Posts tagged neuron
Posts tagged neuron
USC neuroscientists have isolated chills at a cellular level, identifying the sensory network of neurons in the skin that relays the sensation of cold.
David McKemy, associate professor of neurobiology in the USC Dornsife College of Letters, Arts and Sciences, and his team managed to selectively shut off the ability to sense cold in mice while still leaving them able to sense heat and touch.
In prior work, McKemy discovered a link between the experience of cold and a protein known as TRPM8 (pronounced trip-em-ate), which a sensor of cold temperatures in neurons in the skin, as well as a receptor for menthol, the cooling component of mint. Now, in a paper appearing in the Journal of Neuroscience on February 13, McKemy and his co-investigators have isolated and ablated the neurons that express TRPM8, giving them the ability to test the function of these cells specifically.
Using mouse-tracking software program developed by one of McKemy’s students, the researchers tested control mice and mice without TRPM8 neurons on a multi-temperature surface. The surface temperature ranged from 0 degrees to 50 degrees Celsius (32 to 122 degrees Farenheit), and mice were allowed to move freely among the regions.
The researchers found that mice depleted of TRPM8 neurons could not feel cold, but still responded to heat. Control mice tended to stick to an area around 30 degrees Celsius (86 degrees Fahrenheit) and avoided both colder and hotter areas. But mice without TRPM8 neurons avoided only hotter plates and not cold — even when the cold should have been painful or was potentially dangerous.
In tests of grip strength, responses to touch, or coordinated movements, such as balancing onto a rod while it rotated, there was no difference between the control mice and the mice without TRPM8-expressing neurons.
By better understanding the specific ways in which we feel sensations, scientists hope to one day develop better pain treatments without knocking out all ability to feel for suffering patients.
“The problem with pain drugs now is that they typically just reduce inflammation, which is just one potential cause of pain, or they knock out all sensation, which often is not desirable,” McKemy said. “One of our goals is to pave the way for medications that address the pain directly, in a way that does not leave patients completely numb.”
Two species of worms have the same set of 20 neurons that control their foregut (a digestive organ located, naturally, near the front end of the worm). The way those neurons are wired, though, completely changes their behavior.
Caenorhabditis elegans eats bacteria, while its worm cousin Pristionchus pacificus, while able to subsist on bacteria, also eats other worms. While C. elegans uses a grinder to break up bacteria, P. pacificus develops teeth-like denticles to puncture its prey.
“These species are separated by 200 to 300 million years, but have the same cells,” researcher Ralf Sommer told New Scientist. However, they found the synapses were wired vastly differently, leading to a substantial change in the way information flows through their neural system.
In P. pacificus, neural signals pass through more cells before reaching the muscles. That suggests that it’s perfuming more complex motor functions, according to the European Molecular Biology Lab’s Detlev Arendt.
The paper can be found in the January 17 issue of Cell.
The Star-Nosed Mole Reveals Clues to the Molecular Basis of Mammalian Touch
Little is known about the molecular mechanisms underlying mammalian touch transduction. To identify novel candidate transducers, we examined the molecular and cellular basis of touch in one of the most sensitive tactile organs in the animal kingdom, the star of the star-nosed mole. Our findings demonstrate that the trigeminal ganglia innervating the star are enriched in tactile-sensitive neurons, resulting in a higher proportion of light touch fibers and lower proportion of nociceptors compared to the dorsal root ganglia innervating the rest of the body. We exploit this difference using transcriptome analysis of the star-nosed mole sensory ganglia to identify novel candidate mammalian touch and pain transducers. The most enriched candidates are also expressed in mouse somatosesensory ganglia, suggesting they may mediate transduction in diverse species and are not unique to moles. These findings highlight the utility of examining diverse and specialized species to address fundamental questions in mammalian biology.
Studying the links between brain and behavior may have just gotten easier. For the first time, neuroscientists have found a way to watch neurons fire in an independently moving animal. Though the study was done in fish, it may hold clues to how the human brain works.
“This technique will really help us understand how we make sense of the world and why we behave the way we do,” says Martin Meyer, a neuroscientist at King’s College London who was not involved in the work.
The study was carried out in zebrafish, a popular animal model because they’re small and easy to breed. More important, zebrafish larvae are transparent, which gives scientists an advantage in identifying the neural circuits that make them tick. Yet, under a typical optical microscope, neurons that are active and firing look much the same as their quieter counterparts. To see what neurons are active and when, neuroscientists have therefore developed a variety of indicators and dyes. For example, when a neuron fires, it is flooded with calcium ions, which can cause some of the dyes to light up.
Still, the approach has limitations. Traditionally, Meyer explains, researchers would immobilize the head or entire body of a zebrafish larvae so that they could get a clearer picture of what was happening inside the brain. Even so, it was difficult to interpret neural activity for just a few neurons and over a short period of time. Researchers needed a better way to study the zebrafish brain in real time.
Enter Junichi Nakai of Saitama University’s Brain Science Institute in Japan. He and colleagues selected a glowing marker known as green fluorescent protein (GFP) and linked it to a compound that would light up in the presence of large amounts of calcium. The researchers then inserted the DNA that codes for this marker into the zebrafish genome, tying it to a specific protein only found in neurons. This means that only actively firing neurons would fluoresce, and scientists could track neural activity without applying dye. Because the signal was stronger and clearer, researchers didn’t have to immobilize the larvae.
To test the setup, Nakai and colleagues sent the genetically engineered zebrafish larvae hunting for food. When the larvae see a swimming single-celled animal called a paramecium, they engage in what animal behaviorists call a prey capture response: They turn their heads toward the paramecium, swim at it, and finally eat it.
Using their newly developed imaging system, Nakai and colleagues associated the sight of moving paramecium and prey capture behavior with the activation of a group of neurons in the optic tectum, the visual center of the zebrafish brain. The neurons pulsed in tandem with the movements of the paramecium—a sudden dart of the one-celled organism caused a bright flash of neural activity in the zebrafish tectum. The tectum went silent if the paramecium stilled. Only moving prey interested the larvae, the team reports today in Current Biology. These particular neurons, Nakai proposes, are part of a specific visual-motor pathway that links the sight of moving prey with swimming behavior.
“It’s a good proof of principle study,” Meyer says. “The most important thing is that they showed [the technique worked] on freely behaving fish.”
It takes a lot to make a memory. New proteins have to be synthesized, neuron structures altered. While some of these memory-building mechanisms are known, many are not. Some recent studies have indicated that a unique group of molecules called microRNAs, known to control production of proteins in cells, may play a far more important role in memory formation than previously thought.
Now, a new study by scientists on the Florida campus of The Scripps Research Institute has for the first time confirmed a critical role for microRNAs in the development of memory in the part of the brain called the amygdala, which is involved in emotional memory. The new study found that a specific microRNA—miR-182—was deeply involved in memory formation within this brain structure.
“No one had looked at the role of microRNAs in amygdala memory,” said Courtney Miller, a TSRI assistant professor who led the study. “And it looks as though miR-182 may be promoting local protein synthesis, helping to support the synapse-specificity of memories.”
In the new study, published in the Journal of Neuroscience, the scientists measured the levels of all known microRNAs following an animal model of learning. A microarray analysis, which enables rapid genetic testing on a large scale, showed that more than half of all known microRNAs are expressed in the amygdala. Seven of those microRNAs increased and 32 decreased when learning occurred.
The study found that, of the microRNAs expressed in the brain, miR-182 had one of the lowest levels and these decreased further with learning. Despite these very low levels, its overexpression prevented the formation of memory and led to a decrease in proteins that regulate neuronal plasticity (neurons’ ability to adapt) through changes in structure.
These findings suggest that learning-induced suppression of miR-182 is a main supporting factor in the formation of long-term memory in the amagdala, as well as an underappreciated mechanism for regulating protein synthesis during memory consolidation, Miller said.
Further analysis identified miR-182 as a repressor of proteins that control actin—a major component of the cytoskeleton, the scaffolding that holds cells together.
“We know that memory formation requires changes in dendritic spines on the neurons through regulation of the actin cytoskeleton,” Miller said. “When miR-182 is suppressed through learning it halts, at least in part, repression of actin-regulating proteins, so there’s a good chance that miR-182 exerts important control over the actin cytoskeleton.”
Miller is now interested in whether or not high levels of miR-182 accumulate in the aging brain, something that would help to explain a tendency toward memory loss in the elderly. She also notes that other research has shown that animal models lacking miR-182 had no significant physical or cellular abnormalities, suggesting that miR-182 could be a viable target for drug discovery.
The skin is a human being’s largest sensory organ, helping to distinguish between a pleasant contact, like a caress, and a negative sensation, like a pinch or a burn. Previous studies have shown that these sensations are carried to the brain by different types of sensory neurons that have nerve endings in the skin. Only a few of those neuron types have been identified, however, and most of those detect painful stimuli. Now biologists at the California Institute of Technology (Caltech) have identified in mice a specific class of skin sensory neurons that reacts to an apparently pleasurable stimulus.
More specifically, the team, led by David J. Anderson, Seymour Benzer Professor of Biology at Caltech, was able to pinpoint individual neurons that were activated by massage-like stroking of the skin. The team’s results are outlined in the January 31 issue of the journal Nature.
Supported by the commitment of the University of Connecticut and the state to stem cell research, a UConn Health Center researcher is advancing the understanding of the devastating inherited condition known as spinal muscular atrophy.
Xue-Jun Li, assistant professor in the Department of Neuroscience, is corresponding author of a paper published in the prestigious journal Cell Research in December 2012 entitled “Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.” The paper’s other authors are UConn Health Center researcher Zhi-Bo Wang and Xiaoqing Zhang of the Tongji University School of Medicine in Shanghai.
Spinal muscular atrophy (SMA) is a group of inherited diseases that cause muscle damage and debilitation, which progress over time and eventually lead to death. To be affected, a person must inherit the defective gene from both parents. About 1 in 10,000 people have SMA, and most do not survive childhood due to respiratory problems, heart failure and infections.
“There is no effective treatment for spinal muscular atrophy, and one of the roadblocks is not knowing why the spinal motor neuron degenerates,” Li explains. “One of the aspects of our research is to understand how specific types of neurons are specified and degenerated. We are trying to model neurological disorders by using human motor neurons derived from stem cells.”
Establishing human cell models of SMA to mimic motor neuron-specific phenotypes holds the key to understanding this destructive disease, she says. The model described in the journal article provides a unique paradigm for studying how motor neurons degenerate. It also highlights the potential importance of antioxidants for the treatment of SMA.
Understanding how motor neurons are specifically degenerated can lead to effective interventions in the future. “It can help us find some way to rescue the motor neuron degeneration in this disease,” Li points out. “Understanding the role of antioxidants can provide potential clues to finding a treatment.”
A protein associated with neuron damage in people with Alzheimer’s disease is surprisingly useful in promoting neuron growth in the lab, according to a new study by engineering researchers at Brown University. The findings, in press at the journal Biomaterials, suggest a better method of growing neurons outside the body that might then be implanted to treat people with neurodegenerative diseases.
The research compared the effects of two proteins that can be used as an artificial scaffold for growing neurons (nerve cells) from the central nervous system. The study found that central nervous system neurons from rats cultured in apolipoprotein E-4 (apoE4) grew better than neurons cultured in laminin, which had been considered the gold standard for growing mammalian neurons in the lab.
“Most scientists assumed that laminin was the best protein for growing CNS (central nervous system),” said Kwang-Min Kim, a biomedical engineering graduate student at Brown University and lead author of the study, “but we demonstrated that apoE4 has substantially better performance for mammalian CNS neurons.”
Kim performed the research under the direction of Tayhas Palmore, professor of engineering and medical science and Kim’s Ph.D. adviser. Also involved in the project was Janice Vicenty, an undergraduate from the University of Puerto Rico, who was working in the Palmore lab as a summer research fellow through the Leadership Alliance.
The results are surprising partly because of the association of apoE4 with Alzheimer’s. Apolipoproteins are responsible for distributing and depositing cholesterols and other lipids in the brain. They come in three varieties: apoE2, apoE3 and apoE4. People with the gene that produces apoE4 are at higher risk for amyloid plaques and neurofibrillary tangles, the hallmarks of Alzheimer’s. But exactly how the protein itself contributes to Alzheimer’s is not known.
This study suggests that outside the body, where the protein can be separated from the cholesterols it normally carries, apoE4 is actually beneficial in promoting neuron growth.
While the wooly musk ox may like it cold, fruit flies definitely do not. They like it hot, or at least warm. In fact, their preferred optimum temperature is very similar to that of humans—76 degrees F.
Scientists have known that a type of brain cell circuit helps regulate a variety of innate and learned behavior in animals, including their temperature preferences. What has been a mystery is whether or not this behavior stems from a specific set of neurons (brain cells) or overlapping sets.
Now, a new study from The Scripps Research Institute (TSRI) shows that a complex set of overlapping neuronal circuits work in concert to drive temperature preferences in the fruit fly Drosophila by affecting a single target, a heavy bundle of neurons within the fly brain known as the mushroom body. These nerve bundles, which get their name from their bulbous shape, play critical roles in learning and memory.
The study, published in the January 30, 2013 edition of the Journal of Neuroscience, shows that dopaminergic circuits—brain cells that synthesize dopamine, a common neurotransmitter—within the mushroom body do not encode a single signal, but rather perform a more complex computation of environmental conditions.
“We found that dopamine neurons process multiple inputs to generate multiple outputs—the same set of nerves process sensory information and reward-avoidance learning,” said TSRI Assistant Professor Seth Tomchik. “This discovery helps lay the groundwork to better understand how information is processed in the brain. A similar set of neurons is involved in behavior preferences in humans—from basic rewards to more complex learning and memory.”
Using imaging techniques that allow scientists to visualize neuron activity in real time, the study illuminated the response of dopaminergic neurons to changes in temperature. The behavioral roles were then examined by silencing various subsets of these neurons. Flies were tested using a temperature gradient plate; the flies moved from one place to another to express their temperature preferences.
As it turns out, genetic silencing of dopaminergic neurons innervating the mushroom body substantially reduces cold avoidance behavior. “If you give the fly a choice, it will pick San Diego weather every time,” Tomchik said, “but if you shut down those nerves, they suddenly don’t mind being in Minnesota.”
The study also showed dopaminergic neurons respond to cooling with sudden a burst of activity at the onset of a drop in temperature, before settling down to a lower steady-state level. This initial burst of dopamine could function to increase neuronal plasticity—the ability to adapt—during periods of environmental change when the organism needs to acquire new associative memories or update previous associations with temperature changes.
Synapse development is promoted by a variety of cell adhesion molecules that connect neurons and organize synaptic proteins. Many of these adhesion molecules are linked to neurodevelopmental disorders; mutations in neuroligin and neurexin proteins, for example, are associated with autism and schizophrenia. According to a study in The Journal of Cell Biology, another family of proteins linked to these disorders regulates the function of neuroligins and neurexins in order to suppress the development of inhibitory synapses.
Like neurexins and neuroligins, the neuronal proteins MDGA1 and MDGA2 have been linked to autism and schizophrenia, but their function in neurodevelopment was unknown. Both MDGA proteins localize to the plasma membrane, and their extracellular domains are similar to those of cell adhesion molecules. On the other hand, postsynaptic neuroligin proteins are known to help synapses form by associating with neurexins on presynaptic membranes. Neuroligin-2 specifically boosts the development of inhibitory synapses, whereas neuroligin-1 promotes the development of excitatory synapses.
Ann Marie Craig and colleagues from the University of British Columbia investigated the function of MDGAs using co-culture assays, in which postsynaptic proteins like neuroligin-1 or -2 are expressed in non-neuronal cells and then tested for their ability to induce presynaptic differentiation in neighboring neurons. MDGA1 didn’t promote synapse formation in these assays. Instead, it inhibited the ability of neuroligin-2 to promote synapse development. The researchers found that MDGA1’s extracellular domains bound to neuroligin-2, blocking its association with neurexin. The same domains were sufficient to inhibit neuroligin-2’s synapse-promoting activity. In contrast, MDGA1 didn’t show high affinity binding to, or inhibit the function of, neuroligin-1. This suggested that, by inhibiting neuroligin-2, MDGA1 might specifically suppress the development of inhibitory synapses, so Craig and colleagues investigated MDGA1 function in cultured hippocampal neurons.
“Overexpressing MDGA1 in neurons reduced the density of inhibitory synapses without affecting excitatory synapses,” Craig says. Knocking down MDGA1, on the other hand, increased inhibitory synapse development but had no effect on excitatory synapses.
“I can’t think of any other proteins that specifically suppress inhibitory synapse formation,” says Craig. Indeed, very few proteins in general have been identified as negative regulators of synapse development, compared to the many proteins that are known to promote synaptogenesis. The results suggest that function-altering mutations in the MDGA proteins may disrupt the balance of excitatory and inhibitory synapses in the brain, potentially explaining the development of autism and other neurodevelopmental disorders.
“This puts MDGAs in the same pathway as neurexins and neuroligins and strengthens the evidence for the involvement of synaptic organizing proteins in autism and schizophrenia,” Craig explains. As well as investigating the function of MDGA2, the researchers want to explore the therapeutic potential of MDGA1 inhibitors, not only against autism and schizophrenia but also for the treatment of epilepsy, in which excitatory and inhibitory synapses are also imbalanced.