Posts tagged neuron

June 17, 2012

A collaborative research team led by Professor Tadashi ISA from The National Institute for Physiological Sciences, The National Institutes of Natural Sciences and Fukushima Medical University and Kyoto University, developed a “double viral vector transfection technique” which can deliver genes to a specific neural circuit by combining two new kinds of gene transfer vectors. With this method, they found that “indirect pathways”, which were suspected to have been left behind when the direct connection from the brain to motor neurons (which control muscles) was established in the course of evolution, actually plays an important role in the highly developed dexterous hand movements. This study was supported by the Strategic Research Program for Brain Sciences by the MEXT of Japan. This research result will be published in Nature (June 17th, advance online publication).

It is said that the higher primates including human beings accomplished explosive evolution by having acquired the ability to move hands skillfully. It has been thought that this ability to move individual fingers is a result of the evolution of the direct connection from the cerebrocortical motor area to motor neurons of the spinal cord which control the muscles. On the other hand, in lower animals with clumsy hands, such as cats or rats, the cortical motor area is connected to the motor neurons, only through interneurons of the spinal cord. Such “indirect pathway”remains in us, primates, without us fully understanding its functions. Is this “phylogenetically old circuit” still in operation? Or maybe suppressed since it is obstructive? The conclusion was not attached to this argument.

The collaborative research team led by Professor Tadashi ISA, Project Assistant Professor Masaharu KINOSHITA from The National Institute for Physiological Sciences, The National Institutes of Natural Sciences and Fukushima Medical University and Kyoto University developed “the double viral vector transfection technique”which can deliver genes to a specific neural circuit by combining two new kinds of gene transfer vectors.

With this method, they succeeded in the selective and reversible suppression of the propriospinal neurons (spinal interneurons mediating the indirect connection from cortical motor area to spinal motor neurons)

The results revealed that “indirect pathways” play an important role in dexterous hand movements and finally a longtime debate has come to a close.

The key component of this discovery was”the double viral vector transfection technique”in which one vector is retrogradely transported from the terminal zone back to the neuronal cell bodies and the other is transfected at the location of their cell bodies. The expression of the target gene is regulated only in the cells with double transfection by the two vectors. Using this technique, they succeeded in the suppression of the propriospinal neuron selectively and reversibly.

Such an operation was possible in mice in which the inheritable genetic manipulation of germline cells were possible, but impossible in primates until now.

Using this method, further development of gene therapy targeted to a specific neural circuit can be expected.

Professor Tadashi ISA says “this newly developed double viral vector transfection technique can be applied to the gene therapy of the human central nervous system, as we are the same higher primates.

And this is the discovery which reverses the general idea that the spinal cord is only a reflex pathway, but also plays a pivotal role in integrating the complex neural signals which enable dexterous movements.”

Provided by National Institute for Physiological Sciences

Source: medicalxpress.com

June 15, 2012

Whether or not a neuron transmits an electrical impulse is a function of many factors. European research is using a heady mixture of techniques – molecular, microscopy and electrophysiological – to identify the necessary input for nerve transmission in the cortex.

Credit: Thinkstock

In the central nervous system (CNS), a nerve cell or neuron has a ‘forest’ of elaborate dendritic trees arising from the cell body. These literally receive many thousands of synapses (junctions that allow transmission of a signal) at positions around the tree. These inputs then are able to generate an impulse, or ‘spike’, known as an action potential at the initial part of the axon.

Previous research has confirmed that an activated synapse will generate an electric signal as a result of neurotransmitters released from pre-synaptic axons. Electrical recordings from the neocortex have confirmed that, in line with the cable theory prediction, that modulation of potential at the dendrite is highly distance-dependent from the cell body or soma.

The ‘Information processing in distal dendrites of neocortical layer 5 pyramidal neurons’ (Channelrhodopsin) project aimed to shed more light on how more distal sites in the ‘tree’ influence the action potential of the post-synaptic neuron. Furthermore, they investigated exactly how dendritic spikes can be generated, another issue about which there is little information so far.

Recent research has highlighted the importance of activation of N-methyl-D-aspartate (NMDA) receptors to bring about the production of a signal that will proceed to the soma and then result in a spike. There is also indirect evidence that interneurons targeting dendrites can control level of dendrite excitability.

Channelrhodopsin scientists simultaneously recorded the pre- and post-synaptic electrical recordings of identified interneurons and a special type of neuron, pyramidal cells that are primary excitation units in the mammalian cortex.

The project team first characterised the different types of inhibitory neuron deep in the cortex in layer 5 at apical tuft dendrites. The researchers then showed that a special type of inhibitory interneuron in the outer layer of the neocortex can suppress dendritic spiking in layer 5.

Project results show that a superficial inhibitory neuron can impact information processing in a specific pyramidal neuron. The research will have massive implications for neuroscience and help to unravel the integrative operations of CNS neurons.

Provided by CORDIS

Source: medicalxpress.com

ScienceDaily (June 12, 2012) — Studying how nerve cells send and receive messages, Johns Hopkins scientists have discovered new ways that genetic mutations can disrupt functions in neurons and lead to neurodegenerative disease, including amyotrophic lateral sclerosis (ALS).

Neurons are shown in green. A normal neuron is on the left and p150glued mutant neuron is on the right. The red cargo accumulates in the mutant but not in the normal neuron. Areas with the highest cargo accumulation are yellow at the tip of the neuron. (Credit: Image courtesy of Johns Hopkins Medicine)

In a report published April 26 in Neuron, the research team says it has discovered that a mutation responsible for a rare, hereditary motor neuron disease called hereditary motor neuropathy 7B (HMN7B) disrupts the link between molecular motors and the nerve cell tip where they reside. This mutation results in the production of a faulty protein that prevents material from being transported from the cell’s edge, which is located at the muscle and extends back toward its “body” in the central nervous system. In pinpointing how and where this cargo transport is disrupted, the scientists are now closer to understanding mechanisms underlying this condition and ALS.

"An important question we need to answer is how defects in proteins that normally perform important cellular functions for neurons lead to disease," says Alex Kolodkin, Ph.D., a Howard Hughes Medical Institute Investigator and professor of neuroscience at the Johns Hopkins University School of Medicine. "A major issue in understanding neurodegenerative diseases is determining how certain proteins that are expressed in all types of neurons, or even in all cells in the body, can lead to devastating effects in one, or a few, subsets of neurons." Kolodkin notes that many neurodegenerative diseases involve proteins that serve general functions required in nearly every type of cell in the body, including the transport of material between different parts of a cell, yet certain alterations in these proteins can result in specific neurological disorders.

One particular protein, p150glued, is known to play a role in at least two of these disorders, HMN7B, which is similar to ALS, and Perry syndrome, which leads to symptoms similar to Parkinson’s disease. p150glued is part of a larger complex of proteins that forms a molecular “motor” capable of transporting various molecules and other “cargo” from the nerve end toward the cell body. To better understand how mutations in p150glued lead to HMN7B and Perry syndrome, the researchers turned to fruit flies, which are easy to genetically manipulate and where the same protein has been well studied.

They engineered the fruit fly p150glued protein to contain the same mutations as those implicated in the two diseases and used microscopy techniques that enable them to follow in live cells the movement of fluorescently tagged cargo along motor neurons.

They found, surprisingly, that the movement of cargo along the length of the cell was normal. However, at the far end of the cell, they found that the HMN7B-associated mutation caused an unusually large accumulation of cargo. “This was an unexpected finding,” says Thomas Lloyd, M.D., Ph.D., an assistant professor in neurology and neuroscience at the Johns Hopkins School of Medicine. “We need to better understand how this is causing disease.”

Using flies engineered to contain mutations in other motor proteins, and again watching cargo transport in live cells, the team found that p150glued works in concert with another motor to control cargo transport. Their results suggest that when p150glued is compromised, this control is lost and cargo accumulates at the nerve end, leading to disease.

"It’s still unclear how these two different mutations in different regions of the same protein cause very distinct neurodegenerative diseases," Lloyd says. Encouraged by their results, the team plans to continue using fruit flies to unravel the molecular mechanisms underlying these diseases.

Source: Science Daily

June 6, 2012

Ask the average person the street how the brain develops, and they’ll likely tell you that the brain’s wiring is built as newborns first begin to experience the world. With more experience, those connections are strengthened, and new branches are built as they learn and grow.

A new study conducted in a Harvard lab, however, suggests that just the opposite is true.

As reported on June 7 in the journal Neuron, a team of researchers led by Jeff Lichtman, the Jeremy R. Knowles Professor of Molecular and Cellular Biology, has found that just days before birth mice undergo an explosion of neuromuscular branching. At birth, the research showed, some muscle fibers are contacted by as many as 10 nerve cells. Within days, however, all but one of those connections had been pruned away.

"By the time mammals – and humans would certainly be included – are first coming into the world, when they can do almost nothing, the brain is probably very wired up," Lichtman said. "Through experience, the brain works to select, out of this mass of possible circuits, a very small subset…and everything else that could have been there is gone.

"I don’t think anyone suspected that this was taking place – I certainly didn’t," he continued. "In some simple muscles, every nerve cell branches out and contacts every muscle fiber. That is, the wiring diagram is as diffuse as possible. But by the end, only two weeks later, every muscle fiber is the lifelong partner of a single nerve cell, and 90 percent of the wires have disappeared."

Though researchers, including Lichtman, had shown as early as the 1970’s that mice undergo an early developmental period in which target cells including muscle fibers and some neurons are contacted by multiple nerve cells before being reduced to a single connection, those early studies and his current work were hampered by the same problem – technological challenges make it difficult to identify individual nerve cells in earlier and earlier stages of life.

And though the use of mice that have been genetically-engineered to express fluorescent protein molecules in nerve cells has made it easier for researchers to identify nerve cells, it remains challenging to study early stages of development because the fluorescent labeling in the finest nerve cell wires often becomes so weak as to be invisible.

Read more …

ScienceDaily (June 5, 2012) — In an early study, UCLA researchers found that the immune cells of patients with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, may play a role in damaging the neurons in the spinal cord. ALS is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement.

In the ALS spinal cord, a patient’s own immune cells called macrophages (green) impact neurons (live neurons =red, which are also marked by an asterisk (*), and dead neurons = magenta that are marked by an arrow. (Credit: University of California, Los Angeles)

Specifically, the team found that inflammation instigated by the immune system in ALS can trigger macrophages — cells responsible for gobbling up waste products in the brain and body — to also ingest healthy neurons. During the inflammation process, motor neurons, whether healthy or not, are marked for clean-up by the macrophages.

In addition, the team found that a lipid mediator called resolvin D1, which is made in the body from the omega-3 fatty acid DHA, was able to “turn off” the inflammatory response that made the macrophages so dangerous to the neurons. Resolvin D1 blocked the inflammatory proteins being produced by the macrophages, curbing the inflammation process that marked the neurons for clean-up. It inhibited key inflammatory proteins like IL-6 with a potency 1,100 times greater than the parent molecule, DHA. DHA has been shown in studies to be neuroprotective in a number of conditions, including stroke and Alzheimer’s disease.

For the study, the team isolated macrophages from blood samples taken from both ALS patients and controls and spinal cord cells from deceased donors.

The study findings on resolvin D1 may offer a new approach to attenuating the inflammation in ALS. Currently, there is no effective way of administering resolvins to patients, so clinical research with resolvin D1 is still several years away. The parent molecule, DHA, is available in stores, although it has not been tested in clinical trials for ALS. Studies with DHA are in progress for Alzheimer’s disease, stroke and brain injury and have been mostly positive.

Source: Science Daily

June 3, 2012

Unlike their visual cousins, the neurons that control movement are not a predictable bunch. Scientists working to decode how such neurons convey information to muscles have been stymied when trying to establish a one-to-one relationship between a neuron’s behavior and external factors such as muscle activity or movement velocity.

The 19th century mathematician Joseph Fourier showed that two rhythms could be summed to produce a third rhythm. Researchers at Stanford have shown that this principle is behind the brain activity that produces arm movements. Credit: Mark Churchland, Stanford School of Engineering

In an article published online June 3rd by the journal Nature, a team of electrical engineers and neuroscientists working at Stanford University propose a new theory of the brain activity behind arm movements. Their theory is a significant departure from existing understanding and helps to explain, in relatively simple and elegant terms, some of the more perplexing aspects of the activity of neurons in motor cortex.

In their paper, electrical engineering Associate Professor Krishna Shenoy and post-doctoral researchers Mark Churchland, now a professor at Columbia, and John Cunningham of Cambridge University, now a professor at Washington University in Saint Louis, have shown that the brain activity controlling arm movement does not encode external spatial information—such as direction, distance and speed—but is instead rhythmic in nature.

Understanding the brain

Neuroscientists have long known that the neurons responsible for vision encode specific, external-world information—the parameters of sight. It had been theorized and widely suggested that motor cortex neurons function similarly, conveying specifics of movement such as direction, distance and speed, in the same way the visual cortex records color, intensity and form.

"Visual neurons encode things in the world. They are a map, a representation," said Churchland, who is first author of the paper. "It’s not a leap to imagine that neurons in the motor cortex should behave like neurons in the visual cortex, relating in a faithful way to external parameters, but things aren’t so concrete for movement."

Scientists have disagreed about which movement parameters are being represented by individual neurons. They could not look at a particular neuron firing in the motor cortex and determine with confidence what information it was encoding.

"Many experiments have sought such lawfulness and yet none have found it. Our findings indicate an alternative principle is at play," said co-first author Cunningham.

Read more …

May 24, 2012

Within the nervous system, a handful of signaling pathways modulate development of a cornucopia of different neuronal subtypes. “Even small alterations in neuron differentiation pathways can disrupt subsequent circuit organization and catalyze the genesis of neurological disorders,” explains Adrian Moore of the RIKEN Brain Science Institute in Wako.

Figure 1: Interplay between Notch signaling and Hamlet activity gives rise to diverse olfactory receptor neurons (ORNs), each with distinct structures and subsets of olfactory receptors (left). The precursor cell (right) divides to yield two daughter cells, one of which undergoes Notch (N)-mediated gene activation. Hamlet (Ham) subsequently resets Notch’s genetic effects, and the absence or subsequent restoration of Notch signaling determines which type of ORN (Naa or Nab) will result from differentiation. Credit: 2012 Adrian Moore, RIKEN Brain Science Institute

Recent work from Moore’s team, which includes Keita Endo of the University of Tokyo, has revealed mechanisms governing this complexity in the fruit fly olfactory system. Within the antennae—the fly equivalent of the nose—it was known that cells called neuronal precursors undergo multiple rounds of ‘asymmetric division’, wherein each resulting daughter cell follows a distinct developmental path, yielding different combinations of olfactory receptor neurons (ORNs). Moore’s team showed specifically that ORN precursors undergo two rounds of division, yielding four different cellular subtypes, three of which will typically mature into ORNs.

Earlier work from Endo showed that the activation or suppression of signaling by the Notch protein helps differentiate these cellular fates, but other factors were clearly involved. Their joint research demonstrated that a second protein, Hamlet, modulates the effects of Notch. 

“This [process] provides an important foundation for all future studies of odorant receptor expression and axon targeting control on the olfactory system,” says Moore. The researchers found that presence or absence of Notch and Hamlet activity plays a central role in establishing the identity of these subtypes, and this in turn determines both the connections formed by the resulting ORNs as well as the subset of olfactory receptor proteins that will be expressed (Fig. 1). 

Moore and Endo’s study also revealed a surprising mode of action for Hamlet. Chromosomal DNA is wrapped around clusters of protein, and chemical changes to those proteins profoundly alter local gene activity—a mechanism called ‘epigenetic regulation’. They found that Hamlet selectively deactivates genes activated by Notch by triggering such changes. This means that immature ORNs produced by division of a Notch-activated cell can essentially be ‘reset’ by Hamlet. The ultimate developmental fate of those cells is then determined, in part, by whether or not they subsequently undergo a new round of Notch activation. 

Moore and colleagues also observed that, beyond simply switching off active Notch genes, Hamlet may define subsets of target genes that can subsequently be reactivated by Notch signaling. “The modifications induced by Hamlet may help establish cell fate by marking gene promoters for use later during differentiation,” says Moore. “This could prove fundamental to understanding the process of neuronal diversification.”

Provided by RIKEN

Source: medicalxpress.com

May 24, 2012

(Medical Xpress) — Research from Karolinska Institutet shows that the human olfactory bulb - a structure in the brain that processes sensory input from the nose - differs from that of other mammals in that no new neurons are formed in this area after birth. The discovery, which is published in the scientific journal Neuron, is based on the age-determination of the cells using the carbon-14 method, and might explain why the human sense of smell is normally much worse than that of other animals.

"I’ve never been so astonished by a scientific discovery," says lead investigator Jonas Frisén, Tobias Foundation Professor of stem cell research at Karolinska Institutet. "What you would normally expect is for humans to be like other animals, particularly apes, in this respect."

It was long thought that all brain neurons were formed up to the time of birth, after which production stopped. A paradigm shift occurred when scientists found that nerve cells were being continually formed from stem cells in the mammalian brain, which changed scientific views on the plasticity of the brain and raised hopes of being able to replace neurons lost during some types of neurological disease.

In the adult mammal, new nerve cells are formed in two regions of the brain: the hippocampus and the olfactory bulb. While the former has an important part to play in memory, the latter is essential to the interpretation of smells. However, owing to the difficulty of studying the formation of new neurons in humans, the extent to which this phenomenon also occurs in the human brain has remained unclear. In this present study, researchers at Karolinska Institutet and their Austrian and French colleagues made use of the sharp rise in atmospheric carbon-14 caused by Cold War nuclear tests to find an answer to this question.

Carbon-14 is incorporated in DNA, making it possible to gauge the age of the cells by measuring how much of the isotope they contain. Doing this, the team found that the olfactory bulb neurons in their adult human subjects had carbon-14 levels that matched those at the atmosphere at the time of their birth. This is a strong indication that there is no significant generation of new neurons in this part of the brain, something that sets humans apart from all other mammals.

"Humans are less dependent on their sense of smell for their survival than many other animals, which may be related to the loss of new cell generation in the olfactory bulb, but this is just speculation,” says Professor Frisén.

Professor Frisén and his team now plan to study the extent of neuron generation in the hippocampus, a part of the brain that is important for higher cerebral functions in humans.

Provided by Karolinska Institutet

Source: medicalxpress.com