TL;DR
- Researchers have developed a noninvasive way to remove faulty brain circuits that could allow doctors to treat debilitating neurological diseases without the need for conventional brain surgery.
- Advancing our understanding of the human brain will require new insights into how neural circuitry works in mammals, including laboratory mice. These investigations require monitoring brain activity with a microscope that provides resolution high enough to see individual neurons and their neighbors. Two-photon microscopy is a specialized type of fluorescent microscopy. To perform such work, researchers genetically engineer mice so that their neurons contain a fluorescent indicator of neuron activity.
- It’s no secret that jet lag and night-shift work can wreak havoc on the way our body’s internal clock syncs up our daily wake-sleep cycle, known as circadian rhythm, but now researchers say they are a step closer to understanding how the brain creates behavioral rhythms optimized for diurnal, rather than nocturnal, life.
- Pound for pound, the brain consumes vastly more energy than other organs, and, puzzlingly, it remains a fuel-guzzler even when its neurons are not firing signals called neurotransmitters to each other. Now researchers have found that the process of packaging neurotransmitters may be responsible for this energy drain.
- Human beings, like most mammals, need social interactions to live and develop. The processes that drive them towards each other require decision making whose brain machinery is largely misunderstood. To decipher this phenomenon, a team from the University of Geneva (UNIGE) has studied the neurobiological mechanisms at stake when two mice come into contact through learning a task. They observed that the motivation to invest in social interaction is closely linked to the reward system, via the activation of dopaminergic neurons. These results, to be read in the journal Nature Neuroscience, will make it possible to study physiologically the possible dysfunctions of these neurons in diseases affecting social interactions, such as autism, schizophrenia, or depression.
- Scientists can control brain circuits, behavior, and emotion using light. Researchers developed a new optogenetic tool, ‘Opto-vTrap’, which is expected to contribute to treatment for epilepsy, muscle spasms, and skin wrinkles.
- Scientists used animated humanoid avatars to study how nonverbal cues influence people’s behavior. As reported in the Journal of Cognitive Neuroscience, the research offers insight into the brain mechanisms that drive social and economic decision-making.
- Researchers from Uppsala University have been able to document and visualize hearing loss-associated genes in the human inner ear, in a unique collaboration study between otosurgeons and geneticists. The findings illustrate that discrete subcellular structures in the human organ of hearing, the cochlea, are involved in the variation of risk of age-related hearing loss in the population.
- What changes occur in parts of the brain affected by neurodegenerative disease? How does the structure of the neurons change? Some pathological changes in the tissue are easy to identify using standard microscopy. For example, the protein deposits known as “plaques”, which occur in Alzheimer’s disease, can be seen with staining techniques. However, pathological changes can also be of a more subtle nature and easily missed unless there is a complete digitalisation and analysis of the three-dimensional structure. Researchers at the University of Göttingen and University Medical Center Göttingen have now found a new technique to measure and quantify neuronal tissue architecture in three dimensions and at high resolution, which enabled them to identify changes in neurons in Alzheimer’s.
- When mice rest, individual neurons fire in seconds-long, coordinated cascades, triggering activity across the brain, according to new research. Previously, this was thought to be a relatively random process — single neurons firing spontaneously at random times without external stimulation.
- ‘Nature Neuroscience’ December issue is out.
- And more!
Neuroscience market
The global neuroscience market size was valued at USD 28.4 billion in 2016 and it is expected to reach USD 38.9 billion by 2027.
Latest news and researches
Noninvasive disconnection of targeted neuronal circuitry sparing axons of passage and nonneuronal cells
by Yi Wang et al. in Journal of Neurosurgery
University of Virginia School of Medicine researchers have developed a noninvasive way to remove faulty brain circuits that could allow doctors to treat debilitating neurological diseases without the need for conventional brain surgery.
The UVA team, together with colleagues at Stanford University, indicate that the approach, if successfully translated to the operating room, could revolutionize the treatment of some of the most challenging and complex neurological diseases, including epilepsy, movement disorders and more. The approach uses low-intensity focused ultrasound waves combined with microbubbles to briefly penetrate the brain’s natural defenses and allow the targeted delivery of a neurotoxin. This neurotoxin kills the culprit brain cells while sparing other healthy cells and preserving the surrounding brain architecture.
“This novel surgical strategy has the potential to supplant existing neurosurgical procedures used for the treatment of neurological disorders that don’t respond to medication,” said researcher Kevin S. Lee, PhD, of UVA’s Departments of Neuroscience and Neurosurgery and the Center for Brain Immunology and Glia (BIG). “This unique approach eliminates the diseased brain cells, spares adjacent healthy cells and achieves these outcomes without even having to cut into the scalp.”
The new approach is called PING, and it has already demonstrated exciting potential in laboratory studies. For instance, one of the promising applications for PING could be for the surgical treatment of epilepsies that do not respond to medication. Approximately a third of patients with epilepsy do not respond to anti-seizure drugs, and surgery can reduce or eliminate seizures for some of them. Lee and his team, along with their collaborators at Stanford, have shown that PING can reduce or eliminate seizures in two research models of epilepsy. The findings raise the possibility of treating epilepsy in a carefully-targeted and noninvasive manner without the need for traditional brain surgery.
Another important potential advantage of PING is that it could encourage the surgical treatment of appropriate patients with epilepsy who are reluctant to undergo conventional invasive or ablative surgery.
In a new scientific paper in the Journal of Neurosurgery, Lee and his collaborators detail the ability of PING to focally eliminate neurons in a brain region, while sparing non-target cells in the same area. In contrast, currently available surgical approaches damage all cells in a treated brain region.
A key advantage of the approach is its incredible precision. PING harnesses the power of magnetic-resonance imaging (MRI) to let scientists peer inside the skull so that they can precisely guide sound waves to open the body’s natural blood-brain barrier exactly where needed. This barrier is designed to keep harmful cells and molecules out of the brain, but it also prevents the delivery of potentially beneficial treatments.
The UVA group’s new paper concludes that PING allows the delivery of a highly targeted neurotoxin, cleanly wiping out problematic neurons, a type of brain cell, without causing collateral damage.
Another key advantage of the precision of this approach is that it can be used on irregularly shaped targets in areas that would be extremely difficult or impossible to reach through regular brain surgery. “If this strategy translates to the clinic,” the researchers write in their new paper, “the noninvasive nature and specificity of the procedure could positively influence both physician referrals for and patient confidence in surgery for medically intractable neurological disorders.”
“Our hope is that the PING strategy will become a key element in the next generation of very precise, noninvasive, neurosurgical approaches to treat major neurological disorders,” said Lee, who is part of the UVA Brain Institute.
Diesel2p mesoscope with dual independent scan engines for flexible capture of dynamics in distributed neural circuitry
by Che-Hang Yu, Jeffrey N. Stirman, Yiyi Yu, Riichiro Hira, Spencer L. Smith in Nature Communications
Advancing our understanding of the human brain will require new insights into how neural circuitry works in mammals, including laboratory mice. These investigations require monitoring brain activity with a microscope that provides resolution high enough to see individual neurons and their neighbors.
Two-photon fluorescence microscopy has significantly enhanced researchers’ ability to do just that, and the lab of Spencer LaVere Smith, an associate professor in the Department of Electrical and Computer Engineering at UC Santa Barbara, is a hotbed of research for advancing the technology. As principal investigator on the five-year, $9 million NSF-funded Next Generation Multiphoton Neuroimaging Consortium (Nemonic) hub, which was born of President Obama’s BRAIN Initiative and is headquartered at UCSB, Smith is working to “push the frontiers of multi-photon microscopy for neuroscience research.”
mith and his co-authors report the development of a new microscope they describe as “Dual Independent Enhanced Scan Engines for Large Field-of-view Two-Photon imaging (Diesel2p).” Their two-photon microscope provides unprecedented brain-imaging ability. The device has the largest field of view (up to 25 square millimeters) of any such instrument, allowing it to provide subcellular resolution of multiple areas of the brain.
“We’re optimizing for three things: resolution to see individual neurons, a field of view to capture multiple brain regions simultaneously, and imaging speed to capture changes in neuron activity during behavior,” Smith explained. “The events that we’re interested in imaging last less than a second, so we don’t have time to move the microscope; we have to get everything in one shot, while still making sure that the optics can focus ultrafast pulses of laser light.”
The powerful lasers that drive two-photon imaging systems, each costing about $250,000, deliver ultrafast, ultra-intense pulses of light, each of which is more than a billion times brighter than sunlight, and lasts 0.0001 nanosecond. A single beam, with 80 million pulses per second, is split into two wholly independent scan engine arms, enabling the microscope to scan two regions simultaneously, with each configured to different imaging parameters.
In previous iterations of the instrument, the two lasers were yoked and configured to the same parameters, an arrangement that strongly constrains sampling. Optimal scan parameters, such as frame rate and scan region size, vary across distributed neural circuitry and experimental requirements, and the new instrument allows for different scan parameters to be used for both beams. The new device, which incorporates several custom-designed and custom-manufactured elements, including the optical relays, the scan lens, the tube lens and the objective lens, is already being broadly adopted for its ability to provide high-speed imaging of neural activity in widely scattered brain regions.
Smith is committed to ensuring open access to the instrument. Long before this new paper was published, he and his co-authors released a preprint that included the engineering details needed to replicate it. They also shared the technology with colleagues at Boston University, where researchers in Jerry Chen’s lab have already made modifications to suit their own experiments.
“This is exciting,” Smith said. “They didn’t have to start from scratch like we did. They could build off of our work. Jerry’s paper was published back-to-back with ours, and two companies, INSS and CoSys, have sold systems based on our designs. Since there is no patent, and won’t be, this technology is free for all to use and modify however they see fit.”
Two-photon microscopy is a specialized type of fluorescent microscopy. To perform such work in Smith’s lab, researchers genetically engineer mice so that their neurons contain a fluorescent indicator of neuron activity. The indicator was made by combining a fluorescent protein from jellyfish and a calcium-binding protein that exists in nature. The approach leverages the brief, orders-of-magnitude increase in calcium that a neuron experiences when firing. When the laser is pointed at the neuron, and the neuron is firing, calcium comes in, the protein finds the calcium and, ultimately, fluoresces.
Two-photon imaging enhances fluorescence microscopy by employing the quantum behavior of photons in a way that prevents a considerable amount of out-of-focus fluorescence light from being generated. In normal optical microscopy, the light from the source used to excite the sample enters it in a way that produces a vertical cone of light that narrows down to the target focus area, and then an inverted cone below that point. Any light that is not at the narrowest point is out of focus.
The light in a two-photon microscope behaves differently, creating a single point of light (and no cones of light) that is in sharp focus, eliminating all out-of-focus light from reaching the imaging lens.
“The image reveals only light from that plane we’re looking at, without much background signal from above or below the plane,” Smith explained. “The brain has optical properties and a texture like butter; it’s full of lipids and aqueous solutions that make it hard to see through. With normal optical imaging, you can see only the very top of the brain. Two-photon imaging allows us to image deeper down and still attain sub-cellular resolution.”
Another advantage of two-photon excitation light is that it uses lower-energy, longer-wavelength light (in the near-infrared range). Such light scatters less when passing through tissue, so it can be sharply focused deeper into tissue. Moreover, the lower-energy light is less damaging to the sample than shorter wavelengths, such as ultraviolet light.
Smith’s lab tested the device in experiments on mice, observing their brains while they performed tasks such as watching videos or navigating virtual reality environments. Each mouse has received a glass implant in its skull, providing a literal window for the microscope into its brain.
“I’m motivated by trying to understand the computational principles in neural circuitry that let us do interesting things that we can’t currently replicate in machines,” he said. “We can build a machine to do a lot of things better than we can. But for other things, we can’t. We train teenagers to drive cars, but self-driving cars fail in a wide array of situations where humans do not. The systems we use for deep learning are based on insights from the brain, but they are only a few insights, and not the whole story. They work pretty well, but are still fragile. By comparison, I can put a mouse in a room where it has never been, and it will run to someplace where I can’t reach it. It won’t run into any walls. It does this super reliably and runs on about a watt of power.
“There are interesting computational principles that we cannot yet replicate in human-made machines that exist in the brains of mice,” Smith continued, “and I want to start to uncover that. It’s why I wanted to build this microscope.”
Daily electrical activity in the master circadian clock of a diurnal mammal
by Matthew J Moye, Beatriz Bano-Otalora, Timothy Brown, Robert J Lucas, Casey O Diekman, Mino DC Belle in eLife
It’s no secret that jet lag and night-shift work can wreak havoc on the way our body’s internal clock syncs up our daily wake-sleep cycle, known as circadian rhythm, but now researchers say they are a step closer to understanding how the brain creates behavioral rhythms optimized for diurnal, rather than nocturnal, life.
In a new study in the journal eLife, researchers have reported the first-ever recording and modeling of the electrical activity of circadian clock neurons in a diurnal species — the four-striped grass mouse, Rhabdomys pumilio.
Until now, brain recording studies of nocturnal species have primarily been used to form an understanding of the mammalian master circadian clock — located in the brain’s hypothalamic suprachiasmatic nucleus (SCN), where nearly 20,000 neurons synchronize with the light-dark cycle via electrical signals to orchestrate circadian rhythms in our physiology and behavior.
Researchers say the study is an advance toward more precisely exploring the connection between circadian rhythms and human health, including the relationship between daytime light exposure and circadian clock-related sleep disorders.
“Almost everything we know about the brain’s circadian clock comes from studies on night-active rodents such as rats and mice, which complicates translating this knowledge to human circadian rhythms,” said Casey Diekman, co-corresponding author of the study and mathematical biologist at New Jersey Institute of Technology. “This work is the first to describe the intricate electrical landscape of the SCN in a diurnal mammal, and it’s highlighted notable differences from nocturnal animals that may be important in adapting clock neuron function to the specific biological demands of a day-active species.”
“We found that the overall day/night pattern of SCN neuron activity in the diurnal rodent R. pumilio is similar to the pattern previously observed in night-active species,” said Beatriz Bano-Otalora, co-first author of the paper and a biologist working with the labs of Robert Lucas and Timothy Brown at the University of Manchester. “We’ve also found unique features in how R. pumilio’s SCN neurons behave that have never been observed before in nocturnal species.”
The team found that like nocturnal rodents, R. pumilio’s SCN neurons spontaneously fired at a higher rate during daytime hours than at night. This day/night rhythm in firing rate is the main signal the SCN sends to the rest of the brain to communicate the time of day.
“However, when we injected currents to inhibit these neurons, some cells exhibited a pronounced delay before resuming to fire after inhibition was released,” explained Mino Belle, co-corresponding author of the paper and a biologist at the University of Exeter. “This delay-to-fire response is not present in the SCN of nocturnal rodents and may affect how R. pumilio clock neurons respond to inputs they receive from other cells.”
To learn more, the team combined the voltage traces recorded from the rodent’s brain with a newly developed data assimilation algorithm. They built computational models simulating the complex interaction of voltage-gated ion channels that produce action potentials. The simulations showed that increased conductivity of a particular ion channel, the transient A- potassium channel, was responsible for the delay-to-fire response.
“The enhanced conductance of this potassium channel that our models pointed out could be advantageous for a diurnal species,” said the paper’s co-first author Matthew Moye, a postdoctoral fellow at Merck & Co. who began developing the team’s data assimilation algorithms as a Ph.D. student in NJIT’s Department of Mathematical Sciences. “Wakefulness results in inhibitory behavioral feedback signals to the SCN, which in nocturnal animals helps keep SCN firing rates low at night. In diurnal animals, this nighttime inhibitory feedback is not present, so enhanced A-type conductance may be needed to silence the SCN at night and preserve the overall day/night firing pattern.”
The team’s research follows separate findings from Diekman and colleagues at Northwestern University recently published Proceedings of the National Academy of Sciences, which revealed the role of the gene Tango10 as a critical link between the circadian clock and the production of daily wake-up signals at the cellular level. Diekman says the same data assimilation method developed to study R. pumilio neurons was used to construct mathematical models from voltage traces of the fruit fly Drosophila melanogaster, ultimately showing how Tango10 gene mutations contribute to disruptions in daily rhythms.
“Now that we have this powerful tool for extracting information from voltage traces, we hope to continue collaborating with electrophysiology labs and apply data assimilation to recordings not just from circadian clock neurons, but also from neurons that are associated with neurodegenerative diseases such as Alzheimer’s and Huntington’s,” Diekman said.
Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals
by Camila Pulido, Timothy A. Ryan in Science Advances
Pound for pound, the brain consumes vastly more energy than other organs, and, puzzlingly, it remains a fuel-guzzler even when its neurons are not firing signals called neurotransmitters to each other. Now researchers at Weill Cornell Medicine have found that the process of packaging neurotransmitters may be responsible for this energy drain.
In their study, they identified tiny capsules called synaptic vesicles as a major source of energy consumption in inactive neurons. Neurons use these vesicles as containers for their neurotransmitter molecules, which they fire from communications ports called synaptic terminals to signal to other neurons. Packing neurotransmitters into vesicles is a process that consumes chemical energy, and the researchers found that this process, energy-wise, is inherently leaky — so leaky that it continues to consume significant energy even when the vesicles are filled and synaptic terminals are inactive.
“These findings help us understand better why the human brain is so vulnerable to the interruption or weakening of its fuel supply,” said senior author Dr. Timothy Ryan, a professor of biochemistry and of biochemistry in anesthesiology at Weill Cornell Medicine.
The observation that the brain consumes a high amount of energy, even when relatively at rest, dates back several decades to studies of the brain’s fuel use in comatose and vegetative states. Those studies found that even in these profoundly inactive states, the brain’s consumption of glucose typically drops from normal by only about half — which still leaves the brain as a high energy consumer relative to other organs. The sources of that resting energy drain have never been fully understood.
Dr. Ryan and his laboratory have shown in recent years that neurons’ synaptic terminals, bud-like growths from which they fire neurotransmitters, are major consumers of energy when active, and are very sensitive to any disruption of their fuel supply. In the new study they examined fuel use in synaptic terminals when inactive, and found that it is still high.
This high resting fuel consumption, they discovered, is accounted for largely by the pool of vesicles at synaptic terminals. During synaptic inactivity, vesicles are fully loaded with thousands of neurotransmitters each, and are ready to launch these signal-carrying payloads across synapses to partner neurons.
Why would a synaptic vesicle consume energy even when fully loaded? The researchers discovered that there is essentially a leakage of energy from the vesicle membrane, a “proton efflux,” such that a special “proton pump” enzyme in the vesicle has to keep working, and consuming fuel as it does so, even when the vesicle is already full of neurotransmitter molecules.
The experiments pointed to proteins called transporters as the likely sources of this proton leakage. Transporters normally bring neurotransmitters into vesicles, changing shape to carry the neurotransmitter in, but allowing at the same time for a proton to escape — as they do so. Dr. Ryan speculates that the energy threshold for this transporter shape-shift was set low by evolution to enable faster neurotransmitter reloading during synaptic activity, and thus faster thinking and action.
“The downside of a faster loading capability would be that even random thermal fluctuations could trigger the transporter shape-shift, causing this continual energy drain even when no neurotransmitter is being loaded,” he said.
Although the leakage per vesicle would be tiny, there are at least hundreds of trillions of synaptic vesicles in the human brain, so the energy drain would really add up, Dr. Ryan said.
The finding is a significant advance in understanding the basic biology of the brain. In addition, the vulnerability of the brain to the disruption of its fuel supply is a major problem in neurology, and metabolic deficiencies have been noted in a host of common brain diseases including Alzheimer’s and Parkinson’s disease. This line of investigation ultimately could help solve important medical puzzles and suggest new treatments.
“If we had a way to safely lower this energy drain and thus slow brain metabolism, it could be very impactful clinically,” Dr. Ryan said.
VTA dopamine neuron activity encodes social interaction and promotes reinforcement learning through social prediction error
by Clément Solié, Benoit Girard, Beatrice Righetti, Malika Tapparel, Camilla Bellone in Nature Neuroscience
Human beings, like most mammals, need social interactions to live and develop. The processes that drive them towards each other require decision making whose brain machinery is largely misunderstood. To decipher this phenomenon, a team from the University of Geneva (UNIGE) has studied the neurobiological mechanisms at stake when two mice come into contact through learning a task. They observed that the motivation to invest in a social interaction is closely linked to the reward system, via the activation of dopaminergic neurons. These results, to be read in the journal Nature Neuroscience, will make it possible to study physiologically the possible dysfunctions of these neurons in diseases affecting social interactions, such as autism, schizophrenia or depression.
Social interaction is an integral part of our daily lives, although the intention to interact with others requires an effort to act. So why do we do it? What is the mechanism behind the motivation we feel to engage with others? To identify which neurobiological circuit is the basis of social interaction, a team from the UNIGE, a member of the National Centre of Competence in Research (NCCR) Synapsy, observed what happens in the brains of mice seeking contact with their conspecific.
“In order to observe which neurons are activated during social interaction, we taught mice to perform a simple task that allows them to enter in contact with their fellows mice,” explains Camilla Bellone, professor in the Department of Basic Neuroscience at the UNIGE Faculty of Medicine and director of the NCCR Synapsy. Two mice were placed in two different compartments and separated by a door. When the first mouse pressed a lever, the door opened temporarily, allowing social contact to be established with the second mouse through a grid. “As the experiment progressed, the mouse understood that it had to press the lever to join its fellow mouse. With this task, we can measure the effort the mice are willing to put to engage in interaction with conspecifics,” continues Clément Solié, a researcher in Camilla Bellone’s team.
Using electrodes, the scientists measured the activation of neurons.
“We found that the the interaction between two mice, similarly to other natural reward, led to the activation of dopaminergic neurons, which are located within the reward system,” says Camille Bellone.
These neurons release dopamine — the so-called pleasure molecule — which is crucial for several motivated behaviours.
“What is even more interesting is that while during the first sessions, the dopaminergic neurons are activated when the mice interact with the conspecific, as soon as the mouse learn the association between the lever press and the interaction, the activity of dopaminergic neurons precede the reward,” continues Benoit Girard, a researcher in the Department of Basic Neuroscience.
“Similarly, if the mouse presses the lever but the door does not open in the end, there is a sudden drop in the activity of the dopaminergic neurons, indicating great disappointment in the mouse,” explains Camilla Bellone. “This predicting signal is the neural substrate for learning and is crucial for social motivation.”
Several psychiatric diseases such as autism, schizophrenia or depression are characterised by social dysfunctions and social motivation deficits are described in some of these patients. Thanks to this study, scientists now know that these difficulties may result from dysfunctions within the reward system and more precisely at the level of dopaminergic neurons.
“We will now be able to use these neurons as targets to find treatments for these diseases,” says Benoit Girard.
“Furthermore, the reward system is at the basis of the occurrence of addictive behaviours. Whether the excessive use of social media network could hijack the dopaminergic system and be at the basis of maladaptive behaviours toward social media is an interesting hypothesis that can be now tested,” notes Camilla Bellone.
The Geneva team will now focus its research on the study of these psychological illnesses via the functioning of these neurobiological mechanisms.
Opto-vTrap, an optogenetic trap for reversible inhibition of vesicular release, synaptic transmission, and behavior
by Joungha Won, Yuriy Pankratov, Minwoo Wendy Jang, Sunpil Kim, Yeonha Ju, Sangkyu Lee, Seung Eun Lee, Arie Kim, Soowon Park, C. Justin Lee* and Won Do Heo in Neuron
Controlling signal transmission and reception within the brain circuits is necessary for neuroscientists to achieve a better understanding of the brain’s functions. Communication among neuron and glial cells is mediated by various neurotransmitters being released from the vesicles through exocytosis. Thus, regulating vesicular exocytosis can be a possible strategy to control and understand brain circuits.
However, it has been difficult to freely control the activity of brain cells in a spatiotemporal manner using pre-existing techniques. One is an indirect approach that involves artificially controlling the membrane potential of cells, but it comes with problems of changing the acidity of the surrounding environment or causing unwanted misfiring of neurons. Moreover, it is not applicable for use in cells that do not respond to the membrane potential changes, such as glial cells.
To address this problem, South Korean researchers led by Director C. Justin LEE at the Center for Cognition and Sociality within the Institute for Basic Science (IBS) and professor HEO Won Do at Korea Advanced Institute of Science and Technology (KAIST) developed Opto-vTrap, a light-inducible and reversible inhibition system that can temporarily trap vesicles from being released from brain cells. Opto-vTrap directly targets transmitters containing vesicles, and it can be used in various types of brain cells, even the ones that do not respond to membrane potential changes.
In order to directly control the exocytotic vesicles, the research team applied a technology they previously developed in 2014, called light-activated reversible inhibition by assembled trap (LARIAT). This platform can inactivate various types of proteins when illuminated under blue light by instantly trapping the target proteins, like a lariat. Opto-vTrap was developed by applying this LARIAT platform to vesicle exocytosis. When the Opto-vTrap expressing cells or tissues are shined under blue light, the vesicles form clusters and become trapped within the cells, inhibiting the release of transmitters.
Most importantly, the inhibition triggered using this new technique is temporary, which is very important for neuroscience research. Other previous techniques that target vesicle fusion proteins damage them permanently and disable the target neuron for up to 24 hours, which is not appropriate for many behavioral experiments with short time constraints. By comparison, vesicles that were inactivated using Opto-vTrap decluster in about 15 minutes, and the neurons regain their full functions within an hour.
Opto-vTrap directly controls the signal transmitters’ release, enabling the researchers to freely control brain activity. The research team verified the usability of Opto-vTrap in cultured cells and brain tissue slices. Furthermore, they tested the technique in live mice, which enabled them to temporarily remove fear memory from fear-conditioned animals.
In the future, Opto-vTrap will be used to uncover complex interactions between multiple parts of the brain. It will be a highly useful tool for studying how certain brain cell types affect brain function in different circumstances.
Professor Heo stated, “Since Opto-vTrap can be used in various cell types, it is expected to be helpful in various fields of brain science research,” He explained, “We plan to conduct a study to figure out the spatiotemporal brain functions in various brain cell types in a specific environment using Opto-vTrap technology.”
“The usability of Opto-vTrap can extend not only to neuroscience but also to our lives,” explains Director Lee. He added, “Opto-vTrap will contribute not only to elucidate brain circuit mapping but also epilepsy treatment, muscle spasm treatment, and skin tissue expansion technologies.”
Electrophysiological Correlates of Social Decision-making: An EEG Investigation of a Modified Ultimatum Game
by Matthew Moore, Yuta Katsumi, Sanda Dolcos, Florin Dolcos in Journal of Cognitive Neuroscience
Scientists used animated humanoid avatars to study how nonverbal cues influence people’s behavior. As reported in the Journal of Cognitive Neuroscience, the research offers insight into the brain mechanisms that drive social and economic decision-making.
The study revealed that participants were more willing to cooperate with animated avatars than with static figures representing their negotiation partners. It also found — somewhat surprisingly — that people were more willing to accept unfair offers from unfriendly avatars than from friendly ones.
“This work is an extension of previous studies exploring how nonverbal cues influence people’s perceptions of one another,” said Matthew Moore, who led the research at the University of Illinois Urbana-Champaign with psychology professors Florin Dolcos and Sanda Dolcos.
The new research was conducted at the U. of I.’s Beckman Institute for Advanced Science and Technology, where Moore was a postdoctoral fellow.
“Nonverbal interactions represent a huge part of human communication,” Sanda Dolcos said. “We might not be aware of this, but much of the information that we take in is through these nonverbal channels.”
Previous studies often used still photos or other static representations of people engaged in social interactions to study how people form opinions or make decisions, Florin Dolcos said.
“By animating the avatars, we’re capturing interactions that are much closer to what happens in real-life situations,” he said.
To understand how social impressions guide decision-making, the researchers asked participants to play a modified “ultimatum game.”
“In the typical game, a ‘proposer’ player offers to split $10 with you,” Moore said. “If you accept the proposal, then you each get a portion of that $10 as it was proposed. But if you reject the offer, then neither of you get anything.”
The goal of the game is to collect as much money as possible, Moore said. But people are often influenced by other people’s behavior, and don’t always choose to accept unfair offers, even though it would maximize their own gains in the game.
For the new study, participants watched a “responder” avatar engaging with an animated “proposer” avatar. Sometimes the proposer behaved in a friendly manner, smiling, moving closer and grasping the responder’s shoulder. In other trials, the proposer appeared unfriendly, frowning and moving away, with arms folded across her chest. And in control trials, the proposer was represented by an immobile posterboard, with a stance that was neither friendly nor unfriendly.
“Remember, these are not the participants themselves engaged in these interactions,” Florin Dolcos said. “We designed these experiments in a way that will facilitate the participants identifying with the responder avatars.”
The scientists used EEG to track brain activity while participants watched the avatar interactions, then looked for any correspondence between participants’ brain activity and their subsequent acceptance — or rejection — of an avatar’s proposal.
They found that watching the animated avatars interact increased the likelihood that an observer would agree to a proposed split of the $10 — even if it meant accepting an unfair offer. Interactions with static avatars led to more rejections of unfair proposals.
The researchers saw that participants were slightly more consistent in accepting an unfair offer when the proposer avatars behaved in an unfriendly manner, suggesting that participants were more comfortable when the avatars’ social behavior corresponded more closely with what they were proposing.
The team also observed that the pattern of a participant’s brain activity often predicted whether they would accept or reject an offer.
“The EEG patterns, known as event-related spectral perturbations, track changes in spectral power at each frequency in ongoing electrical activity across the brain, and can capture brain responses within hundreds of milliseconds after a person observes a stimulus,” Moore said. “Brain responses associated with processing movement and cognitive control were activated most in trials where — shortly after observing an interaction — participants chose to accept an unfair offer.”
The research is an important step toward understanding how different brain responses contribute to social perception and decision-making, Moore said.
“If we better understand the mechanisms involved, then we can better understand things like how to intervene,” he said. “So, for example, if we have a goal of increasing cooperation or helping people make adaptive decisions, then we have clearer targets for our interventions.”
A combined genome-wide association and molecular study of age-related hearing loss in H. sapiens
Liu W, Johansson Å, Rask-Andersen H, Rask-Andersen M in BMC Med
Researchers from Uppsala University have been able to document and visualise hearing loss-associated genes in the human inner ear, in a unique collaboration study between otosurgeons and geneticists. The findings illustrate that discrete subcellular structures in the human organ of hearing, the cochlea, are involved in the variation of risk of age-related hearing loss in the population.
Hearing loss is a potentially debilitating condition that affects more than 1.23 billion people worldwide. The most common form of hearing loss, which represents 90% of all cases, is related to the degenerative effects of aging on hearing, i.e., age-related hearing loss or presbycusis. However, the molecular mechanisms that underlie the development of age-related hearing loss and individual variation in risk are poorly elucidated.
In the current study, a unique collaboration was established between otologists and geneticists at Uppsala University, which allowed for functional follow-up studies of candidate genes from genome-wide association studies (GWAS) using immunohistochemistry in the human cochlea.
“The cochlea, and in particular the hearing organ, the organ of Corti, is a highly vulnerable structure that is difficult to analyse since it is surrounded by the hardest bone in the body,” says Helge Rask-Andersen, MD and Senior Professor at the Department of Surgical Sciences. “We have been able to study some of the molecular components of human hearing that are critical for the conversion of sound to nerve electric impulses.”
Genetic variants at 67 genomic regions were found to contribute to increased risk of age-related hearing loss. Genome-wide association studies (GWAS) on hearing-related traits were performed in the UK Biobank, which has half a million participants from the United Kingdom. Genetic associations are difficult to interpret by themselves and follow-up experiments are often required before causal genes can be inferred.
“It is an amazing opportunity to be able to follow up our findings in human cochlear samples, since there are molecular differences between the hearing organ of humans and other mammals,” says Mathias Rask-Andersen, Associate Professor at the Department of Immunology, Genetics and Pathology.
Candidate proteins from GWAS were visualised with immunofluorescent antibodies and super-resolution structured illumination microscopy (SR-SIM) by Dr Wei Liu, MD and Associate Professor at the Department of Surgical Sciences. Several proteins were observed within the spiral ganglion, which contains the neuronal cell bodies that innervate the hair cells in the organ of Corti and carry neuronal impulses to the brain via the cochlear nerve.
The researchers could also visualise hearing loss-associated proteins in discrete subcellular domains in the hair cells for the first time in humans, such as TRIO and F-actin-binding protein (TRIOBP) in the hair tufts (stereocilia) and LIM domain only protein 7 (LMO7) in the cuticular plate, which is an actin-rich structure that anchors stereocilia to the cell body. The stereocilia are the microscopic or nano-sized ‘hairs’ that protrude from the hair cells of the organ of Corti. They respond to mechanical vibrations from sounds that reach us and are transferred and amplified from the ear drum to the inner ear by the small middle ear bones.
Taken together, the findings from the current study demonstrate that common genetic variations associated with age-related hearing loss affect the structures of the cochlea, in particular the neuronal processes of the spiral ganglion, but also structures directly involved in the transduction of mechanical stimuli to neuronal impulses. This knowledge may help to better understand the biological mechanisms that lead to age-related hearing loss and generate strategies for prevention such as novel pharmacological treatments.
Three-dimensional virtual histology of the human hippocampus based on phase-contrast computed tomography
by Eckermann M, Schmitzer B, Meer F van der, et al. in PNAS
What changes occur in parts of the brain affected by neurodegenerative disease? How does the structure of the neurons change? Some pathological changes in the tissue are easy to identify using standard microscopy. For example, the protein deposits known as “plaques”, which occur in Alzheimer’s disease, can be seen with staining techniques. However, pathological changes can also be of a more subtle nature and easily missed unless there is a complete digitilisation and analysis of the three-dimensional structure. Researchers at the University of Göttingen and University Medical Center Göttingen have now found a new technique to measure and quantify neuronal tissue architecture in three dimensions and at high resolution, which enabled them to identify changes in neurons in Alzheimer’s.
The team developed a special X-ray imaging method that enabled them to detect a previously unknown transition in neuronal cell nuclei in tissue samples from the hippocampus of Alzheimer’s patients. The changes indicate altered activity of neurons. The scientists examined neuronal tissue from the hippocampus, a brain region where memories are transferred from short-term to long-term memory. Chemically fixed tissue samples just a few millimetres wide were first X-rayed using phase-contrast tomography. The researchers used a special phase-contrast tomograph, which the team, led by Professor Tim Salditt from the Institute of X-ray Physics at the University of Göttingen, has set up at the PETRA III storage ring at the German Electron Synchrotron (DESY). The tomograph can be used to image tissue that only weakly absorbs X-rays, or not at all. This meant that large volumes of tissue could be recorded in their entirety, without damaging the samples and without time-consuming preparation.
“To do this, the three-dimensional image from highly magnified projections must first be focused on the computer using special algorithms in order to obtain a three-dimensional image with pixel sizes in the range of one ten-thousandth of a millimetre,” explains Marina Eckermann, first author of the paper.
Using this “digital twin” of the sample, machine learning can then be used to identify neurons — excitable cells that use electrical impulses and chemical signals to send information between different areas of the brain. Using new mathematical methods from “optimal transport theory”, developed by Professor Bernhard Schmitzer at the Institute of Computer Science at the University of Göttingen, the cell population of different individuals could be compared with each other without having to define which hypotheses were being used or whether the samples belonged to a particular patient group. The comparison of the structural features did not just refer to the average values of the corresponding neurons, but to every single one of the detected cells of each individual.
“These new results show that in Alzheimer’s disease, the cell nuclei in a subsection in the hippocampus change into being more compact and having more of a mixture of different structures,” says Professor Tim Salditt from Göttingen University. “This leads to a higher proportion of densely packed DNA in the cell nucleus and to DNA being read out less frequently. Whether the observed changes in the cell nucleus also play a causal role in development of the disease remains to be seen,” explains Professor Christine Stadelmann-Nessler, Director of the Institute of Neuropathology at the University Medical Center Göttingen.
Single-neuron firing cascades underlie global spontaneous brain events
by Xiao Liu, David A. Leopold, Yifan Yang in Proceedings of the National Academy of Sciences
When mice rest, individual neurons fire in seconds-long, coordinated cascades, triggering activity across the brain, according to research from Penn State and the National Institutes of Health. Previously, this was thought to be a relatively random process — single neurons firing spontaneously at random times without external stimulation.
The finding, published in the Proceedings of the National Academy of Sciences, was made in rodents, but may have implications for better understanding neural activity in humans — especially in elucidating cognitive decline, according to first author Xiao Liu, assistant professor of biomedical engineering and faculty co-hire in the Institute of Computational and Data Sciences.
During rest, the brain appears to restore itself: the hippocampus consolidates memories, while cerebrospinal fluid wases through neural tissue, refreshing the mind. The mechanisms of the apparent tidying and cleaning are not well understood, though.
“Single neurons fire in a highly organized manner as seconds-long cascade events in the resting state,” Liu said. “It’s not random noise. We expected to find neurons firing with some organization during the resting state, but we didn’t expect such a highly organized pattern of activity with the involvement of so many neurons.”
The researchers analyzed a public dataset collected by the Allen Institute. Allen Institute scientists recorded neuronal “spikes” — electrical impulses to transmit information across the brain — of hundreds of neurons in resting and active rodents. They also measured pupil changes and body movements. Overall, Penn State researchers focused their analyses on the individual dynamics of about 10,000 neurons from 44 different brain regions in 14 rodents.
The rodents were analyzed during periods of rest, when their bodies were still; however, it was not known whether the animals were sleeping or simply resting, as they sleep with their eyes open, according to the researchers.
Liu and his team analyzed the frequency of spontaneous spiking activity in fixed time intervals at low frequency. They observed that 70% of the recorded neurons, regardless of brain region or origin, participated in recurring, sequenced cascades of global brain activity lasting five to 10 seconds. The cascade was typified by sequential activations from a group of neurons more active during rest to another group that exhibited more intense spiking during active movement.
Although the significance of the cascading events remains unclear, the researchers propose they may have something to do with brain arousal state and memory, according to their analysis of pupil size, delta waves and ripple activity at the hippocampus — indicators of various neural activities.
“Delta waves in the brain and the pupil size are indicators of the brain’s arousal state,” Liu said. “For example, the rodents’ delta waves are much stronger during sleep than when awake. Hippocampal ripples, on the other hand, are high-frequency oscillatory events important for memory consolidation.”
Liu and his team found that the two arousal indicators — pupil size and delta waves — and the hippocampal ripples systematically changed during the cycle of each global spiking cascade, meaning they were higher or lower at different phases of each cycle. Such coordinated changes in arousal indicators and ripples suggest the cascade events in resting-state brain activity may link the arousal and memory systems of the brain.
According to Liu, the spiking cascades’ connection to the arousal and memory systems also suggests a possible role in Alzheimer’s disease and other cognitive dysfunction, which is often characterized by concurrent dysfunctions of both systems.
Researchers know from functional MRI that, during rest, the brain exhibits surges of global activity, which is coupled with the flow of cerebrospinal fluid over brain tissue, Liu said. Earlier this year, Liu and his team found that this coupling is significantly reduced in people who have cognitive decline as a result of Alzheimer’s disease or Parkinson’s disease.
“The resting state global brain signal measured using fMRI was at the same low frequency and showed other features similar to the spiking cascades of single neurons,” Liu said. “Thus, it may be the macro-level observation of the spiking cascade we found.”
Liu explained that if the global brain signal measured via fMRI resulted from the spiking cascade, it may be responsible for triggering cerebrospinal fluid flow, which clears brain waste. Without cleaning, build-up of such molecules as misfolded Amyloid-beta plaques can hinder cellular communication, resulting in neuron death and cognitive decline.
“If we better understand the functions of neural cascades during rest, we can potentially get closer to the mystery of how Alzheimer’s develops,” Liu said.
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