NS/ Neuronal ripples reveal insight into human memory
Neuroscience biweekly vol. 104, 14th February — 28th February
TL;DR
- Spatial navigation and spatial memory play a central role in our lives. Without these abilities, we would hardly be able to find our way around our surroundings and would find it difficult to remember past events. However, the neuronal basis of spatial memory is far from being fully understood. A research group has gained new insights into this gap in knowledge. They discovered that different types of nerve cells become active together during spatial memory and are coordinated by brain waves (“ripples”). The results have now been published in the journal Nature Neuroscience.
- Results from phase two clinical trials at UT Southwestern Medical Center showed that a suspension of gold nanocrystals taken daily by patients with multiple sclerosis (MS) and Parkinson’s disease (PD) significantly reversed deficits of metabolites linked to energy activity in the brain and resulted in functional improvements. The findings, published in the Journal of Nanobiotechnology, could eventually help bring this treatment to patients with these and other neurodegenerative diseases, according to the authors.
- Researchers unveil groundbreaking research with the potential to alter the treatment landscape for neurodegenerative diseases (NDs). The study, published in the esteemed journal Advanced Materials, titled “Inhibiting the Keap1/Nrf2 Protein-Protein Interaction with Protein-Like Polymers,” introduces a pioneering approach aimed at combating conditions such as Alzheimer’s disease, Parkinson’s disease (PD), and Amyotrophic lateral sclerosis (ALS).
- The way our brain processes different emotional and cognitive tasks may be underpinned by common factors, find scientists from UNSW and Neuroscience Research Australia (NeuRA). In this latest study, recently published in the journal Human Brain Mapping, researchers looked at how both emotion and cognition are influenced by the environment and genetics, using functional MRI (fMRI) scans on twins.
- A new study by Stanford Medicine investigators unveils a new artificial intelligence model that was more than 90% successful at determining whether scans of brain activity came from a woman or a man.
- Researchers have found that inhibiting a key protein can stop the destruction of synapses and dendritic spines commonly seen in Alzheimer’s disease.
- Echoes can make speech harder to understand, and tuning out echoes in an audio recording is a notoriously difficult engineering problem. The human brain, however, appears to solve the problem successfully by separating the sound into direct speech and its echo, according to a new study.
- Our brains are ‘programmed’ to learn more from people we like — and less from those we dislike. This has been shown by researchers in cognitive neuroscience in a series of experiments.
- Fear and addiction exert significant influence within society. Managing them is often challenging, as they are driven by intricate neuronal circuits in our brains. Understanding the underlying molecular mechanisms is crucial to intervene when these processes malfunction. The novel ‘Flash and Freeze-fracture’ technique provides a unique glimpse into the respective brain region.
- Scientists have developed a new machine learning method that reveals surprisingly consistent intrinsic brain patterns across different subjects by disentangling these patterns from the effect of visual inputs.
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.
The latest news and research
Ripple-locked coactivity of stimulus-specific neurons and human associative memory
by Kunz L, Staresina BP, Reinacher PC, et al. in Nature Neuroscience
Spatial navigation and spatial memory play a central role in our lives. Without these abilities, we would hardly be able to find our way around our surroundings and would find it difficult to remember past events. However, the neuronal basis of spatial memory is far from being fully understood. A research group led by Prof. Lukas Kunz, who has recently joined the University Hospital Bonn (UKB), has gained new insights into this gap in knowledge. Together with scientists from New York and Freiburg, he discovered that different types of nerve cells become active together during spatial memory and are coordinated by brain waves (“ripples”).
Associative memory allows different pieces of information to be linked together.
“In the context of spatial memory, associative memory enables us to remember the locations of certain objects in the spatial environment,” explains Prof. Kunz, research group leader for Cognitive and Translational Neuroscience at the Department of Epileptology at the UKB. He is also a member of the Transdisciplinary Research Area (TRA) “Life & Health” at the University of Bonn. “For example, we can remember where in the house we put our keys”. At older age or in certain diseases such as Alzheimer’s, however, this ability is limited. “It is therefore important to investigate the neuronal basis of different forms of human memory,” says Prof. Kunz.
In the long term, this could help develop new therapies for memory impairments.
Nerve cells are active while information is retrieved from memory. To further investigate this phenomenon, the researchers recorded the activity of individual nerve cells in epilepsy patients performing a memory task.
“In a virtual world, the participants were asked to remember the locations of different objects,” explains Prof. Kunz.
The recordings showed that different types of nerve cells became active during this memory task. Some nerve cells responded to certain objects, while other nerve cells activated in response to certain locations. The scientists observed that interactions between the different types of nerve cells became stronger over time when participants remembered the right object in the right place.
In addition to place and object neurons, the researchers observed hippocampal brain waves (“ripples”) that also occurred during the memory task, presumably playing a crucial role in the formation and retrieval of associative memories.
“Ripples could be important for the connection of different types of nerve cells and the formation of complex memories. It will be exciting to further investigate this idea in future studies,” explains Prof. Kunz.
It will also be interesting to study how memory performance is modulated when ripples are suppressed or triggered, providing insights into the causal relevance of ripples.
Prof. Kunz intends to continue the findings that he gained with his colleagues at Columbia University’s School of Engineering and Applied Science in New York and the University of Freiburg at the University Hospital Bonn.
“The department of epileptology at the UKB is well-known for its excellent brain research. The department has the unique opportunity to record the activity of individual nerve cells in the human brain in the video EEG monitoring unit, which is the heart of every epilepsy center. This provides exciting insights into the functioning of the human brain, which is only possible at a few research centers worldwide,” describes Prof. Kunz.
In his interdisciplinary research, he builds on the close exchange with other researchers and medical doctors, which is essential for the development of new research ideas.
Evidence of brain target engagement in Parkinson’s disease and multiple sclerosis by the investigational nanomedicine, CNM-Au8, in the REPAIR phase 2 clinical trials
by Ren J, Dewey RB, Rynders A, et al. in J Nanobiotechnology
Results from phase two clinical trials at UT Southwestern Medical Center showed that a suspension of gold nanocrystals taken daily by patients with multiple sclerosis (MS) and Parkinson’s disease (PD) significantly reversed deficits of metabolites linked to energy activity in the brain and resulted in functional improvements. The findings, published in the Journal of Nanobiotechnology, could eventually help bring this treatment to patients with these and other neurodegenerative diseases, according to the authors.
“We are cautiously optimistic that we will be able to prevent or even reverse some neurological disabilities with this strategy,” said Peter Sguigna, M.D., who leads the active MS trial and is an Assistant Professor of Neurology and an Investigator in the Peter O’Donnell Jr. Brain Institute at UT Southwestern.
Healthy brain function depends on a continuous supply of energy to this organ’s cells through a molecule called adenosine triphosphate (ATP), Dr. Sguigna explained. Age causes a decline in brain energy metabolism, evident in a decrease in the ratio of nicotinamide adenine dinucleotide (NAD+) and its partner, nicotinamide adenine dinucleotide + hydrogen (NADH).
However, studies have shown that in neurodegenerative conditions such as MS, PD, and amyotrophic lateral sclerosis (ALS) — also known as Lou Gehrig’s disease — this decline in the NAD+/NADH ratio is much faster and more severe. Studies in cells, animal models, and human patients have suggested that halting or reversing this energy deficit could lead to a slower decline or even partial recovery for patients with neurodegenerative diseases, Dr. Sguigna said.
Toward that end, he and his colleagues partnered with Clene Nanomedicine, a company developing gold nanocrystals into an orally administered therapeutic agent for neurodegenerative conditions, including an experimental treatment named CNM-Au8. These nanocrystals act as catalysts that improve the NAD+/NADH ratio, positively altering brain cells’ energy balance — a phenomenon demonstrated in cellular and animal models in previous studies.
To determine whether CNM-Au8 was reaching its intended target in human patients, the UTSW researchers recruited 11 participants with relapsing MS and 13 with Parkinson’s for two phase two clinical trials, REPAIR-MS and REPAIR-PD. These participants received an initial brain magnetic resonance (MR) spectroscopy scan to determine their baseline NAD+/NADH ratio and the levels of other molecules associated with cell energy metabolism. After they took a daily dose of CNM-Au8 for 12 weeks, testing included a second MR spectroscopy.
Together, the 24 patients had an average increase in their NAD+/NADH ratios of 10.4% compared with baseline, showing that CNM-Au8 was targeting the brain as intended. Other energetic molecules, including ATP, normalized to the group mean by the end of treatment, another potentially beneficial effect. Using a validated survey for functional outcomes in PD, researchers found that study patients with this condition reported improved “motor experiences of daily living” at one point, suggesting that taking CNM-Au8 could ameliorate functional symptoms of their disease. None of the patients experienced severe adverse side effects linked to CNM-Au8.
While these results are encouraging, additional studies are needed, Dr. Sguigna said. REPAIR-MS will continue to enroll participants to see whether similar findings can be reproduced in progressive MS.
Other UTSW researchers who contributed to this study were Jimin Ren, Ph.D., Associate Professor of Radiology and in the Advanced Imaging Research Center, the study’s first author who led the MR spectroscopy portion of the research, and Benjamin Greenberg, M.D., Professor of Neurology and Pediatrics, Vice Chair of Clinical and Translational Research, a Cain Denius Scholar in Mobility Disorders, and a Distinguished Teaching Professor.
Dr. Sguigna cited support he received from the Physician Scientist Training Program (PSTP) and President’s Research Council at UT Southwestern.
When the trials were conducted, Dr. Greenberg was solely affiliated with UTSW. He was employed by Clene Nanomedicine as a consultant after the conclusion of part one of REPAIR-MS.
Inhibiting the Keap1/Nrf2 protein-protein interaction with protein-like polymers
by Carrow KP, Hamilton HL, Hopps MP, et al. in Advanced Materials
Professors Nathan Gianneschi of the International Institute for Nanotechnology at Northwestern University in collaboration with Jeffrey A. Johnson and Delinda A. Johnson, senior scientist, of the University of Wisconsin–Madison School of Pharmacy, unveil groundbreaking research with the potential to alter the treatment landscape for neurodegenerative diseases (NDs). The study, published in the esteemed journal Advanced Materials, titled “Inhibiting the Keap1/Nrf2 Protein-Protein Interaction with Protein-Like Polymers,” introduces a pioneering approach aimed at combating conditions such as Alzheimer’s disease, Parkinson’s disease (PD), and Amyotrophic lateral sclerosis (ALS).
NDs, characterized by the progressive loss of neurons and glial cell dysfunction, pose a growing threat to the aging population, with Alzheimer’s alone affecting approximately 10.7% of Americans over 65 years of age. This study addresses the critical challenge of oxidative stress in NDs by targeting the Nrf2 pathway, a key regulator of cellular redox homeostasis, whose dysfunction is implicated in the pathology of these conditions.
Alzheimer’s disease, characterized by the accumulation of beta-amyloid plaques and tau protein tangles; Parkinson’s disease, known for its loss of dopaminergic neurons and presence of Lewy bodies; and ALS, involving the degeneration of motor neurons, all share a common thread of oxidative stress contributing to disease pathology.
The study focuses on disrupting the Keap1/Nrf2 protein-protein interaction (PPI), which opens new avenues for treating neurodegenerative diseases by enhancing the body’s antioxidant response, crucial for cellular protection against oxidative stress. By preventing the degradation of Nrf2 through selective inhibition of its interaction with Keap1, the research holds promise for mitigating the cellular damage that underlies these debilitating conditions.
“We established Nrf2 as a principal target for the treatment of NDs over the past two decades, but this novel approach for activating the pathway holds great promise to develop disease-modifying therapies,” said UW–Madison Professor Jeffrey Johnson.
The research team embarked on addressing one of the most challenging aspects of ND treatment: the precise targeting of PPIs within the cell. Traditional methods, including small molecule inhibitors and peptide-based therapies, have fallen short due to a lack of specificity, stability, and cellular uptake.
The study introduces an innovative solution: protein-like polymers, or PLPs, are high-density brush macromolecular architectures synthesized via the ring-opening metathesis polymerization (ROMP) of norbornenyl-peptide-based monomers. These globular, proteomimetic structures display bioactive peptide side chains that can penetrate cell membranes, exhibit remarkable stability, and resist proteolysis.
This targeted approach to inhibit the Keap1/Nrf2 PPI represents a significant leap forward. By preventing Keap1 from marking Nrf2 for degradation, Nrf2 accumulates in the nucleus, activating the Antioxidant Response Element (ARE) and driving the expression of detoxifying and antioxidant genes. This mechanism effectively enhances the cellular antioxidant response, providing a potent therapeutic strategy against the oxidative stress implicated in many forms of ND.
PLPs, developed by Professor Gianneschi’s team, could represent a significant breakthrough in halting or reversing damage, offering hope for improved treatments and outcomes.
Focusing on the challenge of activating processes crucial for the body’s antioxidant response, the team’s research offers a novel solution. The team provides a robust, selective method enabling enhanced cellular protection and offering a promising therapeutic strategy for a range of diseases, including neurodegenerative conditions.
“Through modern polymer chemistry, we can begin to think about mimicking complex proteins. The promise lies in the development of a new modality for the design of therapeutics. This could be a way to address diseases like Alzheimer’s and Parkinson’s among others where traditional approaches have struggled,” said Professor Nathan Gianneschi.
This approach not only represents a significant advance in targeting transcription factors and disordered proteins but also showcases the PLP technology’s versatility and potential to revolutionize the development of therapeutics. The technology’s modularity and efficacy in inhibiting the Keap1/Nrf2 interaction underscore its potential for impact as a therapeutic but also as a tool for studying the biochemistry of these processes.
Highlighting the study’s collaborative nature, Professor Gianneschi’s team worked closely with experts across disciplines, illustrating the rich potential of combining materials science with cellular biology to tackle complex medical challenges.
“We were contacted by Professor Gianneschi and colleagues proposing to use this novel PLP technology in NDs due to our previous work on Nrf2 in models of AD, PD, ALS, and Huntington’s Disease. We had never heard of this approach for Nrf2 activation and immediately agreed to initiate this collaborative effort that led to the generation of great data and this publication,” said Johnson, professor of pharmaceutical sciences at the UW–Madison School of Pharmacy.
This partnership underscores the importance of interdisciplinary research in developing new therapeutic modalities.
With the development of this innovative technology, Professor Nathan Gianneschi, his colleagues at the International Institute for Nanotechnology and the Johnson Lab at the University of Wisconsin–Madison, are not just advancing the field of medicinal chemistry; they are opening new pathways to combat some of the most challenging and devastating NDs faced by society today. As this research progresses towards clinical application, it may soon offer new hope to those suffering from diseases of oxidative stress, such as Alzheimer’s and Parkinson’s disease.
“By controlling materials at the scale of single nanometers, we’re opening new possibilities in the fight against diseases that are more prevalent than ever, yet remain untreatable,” says Professor Gianneschi. “This study is just the beginning. We’re excited about the possibilities as we continue to explore and expand the development of macromolecular drugs, capable of mimicking some of the aspects of proteins using our PLP platform.”
Heritability of cognitive and emotion processing during functional MRI in a twin sample
by Park HRP, Chilver MR, Quidé Y, et al. in Human Brain Mapping
The way our brain processes different emotional and cognitive tasks may be underpinned by common factors, find scientists from UNSW and Neuroscience Research Australia (NeuRA). In this latest study, recently published in the journal Human Brain Mapping, Dr Haeme Park and Associate Professor Justine Gatt, who hold joint positions at UNSW Psychology and NeuRA, looked at how both emotion and cognition are influenced by the environment and genetics, using functional MRI (fMRI) scans on twins.
“There has been quite a lot of research looking at genetic versus environmental influences on brain structure,” says Dr Park, lead author of the study. “But it’s a lot harder to understand the function of our brains.”
The results revealed that the picture is extremely complex. Some emotional and cognitive tasks were partly associated with genetics, and others exclusively with environment.
But they also found that some of the same genetic and environmental factors can play a role in the brain reacting to two different tasks. For example, the analysis showed that some of the same genetic factors are influencing how we process fear and happiness and also how we sustain our attention.
“This study is interesting because we have further insight into how much of our life experiences modulate certain brain processes, which to a certain degree we have more control over, versus your biology, which you can’t change,” says A/Prof. Gatt, Director of the Centre for Wellbeing, Resilience and Recovery. “Knowing what areas of our brain function are linked strongly to our environment can help us develop personalised intervention approaches to promote higher mental wellbeing.”
The so called ‘nature vs nurture’ debate isn’t new.
In fact, twin studies have become a unique research tool used by geneticists and psychologists to evaluate the influence of genetics and the effect of a person’s shared environment (family) and unique environment (the individual events that shape a life) on a particular trait.
“With twin studies, it’s important to recruit both identical and non-identical twins,” says A/Prof. Gatt. “Identical twins share 100 per cent of their genetics and if they’re grown up together, they share the same environment. Whereas with the non-identical twins, they only have 50 per cent shared genetics, but they also have that common environment.”
“In this study, we wanted to bridge lots of gaps in the literature and provide a more robust and thorough picture of how our genetics and environmental factors impact the expression of brain activity during emotional and cognitive tasks, by analysing twins,” says Dr Park.
The most recent paper is one of many from the TWIN-E study, which recruited 1600 identical and non-identical twins from across the country in 2009 and is led by A/Prof. Gatt. A subset of the original cohort participated in this particular study, with a total of 270 adult twins taking part.
“We get participants set up on the fMRI scanner bed which is fitted with goggles that enable them to see the tasks in front of them. The functional tasks involve them viewing different images, different stimuli, through the goggles,” says A Prof. Gatt.
While the participants were completing the tasks, the fMRI machine was scanning their brain to measure its activity.
The twins completed a total of five tasks. Two were linked to emotional responses, such as reactions to various expressions of different faces, and the other three were associated with cognition, such as the ability to sustain attention and short-term memory.
Processing the fMRI scans show you which part of the brain light up for different processes, and how strongly the brain is activated can be measured on a scale.
“So individuals who show a lot of activation in that region have a higher number, whereas those with lower activation have a smaller number. We then use these figures to carry out what we call ‘twin modeling’ processes,” says Dr Park. “This is where we use statistics to break down how much of a role genetics and environment contributes to that number.”
Twin modelling methods revealed two key findings in their analysis of the results.
Firstly, the researchers looked at the genetic versus environmental influence on each individual task.
“We know that we use different brain networks for different processes — for example, processing either a crying face or a happy face is going to use different regions in the brain compared to trying to remember someone’s phone number,” says A/Prof. Gatt. “But we found that for some of these networks, genetics plays a small to moderate, but significant role. And for other processes, it’s only the environment that determines brain function.”
The second part of the analysis found that there were similarities in the genetic and environmental factors that underpinned different tasks.
“For example, we discovered that how the brain processes fear and happiness (which was measured in the emotional tasks) and our ability to sustain attention (which was measured in the cognitive tasks), have some shared genetic factors,” says Dr Park. “This suggests that some common genetic features may underpin these very different processes.”
In contrast, the team also found that our ability to sustain our attention and our working memory have some of the same environmental contributions, suggesting that life experiences — which come from your environment — play a significant role in how brain activity is expressed for these two processes.
While it’s clear that both our genetics and life experiences are important in determining how our brain functions, the puzzle is far from solved.
“There’s still so much more to find out!” says Dr Park. The current participants have already been followed up more recently and have performed the same tasks again after 10 years. A/Prof. Gatt, Dr Park and their team will be reassessing the results to see how the influences of genetics and environment on these brain processes change over time.
“All these results paint a complex picture of the relationship between genes and environment that give rise to the brain activity underlying our cognition and emotion,” says A/Prof. Gatt.
But knowing more precise details may help to develop personalised intervention approaches in order to promote, for instance, higher mental wellbeing, or reduced psychological distress.
In fact, the ongoing TWIN-E study focuses more broadly on mental wellbeing and resilience.
“So, what we’re using this data for, beyond looking at genes and environment, is actually predicting mental wellbeing and resilience trajectories over time, and seeing how differences in markers like brain function and structure might profile people who are a bit more resilient or at more risk to a mental health problem,” says A/Prof. Gatt.
Understanding how much of our life experiences influences certain processes versus the influence of genetics is important when knowing what factors we can change and control, which is particularly significant for people with mood and anxiety disorders, explains A/Prof. Gatt.
“If someone has a tendency to attend to negative stimuli more than positive, and we know that there’s an element of environment contributing to that, with intervention or training, it’s potentially something we can target and improve for the better.”
Deep learning models reveal replicable, generalizable, and behaviorally relevant sex differences in human functional brain organization
by Srikanth Ryali, Yuan Zhang, Carlo de los Angeles, Kaustubh Supekar, Vinod Menon in Proceedings of the National Academy of Sciences
A new study by Stanford Medicine investigators unveils a new artificial intelligence model that was more than 90% successful at determining whether scans of brain activity came from a woman or a man.
The findings, to be published in the Proceedings of the National Academy of Sciences, help resolve a long-term controversy about whether reliable sex differences exist in the human brain and suggest that understanding these differences may be critical to addressing neuropsychiatric conditions that affect women and men differently.
“A key motivation for this study is that sex plays a crucial role in human brain development, in aging, and in the manifestation of psychiatric and neurological disorders,” said Vinod Menon, PhD, professor of psychiatry and behavioral sciences and director of the Stanford Cognitive and Systems Neuroscience Laboratory. “Identifying consistent and replicable sex differences in the healthy adult brain is a critical step toward a deeper understanding of sex-specific vulnerabilities in psychiatric and neurological disorders.”
Menon is the study’s senior author. The lead authors are senior research scientist Srikanth Ryali, PhD, and academic staff researcher Yuan Zhang, PhD.
“Hotspots” that most helped the model distinguish male brains from female ones include the default mode network, a brain system that helps us process self-referential information, and the striatum and limbic network, which are involved in learning and how we respond to rewards.
The investigators noted that this work does notweigh in on whether sex-related differences arise early in life or may be driven by hormonal differences or the different societal circumstances that men and women may be more likely to encounter.
The extent to which a person’s sex affects how their brain is organized and operates has long been a point of dispute among scientists. While we know the sex chromosomes we are born with help determine the cocktail of hormones our brains are exposed to — particularly during early development, puberty and aging — researchers have long struggled to connect sex to concrete differences in the human brain. Brain structures tend to look much the same in men and women, and previous research examining how brain regions work together has also largely failed to turn up consistent brain indicators of sex.
In their current study, Menon and his team took advantage of recent advances in artificial intelligence, as well as access to multiple large datasets, to pursue a more powerful analysis than has previously been employed. First, they created a deep neural network model, which learns to classify brain imaging data: As the researchers showed brain scans to the model and told it that it was looking at a male or female brain, the model started to “notice” what subtle patterns could help it tell the difference.
This model demonstrated superior performance compared with those in previous studies, in part because it used a deep neural network that analyzes dynamic MRI scans. This approach captures the intricate interplay among different brain regions. When the researchers tested the model on around 1,500 brain scans, it could almost always tell if the scan came from a woman or a man.
The model’s success suggests that detectable sex differences do exist in the brain but just haven’t been picked up reliably before. The fact that it worked so well in different datasets, including brain scans from multiple sites in the U.S. and Europe, make the findings especially convincing as it controls for many confounds that can plague studies of this kind.
“This is a very strong piece of evidence that sex is a robust determinant of human brain organization,” Menon said.
Until recently, a model like the one Menon’s team employed would help researchers sort brains into different groups but wouldn’t provide information about how the sorting happened. Today, however, researchers have access to a tool called “explainable AI,” which can sift through vast amounts of data to explain how a model’s decisions are made.
Using explainable AI, Menon and his team identified the brain networks that were most important to the model’s judgment of whether a brain scan came from a man or a woman. They found the model was most often looking to the default mode network, striatum, and the limbic network to make the call.
The team then wondered if they could create another model that could predict how well participants would do on certain cognitive tasks based on functional brain features that differ between women and men. They developed sex-specific models of cognitive abilities: One model effectively predicted cognitive performance in men but not women, and another in women but not men. The findings indicate that functional brain characteristics varying between sexes have significant behavioral implications.
“These models worked really well because we successfully separated brain patterns between sexes,” Menon said. “That tells me that overlooking sex differences in brain organization could lead us to miss key factors underlying neuropsychiatric disorders.”
While the team applied their deep neural network model to questions about sex differences, Menon says the model can be applied to answer questions regarding how just about any aspect of brain connectivity might relate to any kind of cognitive ability or behavior. He and his team plan to make their model publicly available for any researcher to use.
“Our AI models have very broad applicability,” Menon said. “A researcher could use our models to look for brain differences linked to learning impairments or social functioning differences, for instance — aspects we are keen to understand better to aid individuals in adapting to and surmounting these challenges.”
Amyloid-β-induced dendritic spine elimination requires Ca2+-permeable AMPA receptors, AKAP-Calcineurin-NFAT signaling, and the NFAT target gene Mdm2
by Tyler P. Martinez, Matthew E. Larsen, Emily Sullivan, Kevin M. Woolfrey, Mark L. Dell’Acqua in eneuro
Researchers at the University of Colorado Anschutz Medical Campus have found that inhibiting a key protein can stop the destruction of synapses and dendritic spines commonly seen in Alzheimer’s disease.
The study, whose first author is Tyler Martinez, a student in the Pharmacology and Molecular Medicine PhD program at the University of Colorado School of Medicine, was published recently in the journal eNeuro.
The researchers, using rodent neurons, found that targeting a protein called Mdm2 with an experimental cancer drug known as nutlin, stopped neurotoxic amyloid-b peptides that accumulate in Alzheimer’s disease (AD) from overly pruning synapses.
“Cognitive impairments associated with AD correlate with dendritic spine and excitatory synapse loss, particularly within the hippocampus,” said the study’s senior author Professor Mark Dell’Acqua, PhD, vice-chair of the Department of Pharmacology at the CU School of Medicine.
Dell’Acqua said trimming excess dendritic spine synapses is normal in the post-natal brain but can be abnormally accelerated in AD causing loss of memory and learning.
“When this protein Mdm2 is turned on inappropriately it leads to pruning of the synapses when amyloid-b is present,” he said.
Amyloid-b is the main component of amyloid plaques found in the brain of those with AD.
“When we used the drug that inhibits Mdm2 on the neurons it completely blocked dendritic spine loss triggered by amyloid-b. So inhibiting this protein is clearly working.”
Dendritic spines protrude from dendrites, a component of neurons, and receive synaptic signals that are critical in learning and memory.
Dell’Acqua, director of the Neurotechnology Center at the CU School of Medicine, noted that much of the research into AD therapies tends to focus on eradicating amyloid plaques in the brain.
“There are questions if anti-amyloid therapy is the be all and end all of AD therapy,” he said. “Even if you could tolerate the high cost, the effectiveness is questionable. We are saying that it may also be possible to intervene in the process by blocking some of the impacts of amyloid-b. And you could intervene by targeting Mdm2.”
The next step is determining whether they can block AD progression in an animal model.
If so, human trials could happen in the future. Drugs that target Mdm2 are already developed and in clinical trials for cancer but still need FDA approval.
“This is an encouraging first step that gives us a new lead to pursue,” Dell’Acqua said.
Original speech and its echo are segregated and separately processed in the human brain
by Jiaxin Gao, Honghua Chen, Mingxuan Fang, Nai Ding in PLOS Biology
Echoes can make speech harder to understand, and tuning out echoes in an audio recording is a notoriously difficulty engineering problem. The human brain, however, appears to solve the problem successfully by separating the sound into direct speech and its echo, according to a study publishing February 15 in the open-access journal PLOS Biology by Jiaxin Gao from Zhejiang University, China, and colleagues.
The audio signals in online meetings and auditoriums that are not properly designed often have an echo lagging at least 100 milliseconds from the original speech. These echoes heavily distort speech, interfering with slowly varying sound features most important for understanding conversations, yet people still reliably understand echoic speech.
To better understand how the brain enables this, the authors used magnetoencephalography (MEG) to record neural activity while human participants listened to a story with and without an echo.
They compared the neural signals to two computational models: one simulating the brain adapting to the echo, and another simulating the brain separating the echo from the original speech.
Participants understood the story with over 95% accuracy, regardless of echo. The researchers observed that cortical activity tracks energy changes related to direct speech, despite the strong interference of the echo.
Simulating neural adaptation only partially captured the brain response they observed — neural activity was better explained by a model that split original speech and its echo into separate processing streams.
This remained true even when participants were told to direct their attention toward a silent film and ignore the story, suggesting that top-down attention isn’t required to mentally separate direct speech and its echo.
The researchers state that auditory stream segregation may be important both for singling out a specific speaker in a crowded environment and for clearly understanding an individual speaker in a reverberant space.
The authors add, “Echoes strongly distort the sound features of speech and create a challenge for automatic speech recognition. The human brain, however, can segregate speech from its echo and achieve reliable recognition of echoic speech.”
Ingroup sources enhance associative inference
by Marius Boeltzig, Mikael Johansson, Inês Bramão in Communications Psychology
Our brains are “programmed” to learn more from people we like — and less from those we dislike. This has been shown by researchers in cognitive neuroscience in a series of experiments.
Memory serves a vital function, enabling us to learn from new experiences and update existing knowledge. We learn both from individual experiences and from connecting them to draw new conclusions about the world.
This way, we can make inferences about things that we don’t necessarily have direct experience of. This is called memory integration and makes learning quick and flexible. Inês Bramão, associate professor of psychology at Lund University, provides an example of memory integration: Say you’re walking in a park.
You see a man with a dog. A few hours later, you see the dog in the city with a woman. Your brain quickly makes the connection that the man and woman are a couple even though you have never seen them together.
“Making such inferences is adaptive and helpful. But of course, there’s a risk that our brain draws incorrect conclusions or remembers selectively,” says Inês Bramão.
To examine what affects our ability to learn and make inferences, Inês Bramão, along with colleagues Marius Boeltzig and Mikael Johansson, set up experiments where participants were tasked with remembering and connecting different objects.
It could be a bowl, ball, spoon, scissors, or other everyday objects.
It turned out that memory integration, i.e., the ability to remember and connect information across learning events, was influenced by who presented it. If it was a person the participant liked, connecting the information was easier compared to when the information came from someone the participant disliked.
The participants provided individual definitions of ‘like’ and ‘dislike’ based on aspects such as political views, major, eating habits, favorite sports, hobbies, and music.
The findings can be applied in real life, according to the researchers.
Inês Bramão takes a hypothetical example from politics:
“A political party argues for raising taxes to benefit healthcare. Later, you visit a healthcare center and notice improvements have been made. If you sympathize with the party that wanted to improve healthcare through higher taxes, you’re likely to attribute the improvements to the tax increase, even though the improvements might have had a completely different cause.”
There’s already vast research describing that people learn information differently depending on the source and how that characterizes polarization and knowledge resistance.
“What our research shows is how these significant phenomena can partly be traced back to fundamental principles that govern how our memory works,” says Mikael Johansson, professor of psychology at Lund University.
We are more inclined to form new connections and update knowledge from information presented by groups we favor.
Understanding the roots of polarization, resistance to new knowledge, and related phenomena from basic brain functions offers a deeper insight into these complex behaviors, the researchers argue.
So, it’s not just about filter bubbles on social media but also about an innate way of assimilating information.
“Particularly striking is that we integrate information differently depending on who is saying something, even when the information is completely neutral. In real life, where information often triggers stronger reactions, these effects could be even more prominent,” says Mikael Johansson.
GABA B receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles
by Peter Koppensteiner, Pradeep Bhandari, Cihan Önal, Carolina Borges-Merjane, Elodie Le Monnier, Utsa Roy, Yukihiro Nakamura, Tetsushi Sadakata, Makoto Sanbo, Masumi Hirabayashi, JeongSeop Rhee, Nils Brose, Peter Jonas, Ryuichi Shigemoto in Proceedings of the National Academy of Sciences
Fear and addiction exert significant influence within society. Managing them is often challenging, as they are driven by intricate neuronal circuits in our brains. Understanding the underlying molecular mechanisms is crucial to intervene when these processes malfunction. Pioneered by scientists at the Institute of Science and Technology Austria (ISTA), the novel “Flash and Freeze-fracture” technique provides a unique glimpse into the respective brain region. The results were recently published in the journal PNAS.
While looking for food, a bird encounters a fox. It gets away just in time, but the sight and the sound of the predator lingers. The negative experience will form a memory in its brain and will be associated with fear and stress from now on. Whenever it meets a fox again, the fear memory is revived.
The bird’s attention spikes, its heart rate goes up, and it changes its behavior to reduce the risk of predation. Such memory is mediated by a specific brain region called the medial habenula, one of the epicenters for emotional processing.
Peter Koppensteiner, together with Pradeep Bhandari, Cihan Önal and other members of Ryuichi Shigemoto’s research group at the Institute of Science and Technology Austria (ISTA) investigated this particular part of the brain to understand how its neurons (nerve cells) communicate with each other.
Published in the journal PNAS, the results give an unprecedented look into this subject, utilizing a novel visualization technique called “Flash and Freeze-fracture.”
Nerve cells in the medial habenula exhibit unusual behavior, contradicting the general understanding of how neurons transmit signals to each other.
“Typically, communication between neurons is shut down, as soon as a specific molecule on the surface of the cells, known as the ‘GABAB’-receptor, is activated,” explains Peter Koppensteiner, previously a postdoc in the Shigemoto group and now a staff scientist at one of ISTA’s Scientific Service Units (SSUs). In neurons of the medial habenula, the exact opposite happens.
“With the activation of GABAB, communication is elevated, to the extent that it shows the strongest synaptic facilitation throughout the entire brain,” he continues.
The underlying mechanism, however, was still unknown.
Driven by curiosity, the ISTA scientists embarked on a journey to decipher this phenomenon. The goal was to thoroughly examine medial habenula neurons in mice after they had been activated with a light flash.
“It’s a very challenging task,” says Ryuichi Shigemoto. “The processes inside neurons occur in milliseconds, and classical electron microscope methods lack the temporal resolution to capture them.”
A method formulated within the past decade, significantly influenced by Peter Jonas’ research group at ISTA called “Flash and Freeze,” proved to be a great starting point.
It is a powerful tool, where neurons are frozen after being stimulated with light, to analyze the structure of neurons.
The scientists now elevated it to the next level. Their new “Flash and Freeze-fracture” technique introduces the possibility of also depicting proteins and molecules.
This advancement allows researchers to track their trajectories, i.e., where proteins are going after neuronal activation, and reveal why they occupy distinct positions.
The latter is of particular importance. “The communication at the synapse varies depending on the localization of specific proteins. Our new method reveals that rapid position changes of some proteins strengthen the synapses,” explains Koppensteiner.
Two proteins with previously unknown functions in particular, SPO and CAPS2, localize near the synapse, where CAPS2 anchors vesicles — tiny bubbles carrying neurotransmitters — to this region.
A crucial event that enables a strong release of their messenger signals to the next nerve cell, thus facilitating communication between nerve cells.
Understanding these details could potentially open new doors to actively strengthen synapses in neurodegenerative diseases, where they are not functioning properly anymore.
Shigemoto adds, “I’m beyond excited about this remarkable publication that elucidates the mechanism of this peculiar phenomenon in the brain.”
Modeling and dissociation of intrinsic and input-driven neural population dynamics underlying behavior
by Parsa Vahidi, Omid G. Sani, Maryam M. Shanechi in Proceedings of the National Academy of Sciences
Maryam Shanechi, Dean’s Professor of Electrical and Computer Engineering and founding director of the USC Center for Neurotechnology, and her team have developed a new machine learning method that reveals surprisingly consistent intrinsic brain patterns across different subjects by disentangling these patterns from the effect of visual inputs.The work has been published in the Proceedings of the National Academy of Sciences (PNAS).
When performing various everyday movement behaviors, such as reaching for a book, our brain has to take in information, often in the form of visual input — for example, seeing where the book is. Our brain then has to process this information internally to coordinate the activity of our muscles and perform the movement.
But how do millions of neurons in our brain perform such a task?
Answering this question requires studying the neurons’ collective activity patterns, but doing so while disentangling the effect of input from the neurons’ intrinsic (aka internal) processes, whether movement-relevant or not.
That’s what Shanechi, her PhD student Parsa Vahidi, and a research associate in her lab, Omid Sani, did by developing a new machine-learning method that models neural activity while considering both movement behavior and sensory input.
“Prior methods for analyzing brain data have either considered neural activity and input but not behavior, or considered neural activity and behavior but not input,” Shanechi said.
“We developed a method that can consider all three signals — neural activity, behavior, and input — when extracting hidden brain patterns. This allowed us to not only disentangle input-related and intrinsic neural patterns, but also separate out which intrinsic patterns were related to movement behavior and which were not.”
Shanechi and her team used this method to study three publicly available datasets, during which three different subjects performed one of two distinct movement tasks, consisting of moving a cursor on a computer screen over a grid or moving it sequentially to random locations.
“When using methods that did not consider all three signals, the patterns found in neural activity of these three subjects looked different.” Vahidi said.
But when the team used the new method to consider all three signals, a remarkably consistent hidden pattern emerged from neural activity of all three subjects that was relevant to movement.
This similarity was despite the fact that the tasks performed by the three subjects were also different.
“In addition to revealing this new consistent pattern, the method also improved the prediction of neural activity and behavior compared to when all three signals were not considered during machine learning, as in prior work.” Sani said.
“The new method enables researchers to more accurately model neural and behavioral data by accounting for various measured inputs to the brain, such as sensory inputs as in this work, electrical or optogenetic stimulation, or even input from different brain areas.”
This method and the discovered pattern can help understand how our brains perform movements, guided by the information we receive from the external world.
Further, by modeling the effect of input and separating out intrinsic patterns that are behavior-relevant, this method can help develop future brain-computer interfaces that regulate abnormal brain patterns in disorders such as major depression by optimizing external inputs such as deep brain stimulation therapy.
“We are excited about how this algorithm could facilitate both scientific discoveries and the development of future neurotechnologies for millions of patients with neurological or neuropsychiatric disorders,” Shanechi said.
Subscribe to Paradigm!
Medium, Twitter, Telegram, Telegram Chat, LinkedIn, and Reddit.
