Scientists discover external protein network can help stabilize neural connections

The Noelin family of secreted proteins bind to the external portion of AMPA glutamate receptors and stabilize them on the neuronal cellular membrane, a process necessary for transmission of full-strength signals between neurons, according to a study in mice from the National Eye Institute (NEI) and the University of Freiberg, Germany. Without this external, stabilizing protein network, the AMPA receptors are no longer retained at the synapse, leading to weak, short-lived synaptic signals. The findings not only provide insight into processes such as learning and memory but also the development of blinding conditions like glaucoma. The study was published in the journal Neuron. NEI is part of the National Institutes of Health.

"This study shows that Noelins have a crucial job in supporting synapse function in the brain and other neural tissues like the eye's retina," said Stanislav Tomarev, Ph.D., chief of NEI's Section on Retinal Ganglion Cell Biology and co-senior author of the report.

Neurons pass signals from one cell to the next via synapses, specialized connection points between the two cells. The main excitatory synapses in the brain are glutamatergic, meaning that they use the chemical messenger glutamate to transmit their signals across the synapse. The presynaptic "sending" cell emits glutamate, which travels across the synaptic cleft and is sensed by glutamate receptors on the postsynaptic "receiving" cell. These glutamate receptors are ion channels; when the channels sense glutamate, they open, generating a new neuronal signal within the postsynaptic cell. In order to generate a strong signal, sufficient receptors must be present in the correct location of the cell's surface at the synapse.

In a new study, a team of researchers led by Tomarev and Bernd Fakler, M.D., University of Freiberg, used biochemical and genetic methods to explore the complex network of extracellular proteins maintaining the localization of AMPA-type glutamate receptors at neural synapses.

The researchers first took mouse brain tissue, and isolated cellular membranes and their attached proteins. Using mass spectroscopy and specialized analytic techniques, the team worked out which proteins were associating with AMPA receptors in these membranes. The Noelin family of proteins (primarily Noelin 1, but also Noelins 2 and 3, also known as Olfactomedins 1, 2, and 3, respectively), were strongly associated with the AMPA receptors. The researchers also found secreted and membrane-anchored proteins like Neuritin and Brorin, which are known to be present at synapses.

To better understand how the Noelins help regulate neuronal activity, the researchers developed mice lacking all three Noelin proteins. Without Noelins present, synapses in the mouse hippocampus had many fewer AMPA glutamate receptors. And when the researchers attempted to stimulate neurons lacking Noelins, the neuronal signals were much lower than normal.

However, the neuronal signals weren't just lower. One of the key steps in memory formation is long-term neuron signaling, also known as long-term potentiation. This is achieved through recruitment and stabilization of additional glutamate receptors at the synapse over time, leading to a sustained signal through the neuron. In the brains of mice lacking Noelins, this stabilization didn't take place, meaning that not only were the neural signals low, they were short-lived as well.

"While this first study showed the Noelins' role in the brain, these proteins are highly prevalent in the retina as well," Tomarev said. "Our next task is to understand how changes in these secreted protein networks contribute to the development of retinal disorders, including glaucoma."

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Reducing their natural signals: How sneaky germs hide from ants

Not only humans are social, ants are too. Group members are taking care of sick ones by providing collective hygiene measures. This presents germs with a task. They must circumvent the immunity of an individual ant and avoid the group's healthcare. A new study now published in Nature Ecology & Evolution reveals that germs develop a sneaky way to escape the ant colony's defense systems by reducing their detection cues.

Pathogens are disease-causing organisms. By natural selection, they develop evading mechanisms to outsmart the host's immune system and to get the upper hand. One way to support the immune system and fight back is medical intervention. However, this can lead to unwanted adaptions of pathogens as seen in antibiotic-resistant bacteria. Another strategy is social intervention. Some social groups like ants are trying to fight infection with "social immunity," the collective hygiene and health care measures to avoid spreading throughout the community. If and how pathogens can respond to this kind of group behavior, is still unknown.

The latest study by Professor Sylvia Cremer and her research team at the Institute of Science and Technology Austria (ISTA) shows the extraordinary effects of these kinds of host-parasite interactions. Together, with chemical ecologists at the University of Würzburg in Germany, the scientists took a close look at social ants, to see how pathogenic fungi respond to their hosts' social care intervention during infection. The results reveal that fungi reduce their chemical detection signals to outplay social immunity. The study is published today in Nature Ecology & Evolution.

More spores but less grooming

"Fungi infect the ants from the body surface and grow inside, but nestmates groom off many of the spores before they can even cause internal infection," explains Barbara Milutinović, one of the lead authors, former postdoc in the Cremer Group and now Marie Curie Sklodowska Fellow at Ruđer Bošković Institute in Croatia. The scientists set up an experiment where Argentine ants (Linepithemahumile) were infected with pathogenic Metarhizium fungi either in the absence or presence of caregiving colony members. "We found that the fungi fundamentally changed in response to the ant workers' caregiving," Milutinović continues. Over ten infection cycles, fungi which experienced grooming nestmate ants boosted their spore production compared to fungi accompanied by only individual ants. "Producing more spores will help the fungus counteract the spore-removal by helping nestmates. Yet, we were surprised to see that the ants showed less grooming against the spores," Sylvia Cremer adds. "This suggests, that the spores have become more difficult to detect by the ants."

Fungi lose their typical chemical profile

To check why ant workers had difficulties sensing fungi and to analyze possible fungal detection cues, the scientists teamed up with a chemical ecologist from the University of Würzburg. Local Professor Thomas Schmitt explains: "The fungi, that adapted to social hosts were perceived less strongly, due to a strong reduction of a fungi-specific compound called ergosterol." Ergosterol is an essential membrane compound, that all fungi have. By exposing the ants to pure fungal ergosterol or the slightly different non-fungal vertebrate equivalent, the researchers showed, that only the fungal compound induced intense grooming. Milutinović summarizes: "This demonstrates that fungal pathogens react to the presence of caregiving ants by reducing their characteristic fungal signals. They are no longer recognized as a disease threat and can escape the social immunity of the colony."

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Pair of studies uncover surprising new roles for spinal cord and brainstem in touch

The sense of touch is essential to almost everything we do, from routine tasks at home to navigating unfamiliar terrains that may conceal dangers. Scientists have long been interested in understanding exactly how the touch information we obtain with our hands and other parts of the body makes its way to the brain to create the sensations we feel.

Yet, key aspects of touch -- including how the spinal cord and brainstem are involved in receiving, processing, and transmitting signals -- have remained poorly understood.

Now, a pair of papers by scientists at Harvard Medical School reveal critical new insights into how the spinal cord and brainstem contribute to the sense of touch.

Specifically, the research shows that the spinal cord and the brainstem, previously thought to be mere relay centers for touch information, are actively involved in processing touch signals as they travel to higher-order brain regions.

One study, published Nov. 4 in Cell, shows that specialized neurons in the spinal cord form a complex network that processes light touch -- think the brush of a hand or a peck on the cheek -- and sends this information to the brainstem.

In another study, published Nov. 23 in Nature, researchers established that direct and indirect touch pathways work together, converging in the brainstem to shape how touch is processed.

"These studies focus the spotlight on the spinal cord and the brainstem as sites where touch information is integrated and processed to convey different types of touch. We hadn't fully appreciated before how these areas contribute to the brain's representation of vibration, pressure, and other features of tactile stimuli," said David Ginty, the Edward R. and Anne G. Lefler Professor of Neurobiology in the Blavatnik Institute at HMS and the senior author on both papers.

Although the studies were conducted in mice, mechanisms for touch are largely conserved across species, including humans, which means the basics of touch processing could be useful for scientists studying human conditions such as neuropathic pain characterized by touch dysfunction.

"This detailed understanding of tactile sensation -- that is, feeling the world through contact with the skin -- may have profound implications for understanding how disease, disorder, and injury can affect our ability to interact with the environment around us," said James Gnadt, program director at the National Institute of Neurological Disorders and Stroke (NINDS), which provided part of the funding for the studies.

Overlooked and underappreciated

The historical view of touch is that sensory neurons in the skin encounter a touch stimulus such as pressure or vibration and send this information in the form of electrical impulses that travel directly from the skin to the brainstem. There, other neurons relay touch information to the brain's primary somatosensory cortex -- the highest level of the touch hierarchy -- where it is processed into sensation.

However, Ginty and his team wondered if and how the spinal cord and brainstem are involved in processing touch information. These areas occupy the lowest level of the touch hierarchy, and combine to form a more indirect touch pathway into the brain.

"People in the field thought that the diversity and richness of touch came just from sensory neurons in the skin, but that thinking bypasses the spinal cord and brainstem," said Josef Turecek, a postdoctoral fellow in the Ginty lab and the first author on the Nature paper.

Many neuroscientists are not familiar with spinal cord neurons, called postsynaptic dorsal column (PSDC) neurons, that project from the spinal cord into the brainstem -- and textbooks tend to leave PSDC neurons out of diagrams depicting the details of touch, Turecek explained.

For Ginty, the way that the spinal cord and brainstem have been overlooked in touch brings to mind early research on the visual system. Initially, scientists studying vision thought that all processing occurred in the visual cortex of the brain. However, it turned out that the retina, which receives visual information long before it reaches the cortex, is heavily involved in processing this information.

"Analogous to research on the visual system, these two papers address how touch information coming from the skin is processed in the spinal cord and brainstem before it moves up the touch hierarchy to more complex brain regions," Ginty said.

Connecting the dots

In the Cell paper, the researchers used a technique they developed to simultaneously record the activity of many different neurons in the spinal cord as mice experienced various types of touch. They discovered that over 90 percent of neurons in the dorsal horn -- the sensory processing area of the spinal cord -- responded to light touch.

"This was surprising because classically it was thought that dorsal horn neurons in the superficial layers of the spinal cord respond mostly to temperature and painful stimuli. We hadn't appreciated how light-touch information is distributed in the spinal cord," said Anda Chirila, a research fellow in the Ginty lab and the co-lead author on the paper with graduate student Genelle Rankin.

Moreover, these responses to light touch varied considerably across genetically different populations of neurons in the dorsal horn, which were found to form a highly interconnected and complex neural network. This variation in responses, in turn, gave rise to a diversity of touch information carried from the dorsal horn to the brainstem by PSDC neurons. In fact, when the researchers silenced various dorsal horn neurons, they saw a reduction in the diversity of light-touch information conveyed by PSDC neurons.

"We think this information on how touch is encoded in the spinal cord, which is the first site in the touch hierarchy, is important for understanding fundamental aspects of touch processing," Chirila said.

In their other study, published in Nature, scientists focused on the next step in the touch hierarchy: the brainstem. They explored the relationship between the direct pathway from sensory neurons in the skin to the brainstem and the indirect pathway that sends touch information through the spinal cord, as described in the Cell paper.

"Brainstem neurons get both direct and indirect input, and we were really curious about what aspects of touch each pathway brings to the brainstem," Turecek said.

To parse this question, the researchers alternately silenced each pathway and recorded the response of neurons in mouse brainstems. The experiments showed that the direct pathway is important for communicating high-frequency vibration, while the indirect pathway is needed to encode the intensity of pressure on the skin.

"The idea is that these two pathways converge in the brainstem with neurons that can encode both vibration and intensity, so you can shape responses of those neurons based on how much direct and indirect input you have," Turecek explained. In other words, if brainstem neurons have more direct than indirect input, they communicate more vibration than intensity, and vice versa.

Additionally, the team discovered that both pathways can convey touch information from the same small area of skin, with information on intensity detouring through the spinal cord before joining information on vibration that travels directly to the brainstem. In this way, the direct and indirect pathways work together, enabling the brainstem to form a spatial representation of different types of touch stimuli from the same area.

Finally on the map

Up until now, "most people have viewed the brainstem as a relay station for touch, and they haven't even had the spinal cord on the map at all," Ginty said. For him, the new studies "demonstrate that there's a tremendous amount of information processing occurring in the spinal cord and brainstem -- and this processing is critical for how the brain represents the tactile world."

Such processing, he added, likely contributes to the complexity and diversity of the touch information that the brainstem sends to the somatosensory cortex.

Next, Ginty and team plan to repeat the experiments in mice that are awake and behaving, to test the findings under more natural conditions. They also want to expand the experiments to include more types of real-world touch stimuli, such as texture and movement.

The researchers are also interested in how information from the brain -- for example, about an animal's level of stress, hunger, or exhaustion -- affects how touch information is processed in the spinal cord and brainstem. Given that touch mechanisms appear to be conserved across species, such information may be especially relevant for human conditions such as autism spectrum disorders or neuropathic pain, in which neural dysfunction causes hypersensitivity to light touch.

"With these studies we've laid the fundamental building blocks for how these circuits work and what their importance is," Rankin said. "Now we have the tools to dissect these circuits to understand how they're functioning normally, and what's changing when something goes wrong."

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Spinning stars shed new light on strange signal coming from galactic center

Researchers from The Australian National University (ANU) have found an alternative explanation for a mysterious gamma-ray signal coming from the centre of the galaxy, which was long claimed as a signature of dark matter.

Gamma-rays are the form of electromagnetic radiation with the shortest wavelength and highest energy.

Co-author of the study Associate Professor Roland Crocker said this particular gamma-ray signal -- known as the Galactic Centre Excess -- may actually come from a specific type of rapidly-rotating neutron star, the super-dense stellar remnants of some stars much more massive than our sun.

The Galactic Centre Excess is an unexpected concentration of gamma-rays emerging from the centre of our galaxy that has long puzzled astronomers.

"Our work does not throw any doubt on the existence of the signal, but offers another potential source," Associate Professor Crocker said.

"It is based on millisecond pulsars -- neutron stars that spin really quickly -- around 100 times a second.

"Scientists have previously detected gamma-ray emissions from individual millisecond pulsars in the neighbourhood of the solar system, so we know these objects emit gamma-rays. Our model demonstrates that the integrated emission from a whole population of such stars, around 100,000 in number, would produce a signal entirely compatible with the Galactic Centre Excess."

The discovery may mean scientists have to re-think where they look for clues about dark matter.

"The nature of dark matter is entirely unknown, so any potential clues garner a lot of excitement," Associate Professor Crocker said.

"But our results point to another important source of gamma-ray production.

"For instance, the gamma-ray signal from Andromeda, the next closest large galaxy to our own may be mostly due to millisecond pulsars."

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