NS/ “Pop-Up” electrode could help map the brain in 3D
Neuroscience biweekly vol. 77, 18th January — 1st February
TL;DR
- Understanding the neural interface within the brain is critical to understanding aging, learning, disease progression, and more. Existing methods for studying neurons in animal brains to better understand human brains, however, all carry limitations, from being too invasive to not detecting enough information. A newly developed, pop-up electrode device could gather more in-depth information about individual neurons and their interactions with each other while limiting the potential for brain tissue damage.
- Whether conscious of it or not, when entering a new space, we use our sense of smell to assess whether it is safe or a threat. In fact, for much of the animal kingdom, this ability is necessary for survival and reproduction. Researchers at the Del Monte Institute for Neuroscience at the University of Rochester are finding new clues to how the olfactory sensory system aids in threat assessment and have found neurons that “learn” if a smell is a threat.
- A new study has shown that common levels of traffic pollution can impair human brain function in only a matter of hours. The study was the first to show in a controlled experiment using functional magnetic resonance imaging (fMRI) that exposure to diesel exhaust disrupts the ability of different areas of the human brain to interact and communicate with each other.
- It’s clear that chronic stress can impact our behavior, leading to problems like depression, reduced interest in things that previously brought us pleasure, and even PTSD. Now scientists have evidence that a group of neurons in a bow-shaped portion of the brain become hyperactive after chronic exposure to stress. When these POMC neurons become super active, these sorts of behavioral problems result and when scientists reduce their activity, it reduces the behaviors, they report in the journal Molecular Psychiatry.
- A new study has found high-frequency propagating activity patterns in the motor cortex that contain details of upcoming movement — information that could lead to the development of better brain-machine interfaces.
- Traumatic injuries to the brain, spinal cord, and optic nerve in the central nervous system (CNS) are the leading cause of disability and the second leading cause of death worldwide. CNS injuries often result in a catastrophic loss of sensory, motor, and visual functions, which is the most challenging problem faced by clinicians and research scientists. Neuroscientists have recently identified and demonstrated a small molecule that can effectively stimulate nerve regeneration and restore visual functions after optic nerve injury, offering great hope for patients with optic nerve injury, such as glaucoma-related vision loss.
- Researchers describe a new family of nano-scale capsules made of silica that can carry genome-editing tools into many organs around the body and then harmlessly dissolve.
- Neuroscientists identified a specific neural mechanism in the human brain that tags information with emotional associations for enhanced memory. The team demonstrated that high-frequency brain waves in the amygdala, a hub for emotional processes, and the hippocampus, a hub for memory processes, are critical to enhancing memory for emotional stimuli. Disruptions to this neural mechanism, brought on either by electrical brain stimulation or depression, impair memory specifically for emotional stimuli.
- Researchers with the SFU Nanodevice Fabrication Group are developing a new biosensor that can be used to screen for Alzheimer’s disease and other diseases. An overview of their work has been recently published in the journal Nature Communications.
- And more!
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The latest news and research
Foldable three dimensional neural electrode arrays for simultaneous brain interfacing of cortical surface and intracortical multilayers
by Ju Young Lee, Sang Hoon Park, Yujin Kim, Young Uk Cho, Jaejin Park, Jung-Hoon Hong, Kyubeen Kim, Jongwoon Shin, Jeong Eun Ju, In Sik Min, Mingyu Sang, Hyogeun Shin, Ui-Jin Jeong, Yuyan Gao, Bowen Li, Aizhan Zhumbayeva, Kyung Yeun Kim, Eun-Bin Hong, Min-Ho Nam, Hojeong Jeon, Youngmee Jung, Huanyu Cheng, Il-Joo Cho, Ki Jun Yu in npj Flexible Electronics
Understanding the neural interface within the brain is critical to understanding aging, learning, disease progression and more. Existing methods for studying neurons in animal brains to better understand human brains, however, all carry limitations, from being too invasive to not detecting enough information. A newly developed, pop-up electrode device could gather more in-depth information about individual neurons and their interactions with each other while limiting the potential for brain tissue damage.
The researchers, co-led by Huanyu “Larry” Cheng, James L. Henderson, Jr. Memorial Associate Professor of Engineering Science and Mechanics in the College of Engineering, published their results in npj Flexible Electronics.
“It’s a challenge to understand the connectivity in between the large number of neuron cells within the brain,” Cheng said. “In the past, people developed a device that is placed directly on the cortex to detect information on the surface layer, which is less invasive. But without inserting the device into the brain, it’s challenging to detect the intercortical information.”
In response to this limitation, researchers developed probe-based electrodes that are inserted into the brain. The problem with this method is that it is not possible to get a 3D layout of the neurons and brain without doing multiple probes, which are difficult to place on a flexible surface and would be too damaging to the brain tissue.
“To address this issue, we use the pop-up design,” Cheng said. “We can fabricate the sensor electrodes with resolution and performance comparable with the existing fabrication. But at the same time, we can pop them up into the 3D geometry before they are inserted into the brain. They are similar to the children’s pop-up books: You have the flat shape, and then you apply the compressive force. It transforms the 2D into 3D. It provides a 3D device with the performance comparable with the 2D.”
The researchers said that in addition to the unique design that pops up into three dimensions after being inserted into the brain, their device also uses a combination of materials that had not been used in this particular way before. Specifically, they used polyethylene glycol, a material that has been used before, as a biocompatible coating to create stiffness, which is not a purpose for which it has been used previously.
“To insert the device in the brain, it needs to be stiff, but after the device is in the brain, it needs to be flexible,” said co-corresponding author Ki Jun Yu of Yonsei University in the Republic of Korea. “So we used a biodegradable coating that provides a stiff outer layer on the device. Once the device is in the brain, that stiff coating dissolves, restoring the initial flexibility. Taking together the material structure and the geometry of this device, we’ll be able to get input from the brain to study the 3D neuron connectivity.”
Next steps for the research include iterating on the design to make it beneficial not only for gaining a better understanding of the brain but also for surgeries and disease treatments.
“In addition to animal studies, some applications of the device use could be operations or treatments for diseases where you may not need to get the device out, but you’ll certainly want to make sure the device is biocompatible over a long period of time,” Cheng said. “It is beneficial to design the structure as small, soft and porous as possible so that the brain tissue can penetrate into and be able to use the device as a scaffold to grow up on top of that, leading to a much better recovery. We also would like to use biodegradable material that can be dissolved after use.”
A Layered, Hybrid Machine Learning Analytic Workflow for Mouse Risk Assessment Behavior
by Jinxin Wang, Paniz Karbasi, Liqiang Wang, Julian P. Meeks in eneuro
Whether conscious of it or not, when entering a new space, we use our sense of smell to assess whether it is safe or a threat. In fact, for much of the animal kingdom, this ability is necessary for survival and reproduction. Researchers at the Del Monte Institute for Neuroscience at the University of Rochester are finding new clues to how the olfactory sensory system aids in threat assessment and have found neurons that “learn” if a smell is a threat.
“We are trying to understand how animals interact with smell and how that influences their behavior in threatening social and non-social contexts,” said Julian Meeks, PhD, principal investigator of the Chemosensation and Social Learning Laboratory. “Our recent research gives us valuable tools to use in our future work and connects specific sets of neurons in our olfactory system to the memory of threatening smells.”
How the brain responds to a social threat may be guided by smell. In mice, researchers have identified a specific set of neurons in the accessory olfactory system that can learn the scent of another mouse that is a potential threat. These findings are described in a paper recently published in The Journal of Neuroscience.
“We knew that territorial aggression increases in a resident male mouse when it is repeatedly introduced to the same male,” said Kelsey Zuk, PhD, who was the first author of this research. “Previous research has shown this behavior is guided by social smells — our research takes what we know one step further. It identifies where in the olfactory system this is happening. We now know plasticity is happening between the neurons, and the aggression between the male mice may be driven by the memory formed by smell.”
Researchers found that “inhibitory” neurons (nerve cells that act by silencing their synaptic partners) in an area of the brain responsible for interpreting social smells become highly active and change their function when males repeatedly meet and increase their territorial aggression. By disrupting the neurons associated with neuroplasticity — learning — in the accessory olfactory bulb, researchers revealed that territorial aggression decreased, linking changes to cellular function in the pheromone-sensing circuity of the brain to changes in behavioral responses to social threats.
“It abolished the ramping aggression that is typically exhibited,” said Zuk. “It indicates that this early sensory inhibitory neuron population plays a critical role in regulating the behavioral response to social smells.”
Meeks was the senior author of this paper. Additional authors include Jinxin Wang, PhD, of University of Rochester Medical Center and Hillary Cansler, PhD, University of Florida College of Medicine. The research was supported by the National Institutes of Health.
Threat assessment also comes when an animal navigates unknown smells. For example, the smell of a predator it has never encountered. Researchers in the Chemosensation and Social Learning Laboratory have found that a novel predator smell, i.e. the smell of a snake to a mouse, caused the animal to engage in a threat assessment behavior — neither acting “fearful” nor “safe.”
“This offers clues into how chemical odors given off by predators stimulate threat assessment in the brain,” said Jinxin Wang, PhD, first author of a paper out in eNeuro. “Identifying changes in patterns of animal behavior helps us better understand how threatening smells are processed in the brain.”
Researchers used video tracking to observe the movement and posture of mice exploring familiar environments with different odors — like other mice and snakes. Wang and colleagues developed a hybrid machine learning approach that helped them to uncover that mice respond to novel predator odors in ways that were unique and distinguishable from how mice reacted to non-predator odors. These behaviors were neither fearful nor safe but rather a state of assessment.
“These findings offer new clues into how smells impact social behavior and what it may mean for survival, but this study also offers new tools that will propel this science forward,” said Meeks, senior author of this study. “We combined methods that had known limitations to improve the accuracy, information depth, and human-interpretability of the collected data. We think this approach will be valuable for future research into how the blends of chemical odorants given off by predators stimulate threat assessment in the brain.”
Brief diesel exhaust exposure acutely impairs functional brain connectivity in humans: a randomized controlled crossover study
by Jodie R. Gawryluk, Daniela J. Palombo, Jason Curran, Ashleigh Parker, Chris Carlsten in Environmental Health
A new study by researchers at the University of British Columbia and the University of Victoria has shown that common levels of traffic pollution can impair human brain function in only a matter of hours.
The peer-reviewed findings, published in the journal Environmental Health, show that just two hours of exposure to diesel exhaust causes a decrease in the brain’s functional connectivity — a measure of how The study provides the first evidence in humans, from a controlled experiment, of altered brain network connectivity induced by air pollution.
“For many decades, scientists thought the brain may be protected from the harmful effects of air pollution,” said senior study author Dr. Chris Carlsten, professor and head of respiratory medicine and the Canada Research Chair in occupational and environmental lung disease at UBC. “This study, which is the first of its kind in the world, provides fresh evidence supporting a connection between air pollution and cognition.”
For the study, the researchers briefly exposed 25 healthy adults to diesel exhaust and filtered air at different times in a laboratory setting. Brain activity was measured before and after each exposure using functional magnetic resonance imaging (fMRI).
The researchers analyzed changes in the brain’s default mode network (DMN), a set of inter-connected brain regions that play an important role in memory and internal thought. The fMRI revealed that participants had decreased functional connectivity in widespread regions of the DMN after exposure to diesel exhaust, compared to filtered air.
“We know that altered functional connectivity in the DMN has been associated with reduced cognitive performance and symptoms of depression, so it’s concerning to see traffic pollution interrupting these same networks,” said Dr. Jodie Gawryluk, a psychology professor at the University of Victoria and the study’s first author. “While more research is needed to fully understand the functional impacts of these changes, it’s possible that they may impair people’s thinking or ability to work.”
Notably, the changes in the brain were temporary and participants’ connectivity returned to normal after the exposure. Dr. Carlsten speculated that the effects could be long-lasting where exposure is continuous. He said that people should be mindful of the air they’re breathing and take appropriate steps to minimize their exposure to potentially harmful air pollutants like car exhaust.
“People may want to think twice the next time they’re stuck in traffic with the windows rolled down,” said Dr. Carlsten. “It’s important to ensure that your car’s air filter is in good working order, and if you’re walking or biking down a busy street, consider diverting to a less busy route.”
While the current study only looked at the cognitive impacts of traffic-derived pollution, Dr. Carlsten said that other products of combustion are likely a concern.
“Air pollution is now recognized as the largest environmental threat to human health and we are increasingly seeing the impacts across all major organ systems,” says Dr. Carlsten. “I expect we would see similar impacts on the brain from exposure to other air pollutants, like forest fire smoke. With the increasing incidence of neurocognitive disorders, it’s an important consideration for public health officials and policymakers.”
Increased intrinsic and synaptic excitability of hypothalamic POMC neurons underlies chronic stress-induced behavioral deficits
by Xing Fang, Yuting Chen, Jiangong Wang, Ziliang Zhang, Yu Bai, Kirstyn Denney, Lin Gan, Ming Guo, Neal L. Weintraub, Yun Lei, Xin-Yun Lu in Molecular Psychiatry
It’s clear that chronic stress can impact our behavior, leading to problems like depression, reduced interest in things that previously brought us pleasure, even PTSD. Now scientists have evidence that a group of neurons in a bow-shaped portion of the brain become hyperactive after chronic exposure to stress. When these POMC neurons become super active, these sort of behavioral problems result and when scientists reduce their activity, it reduces the behaviors, they report in the journal Molecular Psychiatry.
Scientists at the Medical College of Georgia at Augusta University looked in the hypothalamus, key to functions like releasing hormones and regulating hunger, thirst, mood, sex drive and sleep, at a population of neurons called the proopiomelanocortin, or POMC, neurons, in response to 10 days of chronic, unpredictable stress. Chronic unpredictable stress is widely used to study the impact of stress exposure in animal models, and in this case that included things like restraint, prolonged wet bedding in a tilted cage and social isolation.
They found the stressors increased spontaneous firing of these POMC neurons in male and female mice, says corresponding author Xin-Yun Lu, MD, PhD, chair of the MCG Department of Neuroscience and Regenerative Medicine and Georgia Research Alliance Eminent Scholar in Translational Neuroscience.
When they directly activated the neurons, rather than letting stress increase their firing, it also resulted in the apparent inability to feel pleasure, called anhedonia, and behavioral despair, which is essentially depression. In humans, indicators of anhedonia might include no longer interacting with good friends and a loss of libido. In mice, their usual love for sugar water wains, and male mice, who normally like to sniff the urine of females when they are in heat, lose some of their interest as well.
Conversely, when the MCG scientists inhibited the neurons’ firing, it reduced these types of stress-induced behavioral changes in both sexes.
The results indicate POMC neurons are “both necessary and sufficient” to increase susceptibility to stress, and their increased firing is a driver of resulting behavioral changes like depression. In fact, stress overtly decreased inhibitory inputs onto POMC neurons, Lu says.
The POMC neurons are in the arcuate nucleus, or ARC, of the hypothalamus, a bow-shaped brain region already thought to be important to how chronic stress affects behavior.
Occupying the same region is another population of neurons, called AgRP neurons, which are important for resilience to chronic stress and depression, Lu and her team reported.
In the face of chronic stress, Lu’s lab reported that AgRP activation goes down as behavioral changes like anhedonia occur, and that when they stimulated those neurons the behaviors diminished. Her team also wanted to know what chronic stress does to the POMC neurons.
AgRP neurons, better known for their role in us seeking food when we are hungry, are known to have a yin-yang relationship with POMC neurons: When AgRP activation goes up, for example, POMC activation goes down.
“If you stimulate AgRP neurons it can trigger immediate, robust feeding,” Lu says. Food deprivation also increases the firing of these neurons. It’s also known that when excited by hunger signals, AgRP neurons send direct messages to the POMC neurons to release the brake on feeding.
Their studies found that chronic stress disrupts the yin-yang balance between these two neuronal populations. Although AgRP’s projection to POMC neurons is clearly important for their firing activity, the intrinsic mechanism is probably the major mechanism underlying hyperactivity of POMC neurons by chronic stress, Lu says.
The intrinsic mechanism may include potassium channels in POMC neurons that are known to respond to a range of different signals, and when open, lead to potassium flowing out of the cell, which dampens neuronal excitation. While the potential role of these potassium channels in POMC neurons in response to stress needs study, the scientists suspect stress also affects the potassium channels and that opening those channels might be a possible targeted treatment to restrain the wildly firing POMC neurons.
Excessive activity of neurons is also known to produce seizures and there are anticonvulsants given to open potassium channels and decrease that excessive firing. There is even some early clinical evidence that these drugs might also be helpful in treating depression and anhedonia, and what the Lu lab is finding may help explain why.
Lu hasn’t looked yet, but she wants to further explore the role of these channels to better understand how stress affects them in POMC neurons and how best to target the channels if their findings continue to indicate they play a key role in exciting POMC neurons.
Chronic stress affects all body systems, according to the American Psychological Association. Even muscles tense to keep our guard up against injury and pain. Stress can cause shortness of breath, particularly in those with preexisting respiratory problems like asthma. Longer term, it can increase the risk for hypertension, heart attack and stroke, even alter the good bacteria in our gut that helps us digest food.
Propagating spatiotemporal activity patterns across macaque motor cortex carry kinematic information
by Wei Liang, Karthikeyan Balasubramanian, Vasileios Papadourakis, Nicholas G. Hatsopoulos in Proceedings of the National Academy of Sciences
Nicholas G. Hatsopoulos, PhD, Professor of Organismal Biology and Anatomy at the University of Chicago, has long been interested in space. Specifically, the physical space occupied by the brain.
“Inside our heads, the brain is all crumpled up. If you flattened out the human cortex into a single 2D sheet, it would cover two and a half square feet of space — roughly the size of four pieces of paper. You would think that the brain would take advantage of all that space when organizing activity patterns, but aside from knowing that one patch of the brain controls the arm and another controls the leg, we’ve mostly ignored how the brain might use that spatial organization.”
Now in a new study published in Proceedings of the National Academy of Sciences, Hatsopoulos and his team have found evidence that the brain does indeed use the spatial organization of high frequency propagating waves of neuronal activity during movement.
The presence of propagating waves of neuronal activity has been well-established, but they are traditionally associated with the general behavioral state of an animal (such as awake or asleep). This study is the first evidence that spatially organized recruitment of neuronal activity across the motor cortex can inform details of a planned movement.
The team hopes the work will help inform how researchers and engineers decode motor information to build better brain-machine interfaces.
To conduct the study, the researchers recorded the activity from multielectrode arrays implanted in the primary motor cortex of macaque monkeys while the monkeys did a task that required them to move a joystick. Then, they looked for wave-like patterns of activity, specifically those of high-amplitude.
“We focused on the high frequency band signals given its rich information, ideal spatial reach and easiness of obtaining signal in every electrode,” said Wei Liang, first author on the study and a graduate student in the Hatsopoulos lab.
They found that these propagating waves, comprised of the activity of hundreds of neurons, traveled in different directions across the cortical surface based on which direction the monkey pushed the joystick.
“It’s like a series of dominoes falling,” said Hatsopoulos. “All of the wave patterning we’ve seen in the past didn’t tell us what the animal was doing, it would just happen. This is very exciting because now we’re looking at this propagating wave pattern and shown that the direction the wave goes tells you something about what the animal is about to do.”
The results provide a new way of looking at cortical function.
“This shows that space does matter,” Hatsopoulos said. “Instead of just looking at what populations of neurons do and care about, we’re seeing that there is spatially organized patterning that carries information. This is a very different way of thinking about things.”
The research was challenging due to the fact that they were studying the activity patterns from individual movements, rather than averaging the recordings over repeated trials, which can be quite noisy. The team was able to develop a computational method for cleaning up the data to provide clarity on the signals being recorded without losing important information.
“If you average across trials, you miss information,” said Hatsopoulos. “If we want to implement this system as part of a brain-machine interface, we can’t be averaging trials — your decoder has to do it on the fly, as the movement is happening, for the system to work effectively.”
Knowing that these waves contain information about movement opens the door to a new dimension of understanding how the brain moves the body, which can in turn provide additional information for the computational systems that will drive the brain-machine interfaces of the future.
“The spatial dimension has been mostly ignored thus far, but it’s a new angle we can use for understanding cortical function,” said Hatsopoulos. “When we try to understand the computations the cortex is doing, we should consider how the neurons are spatially laid out.”
Future studies will examine whether similar wave patterns are seen in more complicated movements, such as sequential movements as opposed to simple point-to-point reaching, and whether or not wave-like electrical stimulation of the brain can bias the monkey’s movement.
A small molecule M1 promotes optic nerve regeneration to restore target-specific neural activity and visual function
by Ngan Pan Bennett Au, Raza Chand, Gajendra Kumar, Pallavi Asthana, Wing Yip Tam, Kin Man Tang, Chi-Chiu Ko, Chi Him Eddie Ma in Proceedings of the National Academy of Sciences
Traumatic injury to the brain, spinal cord and optic nerve in the central nervous system (CNS) are the leading cause of disability and the second leading cause of death worldwide. CNS injuries often result in a catastrophic loss of sensory, motor and visual functions, which is the most challenging problem faced by clinicians and research scientists. Neuroscientists from City University of Hong Kong (CityU) recently identified and demonstrated a small molecule that can effectively stimulate nerve regeneration and restore visual functions after optic nerve injury, offering great hope for patients with optic nerve injury, such as glaucoma-related vision loss.
“There is currently no effective treatment available for traumatic injuries to the CNS, so there is an immediate need for potential drug to promote CNS repair and ultimately achieve full function recovery, such as visual function, in patients,” said Dr Eddie Ma Chi-him, Associate Head and Associate Professor in the Department of Neuroscience and Director of the Laboratory Animal Research Unit at CityU, who led the research.
Axons, which are a cable-like structure that extends from neurons (nerve cells), are responsible for transmitting signals between neurons and from the brain to muscles and glands. The first step for successful axon regeneration is to form active growth cones and the activation of a regrowth programme, involving the synthesis and transport of materials to regrow axons. These are all energy-demanding processes, which require the active transport of mitochondria (the powerhouse of the cell) to injured axons at the distal end.
Injured neurons therefore face special challenges that require long-distance transport of mitochondria from the soma (cell body) to distal regenerating axons, where axonal mitochondria in adults are mostly stationary and local energy consumption is critical for axon regeneration.
A research team led by Dr Ma identified a therapeutic small molecule, M1, which can increase the fusion and motility of mitochondria, resulting in sustained, long-distance axon regeneration. Regenerated axons elicited neural activities in target brain regions and restored visual functions within four to six weeks after optic nerve injury in M1-treated mice.
“Photoreceptors in the eyes [retina] forward visual information to neurons in the retina. To facilitate the recovery of visual function after injury, the axons of the neurons must regenerate through the optic nerve and relay nerve impulses to visual targets in the brain via the optic nerve for image processing and formation,” explained Dr Ma.
To investigate whether M1 could promote long-distance axon regeneration after CNS injuries, the research team assessed the extent of axon regeneration in M1-treated mice four weeks after injury. Strikingly, most of the regenerating axons of M1-treated mice reached 4mm distal to the crush site (i.e. near optic chiasm), while no regenerating axons were found in vehicle-treated control mice. In M1-treated mice, the survival of retinal ganglion cells (RGCs, neurons that transmit visual stimuli from the eye to the brain) was significantly increased from 19% to 33% four weeks after optic nerve injury.
“This indicates that the M1 treatment sustains long-distance axon regeneration from the optic chiasm, i.e. midway between the eyes and target brain region, to multiple subcortical visual targets in the brain. Regenerated axons elicit neural activities in target brain regions and restore visual functions after M1 treatment,” Dr Ma added.
To further explore whether M1 treatment can restore visual function, the research team gave the M1-treated mice a pupillary light reflex test six weeks after the optic nerve injury. They found that the lesioned eyes of M1-treated mice restored the pupil constriction response upon blue light illumination to a level similar to that of non-lesioned eyes, suggesting that M1 treatment can restore the pupil constriction response after optic nerve injuries.
In addition, the research team assessed the response of the mice to a looming stimulus — a visually induced innate defensive response to avoid predators. The mice were placed into an open chamber with a triangular prism-shaped shelter and a rapidly expanding overhead-black circle as a looming stimulus, and their freeze and escape behaviours were observed. Half of the M1-treated mice responded to the stimulus by hiding in a shelter, showing that M1 induced robust axon regeneration to reinnervate subcortical visual target brain regions for complete recovery of their visual function.
The seven-year-long study highlights the potential of a readily available, non-viral therapy for CNS repair, which builds on the team’s previous research on peripheral nerve regeneration using gene therapy.
“This time we used the small molecule, M1, to repair the CNS simply by intravitreal injection into the eyes, which is an established medical procedure for patients, e.g. for macular degeneration treatment. Successful restoration of visual functions, such as pupillary light reflex and response to looming visual stimuli was observed in M1-treated mice four to six weeks after the optic nerve had been damaged,” said Dr Au Ngan-pan, Research Associate in the Department of Neuroscience.
The team is also developing an animal model for treating glaucoma-related vision loss using M1 and possibly other common eye diseases and vision impairments such as diabetes-related retinopathy, macular degeneration and traumatic optic neuropathy. Thus, further investigation is warranted to evaluate the potential clinical application of M1.
“This research breakthrough heralds a new approach that could address unmet medical needs in accelerating functional recovery within a limited therapeutic time window after CNS injuries,” said Dr Ma.
Overcoming the Blood–Brain Barrier for Gene Therapy via Systemic Administration of GSH‐Responsive Silica Nanocapsules
by Yuyuan Wang, Xiuxiu Wang, Ruosen Xie, Jacobus C. Burger, Yao Tong, Shaoqin Gong in Advanced Materials
Gene therapies have the potential to treat neurological disorders like Alzheimer’s and Parkinson’s diseases, but they face a common barrier — the blood-brain barrier. Now, researchers at the University of Wisconsin-Madison have developed a way to move therapies across the brain’s protective membrane to deliver brain-wide therapy with a range of biological medications and treatments.
“There is no cure yet for many devastating brain disorders,” says Shaoqin “Sarah” Gong, UW-Madison professor of ophthalmology and visual sciences and biomedical engineering and researcher at the Wisconsin Institute for Discovery. “Innovative brain-targeted delivery strategies may change that by enabling noninvasive, safe and efficient delivery of CRISPR genome editors that could, in turn, lead to genome-editing therapies for these diseases.”
CRISPR is a molecular toolkit for editing genes (for example, to correct mutations that may cause disease), but the toolkit is only useful if it can get through security to the job site. The blood-brain barrier is a membrane that selectively controls access to the brain, screening out toxins and pathogens that may be present in the bloodstream. Unfortunately, the barrier bars some beneficial treatments, like certain vaccines and gene therapy packages, from reaching their targets because it lumps them in with hostile invaders.
Injecting treatments directly into the brain is one way to get around the blood-brain barrier, but it’s an invasive procedure that provides access only to nearby brain tissue.
“The promise of brain gene therapy and genome-editing therapy relies on the safe and efficient delivery of nucleic acids and genome editors to the whole brain,” Gong says.
In a study recently published in the journal Advanced Materials, Gong and her lab members, including postdoctoral researcher and first author of the study Yuyuan Wang, describe a new family of nano-scale capsules made of silica that can carry genome-editing tools into many organs around the body and then harmlessly dissolve.
By modifying the surfaces of the silica nanocapsules with glucose and an amino acid fragment derived from the rabies virus, the researchers found the nanocapsules could efficiently pass through the blood-brain barrier to achieve brain-wide gene editing in mice. In their study, the researchers demonstrated the capability of the silica nanocapsule’s CRISPR cargo to successfully edit genes in the brains of mice, such as one related to Alzheimer’s disease called amyloid precursor protein gene.
Because the nanocapsules can be administered repeatedly and intravenously, they can achieve higher therapeutic efficacy without risking more localized and invasive methods.
The researchers plan to further optimize the silica nanocapsules’ brain-targeting capabilities and evaluate their usefulness for the treatment of various brain disorders. This unique technology is also being investigated for the delivery of biologics to the eyes, liver and lungs, which can lead to new gene therapies for other types of disorders.
Neuronal activity in the human amygdala and hippocampus enhances emotional memory encoding
by Salman E. Qasim, Uma R. Mohan, Joel M. Stein, Joshua Jacobs in Nature Human Behaviour
Columbia Engineering neuroscientists identified a specific neural mechanism in the human brain that tags information with emotional associations for enhanced memory. The team demonstrated that high-frequency brain waves in the amygdala, a hub for emotional processes, and the hippocampus, a hub for memory processes, are critical to enhancing memory for emotional stimuli. Disruptions to this neural mechanism, brought on either by electrical brain stimulation or depression, impair memory specifically for emotional stimuli.
Most people remember emotional events, like their wedding day, very clearly, but researchers are not sure how the human brain prioritizes emotional events in memory. In a study, Joshua Jacobs, associate professor of biomedical engineering at Columbia Engineering, and his team identified a specific neural mechanism in the human brain that tags information with emotional associations for enhanced memory. The team demonstrated that high-frequency brain waves in the amygdala, a hub for emotional processes, and the hippocampus, a hub for memory processes, are critical to enhancing memory for emotional stimuli. Disruptions to this neural mechanism, brought on either by electrical brain stimulation or depression, impair memory specifically for emotional stimuli.
The rising prevalence of memory disorders such as dementia has highlighted the damaging effects that memory loss has on individuals and society. Disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD) can also feature imbalanced memory processes, and have become increasingly prevalent during the COVID-19 pandemic. Understanding how the brain naturally regulates what information gets prioritized for storage and what fades away could provide critical insight for developing new therapeutic approaches to strengthening memory for those at risk of memory loss, or for normalizing memory processes in those at risk of dysregulation.
“It’s easier to remember emotional events, like the birth of your child, than other events from around the same time,” says Salman E. Qasim, lead author of the study, who started this project during his PhD in Jacobs’ lab at Columbia Engineering. “The brain clearly has a natural mechanism for strengthening certain memories, and we wanted to identify it.”
Most investigations into neural mechanisms take place in animals such as rats, because such studies require direct access to the brain to record brain activity and perform experiments that demonstrate causality, such as careful disruption of neural circuits. But it is difficult to observe or characterize a complex cognitive phenomenon like emotional memory enhancement in animal studies.
To study this process directly in humans. Qasim and Jacobs analyzed data from memory experiments conducted with epilepsy patients undergoing direct, intracranial brain recording for seizure localization and treatment. During thse recordings, epilepsy patients memorized lists of words while the electrodes placed in their hippocampus and amygdala recorded the brain’s electrical activity.
By systematically characterizing the emotional associations of each word using crowd-sourced emotion ratings, Qasim found that participants remembered more emotional words, such as “dog” or “knife,” better than more neutral words, such as “chair.” When looking at the associated brain activity, the researchers noted that whenever participants successfully remembered emotional words, high-frequency neural activity (30–128 Hz) would become more prevalent in the amygdala-hippocampal circuit. When participants remembered more neutral words, or failed to remember a word altogether, this pattern was absent. The researchers analyzed this pattern across a large data set of 147 patients and found a clear link between participants’ enhanced memory for emotional words and the prevalence in their brains of high-frequency brain waves across the amygdala-hippocampal circuit.
“Finding this pattern of brain activity linking emotions and memory was very exciting to us, because prior research has shown how important high-frequency activity in the hippocampus is to non-emotional memory,” said Jacobs. “It immediately cued us to think about the more general, causal implications — if we elicit high-frequency activity in this circuit, using therapeutic interventions, will we be able to strengthen memories at will?”
In order to establish whether this high-frequency activity actually reflected a causal mechanism, Jacobs and his team formulated a unique approach to replicate the kind of experimental disruptions typically reserved for animal research. First, they analyzed a subset of these patients who had performed the memory task while direct electrical stimulation was applied to the hippocampus for half of the words that participants had to memorize. They found that electrical stimulation, which has a mixed history of either benefiting or diminishing memory depending on its usage, clearly and consistently impaired memory specifically for emotional words.
Uma Mohan, another PhD student in Jacobs’ lab at the time and co-author on the paper, noted that this stimulation also diminished high-frequency activity in the hippocampus. This provided causal evidence that — by knocking out the pattern of brain activity that correlated with emotional memory — stimulation was also selectively diminishing emotional memory.
Qasim further hypothesized that depression, which can involve dysregulated emotional memory, might act similarly to brain stimulation. He analyzed patients’ emotional memory in parallel with mood assessments the patients took to characterize their psychiatric state. And, in fact, in the subset of patients with depression, the team observed a concurrent decrease in emotion-mediated memory and high-frequency activity in the hippocampus and amygdala.
“By combining stimulation, recording, and psychometric assessment, they were able to demonstrate causality to a degree that you don’t always see in studies with human brain recordings,” said Bradley Lega, a neurosurgeon and scientist at the University of Texas Southwestern Medical Center and not an author on the paper. “We know high-frequency activity is associated with neuronal firing, so these findings open new avenues of research in humans and animals about how certain stimuli engage neurons in memory circuits.”
Qasim, who is currently a postdoctoral researcher at the Icahn School of Medicine at Mt. Sinai, is now pursuing this avenue of research by investigating how individual neurons in the human brain fire during emotional memory processes. Qasim and Jacobs hope that their work might also inspire animal research exploring how this high-frequency activity is linked to norepinephrine, a neurotransmitter linked to attentional processes that they theorize might be behind the enhanced memory for emotional stimuli. Finally, they hope that future research will target high-frequency activity in the amygdala-hippocampal circuit to strengthen and protect memory — particularly emotional memory.
“Our emotional memories are one of the most critical aspects of the human experience, informing everything from our decisions to our entire personality,” Qasim added. “Any steps we can take to mitigate their loss in memory disorders or prevent their hijacking in psychiatric disorders is hugely exciting.”
Ultrasensitive rapid cytokine sensors based on asymmetric geometry two-dimensional MoS2 diodes
by Thushani De Silva, Mirette Fawzy, Amirhossein Hasani, Hamidreza Ghanbari, Amin Abnavi, Abdelrahman Askar, Yue Ling, Mohammad Reza Mohammadzadeh, Fahmid Kabir, Ribwar Ahmadi, Miriam Rosin, Karen L. Kavanagh, Michael M. Adachi in Nature Communications
Researchers with the SFU Nanodevice Fabrication Group are developing a new biosensor that can be used to screen for Alzheimer’s disease and other diseases. An overview of their work has been recently published in the journal Nature Communications.
Their sensor works by detecting a particular type of small protein, in this case, a cytokine known as Tumour Necrosis Factor alpha (TNF alpha), which is involved with inflammation in the body. Abnormal cytokine levels have been linked to a wide variety of diseases including Alzheimer’s disease, cancers, heart disease, autoimmune and cardiovascular disease.
TNF alpha can act as a biomarker, a measurable characteristic indicating health status.
COVID-19 can also cause inflammatory reactions known as ‘cytokine storms,’ and studies have shown that cytokine inhibitors are an effective treatment for improving chances of survival.
“Our goal is to develop a sensor that’s less invasive, less expensive and simpler to use than existing methods,” says Engineering Science Assistant Professor Michael Adachi, the project’s co-lead.
“These sensors are also small and have potential to be placed in doctor’s offices to help diagnose different diseases, including Alzheimer’s disease.”
Adachi says that there are a number of established methods for detecting biomarker proteins such as enzyme-linked immunosorbent assay (ELISA) and mass spectrometry, but they have several drawbacks. These existing methods are expensive, samples need to be sent away to a lab for testing and it can take a day or more to receive the results.
He notes that their biosensor is extremely sensitive and can detect TNF alpha in very low concentrations (10 fM) — well below the concentrations normally found in healthy blood samples (200–300 fM).
Current screening tests for Alzheimer’s disease include a questionnaire to determine if the person has symptoms, brain imaging, or a spinal tap process which involves testing for the biomarker proteins in the cerebral spinal fluid of the potential patient.
The team has completed the proof-of-concept stage, proving that the two-electrode diode sensor is effective in detecting TNF alpha in a laboratory setting. They plan to test the biosensor in clinical trials to ensure it would be able to effectively detect biomarker proteins within a blood sample containing many different interfering proteins and other substances.
“We will continue testing the device’s ability to detect the same proteins using body fluid like blood samples,” says engineering science PhD student Hamidreza Ghanbari. “The other objective is to use the same device but a different receptor to detect proteins that are more specific to Alzheimer’s disease.”
The researchers have also filed a provisional patent application with the Technology Licensing Office (TLO) at SFU. The project takes an interdisciplinary approach combining leadership from Adachi in Engineering Science and professors Karen Kavanagh in the Dept. of Physics and Miriam Rosin in Biomedical Physiology and Kinesiology (BPK).
“We need to be sure each sensor is made exactly the same to the tolerance required for the concentration we’re trying to predict or detect, and that’s the real challenge,” says Kavanagh.
Kavanagh says their sensor depends on properties of a type of semiconductor that is being studied for its two-dimensional (2D) properties, molybdenum disulfide (MoS2). This compound has different properties compared to common semiconductors, silicon or gallium arsenide (GaAs), which are much more widely used and well-understood.
Thushani De Silva is an Engineering Science Master’s graduate who worked on the project and emphasizes that the device is based on electrical measurement.
“Basically, we have a semiconductor on the sensing area and when the targeted protein interacts with the sensor, it changes the electrical signal output,” she explains. “By measuring this change, we can measure the concentration of the protein present in the body fluids.”
The team uses a type of nanomaterial called two-dimensional materials, which are potentially atomically thin and used as the sensing layer. DNA sequences called aptamers are applied on top of these 2D materials.
Once a biomarker protein is introduced onto the sensor’s surface it causes minute changes in the electrical properties. By looking at the electrical output of the sensing layer they can determine the concentration of these biomarker proteins in a simple solution.
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