally. In this new effort the researchers looked at a part of the brain called the suprachiasmatic nucleus—it’s believed to be the main region involved in monitoring the passage of time and hence the circadian clock. Upon closer scrutiny, they found that many of the neurons in that part of the brain had receptors that were sensitive to vasopressin.
To find out why, they genetically altered test mice to inhibit such receptors and then artificially altered their day/night schedule. They found that without the receptors the mice were able to adjust to a radically altered time schedule in just one day, as opposed to the week or more it took unaltered mice. Next, they tried giving test mice a chemical that is known to block the same receptors, but only in the brain (neurons with vasopressin sensitive receptors are found throughout the nervous system) and found the mice were able to readjust their internal clocks in three days, much faster than normal, but still not as fast as those without the receptors.
The findings by the team suggest that a cure for jet-lag may be on the way. The chemical given to the mice has not been tested yet to see if it has other side-effects, most particularly, whether it causes problems with the kidneys—vasopressin is known to play a role in causing the kidneys to retain water to help regulate salt levels throughout the body.
Cell auto-cleaning mechanism mediates the formation of plaques in Alzheimer’s
Autophagy, a key cellular auto-cleaning mechanism, mediates the formation of amyloid beta plaques, one of the hallmarks of Alzheimer’s disease. It might be a potential drug target for the treatment of the disease, concludes new research from the RIKEN Brain Science Institute in Japan. The study sheds light on the metabolism of amyloid beta, and its role in neurodegeneration and memory loss.
In a study published today in the journal Cell Reports, Drs. Per Nilsson, Takaomi Saido and their team show for the first time using transgenic mice that a lack of autophagy in neurons prevents the secretion of amyloid beta and the formation of amyloid beta plaques in the brain. The study also reveals that an accumulation of amyloid beta inside neurons is toxic for the cells.
Alzheimer’s disease, the most common form of dementia, affects nearly 36 million people worldwide, and this number is set to double over the next 20 years. However, the causes of the disease are not well understood and no disease-modifying treatment is available today.
Patients with Alzheimer’s disease have elevated levels of the peptide amyloid beta in their brain and amyloid beta plaques form outside their neurons. This accumulation of amyloid beta causes the neurons to die, but until now the underlying mechanism remained a mystery. And whether the elevated levels of the peptide inside or outside the cells are to blame was unknown.
Autophagy is a cellular cleaning mechanism that normally clears any protein aggregates or other ‘trash’ within the cells, but that is somewhat disturbed in Alzheimer’s patients.
To investigate the role of autophagy in amyloid beta metabolism, Nilsson et al. deleted an important gene for autophagy, Atg7, in a mouse model of Alzheimer’s disease. Contrary to what they were expecting, their results showed that a complete lack of autophagy within neurons prevents the formation of amyloid beta plaque around/outside the cells. Instead, the peptide accumulates inside the neurons, where it causes neuronal death, which in turn leads to memory loss.
“Our study explains how amyloid beta is secreted from the neurons, via autophagy, which wasn’t well understood,” comments Dr Nilsson. “To control amyloid beta metabolism including its secretion is a key to control the disease. Autophagy might therefore be a potential drug target for the treatment of Alzheimer’s disease,” he adds.
Blocking nerve cells could halt symptoms of eczema
Some 10 percent of the population suffers from eczema at some point in their lives. The chronic skin condition, for which there are no cures or good treatments, causes symptoms ranging from dry, flaky and itchy skin to flaming red rashes and, particularly in children, nasal allergies and asthma.
Scientists at the University of California, Berkeley, have developed a new picture of how the nervous system interacts with the immune system to cause the itch and inflammation associated with eczema. Their findings could lead to new therapies for the disease.
Eczema’s cause is unknown, but most research today focuses on the immune system’s role in reacting to chemicals that cause itching and inflammation. UC Berkeley neuroscientist Diana M. Bautista and graduate students Sarah R. Wilson and Lydia Thé, however, discovered that sensory nerves in the skin are the first to react to these chemicals, and that blocking the skin’s itch receptors not only stops the scratching, but may head off the worst consequences of eczema.
“Most drug development has focused on trying to find a way to inhibit the immune response,” said Bautista, assistant professor of molecular and cell biology and a member of the Helen Wills Neuroscience Institute. “Now that we have found that sensory neurons may be the first responders, that changes how we think about the disease.”
“By just blocking what is happening in the neurons, you could block the symptoms of chronic itch, including the big immune response leading to asthma and allergy,” Wilson added. “And you prevent the patient from scratching, which damages skin cells and makes them release more chemicals that cause inflammation and help maintain chronic itch.”
The researchers already have identified a potential drug, now in Phase 1 clinical trials for a different inflammatory disease, that stops mice from scratching when it is applied to the skin.
Their new model of eczema is based on findings reported online today (Thursday, Oct. 3) in the journal Cell by Bautista, Wilson, Thé and their UC Berkeley colleagues.
Block that wasabi
“We started out looking at acute itch and asked the question, ‘Why do we scratch? Why do we have that urge, and how does it work that scratching gives you some relief, when normally it feels terrible if you don’t have an itch and scratch yourself that hard?’” Bautista said. “But the many types of chronic itch that humans experience are all very different. We believe that, through identifying molecular mechanisms, we can find new treatments and therapies for these diseases.”
Immunologists several years ago identified a chemical – TSLP (thymic stromal lymphopoietin), a so-called cytokine – that induces itch when expressed in the skin. Because immune cells have receptors for this chemical, TSLP triggers them to release chemicals that attract other immune cells and to create the red, itchy inflammation typical of eczema. These inflammatory chemicals seem to spread through the body and induce inflammation in the lungs, gut and nasal passages that lead to asthma and allergies, Bautista said.
Wilson and Bautista, however, focused on what causes the immediate or acute itch. Probing itch-sensitive neurons in the skin, they found that these neurons also have receptors for TSLP, and that TSLP makes these neurons, like immune cells, release chemical mediators that cause inflammation. Furthermore, by looking at human skin cells (keratinocytes) in culture, they discovered the triggers that make skin cells release TSLP in the first place.
“Our hypothesis is that skin cells release TSLP, which triggers neurons to release mediators that lead to more inflammation and recruitment of immune cells,” helping to set up chronic inflammation, Bautista said.
“These itch-sensitive neurons are a small population,” she added. “If we could just block the 2 percent of neurons that respond to TSLP, we could have a really selective drug that treats chronic itch, but keeps all of the important functions of skin – normal pain function, normal temperature and tactile sensations – and the many parts of the immune system intact.”
Interestingly, the TSLP receptor works through an ion channel, TRPA1, that Bautista discovered when she was a post-doctoral researcher. The channel was named the wasabi ion channel because it is sensitive to “mustard compounds” like those found in Dijon or wasabi. Blockers of the wasabi channel thus would block the action of TSLP and stop itch.
Alternatively, Wilson said, drug developers could look for chemicals that block the release of TSLP from damaged skin cells.
Bautista and her colleagues are continuing to explore the relative contributions of different types of nerve and immune cells to atopic dermatitis and chronic itch and are developing mouse models in which to test their hypotheses.