Neuroscience biweekly vol. 67, 14th September — 28th September
TL;DR
- Dog owners whose pets meet during a walk are familiar with the immediate sniffing investigation that typically ensues. Initially, the owners cannot tell whether their dogs will wind up fighting, playing, or trying to mount each other. Something is clearly happening in the dog’s brain to make it decide how to behave toward the other dog — but what is going on? A new study from Caltech examines this question in mice: namely, how does a male mouse sniffing a newly encountered fellow mouse decide whether to make love or war — or to do neither and just mind its own business? The research reveals the neural circuitry that connects olfactory information about another mouse’s sex to decision-making points in the mouse brain that determine its behavior.
- Scientists have identified a previously unknown barrier that separates the bloodstream from smelling cells in the upper airway of mice. But this barrier ends up keeping some of the larger molecules of the body’s immune system out, and that may be hindering the effectiveness of vaccines. The barrier, named the BOB, Blood-Olfactory Barrier, like Blood-Brain Barrier, might partially explain the prevalence of breakthrough COVID infections and why they are often associated with smell loss.
- Researchers have discovered a biological mechanism that increases the strength with which fear memories are stored in the brain. The study, done in rats, provides new knowledge on the mechanisms behind anxiety-related disorders and identifies shared mechanisms behind anxiety and alcohol dependence.
- A study by the Human Brain Project (HBP), led by scientists from the University of Liège (Belgium), has explored new techniques that may help distinguish between two different neurological conditions in patients with severe brain damage and or in a coma. The results of this study have just been published in open access in the journal eLife.
- While not all impulsive behavior speaks of mental illness, a wide range of mental health disorders that often emerge in adolescence, including depression and substance abuse, have been linked to impulsivity. So, finding a way to identify and treat those who may be particularly vulnerable to impulsivity early in life is especially important. Researchers have developed a genetically based score that could help identify, with a high degree of accuracy (greater than that of any impulsivity scores currently in use), the young children who are most at risk of impulsive behavior.
- Aggregates of the protein alpha-synuclein spread in the brains of people with Parkinson’s disease through a cellular waste-ejection process, suggests a new study led by Weill Cornell Medicine researchers.
- Our ability to think, decide, remember recent events, and more, comes from our brain’s neocortex. Now University of California, Irvine neuroscientists have discovered key aspects of the mechanisms behind these functions. Their findings could ultimately help improve treatments for certain neuropsychiatric disorders and brain injuries. Their study appears in Neuron.
- A study has found an association, in children aged 9–12, between exposure to air pollutants in the womb and during the first 8.5 years of life and alterations in white matter structural connectivity in the brain. The greater the child’s exposure before age 5, the greater the brain structure alteration observed in preadolescence.
- Williams-Beuren syndrome (WBS) is a rare disorder that causes neurocognitive and developmental deficits. However, musical and auditory abilities are preserved or even enhanced in WBS patients. Scientists at St. Jude Children’s Research Hospital have identified the mechanism responsible for this ability in models of the disease. The findings were published in Cell.
- Special blood vessels in whale brains may protect them from pulses, caused by swimming, in their blood that would damage the brain, new UBC research has suggested.
- And more!
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Latest news and research
Transformations of neural representations in a social behaviour network
by Yang B, Karigo T, Anderson DJ in Nature
Dog owners whose pets meet during a walk are familiar with the immediate sniffing investigation that typically ensues. Initially, the owners cannot tell whether their dogs will wind up fighting, playing, or trying to mount each other. Something is clearly happening in the dog’s brain to make it decide how to behave toward the other dog — but what is going on? A new study from Caltech examines this question in mice: namely, how does a male mouse sniffing a newly encountered fellow mouse decide whether to make love or war — or to do neither and just mind its own business? The research reveals the neural circuitry that connects olfactory information about another mouse’s sex to decision-making points in the mouse brain that determine its behavior.
The study was led by postdoctoral scholars Bin Yang and Tomomi Karigo, and conducted in the laboratory of David Anderson, Seymour Benzer Professor of Biology, Tianqiao and Chrissy Chen Institute for Neuroscience Leadership Chair, Howard Hughes Medical Institute Investigator, and director of the Tianqiao and Chrissy Chen Institute for Neuroscience. A paper describing the findings appeared online in the journal Nature on August 3.
“Understanding how a mouse chooses whether to mate or fight with a fellow mouse represents decision-making in the brain at its most basic level, and can serve as a model for more complex decision-making processes, even in our own brains,” Anderson says.
When encountering another mouse, the male mouse’s brain has to decide how to behave by answering two questions about the new animal:
“What is it?”, and “What should I do about it?” Answering these questions requires that the brain decode the sex identity of the other animal and transform that sex code into a plan of action.
This process occurs as electrical activity — triggered in the mouse’s nose by the smell of a male or female — flows into the brain through a series of structures, or nodes, until reaching a decision point that controls the choice of behavior: mating or fighting. The problem is to understand what each of these nodes is doing during this process, and how they perform their function.
It was previously known that the initial decoding of the sex identity of another mouse occurs in a node called the medial amygdala, which receives input from the olfactory system. It was also known that further “downstream” in the circuit, mating or fighting behavior are controlled by two nodes in the hypothalamus called the MPOA and VMHvl, respectively. But in between the amygdala and the hypothalamus lies an enigmatic node called the “BNST” (Bed Nucleus of the Stria Terminalis). What does the BNST do, and how does it do it?
Earlier studies showed that if neurons in the BNST are killed or electrically silenced, male mice encountering a female fail to transition from sniffing to mounting, while those encountering a male fail to transition from sniffing to attack. These findings suggested that BNST serves as a kind of gate that controls whether the sex identity of the mouse (initially decoded by the amygdala) is used to drive the initiation of mounting or attack. But how exactly is that brain “gate” opened?
To answer this question, Yang and the team visualized neuronal activity in BNST by using a miniature microscope attached to a male mouse’s head while it interacted with another mouse (either a male or a female). The male mouse has been genetically engineered so that individual neurons glow with light when activated, and the microscope detects these pinpoint flashes. The question is which neurons are active, and what do they do? The team found that there are two types of neurons in the BNST: those that respond preferentially to female mice (female tuned), and those that respond preferentially to males (male tuned). Interestingly, the female-tuned neurons outnumbered the male-tuned neurons in BNST by almost two to one, like those in the amygdala. This indicated that the coding of sex identity by the amygdala was relayed to the BNST and mapped onto its neurons.
The predominance of female-responsive neurons is also observed in MPOA, the structure that lies downstream of BNST and controls male mating behavior. Evidently, the entire circuit appears wired to preferentially respond to females. The one exception to this rule was VMHvl, the node that controls intermale aggression. In this structure, male-tuned neurons outnumber female-tuned neurons by about two to one — the opposite of what is seen in the other circuit nodes. Apparently, VMHvl is like an island of neurons dominated by male responses in a sea of surrounding circuitry otherwise dominated by female responses.
To understand how this inversion of sex-tuning dominance occurs in VMHvl, Yang investigated next how patterns of neuronal activity in this node were altered by silencing neurons in BNST. Surprisingly, he found that when BNST neurons were turned off, the dominance of male-tuned neurons in VMHvl was flipped to a female-dominant response like that observed in MPOA and BNST. This may explain why silencing BNST blocks the transition to aggression: there are no longer enough male-tuned neurons in VMHvl to activate the region sufficiently to produce attack.
By contrast, in the case of MPOA, there was no obvious change in the ratio of female-tuned to male-tuned neurons when BNST neurons were silenced. However, close inspection of neuronal activity in MPOA during interactions with a female revealed that as males transitioned from sniffing to mounting, different neurons were activated in a sequence. During sniffing, one population of neurons was active, but as the animals began to mount, that population was switched off, and a different population of MPOA neurons became active. When BNST neurons were silenced, however, the “sniffing” neurons continued to be active and the “mounting” neurons never turned on.
Thus, BNST neurons are required to “open” a neural gate that allows the transition from sniffing to mounting (toward a female), or to attack (toward a male). Unexpectedly, however, it controls this gate using different mechanisms for attack versus mounting. In the case of attack, BNST operates via quantity control: it ensures that a sufficient number of male-selective neurons are active in VMHvl to reach a threshold for attack. In the case of mounting, BNST operates via quality control: it ensures that sniff-tuned neurons in MPOA are switched off and replaced by mount-tuned neurons.
“These studies begin to shed light on the fundamental question of how the brain transforms a neural representation of object identity into a decision to execute a particular behavior,” Yang says. “Future studies should help to uncover how this transformation is implemented at the level of specific synapses.”
Mucosal plasma cells are required to protect the upper airway and brain from infection
by Sebastian A. Wellford, Annie Park Moseman, Kianna Dao, Katherine E. Wright, Allison Chen, Jona E. Plevin, Tzu-Chieh Liao, Naren Mehta, E. Ashley Moseman in Immunity
Duke scientists have identified a previously unknown barrier that separates the bloodstream from smelling cells in the upper airway of mice, likely as a way to protect the brain.
But this barrier also ends up keeping some of the larger molecules of the body’s immune system out, and that may be hindering the effectiveness of vaccines.
It makes sense to have a protective barrier for the olfactory cells lining the nose, because they offer a direct path to the olfactory bulb of the brain, making them effectively extensions of the brain itself, said lead researcher Ashley Moseman, an assistant professor of immunology in the Duke School of Medicine.
However, the new barrier, which his team has dubbed the BOB — the blood-olfactory barrier — also might be keeping vaccines against respiratory viruses from being more effective by preventing those antibodies from reaching the mucous on the surface of the nose, the first barrier a virus encounters.
The team was trying to understand better how the immune system protects the upper respiratory tract by infecting mice with a virus called vesicular stomatitis virus, or VSV, that is known to penetrate to the central nervous system. Once inhaled, VSV readily infects the olfactory sensing cells and rapidly replicates, reaching the olfactory bulb of the brain within a day. Although it can lead to paralysis and death, it is usually cleared by a T cell response.
“VSV is excellent at infecting olfactory sensory neurons, and when it can do that, it will get into the brain,” Moseman said. “Even if you have antibodies in circulation, the blood-olfactory barrier prevents these antibodies from reaching the airway surface, and VSV will get into the brain.”
They wanted to understand better how a prior infection could provide protection against subsequent infection. What they found was that while the BOB prevented circulating antibody protection, it does allow antibody secreting plasma cells to enter olfactory tissues and locally produce neutralizing antibodies.
The researchers weren’t looking at this question because of COVID, but the SARS-CoV-2 virus is known to infect olfactory cells and cause smell loss in many infected individuals. They now think that this new barrier might partially explain not only the prevalence of so-called breakthrough infections, but also why these infections are far more often associated with smell loss than with pulmonary symptoms.
“The reason that COVID infections typically stay in the upper airways and less commonly reach the lungs of vaccinated people may involve this gap in immune protection,” Moseman said.
“You could have a situation where you have perfectly good (amounts of) antibody in circulation from a COVID vaccination, but these antibodies are prevented from reaching the olfactory cells,” Moseman said. “You’d be protected against severe pulmonary disease, which is great, but you could still have these replicating events going on in the olfactory epithelium because the systemic antibody doesn’t get there. This is obviously unpleasant for the individual, and may contribute to continued community spread.”
Moseman said the finding also gets his team closer to another tantalizing question: How is it that an infection can drive antibody-secreting B cells into tissues, but many immunizations fail to do that?
“Vaccines create antibody-secreting cells that make antibody and give you a nice blood antibody titer, but those cells don’t necessarily enter and protect these tissues,” he said. “Antibodies that are in circulation don’t get to the olfactory surface where they can protect against the viral infection.”
Understanding how the immune system knows the difference between an infection and a vaccination could lead to more effective vaccinations, Moseman said.
“What you need to have is antibody-producing cells that go past the BOB, and then sit in those tissues and locally make antibodies.”
Next, the researchers need to understand better what the BOB is made of so that they can go looking for it in other animals and humans.
“It’s a relatively small area and it could be quite technically challenging to analyze in humans,” Moseman said. “If you understood what constitutes it, what factors maintain it and all these kinds of things in the mouse, then it will be a little bit easier to try to transfer that knowledge and look for it in human tissue.”
“We think it’s certainly plausible that this would exist in humans. We just haven’t actually been able to test it directly,” Moseman said. “There are a lot of questions.”
An epigenetic mechanism for over-consolidation of fear memories
by Barchiesi Riccardo, Chanthongdee Kanat, Petrella Michele, Xu Li, Söderholm Simon, Domi Esi, Augier Gaelle, Coppola Andrea, Joost Wiskerke, Ilona Szczot, Domi Ana, Adermark Louise, Augier Eric, Cantù Claudio, Heilig Markus, Barbier Estelle in Molecular Psychiatry
Researchers at Linköping University, Sweden, have discovered a biological mechanism that increases the strength with which fear memories are stored in the brain. The study, carried out in rats, is published in the scientific journal Molecular Psychiatry. It provides new knowledge on the mechanisms behind anxiety-related disorders, and identifies shared mechanisms behind anxiety and alcohol dependence.
The ability to experience fear is essential to escape life-threatening situations and learn to avoid them in the future. In some conditions, however, such as post-traumatic stress disorder (PTSD) and other anxiety-related disorders, the fear reactions become excessive and persist even when they are no longer appropriate. This triggers intense anxiety even though the danger is no longer present, and leads to disability for the person who is affected. Researchers suspect that certain individuals have a greater tendency to develop pathological fears, and that this is caused by disorders in the way that the brain processes fearful memories.
Some areas of the brain are particularly important for processing fear-related memories. The amygdala is activated when threats are experienced, and works together with parts of the frontal brain lobes, the “prefrontal cortex,” which are important for regulating emotions.
“We know that the network of nerve cells that connects the frontal lobes to the amygdala is involved in fear responses. The connections between these brain structures are altered in people with PTSD and other anxiety disorders,” says Estelle Barbier, assistant professor in the Center for Social and Affective Neuroscience (CSAN), and the Department of Biomedical and Clinical Sciences (BKV) at Linköping University, who led the study.
However, the molecular mechanisms involved have long remained unknown. The researchers in the current study have investigated a protein known as PRDM2, an epigenetic enzyme that suppresses the expression of many genes. Researchers have previously found that levels of PRDM2 are lower in alcohol dependence, and lead to exaggerated stress responses. In people, it is very common for alcohol dependence and anxiety-related conditions to be present at the same time, and the researchers suspect that this is caused by common mechanisms behind these conditions.
In order for new memories to last, they must be stabilised and preserved as long-term memories. This process is known as “consolidation.” The researchers in the current study have investigated the effects of reduced levels of PRDM2 on the way fear memories are processed.
“We have identified a mechanism in which increased activity in the network between the frontal lobes and the amygdala increases learned fear reactions. We show that down-regulation of PRDM2 increases the consolidation of fear-related memories,” says Estelle Barbier.
The researchers have also identified genes that are affected when the level of PRDM2 is reduced. It became clear that this resulted in an increase in the activity of nerve cells that connect the frontal lobes and the amygdala.
“Patients with anxiety disorders may benefit from treatments that weaken or erase fear memories. The biological mechanism that we have identified involves down-regulation of PRDM2, and we currently do not have any way of increasing it. But the mechanism may be part of the explanation of why some individuals have a greater vulnerability to developing anxiety-related conditions. It may also explain why these conditions and alcohol dependence so often are present together,” says Estelle Barbier.
Retia mirabilia: Protecting the cetacean brain from locomotion-generated blood pressure pulses
by M. A. Lillie, A. W. Vogl, S. G. Gerard, S. Raverty, R. E. Shadwick in Science
Special blood vessels in whale brains may protect them from pulses, caused by swimming, in their blood that would damage the brain, new UBC research has suggested.
There are many theories as to the exact use of these networks of blood vessels cradling a whale’s brain and spine, known as ‘retia mirabilia’, or ‘wonderful net’, but now UBC zoologists believe they’ve solved the mystery, with computer modeling backing their predictions.
Land mammals such as horses experience ‘pulses’ in their blood when galloping, where blood pressures inside the body go up and down on every stride. In a new study, lead author Dr. Margo Lillie and her team have suggested for the first time that the same phenomenon occurs in marine mammals that swim with dorso-ventral movements; in other words, whales. And, they may have found out just why whales avoid long-term damage to the brain for this.
In all mammals, average blood pressure is higher in arteries, or the blood exiting the heart, than in veins. This difference in pressure drives the blood flow in the body, including through the brain, says Dr. Lillie, a research associate emerita in the UBC department of zoology. However, locomotion can forcefully move blood, causing spikes in pressure, or ‘pulses’ to the brain. The difference in pressure between the blood entering and exiting the brain for these pulses can cause damage.
Long-term damage of this kind can lead to dementia in human beings, says Dr. Lillie. But while horses deal with the pulses by breathing in and out, whales hold their breath when diving and swimming.
“So if cetaceans can’t use their respiratory system to moderate pressure pulses, they must have found another way to deal with the problem,” says Dr. Lillie.
Dr. Lillie and colleagues theorized that the retia use a ‘pulse-transfer’ mechanism to ensure there is no difference in blood pressure in the cetacean’s brain during movement, on top of the average difference. Essentially, rather than dampening the pulses that occur in the blood, the retia transfer the pulse in the arterial blood entering the brain to the venous blood exiting, keeping the same ‘amplitude’ or strength of pulse, and so, avoiding any difference in pressure in the brain itself.
The researchers collected biomechanic parameters from 11 cetacean species, including, fluking frequency, and input these data into a computer model.
“Our hypothesis that swimming generates internal pressure pulses is new, and our model supports our prediction that locomotion-generated pressure pulses can be synchronized by a pulse transfer mechanism that reduces the pulsatility of resulting flow by up to 97 per cent,”says senior author Dr. Robert Shadwick, professor emeritus in the UBC department of zoology.
The model could potentially be used to ask questions about other animals and what’s happening with their blood pressure pulses when they move, including humans, says Dr. Shadwick. And while the researchers say the hypothesis still needs to be tested directly by measuring blood pressures and flow in the brain of swimming cetaceans, this is currently not ethically and technically possible, as it would involve putting a probe in a live whale.
“As interesting as they are, they’re essentially inaccessible,” he says. “They are the biggest animals on the planet, possibly ever, and understanding how they manage to survive and live and do what they do is a fascinating piece of basic biology.”
“Understanding how the thorax responds to water pressures at depth and how lungs influence vascular pressures would be an important next step,” says co-author Dr. Wayne Vogl, professor in the UBC department of cellular and physiological sciences. “Of course, direct measurements of blood pressure and flow in the brain would be invaluable, but not technically possible at this time.”
Disruption in structural–functional network repertoire and time-resolved subcortical fronto-temporoparietal connectivity in disorders of consciousness
by Rajanikant Panda, Aurore Thibaut, Ane Lopez-Gonzalez, Anira Escrichs, Mohamed Ali Bahri, Arjan Hillebrand, Gustavo Deco, Steven Laureys, Olivia Gosseries, Jitka Annen, Prejaas Tewarie in eLife
A study by the Human Brain Project (HBP), led by scientists from the University of Liège (Belgium), has explored new techniques that may help distinguish between two different neurological conditions in patients with severe brain damage and or in a coma. The results of this study have just been published in open access in the journal eLife.
One of the greatest challenges in the field of neurology and critical care medicine is to correctly diagnose the level of consciousness of a patient in a coma due to a severe brain injury. Scientists at the Human Brain Project (HBP) — an international project involving more than 500 researchers that aims to gain a deeper understanding of the complex structure and function of the human brain through a unique interdisciplinary approach at the interface of neuroscience and technology — have been exploring new techniques that could help distinguish between two different neurological conditions.
The results of this new study, just published in the journal eLife, reveal important information about the mechanisms of consciousness disorders. The team of researchers from the University of Liège (GIGA Consciousness Research Unit, Coma Science Group, Faculty of Medicine) and the University Hospital of Liège (Belgium), the Universitat Pompeu Fabra (Spain), the Vrije Universiteit Amsterdam (Netherlands), among others, assessed the states of functional brain networks as a marker of consciousness in order to potentially distinguish between patients in unresponsive wakefulness syndromes (UWS) and the state of minimal consciousness (MCS).
“Previously known as the ‘vegetative state’, unresponsive arousal syndrome is the state of a patient who wakes up from coma, i.e. opens his or her eyes, but does not respond to the environment and verbal commands, showing only reflex movements,” explains Rajanikant Panda, first author of the paper and researcher at the GIGA Consciousness and Coma Science Group at ULiège. “In contrast, patients in a minimally conscious state show minimal signs of awareness such as following movements with their eyes or moving a finger when asked.” The differentiation of these states is essential for proper diagnosis, prognosis and rehabilitation treatment and is linked to important quality of life and even end-of-life decisions.
The study included 34 healthy controls, 30 minimally conscious patients and 14 unresponsive awake patients. These patients were sent from all over Europe to the Coma Science Group — led by neurologist Steven Laureys — and the University Hospital of Liege for a second opinion. Data sharing and analysis benefited from the EBRAINS infrastructure of the HBP and the collaboration of the study teams led by Jitka Annen (Coma Science Group/ ULiège Faculty of Medicine) and Prejaas Tewarie (Vrije Universiteit Amsterdam).
We used state-of-the-art techniques to assess different aspects of brain structure and its relationship to network dynamics,” says Jitka Annen, “and demonstrated that these techniques were sensitive in detecting clinically relevant differences in the diagnosis of patients with the minimally conscious state and unresponsive wakefulness syndrome.”
Specifically, the researchers used functional magnetic resonance imaging (fMRI) data to analyse dynamic functional connectivity, or how brain regions interact with each other, between neuronal populations and its association with structural white matter connections.
We observed that, compared to the minimally conscious state, patients with unresponsive wakefulness syndrome showed less activity in functional networks, reduced metastability (a state of stable functional connectivity different from the natural steady state) and increased coupling of functional connectivity to the structural framework,” explains Aurore Thibaut, FNRS researcher at GIGA Consciousness and Coma Science Group.
“This new approach also revealed a brain network that most differentiates between unconscious and conscious states — a network encompassing subcortical regions and frontotemporoparietal cortical areas.”
These findings support previous ideas about the mechanisms underlying the loss and recovery of consciousness, such as the global neural workspace theory and the mesocircuit hypothesis, which suggest that the failure to recover consciousness is related to a loss of connectivity between subcortical and frontoparietal brain areas, as well as a loss of the range of functional network states.
Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children
by Jose M. Restrepo-Lozano, Irina Pokhvisneva, Zihan Wang, Sachin Patel, Michael J. Meaney, Patricia P. Silveira, Cecilia Flores in Molecular Psychiatry
While not all impulsive behaviour speaks of mental illness, a wide range of mental health disorders that often emerge in adolescence, including depression and substance abuse, have been linked to impulsivity. So, finding a way to identify and treat those who may be particularly vulnerable to impulsivity early in life is especially important.
A group of researchers, led by scholars at McGill University, have developed a genetically based score that could help identify, with a high degree of accuracy (greater than that of any impulsivity scores currently in use), the young children who are most at risk of impulsive behaviour.
Their findings are especially compelling because the score they have developed was able to detect those at a higher risk of impulsivity within three ethnically diverse community samples of children, from a cohort of close to 6,000 children.
This discovery of a novel score for impulsivity in early life can inform prevention strategies and programs for children and adolescents who are at risk for psychiatric disorders. In addition, by describing the function of the gene networks comprising the score, the study can stimulate the development of new therapies in the future.
The impulsivity risk score was developed by looking at the co-expression of a number of genes in the prefrontal cortex and the striatum, areas of the brain that play a role in decision-making and emotional regulation, among other things.
“Typically, genetic approaches to identifying the neurobiological signature for impulsivity (or any other condition or disease) tend to focus on identifying the variation in a few genetic markers that might be responsible for the problem,” said Patricia Pelufo Silveira, an Associate Professor in the Department of Psychiatry and Researcher at the Douglas Research Centre and one of the two senior authors on the recent paper in Molecular Psychiatry. “We came at the problem from the opposite direction, by focusing on a gene known to be associated with the maturation of the brain in these two key areas and then looking for a network of other genes that were most closely associated with it.”
This approach was based on earlier work in mice models, led by Cecilia Flores, a co-senior author on the paper and a Full Professor, in the Department of Psychiatry which had identified the importance of a specific gene (known as DCC), which acts as a “guidance cue” that determines when and precisely where brain dopamine cells form connections in the prefrontal cortex and striatum. This coordinated development is essential for the maturation of impulse control.
But to create the new impulsivity score, it took a lot of hunting to narrow down the genes most closely associated with DCC.
“Our approach exploits the fact that genes operate within complex networks that, ultimately, perform very precise biological functions. These so-called gene networks have the property of being highly tissue-specific, so we began with an unbiased look at groups of genes that are co-expressed with DCC in brain regions known to play an important role supporting inhibitory control,” says co-author Jose Maria Restrepo, a PhD student in the Integrated Program in Neuroscience at McGill University.
“The results underline the importance of data sharing and open science,” adds Flores. “Imagine if we had had to collect this information in all these countries over all these years. Our discovery was only possible because we had access to all these data.”
Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models
by Ying Xue Xie, Nima N. Naseri, Jasmine Fels, Parinati Kharel, Yoonmi Na, Diane Lane, Jacqueline Burré, Manu Sharma in Nature Communications
Aggregates of the protein alpha-synuclein spread in the brains of people with Parkinson’s disease through a cellular waste-ejection process, suggests a new study led by Weill Cornell Medicine researchers.
During the process, called lysosomal exocytosis, neurons eject protein waste they cannot break down and recycle. The discovery could resolve one of the mysteries of Parkinson’s disease and lead to new strategies for treating or preventing neurological disorder.
“Our results also suggest that lysosomal exocytosis could be a general mechanism for the disposal of aggregated and degradation-resistant proteins from neurons — in normal, healthy circumstances and in neurodegenerative diseases,” said study senior author Dr. Manu Sharma, an assistant professor of neuroscience in the Feil Family Brain and Mind Research Institute and Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine.
Parkinson’s is a disorder that features the deaths of neurons in a characteristic pattern of spread through the brain, normally unfolding over decades. The disease is best known for causing hand tremors, muscle rigidity, slowed gait and other impairments of normal movement. But it affects a broad set of brain regions, resulting in many different symptoms, including dementia in late stages. Approximately 1 million people in the United States have Parkinson’s. Available treatments can alleviate some movement abnormalities but do not stop disease progression — essentially because researchers don’t yet have a full understanding of that process.
One important finding that has emerged from the past few decades of Parkinson’s research is that the deaths of neurons in the disease follow the spread, within the brain, of abnormal aggregates of alpha synuclein, a neuronal protein. This spread is an infection-like, chain-reaction process in which aggregates induce normal alpha synuclein to join them, and — as they grow larger — break into smaller aggregates that continue to propagate. Experiments in mice and non-human primates have shown that injecting these aggregates into the brain can initiate this spread as well as some Parkinson’s-like neurodegeneration. But the details of how neurons transmit them to other neurons, have never been well understood.
In the study, Dr. Sharma and his team, including co-first author Ying Xue Xie, a doctoral candidate in the Weill Cornell Graduate School of Medical Sciences, showed with detailed studies of Parkinson’s mouse models that alpha synuclein aggregates — capable of spreading and causing neurodegeneration — originated within neurons. These aggregates, they found, then accumulate within capsule-like waste bins in cells called lysosomes.
Lysosomes contain enzymes that can break down, or “lyse,” proteins and other molecular waste into their building blocks, essentially digesting and recycling them. But the researchers found evidence that alpha synuclein aggregates, which are knit together with tight bonds in a close-fitting/snugly layered structure called “amyloid,” are not broken down well within lysosomes; instead, they were often found to be simply dumped from their originating neurons. In this process, called exocytosis, the lysosome moves to the cell membrane and merges with it, so that the lysosome contents are discharged — as-is, without any encapsulation — into the fluid surrounding the cell. The finding helps resolve a hotly debated question in the field.
The researchers also showed in further experiments that by reducing the rate of lysosomal exocytosis, they could reduce the apparent concentration of spread-capable aggregates. That, Dr. Sharma said, suggests a future approach to treating Parkinson’s.
“We don’t know yet, but neurons might be better off, even in the long term, if they keep these aggregates inside their lysosomes,” he said. “We see a similar impairment of lysosomal function in some genetic disorders, but these don’t necessarily lead to a Parkinson’s level of disease.”
Cell-type-specific integration of feedforward and feedback synaptic inputs in the posterior parietal cortex
by Daniel J. Rindner, Archana Proddutur, Gyorgy Lur in Neuron
Our ability to think, decide, remember recent events and more, comes from our brain’s neocortex. Now University of California, Irvine neuroscientists have discovered key aspects of the mechanisms behind these functions. Their findings could ultimately help improve treatments for certain neuropsychiatric disorders and brain injuries. Their study appears in Neuron.
Scientists have long known that the neocortex integrates what is called feedforward and feedback information streams. Feedforward data is relayed by the brain’s sensory systems from the periphery (our senses) to the neocortex’s higher order areas. These high-level brain regions then send feedback information to refine and adjust sensory processing. This back-and-forth communication allows the brain to pay attention, retain short-term memories, and make decisions.
“A simple example is when you want to cross a busy road,” said corresponding author Gyorgy Lur, Ph.D., an assistant professor of neurobiology & behavior in the School of Biological Sciences. “There are trees, people, moving vehicles, traffic signals, signs and more. Your higher-level neocortex tells your sensory system which merit attention for deciding when to go across.”
The interaction between higher- and lower-level systems also allows us to remember what we saw when we glanced both ways to gather the information.
“If you didn’t have that short-term memory, you would just keep looking back and forth and never move,” he said. “In fact, if our feedforward and feedback streams weren’t constantly working together, we would do very little except respond by reflexes.”
Until now, scientists have not been sure how neurons in the brain participate in these complex processes. Lur and his colleagues discovered that feedforward and feedback signals converge onto single neurons in the parietal regions of the neocortex. The researchers also found that distinct types of cortical neurons merge the two information streams on markedly different time scales and identified the cellular and circuit architecture underpinning these differences.
“Scientists already knew that integrating multiple senses enhances neuronal responses,” Lur said. “If you only see something or just hear it, your reaction time is slower than when experiencing them with both senses simultaneously. We’ve identified the underlying mechanisms making this possible.”
He noted that the study data suggests the same principles apply if one information stream is sensory and the other is cognitive.
Understanding these processes is critical for developing future treatments for neuropsychiatric ailments like sensory-processing disorders, schizophrenia and ADHD, as well as for strokes and other injuries to the neocortex.
Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice
by Christopher M. Davenport, Brett J.W. Teubner, Seung Baek Han, Mary H. Patton, Tae-Yeon Eom, Dusan Garic, Benjamin J. Lansdell, Abbas Shirinifard, Ti-Cheng Chang, Jonathon Klein, Shondra M. Pruett-Miller, Jay A. Blundon, Stanislav S. Zakharenko in Cell
Williams-Beuren syndrome (WBS) is a rare disorder that causes neurocognitive and developmental deficits. However, musical and auditory abilities are preserved or even enhanced in WBS patients. Scientists at St. Jude Children’s Research Hospital have identified the mechanism responsible for this ability in models of the disease. The findings were published in Cell.
Understanding what causes the superior auditory ability in WBS patients may provide a target for treating the disease in addition to helping advance research on the ability to discriminate between sounds. WBS offers insight into the mechanisms that underlie enhanced auditory abilities. For instance, some people with WBS have perfect pitch, which is the ability to differentiate between notes or frequencies without a reference guide.
“WBS stands out among neurodevelopmental disorders because children with the disorder, despite profound learning disabilities, can have a higher prevalence of superior musical and linguistic abilities than children in the general population,” said corresponding author Stanislav Zakharenko, M.D., Ph.D., St. Jude Department of Developmental Neurobiology. “We were fascinated by that and wanted to know more about how a disorder that is caused by a loss of 27 genes could help individuals gain a better than normal ability for auditory processing.”
Mouse models of WBS have an enhanced ability to discriminate between sound frequencies. These mice also have improved frequency coding in the auditory cortex, the part of the brain that processes sound. The researchers showed that the enhanced ability to discriminate between frequencies is caused by hyperexcitable interneurons in the auditory cortex.
To understand the cellular biology that underlies enhanced auditory abilities in WBS patients, the researchers conducted an RNAseq experiment. The data led the researchers to a neuropeptide receptor called VIPR1, which is reduced in the auditory cortex of individuals with WBS. The reduction in VIPR1 was also found in cerebral organoids, advanced models made in the laboratory using human-induced pluripotent stem cells.
The scientists found that the transcription factor Gtf2ird1, encoded by one of the 27 genes lost in those with WBS, regulates VIPR1. Deleting or overexpressing VIPR1 in the auditory cortex can mimic or reverse the auditory effects seen in WBS. Thus, it is Gtf2ird1 downregulating VIPR1 that is responsible for the impact of WBS on auditory ability.
“I didn’t know a lot about VIPR1 before it popped up in our data because the role of this family of receptors in the brain is under-appreciated compared to other neuromodulator or neurotransmitter receptors,” said first-author Christopher Davenport, St. Jude Department of Developmental Neurobiology. “Our findings show that they can strongly impact information processing and behavior and are likely relevant for other behaviors and diseases as well.”
“This work suggests that reducing neuronal hyperexcitability might be a general mechanism for treating WBS through targeting VIPR1,” Zakharenko said. “It also opens up new directions to learn about musicality and how our brain differentiates sounds based on these findings in models of WBS.”
Air pollution, white matter microstructure, and brain volumes: Periods of susceptibility from pregnancy to preadolescence
by Anne-Claire Binter, Michelle S.W. Kusters, Michiel A. van den Dries, Lucia Alonso, Małgorzata J. Lubczyńska, Gerard Hoek, Tonya White, Carmen Iñiguez, Henning Tiemeier, Mònica Guxens in Environmental Pollution
A study published in the journal Environmental Pollution has found an association, in children aged 9–12, between exposure to air pollutants in the womb and during the first 8.5 years of life and alterations in white matter structural connectivity in the brain. The greater the child’s exposure before age 5, the greater the brain structure alteration observed in preadolescence. The study was led by the Barcelona Institute for Global Health (ISGlobal), a research centre supported by the “la Caixa” Foundation.
Tracts or bundles of cerebral white matter ensure structural connectivity by interconnecting the different areas of the brain. Connectivity can be measured by studying the microstructure of this white matter, a marker of typical brain development. Abnormal white matter microstructure has been associated with psychiatric disorders (e.g., depressive symptoms, anxiety and autism spectrum disorders).
In addition to the association between air pollution and white matter microstructure, the study also found a link between specific exposure to fine particulate matter (PM2.5) and the volume of the putamen, a brain structure involved in motor function, learning processes and many other functions. As the putamen is a subcortical structure, it has broader and less specialised functions than cortical structures. The study found that the greater the exposure to PM2.5, especially during the first 2 years of life, the greater the volume of the putamen in preadolescence.
“A larger putamen has been associated with certain psychiatric disorders (schizophrenia, autism spectrum disorders, and obsessive-compulsive spectrum disorders),” says Anne-Claire Binter, ISGlobal researcher and first author of the study.
“The novel aspect of the present study is that it identified periods of susceptibility to air pollution” Binter goes on to explain. “We measured exposure using a finer time scale by analysing the data on a month-by-month basis, unlike previous studies in which data was analysed for trimesters of pregnancy or childhood years. In this study, we analysed the children’s exposure to air pollution from conception to 8.5 years of age on a monthly basis.
Another strong point of this study is that the data analysed came from a large cohort of 3,515 children enrolled in the Generation R Study in Rotterdam (Netherlands).
To determine each participant’s exposure to air pollution during the study period, the researchers estimated the daily levels of nitrogen dioxide (NO2) and particulate matter (PM2.5 and PM2.5 absorbance) at their homes during the mother’s pregnancy and until they reached 8.5 years of age. When participants were between 9 and 12 years analysed of age they underwent brain magnetic resonance imaging to examine the structural connectivity and the volumes of various brain structures at that time.
The levels of NO2 and PM2.5 recorded in the present study exceeded the annual thresholds limits specified in the current World Health Organization guidelines (10 µg/m3 and 5 µg/m3, respectively) but met European Union (EU) standards, an indication that brain development can be affected by exposure to air pollution at levels lower than the current EU air quality limit values.
“One of the important conclusions of this study” explains Binter “is that the infant’s brain is particularly susceptible to the effects of air pollution not only during pregnancy, as has been shown in earlier studies, but also during childhood.”
“We should follow up and continue to measure the same parameters in this cohort to investigate the possible long-term effects on the brain of exposure to air pollution” concludes Mònica Guxens, ISGlobal researcher and last author of the study.
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