Diversity of neurons affects memory

Neurons in a key area of the brain have different functions based on their exact genetic identity, and understanding this diversity could lead to better understanding of the brain’s computational flexibility and memory capacity, potentially informing disease treatment options, Cornell researchers report in a new study.

Pyramidal cells in the CA1 region of the hippocampus, once thought to be a uniform collection of neurons, have recently been found to be highly diverse. But the role of this diversity in cognitive functions had not been closely examined until now.

“Most memory studies assume the hippocampus and the cortex are like black boxes – monolithic structures, homogeneous sets of neurons,” said co-senior author Antonio Fernandez-Ruiz, assistant professor of neurobiology and behavior, and Nancy and Peter Meinig Family Investigator in the Life Sciences, in the College of Arts and Sciences (A&S). “So basically, you have two black boxes that talk to each other, but you don’t know exactly the components of these two boxes.”

“Hippocampo-Cortical Circuits for Selective Memory Encoding, Routing, and Replay” published in the journal Neuron. Co-senior author is Azahara Oliva, assistant professor of neurobiology and behavior (A&S).

What Fernandez-Ruiz and his team found, in testing on rats, was that CA1 neurons encode task-related information simultaneously, but then send impulses to different targets depending on whether the neurons are deep in the hippocampus or on the surface.

“We discovered that there are at least two different ways in which these structures talk to each other,” he said. “And there are specialized circuits integrated by different cell types that are coding different types of information, and sending them to different parts of the brain.”

For their study, using rats engaged in both memory tasks and sleep, the lab examined a large number of simultaneously recorded neurons, using high-density silicon probes. The probes detect the encoding activity of cells, coordinated by synchronous oscillations known as sharp-wave ripples.

As they found in previous studies, CA1 pyramidal cells (named for their shape) differed in some of their physiological properties depending on where they were located in the hippocampus (deep, middle or superficial). This diversity is key in memory development, Fernandez-Ruiz said.

A key discovery in this work: While deep CA1 pyramidal cells were the major contributors to sequence and assembly dynamics, superficial cells were specifically recruited during the replay of novel experiences, and drove memory formation.

“When you learn something new,” he said, “these aspects of experience can be segregated and encoded by specialized populations of neurons, then transmitted to different areas, which are specialized in processing different types of information. We believe this is important because this provides a system with more flexibility.”

The researchers also characterized a previously unknown circuit involving the hippocampus and cortex, which plays a role in memory consolidation. This increased understanding of the hippocampus’s neuronal diversity could help target areas affected by dementia, Oliva said.

“A disease like Alzheimer’s is characterized by impairments of this communication between the hippocampus and the cortex,” she said, “but we don’t know whether the whole structures are disrupted or, more likely, some specific neuron types in these structures are the more affected.

“If you could determine which aspect of memory is disrupted,” she said, “then maybe you could trace that back to the specialization of different cell types, and perhaps employ new, more targeted therapies.”

New insights into the complex neurochemistry of ants

Ants’ brains are amazingly sophisticated organs that enable them to coordinate complex behaviour patterns such as the organisation of colonies. Now, a group of researchers led by Christian Gruber of MedUni Vienna's Institute of Pharmacology have developed a method that allows them to study ants’ brain chemistry and gain insights into the insects’ neurobiological processes. The findings could help to explain the evolution of social behaviour in the animal kingdom, and shed light on the biochemistry of certain hormone systems that have developed similarly in both ants and humans. For the study, the researchers used a combination of high-resolution mass spectrometry imaging (MSI) and micro-computed tomography (µCT) to map the three-dimensional distribution of neuropeptides in the brains of two ant species: the leafcutter ant (Atta sexdens) and the black garden ant (Lasius niger).

Researchers from MedUni Vienna, the Max Planck Institute for Marine Microbiology in Bremen and the University of Bremen have developed a new method for studying social insects’ brains, which measure only a few millimetres in size. In future, their approach could play a decisive role in research into fundamental neurobiological processes. The method integrates three-dimensional chemical data into a high-definition anatomical model, allowing for unbiased visualisation of 3D neurochemistry in its particular anatomical environment. Published in the journal PNAS Nexus, the study showed that some ant peptides, such as the tachykinin-related peptides TK1 and TK4, are widely distributed in many areas of both species’ brains, while other peptides, including myosuppressin, are only found in particular regions. The researchers also noticed differences between the two species – a large number of peptides were found in the optic lobe of L. niger, but only one (an ITG-like peptide) was identified in the same region in A. sexdens.

The key feature of the new method is that a correlative approach is used to analyse data. This means that 3D maps of the distribution of neuropeptides and 3D anatomical models are precisely collated, generating two maps that help to navigate the ants’ brains. Each map contains different information, which is critical for studying organs with high plasticity, such as the brains of social insects, which are particularly hard to analyse due to the complex division of labour and caste system in ant colonies. Building on previous studies of MS imaging of neuropeptides in invertebrate model systems, this approach represents a promising method for studying fundamental neurobiological processes by visualising distortion-free 3D neurochemistry in its own complex anatomical environment. “These findings have the potential to fundamentally alter the way we study complex neurobiological processes. Our method opens up new perspectives when it comes to observing the brains of social insects more closely and better understanding the functioning of nervous systems where chemistry and anatomy are fully attuned,” commented lead author Benedikt Geier, who worked alongside co-lead author Esther Gil Mansilla. “In terms of neurobiology, ants are a model species. Due to the extremely complex structures in ant colonies, this method could be applied in future to gain an understanding of various factors, including the evolution of social behaviour in the animal kingdom, or the biochemistry of certain hormone systems that have developed in a similar fashion in both ants and humans,” reported Christian Gruber.

Brain signatures for chronic pain identified in a small group of individuals

For the first time, researchers have recorded pain-related data from inside the brain of individuals with chronic pain disorders caused by stroke or amputation (phantom limb pain). A long sought-after goal has been to understand how pain is represented by brain activity and how to modulate that activity to relieve suffering from chronic pain. Data were collected over months while patients were at home, and they were analyzed using machine learning tools. Doing so, the researchers identified an area of the brain associated with chronic pain and objective biomarkers of chronic pain in individual patients. These findings, published in Nature Neuroscience, were funded by both the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative and the Helping to End Addiction Long-term Initiative, or NIH HEAL Initiative, represent a first step towards developing novel methods for tracking and treating chronic pain.

“This is a great example of how tools for measuring brain activity originating from the BRAIN Initiative have been applied to the significant public health problem of relieving persistent, severe chronic pain,” said Walter Koroshetz, M.D., director of the National Institute of Neurological Disorders and Stroke. “We are hopeful that building from these preliminary findings could lead to effective, non-addictive pain treatments.”

Chronic pain is one of the largest contributors to disability worldwide. Neuropathic pain is caused by damage to the nervous system itself. It most commonly occurs due to injury to the nerves in our bodies, but for the individuals in this study, their pain is thought to originate from the brain itself. This kind of pain does not respond well to current treatments and can be debilitating for people living with it.

“When you think about it, pain is one of the most fundamental experiences an organism can have,” said Prasad Shirvalkar, M.D., Ph.D., associate professor of anesthesia and neurological surgery at the University of California, San Francisco, and lead author of this study. “Despite this, there is still so much we don’t understand about how pain works. By developing better tools to study and potentially affect pain responses in the brain, we hope to provide options to people living with chronic pain conditions.”

Traditionally, researchers gather data about chronic pain through self-reports from those living with the condition. Examples of this type of data include questionnaires about pain intensity and emotional impact of pain. This study however, also looked directly at changes in brain activity in two regions where pain responses are thought to occur—the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC)—as participants reported their current levels of chronic pain.

“Functional MRI studies show that the ACC and OFC regions of the brain light up during acute pain experiments. We were interested to see whether these regions also played a role in how the brain processes chronic pain,” said Dr. Shirvalkar. “We were most interested in questions like how pain changes over time, and what brain signals might correspond to or predict high levels of chronic pain?” 

Four participants, three with post-stroke pain and one with phantom limb pain, were surgically implanted with electrodes targeting their ACC and OFC. Several times a day, each participant was asked to answer questions related to how they would rate the pain they were experiencing, including strength, type of pain, and how their level of pain was making them feel emotionally. They would then initiate a brain recording by clicking a remote-control device, which provided a snapshot of the activity in the ACC and OFC at that exact moment. Using machine learning analyses, the research team was able to use activity in the OFC to predict the participants’ chronic pain state. 

In a separate study, the researchers looked at how the ACC and OFC responded to acute pain, which was caused by applying heat to areas of the participants’ bodies. In two of the four patients, brain activity could again predict pain responses, but in this case the ACC appeared to be the region most involved. This suggests that the brain processes acute vs. chronic pain differently, though more studies are needed given that data from only two participants were used in this comparison.

This study represents an initial step towards uncovering the patterns of brain activity that underly our perception of pain. Identifying such a pain signature will enable the development of new therapies that can alter brain activity to relieve suffering due to chronic pain. The most immediate benefit may be in informing ongoing studies in HEAL and BRAIN to employ deep brain stimulation (DBS) to treat chronic pain. Ongoing and future work involving more participants will be key in determining whether different pain conditions share the OFC activity seen in these patients or how the signatures differ among persons with different pain conditions. 

More modern approaches to DBS that fine-tune the stimulation based on activity biomarkers from the brain have been used to successfully treat some brain disorders including Parkinson’s disease and major depressive disorder, but those successes have required well-established brain biomarkers. For conditions such as chronic pain, the identification of biomarkers is in the early stages.

Effective and non-addictive treatments for chronic pain conditions is a main goal of NIH HEAL Initiative efforts to find scientific solutions to stem the opioid public health crisis. The findings are a key step to identifying pain-specific biomarkers toward personalizing pain management for individuals, leading to the development of new technologies and advances to better understand brain circuit, a major component of the NIH BRAIN Initiative.

From molecular to whole-brain scale in a simple animal, study reveals serotonin’s effects

Because serotonin is one of the primary chemicals the brain uses to influence mood and behavior, it is also the most common target of psychiatric drugs. To improve those drugs and to invent better ones, scientists need to know much more about how the molecule affects brain cells and circuits both in health and amid disease. In a new study, researchers at The Picower Institute for Learning and Memory at MIT working in a simple animal model present a comprehensive accounting of how serotonin affects behavior from the scale of individual molecules all the way to the animal’s whole brain.

“There have been major challenges in rationally developing psychiatric drugs that target the serotonergic system,” said Steve Flavell, associate professor in The Picower Institute and MIT’s Department of Brain and Cognitive Sciences, and senior author of the study in Cell. “The system is wildly complex. There are many different types of serotonergic neurons with widespread projections throughout the brain and serotonin acts through many different receptors, which are often activated in concert to change the way that neural circuits work.”

These same complexities that scientists face in people are all afoot in the nematode worm C. elegans, but to a more manageably limited degree. C. elegans has only 302 neurons (rather than billions) and only six serotonin receptors (rather than the 14 found in people). Moreover, all C. elegans neurons and their connections have been mapped out and its cells are accessible for genetic manipulation. Finally, Flavell’s team has developed imaging technologies that enable them to track and map neural activity across the worm’s brain simultaneously. For all these reasons, the lab was able to produce a novel study revealing how the far-reaching molecular activity of serotonin changes brain-wide activity and behavior.

“These results provide a global view of how serotonin acts on a diverse set of receptors distributed across a connectome to modulate brain-wide activity and behavior,” the research team wrote in Cell.

The study’s co-lead authors are Picower Institute postdoc Ugur Dag, MIT Brain and Cognitive Sciences graduate student Di Kang, and former research technician Ijeoma Nwabudike, who is now a MD-PhD student at Yale.

Slowing for savoring

Flavell showed in Cell in 2013 that C. elegans uses serotonin to slow down when it reaches a patch of food and traced its source to a neuron called NSM. In the new study, the team used their many new capabilities developed since then at MIT to examine serotonin’s effects comprehensively.

First, they focused on identifying the functional roles of the worm’s six serotonin receptors. To do that they created 64 different mutant strains covering the different combinations of knocking out the various receptors. For instance, one strain would have just one receptor knocked out while another strain would have all but that one missing and another would be missing three. In each of these worms the team stimulated serotonin release from the NSM neuron to prompt slowing behaviors. Analysis of all the resulting data revealed at least two key findings: One was that three receptors primarily drove the slowing behavior. The second was that the other three receptors “interacted” with the receptors that drive slowing and modulated how they function. These complex interactions between serotonin receptors in the control of behavior is likely to be directly relevant to psychiatric drugs that target these receptors, Flavell said.

The researchers also gained other important insights into serotonin’s actions. One was that different receptors respond to different patterns of serotonin release in live animals. For example, the SER-4 receptor only responded to sudden increases in serotonin release by the NSM neuron. But, the MOD-1 receptor responded to continuous “tonic” changes in serotonin release by NSM. This suggests that different serotonin receptors are engaged at different times in the live animal.

Brain-wide mapping

Having teased out the roles of the serotonin receptors in the control of C. elegans behavior, the research team then used their imaging technologies to see how serotonin’s effects worked at a circuit level. For instance, they fluorescently tagged each receptor gene in each neuron across the brain so that they could see all the specific cells that expressed each receptor, providing a brain-wide map of where the serotonin receptors are located in C. elegans. About half of the worm’s neurons express serotonin receptors with some neurons expressing as many as five different types.

(Image caption: A wiring diagram of the C. elegans worm shows neurons and muscle cells (dots) that express receptors for serotonin. Each color denotes a specific receptor. Some neurons express more than one. The diagram appears as a figure in the research paper. Credit: Di Kang).

Finally, the team used their ability to track all neuron activity (based on their calcium fluctuations) and all behaviors to watch how the serotonergic neuron NSM affected other cells’ activity as worms freely explored their surroundings. About half of the neurons across the worm’s brain changed activity when serotonin was released. Since they knew which exact neurons they were recording from, the research team asked whether knowing which serotonin receptors each cell expressed could predict how they responded to serotonin. Indeed, knowing which receptors were expressed in each neuron and its input neurons gave strong predictive power of how each neuron was impacted by serotonin.

“We performed brain-wide calcium imaging in freely-moving animals with knowledge of cellular identity during serotonin release, providing, for the first time, a view of how serotonin release is associated with changes in activity across the defined cell types of an animal’s brain,” the researchers concluded.

All these findings shed light on the kinds of complexities and opportunities facing drug developers, Flavell noted. The study’s findings show how the effects of targeting one serotonin receptor could depend on how other receptors or the cell types that express them are functioning. In particular, the study highlights how the serotonin receptors act in concert to change the activity states of neural circuits.

Brain-Belly Connection: Gut Health May Influence Likelihood of Developing Alzheimer’s

Could changing your diet play a role in slowing or even preventing the development of dementia? We’re one step closer to finding out, thanks to a new UNLV study that bolsters the long-suspected link between gut health and Alzheimer’s disease.

The analysis — led by a team of researchers with the Nevada Institute of Personalized Medicine (NIPM) at UNLV and published this spring in the Nature journal Scientific Reports — examined data from dozens of past studies into the belly-brain connection. The results? There’s a strong link between particular kinds of gut bacteria and Alzheimer’s disease.

Between 500 and 1,000 species of bacteria exist in the human gut at any one time, and the amount and diversity of these microorganisms can be influenced by genetics and diet.

The UNLV team’s analysis found a significant correlation between 10 specific types of gut bacteria and the likelihood of developing Alzheimer’s disease. Six categories of bacteria — Adlercreutzia, Eubacterium nodatum group, Eisenbergiella, Eubacterium fissicatena group, Gordonibacter, and Prevotella9 — were identified as protective, and four types of bacteria — Collinsella, Bacteroides, Lachnospira, and Veillonella — were identified as a risk factor for Alzheimer’s disease.

Certain bacteria in humans’ guts can secrete acids and toxins that thin and seep through the intestinal lining, interact with the APOE (a gene identified as a major risk factor for Alzheimer’s disease), and trigger a neuroinflammatory response — affecting brain health and numerous immune functions, and potentially promoting development of the neurodegenerative disorder.   

Researchers said their novel discovery of the distinct bacterial groups associated with Alzheimer’s disease provides new insights into the relationship between gut microbiota and the world’s most common form of dementia. The findings also advance scientists’ understanding of how an imbalance of that bacteria may play a role in the disorder’s development. 

“Most of the microorganisms in our intestines are considered good bacteria that promote health, but an imbalance of those bacteria can be toxic to a person’s immune system and linked to various diseases, such as depression, heart disease, cancer, and Alzheimer’s disease,” said UNLV research professor Jingchun Chen. “The take-home message here is that your genes not only determine whether you have a risk for a disease, but they can also influence the abundance of bacteria in your gut.” 

While their analysis established overarching categories of bacteria typically associated with Alzheimer’s disease, the UNLV team said further research is needed to drill down into the specific bacterial species that influence risk or protection. 

The hope is to one day develop treatments that are customized for an individual patient and their genetic makeup, such as medications or lifestyle change. Studies have shown that changes in gut microbiome through probiotic use and dietary adjustments can positively impact the immune system, inflammation, and even brain function. 

“With more research it would be possible to identify a genetic trajectory that could point to a gut microbiome that would be more or less prone to developing diseases such as Alzheimer’s,” said study lead author and UNLV graduate student Davis Cammann, “but we also have to remember that the gut biome is influenced by many factors including lifestyle and diet.” 

The brain reacts differently to touch depending on context

The touch of another person may increase levels of the “feelgood” hormone oxytocin. But the context really matters. The situation impacts oxytocin levels not only in the moment, but also later, as is shown by researchers at Linköping University and the University of Skövde.

An embrace from a parent, a warm hand on your shoulder or a caress from a romantic partner are examples of how touch can strengthen social bonds between people and influence emotions. But although touch and the sense of touch have a very important function, knowledge of how this actually works is still lacking.

Studies in animals have shown that the hormone oxytocin is linked to touch and social bonding. However, many questions remain unanswered when it comes to oxytocin’s role in human social interactions and how this hormone can influence and be influenced by the brain. To study this closer, researchers have examined what happens in the body when we feel a soft touch.

“We saw that the body’s oxytocin response to touch was influenced by the situation: what had happened a few moments earlier and with whom the interaction takes place. The hormone does not function like an on/off button, but more like a dimmer switch,” says India Morrison, senior associate professor at the Department of Biomedical and Clinical Sciences at Linköping University.

42 women took part in the study, published in eLife. The actual experiment consisted of the woman’s male partner stroking her arm with his hand, while her brain activity was monitored using functional magnetic resonance imaging, fMRI.

The experiment also involved repeatedly taking blood tests to see whether oxytocin levels in the woman’s blood changed over time. Combining the various measurements allowed the researchers to examine whether hormone levels were linked to brain activity.

The measurements from the social interaction between the woman and her partner were compared with what happened when instead an unknown, non-threatening man touched her arm in the same way. In half of the experiments, her partner was the first to stroke her arm, and in the other half it was the stranger. The participating women were informed of who was stroking their arm.

“Our basic question was whether oxytocin levels would be higher when the woman’s partner touched her arm than when a stranger did it. The answer was yes, but only when her partner was the first to stroke her arm,” says India Morrison.

The researchers found that when her partner was first, the women’s oxytocin levels increased during the social interaction, then fell, only to increase again when the stranger did the same thing. However, when the stranger touched her first, there was no change in oxytocin levels. And when her partner then stroked her arm, there was only a slight increase. The changes in oxytocin levels were linked to activity in regions of the brain important for the contextualisation of events.

Oxytocin is released in a variety of situations and has several functions in the body.

“It might be good to bear in mind that context matters, for instance when providing synthetic oxytocin in the form of a nasal spray as part of the treatment of mood-affecting conditions,” says India Morrison.

Restoring a Key Brain Rhythm Has the Potential to Help Treat Depression

Led by researchers from NYU Grossman School of Medicine and Hungary’s University of Szeged, a new study in mice and rats found that restoring certain signals in a brain region that processes smells countered depression.

Published online in the journal Neuron, the study results revolve around nerve cells, also called neurons, which “fire”—emit electrical signals—to transmit information. Researchers in recent years discovered that effective communication between brain regions requires groups of neurons to synchronize their activity patterns in oscillations of joint silence followed by joint activity. One such rhythm, called gamma, repeats 30 times or more in a second and is an important timing pattern for the encoding of complex information, potentially including emotions.

Although the causes of depression remain poorly understood, it is reflected in gamma oscillation changes, according to past studies, as an electrophysiological marker of the disease in brain regions that manage the sense of smell, which have also been tied to emotions. These regions include the olfactory bulb adjacent to the nasal cavity, which is thought to be a source and conductor of gamma oscillations throughout the brain.

To test this theory, the current study authors shut down the function of the olfactory bulb in study rodents using genetic and cell signaling techniques, observed a related increase of depression-like behaviors in the subjects, and then reversed these behaviors using a device that boosted gamma signals of the brain at their natural pace.

“Our experiments revealed a mechanistic link between deficient gamma activity and behavioral decline in mice and rat models of depression, with the signal changes in the olfactory and connected limbic systems similar to those seen in depressed patients,” said corresponding study author Antal Berényi, MD, PhD, adjunct assistant professor in the Department of Neuroscience and Physiology at NYU Langone Health. “This work demonstrates the power of gamma enhancement as a potential approach for countering depression and anxiety in cases where available medications are not effective.”

Major depressive disorder is a common, severe psychiatric illness often resistant to drug therapy, the researchers say. The prevalence of the condition has dramatically increased since the start of the pandemic, with more than 53 million new cases estimated.

Gamma Waves Linked to Emotions

Disease-causing changes in the timing and strength of gamma signals, potentially caused by infections, trauma, or drugs, from the olfactory bulb to other brain regions of the limbic system, such as the piriform cortex and hippocampus, may alter emotions. However, the research team is not sure why. In one theory, depression arises not within the olfactory bulb but in changes to its outgoing gamma patterns to other brain targets.

Removal of the bulb represents an older animal model for the study of major depression, but the process causes structural damage that may cloud researchers’ view of disease mechanisms. To avoid this damage, the current research team designed a reversible method, starting with a single engineered strand of DNA encapsulated in a harmless virus. When injected into neurons in the olfactory bulbs of rodents, the DNA caused the cells to build certain protein receptors on their surfaces.

This let the researchers inject the rodents with a drug that spread system-wide but only shut down the neurons in the bulb that had been engineered to have the designed drug-sensitive receptors. This way the investigators could selectively and reversibly switch off the communication between the bulb partner brain regions. These tests revealed that chronic suppression of olfactory bulb signals, including gamma, not only induced depressive behaviors during the intervention, but for days afterward.

To show the effect of the loss of gamma oscillation in the olfactory bulb, the team used several standard rodent tests of depression, including measures of the anxiety that is one of its main symptoms. The field recognizes that animal models of human psychiatric conditions will be limited, and so uses a battery of tests to measure depressed behaviors that have proven useful over time.

Specifically, the tests looked at how long animals would spend in an open space, a measure of anxiety; whether they stopped swimming earlier when submerged, a measure of despair; whether they stopped drinking sugar water, a sign of taking less pleasure in things; and whether they refused to enter a maze, a sign they were avoiding stressful situations.

The researchers next used a custom-made device that recorded the natural gamma oscillations from the olfactory bulb, and sent those paced signals back into the rodents’ brains as closed-loop electrical stimulation. The device was able to suppress gamma in healthy animals or amplify it. Suppression of gamma oscillations in the olfactory lobe induced behaviors resembling depression in humans. In addition, feeding an amplified olfactory bulb signal back into the brains of depressed rats restored normal gamma function in the limbic system, and reduced the depressive behaviors by 40 percent, almost back to normal.

“No one yet knows how the firing patterns of gamma waves are converted into emotions,” said senior study author György Buzsáki, MD, PhD, the Biggs Professor of Neuroscience in the Department of Neuroscience and Physiology and a faculty member of the Neuroscience Institute. “Moving forward, we will be working to better understand this link in the bulb, and in the regions it connects to, as behavior changes.”

New research sheds light on how human vision perceives scale

Researchers from Aston University and the University of York have discovered new insights into how the human brain makes perceptual judgements of the external world. 

The study, published in the journal PLOS One, explored the computational mechanisms used by the human brain to perceive the size of objects in the world around us. 

The research, led by Professor Tim Meese, in the School of Optometry at Aston University and Dr Daniel Baker in the Department of Psychology at University of York, tells us more about how our visual system can exploit ‘defocus blur’ to infer perceptual scale, but that it does so crudely.

It is well known that to derive object size from retinal image size, our visual system needs to estimate the distance to the object. The retinal image contains many pictorial cues, such as linear perspective, which help the system derive the relative size of objects. However, to derive absolute size, the system needs to know about spatial scale.

By taking account of defocus blur, like the blurry parts of an image outside the depth of focus of a camera, the visual system can achieve this. The maths behind this has been well worked out by others, but the study asked the question: does human vision exploit this maths?

The research team presented participants with photographic pairs of full-scale railway scenes subject to various artificial blur treatments and small-scale models of railway scenes taken with a long exposure and small aperture to diminish defocus blur. The task was to detect which photograph in each pair was the real full-scale scene.

When the artificial blur was appropriately oriented with the ground plane (the horizontal plane representing the ground on which the viewer is standing) in the full-scale scenes, participants were fooled and believed the small models to be the full-scale scenes.

Remarkably, this did not require the application of realistic gradients of blur. Simple uniform bands of blur at the top and bottom of the photographs achieved almost equivalent miniaturisation effects.

Tim Meese, professor of vision science at Aston University, said: "Our results indicate that human vision can exploit defocus blur to infer perceptual scale but that it does this crudely – more a heuristic than a metrical analysis. Overall, our findings provide new insights into the computational mechanisms used by the human brain in perceptual judgments about the relation between ourselves and the external world."

Daniel Baker, senior lecturer in psychology at the University of York, said: "These findings demonstrate that our perception of size is not perfect and can be influenced by other properties of a scene. It also highlights the remarkable adaptability of the visual system. This might have relevance for understanding the computational principles underlying our perception of the world. For example, when judging the size and distance of hazards when driving.”

Researchers develop model for how the brain acquires essential omega-3 fatty acids

Researchers at the UCLA David Geffen School of Medicine, the Howard Hughes Medical Institute at UCLA and the National Institutes of Health have developed a zebrafish model that provides new insight into how the brain acquires essential omega-3 fatty acids, including docosahexaenoic acid (DHA) and linolenic acid (ALA). Their findings, published in Nature Communications, have the potential to improve understanding of lipid transport across the blood-brain barrier and of disruptions in this process that can lead to birth defects or neurological conditions. The model may also enable researchers to design drug molecules that are capable of directly reaching the brain.

Omega-3 fatty acids are considered essential because the body cannot make them and must obtain them through foods, such as fish, nuts and seeds. DHA levels are especially high in the brain and important for a healthy nervous system. Infants obtain DHA from breastmilk or formula, and deficiencies of this fatty acid have been linked to problems with learning and memory. To get to the brain, omega-3 fatty acids must pass through the blood-brain barrier via the lipid transporter Mfsd2a, which is essential for normal brain development. Despite its importance, scientists did not know precisely how Mfsd2a transports DHA and other omega-3 fatty acids.

In the study, the research team provides images of the structure of zebrafish Mfsd2a, which is similar to its human counterpart. The snapshots are the first to detail precisely how fatty acids move across the cell membrane. The study team also identified three compartments in Mfsd2a that suggest distinct steps required to move and flip fatty acids through the transporter, as opposed to movement through a linear tunnel or along the surface of the protein complex. The findings provide key information on how Mfsd2a transports omega-3 fatty acids into the brain and may enable researchers to optimize drug delivery via this route. The study also provides foundational knowledge on how other members of this transporter family, called the major facilitator superfamily (MFS), regulate important cellular functions.

Neuropathic pain: The underlying mechanism and a potential therapeutic target are revealed in mice

Neuropathic pain — abnormal hypersensitivity to stimuli — is associated with impaired quality of life and is often poorly managed. Estimates suggest that 3 percent to 17 percent of adults suffer from neuropathic pain, including a quarter of people with diabetes and a third of people with HIV.

In a paper published in the journal Neuron, researchers report that a mechanism involving the enzyme Tiam1 in dorsal horn excitatory neurons of the spinal cord both initiates and maintains neuropathic pain. Moreover, they show that targeting spinal Tiam1 with anti-sense oligonucleotides injected into the cerebrospinal fluid effectively alleviated neuropathic pain hypersensitivity. 

“Thus, our study has uncovered a pathophysiological mechanism that initiates, transitions and sustains neuropathic pain, and we have identified a promising therapeutic target for treating neuropathic pain with long-lasting consequences,” said Lingyong Li, Ph.D., an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine. “Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to treat chronic pain effectively.”

Li and Kimberley Tolias, Ph.D., a professor at Baylor College of Medicine in Houston, Texas, were co-leaders of the research. 

It was known that one feature of neuropathic pain is maladaptive changes in neurons of the spinal dorsal horn — increases in the size and density of dendritic spines, the primary postsynaptic sites of excitatory synapses. However, the mechanisms driving this synaptic plasticity were unclear. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons. The spinal dorsal horn is one of the three gray columns of the spinal cord.

In related work, Li and Tolias last year found that chronic pain in a mouse model leads to an activated Tiam1 in anterior cingulate cortex pyramidal neurons of the brain, resulting in an increased number of spines on the neural dendrites. This higher spine density increased the number of connections, and the strength of those connections, between neurons, a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with chronic pain-related depression in the mouse model.

The current neuropathic pain study by Li and Tolias used mouse models of neuropathic pain caused by nerve injury, chemotherapy or diabetes. The researchers showed that Tiam1 is activated in the spinal dorsal horn of mice subjected to neuropathic pain and that global knockout of Tiam1 in mice prevented the development of neuropathic pain. Global knockout causes no other apparent abnormalities in the mice.

The UAB and Baylor researchers found that Tiam1 expression in the spinal dorsal horn neurons — but not in the dorsal root ganglion neurons or excitatory forebrain neurons — was essential for the development of neuropathic pain. Furthermore, they found that neuropathic pain development depended on Tiam1 expression in excitatory neurons — not in inhibitory neurons.

After showing where Tiam1 acts in neuropathic pain, Li, Tolias and colleagues showed what Tiam1 does. Tiam1 is known to modulate the activity of other proteins that help build or unbuild the cytoskeletons of cells, and the building of cytoskeleton actin filaments is part of dendritic spine creation. The researchers found that Tiam1 is necessary during the development of neuropathic pain to increase the density of dendritic spines on wide dynamic range neurons from the spinal dorsal horn and to increase synaptic NMDA receptor activity of spinal dorsal horn neurons. 

Tiam1 functions to activate the small GTPase Rac1 enzyme that promotes actin polymerization. The researchers showed that the development of Tiam1-mediated neuropathic pain was dependent on Tiam1-Rac1 signaling. They then used a small molecule inhibitor to block Rac1 activation at three different time points — right after peripheral nerve injury, four days after nerve injury when neuropathic pain hypersensitivity gradually develops, or three weeks after nerve injury when chronic neuropathic pain is fully established. They found that neuropathic pain was prevented or reversed at each time point. Thus, Tiam1-Rac1 signaling is essential for the initiation, transition and maintenance of neuropathic pain.

Since Tiam1 appeared to be a promising therapeutic target for treating neuropathic pain, Li and Tolias also tested whether they could reduce neuropathic pain by injecting antisense oligonucleotides, or ASOs — short, synthetic, single-stranded oligodeoxynucleotides designed to alter Tiam1 expression by modulating its mRNA processing or degradation — into the cerebrospinal fluid of the spine.

In a rat model, they found that injecting an ASO against Tiam1 decreased Tiam1 protein levels in the spinal dorsal horn by 50 percent and significantly reduced neuropathic pain hypersensitivity one week after injection, a reduction that lasted another two weeks.

Therefore, Tiam1 is an essential player in the pathogenesis of neuropathic pain that coordinates actin cytoskeletal dynamics, dendritic spine morphogenesis and synaptic receptor function in spinal dorsal horn excitatory neurons in response to nerve damage, Li and Tolias say. 

The two researchers are corresponding authors of the study, “Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain.” 

The influence of AI on trust in human interaction

As AI becomes increasingly realistic, our trust in those with whom we communicate may be compromised. Researchers at the University of Gothenburg have examined how advanced AI systems impact our trust in the individuals we interact with.

In one scenario, a would-be scammer, believing he is calling an elderly man, is instead connected to a computer system that communicates through pre-recorded loops. The scammer spends considerable time attempting the fraud, patiently listening to the "man's" somewhat confusing and repetitive stories. Oskar Lindwall, a professor of communication at the University of Gothenburg, observes that it often takes a long time for people to realize they are interacting with a technical system.

He has, in collaboration with Professor of informatics Jonas Ivarsson, written an article titled Suspicious Minds: The Problem of Trust and Conversational Agents, exploring how individuals interpret and relate to situations where one of the parties might be an AI agent. The article highlights the negative consequences of harboring suspicion toward others, such as the damage it can cause to relationships.

Ivarsson provides an example of a romantic relationship where trust issues arise, leading to jealousy and an increased tendency to search for evidence of deception. The authors argue that being unable to fully trust a conversational partner's intentions and identity may result in excessive suspicion even when there is no reason for it.

Their study discovered that during interactions between two humans, some behaviors were interpreted as signs that one of them was actually a robot.

The researchers suggest that a pervasive design perspective is driving the development of AI with increasingly human-like features. While this may be appealing in some contexts, it can also be problematic, particularly when it is unclear who you are communicating with. Ivarsson questions whether AI should have such human-like voices, as they create a sense of intimacy and lead people to form impressions based on the voice alone.

In the case of the would-be fraudster calling the "older man," the scam is only exposed after a long time, which Lindwall and Ivarsson attribute to the believability of the human voice and the assumption that the confused behavior is due to age. Once an AI has a voice, we infer attributes such as gender, age, and socio-economic background, making it harder to identify that we are interacting with a computer.

The researchers propose creating AI with well-functioning and eloquent voices that are still clearly synthetic, increasing transparency.

Communication with others involves not only deception but also relationship-building and joint meaning-making. The uncertainty of whether one is talking to a human or a computer affects this aspect of communication. While it might not matter in some situations, such as cognitive-behavioral therapy, other forms of therapy that require more human connection may be negatively impacted.

Machine Learning Model Sheds Light on How Brains Recognize Communication Sounds

In a paper published today in Communications Biology, auditory neuroscientists at the University of Pittsburgh describe a machine learning model that helps explain how the brain recognizes the meaning of communication sounds, such as animal calls or spoken words.

The algorithm described in the study models how social animals, including marmoset monkeys and guinea pigs, use sound-processing networks in their brain to distinguish between sound categories – such as calls for mating, food or danger — and act on them.

The study is an important step toward understanding the intricacies and complexities of neuronal processing that underlies sound recognition. The insights from this work pave the way for understanding, and eventually treating, disorders that affect speech recognition, and improving hearing aids.

“More or less everyone we know will lose some of their hearing at some point in their lives, either as a result of aging or exposure to noise. Understanding the biology of sound recognition and finding ways to improve it is important,” said senior author and Pitt assistant professor of neurobiology Srivatsun Sadagopan, Ph.D. “But the process of vocal communication is fascinating in and of itself. The ways our brains interact with one another and can take ideas and convey them through sound is nothing short of magical.”

Humans and animals encounter an astounding diversity of sounds every day, from the cacophony of the jungle to the hum inside a busy restaurant. No matter the sound pollution in the world that surrounds us, humans and other animals are able to communicate and understand one another, including pitch of their voice or accent. When we hear the word “hello,” for example, we recognize its meaning regardless of whether it was said with an American or British accent, whether the speaker is a woman or a man, or if we’re in a quiet room or busy intersection.

The team started with the intuition that the way the human brain recognizes and captures the meaning of communication sounds may be similar to how it recognizes faces compared with other objects. Faces are highly diverse but have some common characteristics.

Instead of matching every face that we encounter to some perfect “template” face, our brain picks up on useful features, such as the eyes, nose and mouth, and their relative positions, and creates a mental map of these small characteristics that define a face.

In a series of studies, the team showed that communication sounds may also be made up of such small characteristics. The researchers first built a machine learning model of sound processing to recognize the different sounds made by social animals. To test if brain responses corresponded with the model, they recorded brain activity from guinea pigs listening to their kin’s communication sounds. Neurons in regions of the brain that are responsible for processing sounds lit up with a flurry of electrical activity when they heard a noise that had features present in specific types of these sounds, similar to the machine learning model.

They then wanted to check the performance of the model against the real-life behavior of the animals.

Guinea pigs were put in an enclosure and exposed to different categories of sounds — squeaks and grunts that are categorized as distinct sound signals. Researchers then trained the guinea pigs to walk over to different corners of the enclosure and receive fruit rewards depending on which category of sound was played.

Then, they made the tasks harder: To mimic the way humans recognize the meaning of words spoken by people with different accents, the researchers ran guinea pig calls through sound-altering software, speeding them up or slowing them down, raising or lowering their pitch, or adding noise and echoes.

Not only were the animals able to perform the task as consistently as if the calls they heard were unaltered, they continued to perform well despite artificial echoes or noise. Better yet, the machine learning model described their behavior (and the underlying activation of sound-processing neurons in the brain) perfectly.

As a next step, the researchers are translating the model’s accuracy from animals into human speech.

“From an engineering viewpoint, there are much better speech recognition models out there. What’s unique about our model is that we have a close correspondence with behavior and brain activity, giving us more insight into the biology. In the future, these insights can be used to help people with neurodevelopmental conditions or to help engineer better hearing aids,” said lead author Satyabrata Parida, Ph.D., postdoctoral fellow at Pitt’s department of neurobiology.

“A lot of people struggle with conditions that make it hard for them to recognize speech,” said Manaswini Kar, a student in the Sadagopan lab. “Understanding how a neurotypical brain recognizes words and makes sense of the auditory world around it will make it possible to understand and help those who struggle.”

(Image caption: Noisy sound inputs pass through networks of excitatory and inhibitory neurons in the auditory cortex that clean up the signal (in part guided by the listener paying attention) and detect characteristic features of sounds, allowing the brain to recognize communication sounds regardless of variations in how they are uttered by the speaker and surrounding noise. Credit: Manaswini Kar)

Scientists discover anatomical changes in the brains of the newly sighted

For many decades, neuroscientists believed there was a “critical period” in which the brain could learn to make sense of visual input, and that this window closed around the age of 6 or 7.

Recent work from MIT Professor Pawan Sinha has shown that the picture is more nuanced than that. In many studies of children in India who had surgery to remove congenital cataracts beyond the age of 7, he has found that older children can learn visual tasks such as recognizing faces, distinguishing objects from a background, and discerning motion.

In a new study, Sinha and his colleagues have now discovered anatomical changes that occur in the brains of these patients after their sight is restored. These changes, seen in the structure and organization of the brain’s white matter, appear to underlie some of the visual improvements that the researchers also observed in these patients.

The findings further support the idea that the window of brain plasticity, for at least some visual tasks, extends much further than previously thought.

“Given the remarkable level of remodeling of brain structure that we are seeing, it reinforces the point that we have been trying to make with our behavioral results, that all children ought to be provided treatment,” says Pawan Sinha, an MIT professor of brain and cognitive sciences and one of the authors of the study.

Bas Rokers, an associate professor and director of the Neuroimaging Center at New York University Abu Dhabi, is the senior author of the study, which appeared in the Proceedings of the National Academy of Sciences. The paper’s lead authors are Caterina Pedersini, a postdoc at New York University Abu Dhabi; Nathaniel Miller, who is studying medicine at the University of Minnesota Medical School; and Tapan Gandhi, a former postdoc in the Sinha Lab who is now an associate professor at the Indian Institute of Technology. Sharon Gilad-Gutnick, an MIT research scientist, and Vidur Mahajan, director of the Center for Advanced Research on Imaging, Neuroscience, and Genomics, are also authors of the paper.

White matter plasticity

In developed nations such as the United States, infants born with cataracts are treated within a few weeks of birth. However, in developing nations such as India, a higher percentage of these cases go untreated.

Nearly 20 years ago, Sinha launched an initiative called Project Prakash, with the mission to offer medical treatment to blind and vision-impaired children in India. Each year, the project screens thousands of children, many of whom are provided with glasses or more advanced interventions such as surgical removal of cataracts. Some of these children, with their families’ permission, also participate in studies of how the brain’s visual system responds after sight is restored.

In the new study, the researchers wanted to explore whether they could detect any anatomical changes in the brain that might correlate with the behavioral changes that they have previously seen in children who received treatment. They scanned 19 participants, ranging in age from 7 to 17 years of age, at several time points after they had surgery to remove congenital cataracts.

To analyze anatomical changes in the brain, the researchers used a specialized type of magnetic resonance imaging called diffusion tensor imaging. This type of imaging can reveal changes in the organization of the white matter — bundles of nerve fibers that connect different regions of the brain.

Diffusion tensor imaging, which tracks the movement of hydrogen nuclei in water molecules, produces two measurements: mean diffusivity, a measure of how freely water molecules can move, and fractional anisotropy, which reveals the extent to which water is forced to move in one direction over another.

An increase in fractional anisotropy suggests that water molecules are more constrained because nerve fibers in the white matter are oriented in a particular direction.

“If you see increasing fractional anisotropy and decreasing mean diffusivity, then you can infer that what’s happening is that the nerve fibers are growing in volume and they’re getting more organized in terms of their alignment,” Sinha says. “When we look at the white matter of the brain, then we see precisely these kinds of changes in some of the white matter bundles.”

The researchers observed these changes specifically in white matter pathways that are part of the later stages of the visual system, which is believed to be involved in higher-order functions such as face perception. These improvements occurred gradually over several months following the surgery.

“You see anatomical changes in the white matter, but in separate studies using functional neuroimaging, you also see increasing specialization, as a function of visual experience, similar to what happens in typical development,” Gilad-Gutnick says.

The researchers also tested the participants’ performance on a variety of visual tasks and found that their ability to distinguish faces from other objects was correlated with the amount of structural change in the white matter pathways associated with higher-order visual function.

In comparison, while the treated children showed some improvements in visual acuity — the ability to clearly see details of objects at a distance — their acuity never fully recovered, and they showed only minimal changes in the white matter organization of the early visual pathways.

“The notion that plasticity is a time-limited resource and that past a certain window we can’t expect much improvement, that does seem to hold true for low-level visual function like acuity,” Sinha says. “But when we talk about a higher-order visual skill, like telling a face from a non-face, there we do see behavioral improvements over time, and we also find there to be a correlation between the improvement that we are seeing behaviorally and the changes that we see anatomically.”

Benefits of treatment

The researchers also found that children who had cataracts removed at a younger age showed greater, and faster, gains in face-perception ability than older children. However, all of the children showed at least some improvement in this skill, along with changes in the structure of the white matter.

The findings suggest that older children can benefit from this kind of surgery and offers further evidence that it should be offered to them, Sinha says.

“If the brain has such outstanding abilities to reconfigure itself and even to change its structure, then we really ought to capitalize on that plasticity and provide children with treatment, irrespective of age,” he says.

Sinha’s lab is now analyzing additional imaging data from Project Prakash patients. In one study, the researchers are investigating whether the patients show any changes in the thickness of their gray matter, especially in the brain’s sensory processing areas, after treatment. The researchers are also using functional MRI to try to localize visual functions such as face perception, to see if they arise in the same parts of the brain that they do in people born with normal sight.

(Image caption: MIT neuroscientists discovered anatomical changes that occur in the white matter pathways linking visual-processing areas of the brain in children who have congenital cataracts surgically removed. This image shows the late-visual pathways in the brain. Credit: Courtesy of the researchers)

Our thoughts alter our tactile perception

Do we always perceive the world in the same way? A hypnosis experiment proves that we certainly don’t.

If we sincerely believe that our index finger is five times bigger than it really is, our sense of touch improves. Researchers at Ruhr University Bochum demonstrated that this is the case in an experiment in which the participants were put under professional hypnosis. When the participants signalled that they understood the opposite hypnotic suggestion that their index finger was five times smaller than it actually was, their sense of touch deteriorated accordingly. The study shows that our tactile perception is affected and can be altered by our mental processes. The scientific community has been divided on this issue. Headed by PD Dr. Hubert Dinse, Professor Albert Newen and Professor Martin Tegenthoff, the researchers published their findings in the journal Scientific Reports.

Two needles feel like one

The researchers measured the tactile perception of their 24 test participants using the two-point discrimination method. This involves the index finger lying relaxed on a device with two needles repeatedly touching the finger painlessly but perceptibly. “If the needles are far enough apart, we can easily distinguish two points of contact,” explains Hubert Dinse from the Neurological Clinic of Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil. “But if the needles are very close together, we only feel the touch in one place.” At a certain distance between the needles, the sensation changes from feeling two needles to feeling just one, although two are presented. This discrimination threshold is stable for each person given normal everyday consciousness.

If the finger were five times bigger

“We wanted to find out whether it’s possible to change this sensation threshold by activating a verbally articulated thought in a person,” explains Albert Newen from the Philosophy Institute II at Ruhr University Bochum. The research team chose two thought cues: “Imagine your index finger is five times smaller” and “Imagine your index finger is five times bigger.” To specifically activate these semantic contents, the researchers used hypnotic suggestion. During a controlled state of hypnosis induced by a professional hypnotist, the participant was asked to sincerely accept the first belief for a series of tests and then the second.

The subjects took part in a total of four experiments to determine the sensation threshold in each case: under normal everyday consciousness, under hypnosis without suggestion, and under two hypnotic conditions with the suggestions of a bigger or smaller index finger.

Changes in the sense of touch

“Discrimination thresholds did not differ when measured during normal consciousness and hypnosis without suggestion. This supports our preliminary assumption that hypnosis alone doesn’t lead to changes,” says Martin Tegenthoff. “However, if the beliefs are induced as suggestions under hypnosis, we observe a systematic change in the tactile discrimination threshold.” When a test person imagined that their index finger was five times bigger than it actually was, their discrimination threshold improved and they were able to feel two needles, even when they were closer together. When the suggestion was that their index finger was five times smaller, the discrimination threshold worsened. This means that it is the beliefs that change perception. The behavioural results were supported by parallel recordings of brain activity such as spontaneous EEG and sensory evoked potentials.

The scientific community is divided on the question of whether or not perceptual processes can be influenced by semantic content alone – experts refer to this as the question of cognitive penetrability of perception. “Our study provides another building block supporting the idea that such top-down influences of beliefs on perception do indeed exist,” stresses Hubert Dinse. “The beliefs we hold do indeed change how we experience the world.”

Human eyes really do play ‘tricks’ on the mind

A new study has shown that the human visual system can ‘trick’ the brain into making inaccurate assumptions about the size of objects in the world around them.

The research findings could have implications for many aspects of everyday life, such as driving, how eye witness accounts are treated in the criminal justice system, and security issues, such as drone sightings. 

The research team from the University of York and Aston University presented participants with photographs of full-scale railway scenes, which had the upper and lower parts of the image blurred, as well photographs of small-scale models of railways that were not blurred. 

Real v model

Participants were asked to compare each image and decide which was the ‘real’ full-scale railway scene. The results were that participants perceived that the blurred real trains were smaller than the models.

Dr Daniel Baker, from the University of York’s Department of Psychology, said: “In order for us to determine the real size of objects that we see around us, our visual system needs to estimate the distance to the object.  

“To arrive at an understanding of absolute size it can take into account the parts of the image that are blurred out - a bit like the out-of-focus areas that a camera produces - which involves a bit of complicated mathematics to give the brain the knowledge of spatial scale.

“This new study, however, shows that we can be fooled in our estimates of object size. Photographers take advantage of this using a technique called ‘tilt-shift miniaturisation’, that can make life-size objects appear to be scale models.” 

Flexible system

The findings demonstrate that the human visual system is highly flexible - sometimes capable of accurate perception of size by exploiting what is known as ‘defocus blur’, but at other times subject to other influences and failing to make sense of real-world object size.

Professor Tim Meese, from Aston University, said: “Our results indicate that human vision can exploit defocus blur to infer perceptual scale but that it does this crudely. 

“Overall, our findings provide new insights into the computational mechanisms used by the human brain in perceptual judgments about the relation between ourselves and the external world.”

The brain reacts differently to touch depending on context

The touch of another person may increase levels of the “feelgood” hormone oxytocin. But the context really matters. The situation impacts oxytocin levels not only in the moment, but also later, as is shown by researchers at Linköping University and the University of Skövde.

An embrace from a parent, a warm hand on your shoulder or a caress from a romantic partner are examples of how touch can strengthen social bonds between people and influence emotions. But although touch and the sense of touch have a very important function, knowledge of how this actually works is still lacking.

Studies in animals have shown that the hormone oxytocin is linked to touch and social bonding. However, many questions remain unanswered when it comes to oxytocin’s role in human social interactions and how this hormone can influence and be influenced by the brain. To study this closer, researchers have examined what happens in the body when we feel a soft touch.

“We saw that the body’s oxytocin response to touch was influenced by the situation: what had happened a few moments earlier and with whom the interaction takes place. The hormone does not function like an on/off button, but more like a dimmer switch,” says India Morrison, senior associate professor at the Department of Biomedical and Clinical Sciences at Linköping University.

42 women took part in the study, published in eLife. The actual experiment consisted of the woman’s male partner stroking her arm with his hand, while her brain activity was monitored using functional magnetic resonance imaging, fMRI.

The experiment also involved repeatedly taking blood tests to see whether oxytocin levels in the woman’s blood changed over time. Combining the various measurements allowed the researchers to examine whether hormone levels were linked to brain activity.

The measurements from the social interaction between the woman and her partner were compared with what happened when instead an unknown, non-threatening man touched her arm in the same way. In half of the experiments, her partner was the first to stroke her arm, and in the other half it was the stranger. The participating women were informed of who was stroking their arm.

“Our basic question was whether oxytocin levels would be higher when the woman’s partner touched her arm than when a stranger did it. The answer was yes, but only when her partner was the first to stroke her arm,” says India Morrison.

The researchers found that when her partner was first, the women’s oxytocin levels increased during the social interaction, then fell, only to increase again when the stranger did the same thing. However, when the stranger touched her first, there was no change in oxytocin levels. And when her partner then stroked her arm, there was only a slight increase. The changes in oxytocin levels were linked to activity in regions of the brain important for the contextualisation of events.

Oxytocin is released in a variety of situations and has several functions in the body.

“It might be good to bear in mind that context matters, for instance when providing synthetic oxytocin in the form of a nasal spray as part of the treatment of mood-affecting conditions,” says India Morrison.

A special omega-3 fatty acid lipid will change how we look at the developing and ageing brain

Scientists from Singapore have demonstrated the critical role played by a special transporter protein in regulating the brain cells that ensure nerves are protected by coverings called myelin sheaths. The findings, reported by researchers at Duke-NUS Medical School and the National University of Singapore in the Journal of Clinical Investigation, could help to reduce the damaging impacts of ageing on the brain.

An insulating membrane encasing nerves, myelin sheaths facilitate the quick and effective conduction of electrical signals throughout the body’s nervous system. When the myelin sheath gets damaged, nerves may lose their ability to function and cause neurological disorders. With ageing, myelin sheaths may naturally start to degenerate, which is often why the elderly lose their physical and mental abilities.

“Loss of myelin sheaths occurs during the normal ageing process and in neurological diseases, such as multiple sclerosis and Alzheimer’s disease,” said Dr Sengottuvel Vetrivel, Senior Research Fellow with Duke-NUS’ Cardiovascular & Metabolic Disorders (CVMD) Programme and lead investigator of the study. “Developing therapies to improve myelination—the formation of the myelin sheath—in ageing and disease is of great importance to ease any difficulties caused by declining myelination.”

To pave the way for developing such therapies, the researchers sought to understand the role of Mfsd2a, a protein that transports lysophosphatidylcholine (LPC)—a lipid that contains an omega-3 fatty acid—into the brain as part of the myelination process. From what is known, genetic defects in the Mfsd2a gene leads to significantly reduced myelination and a birth defect called microcephaly, which causes the baby’s head to be much smaller than it should be. 

In preclinical models, the team showed that removing Mfsd2a from precursor cells that mature into myelin-producing cells—known as oligodendrocytes—in the brain led to deficient myelination after birth. Further investigations, including single-cell RNA sequencing, demonstrated that Mfsd2a’s absence caused the pool of fatty acid molecules—particularly omega-3 fats—to be reduced in the precursor cells, preventing these cells from maturing into oligodendrocytes that produce myelin.

“Our study indicates that LPC omega-3 lipids act as factors within the brain to direct oligodendrocyte development, a process that is critical for brain myelination,” explained Professor David Silver, the senior author of the study and Deputy Director of the CVMD Programme. “This opens up potential avenues to develop therapies and dietary supplements based on LPC omega-3 lipids that might help retain myelin in the ageing brain—and possibly to treat patients with neurological disorders stemming from reduced myelination.”

Previously, Prof Silver and his lab discovered Mfsd2a and worked closely with other teams to determine the function of LPC lipids in the brain and other organs. The current research provides further insights into the importance of lipid transport for oligodendrocyte precursor cell development.

“We’re now aiming to conduct preclinical studies to determine if dietary LPC omega-3 can help to re-myelinate damaged axons in the brain,” added Prof Silver. “Our hope is that supplements containing these fats can help to maintain—or even improve—brain myelination and cognitive function during ageing.”

“Prof Silver has been relentless in investigating the far-reaching role of Msdf2a ever since he discovered this important lipid transport protein, alluding to the many possible ways of treating not only the ageing brain but also other organs in which the protein plays a role,” said Professor Patrick Casey, Senior-Vice Dean for Research. “It’s exciting to watch Prof Silver and his team shape our understanding of the roles that these specialised lipids play through their many discoveries.”

(Image caption: The developing preclinical model’s brain with myelinated axons (shown in green color). Credit: Vetrivel Sengottuvel)

Neuropathic pain: The underlying mechanism and a potential therapeutic target are revealed in mice

Neuropathic pain — abnormal hypersensitivity to stimuli — is associated with impaired quality of life and is often poorly managed. Estimates suggest that 3 percent to 17 percent of adults suffer from neuropathic pain, including a quarter of people with diabetes and a third of people with HIV.

In a paper published in the journal Neuron, researchers report that a mechanism involving the enzyme Tiam1 in dorsal horn excitatory neurons of the spinal cord both initiates and maintains neuropathic pain. Moreover, they show that targeting spinal Tiam1 with anti-sense oligonucleotides injected into the cerebrospinal fluid effectively alleviated neuropathic pain hypersensitivity. 

“Thus, our study has uncovered a pathophysiological mechanism that initiates, transitions and sustains neuropathic pain, and we have identified a promising therapeutic target for treating neuropathic pain with long-lasting consequences,” said Lingyong Li, Ph.D., an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine. “Understanding the pathophysiological mechanisms underlying neuropathic pain is critical for developing new therapeutic strategies to treat chronic pain effectively.”

Li and Kimberley Tolias, Ph.D., a professor at Baylor College of Medicine in Houston, Texas, were co-leaders of the research. 

It was known that one feature of neuropathic pain is maladaptive changes in neurons of the spinal dorsal horn — increases in the size and density of dendritic spines, the primary postsynaptic sites of excitatory synapses. However, the mechanisms driving this synaptic plasticity were unclear. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons. The spinal dorsal horn is one of the three gray columns of the spinal cord.

In related work, Li and Tolias last year found that chronic pain in a mouse model leads to an activated Tiam1 in anterior cingulate cortex pyramidal neurons of the brain, resulting in an increased number of spines on the neural dendrites. This higher spine density increased the number of connections, and the strength of those connections, between neurons, a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with chronic pain-related depression in the mouse model.

The current neuropathic pain study by Li and Tolias used mouse models of neuropathic pain caused by nerve injury, chemotherapy or diabetes. The researchers showed that Tiam1 is activated in the spinal dorsal horn of mice subjected to neuropathic pain and that global knockout of Tiam1 in mice prevented the development of neuropathic pain. Global knockout causes no other apparent abnormalities in the mice.

The UAB and Baylor researchers found that Tiam1 expression in the spinal dorsal horn neurons — but not in the dorsal root ganglion neurons or excitatory forebrain neurons — was essential for the development of neuropathic pain. Furthermore, they found that neuropathic pain development depended on Tiam1 expression in excitatory neurons — not in inhibitory neurons.

After showing where Tiam1 acts in neuropathic pain, Li, Tolias and colleagues showed what Tiam1 does. Tiam1 is known to modulate the activity of other proteins that help build or unbuild the cytoskeletons of cells, and the building of cytoskeleton actin filaments is part of dendritic spine creation. The researchers found that Tiam1 is necessary during the development of neuropathic pain to increase the density of dendritic spines on wide dynamic range neurons from the spinal dorsal horn and to increase synaptic NMDA receptor activity of spinal dorsal horn neurons. 

Tiam1 functions to activate the small GTPase Rac1 enzyme that promotes actin polymerization. The researchers showed that the development of Tiam1-mediated neuropathic pain was dependent on Tiam1-Rac1 signaling. They then used a small molecule inhibitor to block Rac1 activation at three different time points — right after peripheral nerve injury, four days after nerve injury when neuropathic pain hypersensitivity gradually develops, or three weeks after nerve injury when chronic neuropathic pain is fully established. They found that neuropathic pain was prevented or reversed at each time point. Thus, Tiam1-Rac1 signaling is essential for the initiation, transition and maintenance of neuropathic pain.

Since Tiam1 appeared to be a promising therapeutic target for treating neuropathic pain, Li and Tolias also tested whether they could reduce neuropathic pain by injecting antisense oligonucleotides, or ASOs — short, synthetic, single-stranded oligodeoxynucleotides designed to alter Tiam1 expression by modulating its mRNA processing or degradation — into the cerebrospinal fluid of the spine.

In a rat model, they found that injecting an ASO against Tiam1 decreased Tiam1 protein levels in the spinal dorsal horn by 50 percent and significantly reduced neuropathic pain hypersensitivity one week after injection, a reduction that lasted another two weeks.

Therefore, Tiam1 is an essential player in the pathogenesis of neuropathic pain that coordinates actin cytoskeletal dynamics, dendritic spine morphogenesis and synaptic receptor function in spinal dorsal horn excitatory neurons in response to nerve damage, Li and Tolias say. 

The two researchers are corresponding authors of the study, “Tiam1 coordinates synaptic structural and functional plasticity underpinning the pathophysiology of neuropathic pain.” 

Scientists discover how mutations in a language gene produce speech deficits

Mutations of a gene called Foxp2 have been linked to a type of speech disorder called apraxia that makes it difficult to produce sequences of sound. A new study from MIT and National Yang Ming Chiao Tung University sheds light on how this gene controls the ability to produce speech.

In a study of mice, the researchers found that mutations in Foxp2 disrupt the formation of dendrites and neuronal synapses in the brain’s striatum, which plays important roles in the control of movement. Mice with these mutations also showed impairments in their ability to produce the high-frequency sounds that they use to communicate with other mice.

Those malfunctions arise because Foxp2 mutations prevent the proper assembly of motor proteins, which move molecules within cells, the researchers found.

“These mice have abnormal vocalizations, and in the striatum there are many cellular abnormalities,” says Ann Graybiel, an MIT Institute Professor, a member of MIT’s McGovern Institute for Brain Research, and an author of the paper. “This was an exciting finding. Who would have thought that a speech problem might come from little motors inside cells?”

Fu-Chin Liu PhD ’91, a professor at National Yang Ming Chiao Tung University in Taiwan, is the senior author of the study, which appeared in the journal Brain. Liu and Graybiel also worked together on a 2016 study of the potential link between Foxp2 and autism spectrum disorder. The lead authors of the new Brain paper are Hsiao-Ying Kuo and Shih-Yun Chen of National Yang Ming Chiao Tung University.

Speech control

Children with Foxp2-associated apraxia tend to begin speaking later than other children, and their speech is often difficult to understand. The disorder is believed to arise from impairments in brain regions, such as the striatum, that control the movements of the lips, mouth, and tongue. Foxp2 is also expressed in the brains of songbirds such as zebra finches and is critical to those birds’ ability to learn songs.

Foxp2 encodes a transcription factor, meaning that it can control the expression of many other target genes. Many species express Foxp2, but humans have a special form of Foxp2. In a 2014 study, Graybiel and colleagues found evidence that the human form of Foxp2, when expressed in mice, allowed the mice to accelerate the switch from declarative to procedural types of learning.   

In that study, the researchers showed that mice engineered to express the human version of Foxp2, which differs from the mouse version by only two DNA base pairs, were much better at learning mazes and performing other tasks that require turning repeated actions into behavioral routines. Mice with human-like Foxp2 also had longer dendrites — the slender extensions that help neurons form synapses — in the striatum, which is involved in habit formation as well as motor control.

In the new study, the researchers wanted to explore how the Foxp2 mutation that has been linked with apraxia affects speech production, using ultrasonic vocalizations in mice as a proxy for speech. Many rodents and other animals such as bats produce these vocalizations to communicate with each other.

While previous studies, including the work by Liu and Graybiel in 2016, had suggested that Foxp2 affects dendrite growth and synapse formation, the mechanism for how that occurs was not known. In the new study, led by Liu, the researchers investigated one proposed mechanism, which is that Foxp2 affects motor proteins.

One of these molecular motors is the dynein protein complex, a large cluster of proteins that is responsible for shuttling molecules along microtubule scaffolds within cells.

“All kinds of molecules get shunted around to different places in our cells, and that's certainly true of neurons,” Graybiel says. “There’s an army of tiny molecules that move molecules around in the cytoplasm or put them into the membrane. In a neuron, they may send molecules from the cell body all the way down the axons.”

A delicate balance

The dynein complex is made up of several other proteins. The most important of these is a protein called dynactin1, which interacts with microtubules, enabling the dynein motor to move along microtubules. In the new study, the researchers found that dynactin1 is one of the major targets of the Foxp2 transcription factor.

The researchers focused on the striatum, one of the regions where Foxp2 is most often found, and showed that the mutated version of Foxp2 is unable to suppress dynactin1 production. Without that brake in place, cells generate too much dynactin1. This upsets the delicate balance of dynein-dynactin1, which prevents the dynein motor from moving along microtubules.

Those motors are needed to shuttle molecules that are necessary for dendrite growth and synapse formation on dendrites. With those molecules stranded in the cell body, neurons are unable to form synapses to generate the proper electrophysiological signals they need to make speech production possible.

Mice with the mutated version of Foxp2 had abnormal ultrasonic vocalizations, which typically have a frequency of around 22 to 50 kilohertz. The researchers showed that they could reverse these vocalization impairments and the deficits in the molecular motor activity, dendritic growth, and electrophysiological activity by turning down the gene that encodes dynactin1.

Mutations of Foxp2 can also contribute to autism spectrum disorders and Huntington’s disease, through mechanisms that Liu and Graybiel previously studied in their 2016 paper and that many other research groups are now exploring. Liu’s lab is also investigating the potential role of abnormal Foxp2 expression in the subthalamic nucleus of the brain as a possible factor in Parkinson’s disease.

(Image caption: A new study shows that when the gene Foxp2 is knocked out in mouse striatal neurons (top right panel), the protein dynactin (stained red) and the chain that binds dynactin and dynein (stained green) show abnormal spacing compared to wildtype neurons (top left panel). This suggests that the functions of the motor complexes formed by these proteins may be impaired. The bottom panels show close-ups of the green and red labeled molecules. Credit: Fu-Chin Liu)

Sleep Phase Can Reduce Anxiety in People with PTSD

A new study shows that sleep spindles, brief bursts of brain activity occurring during one phase of sleep and captured by EEG, may regulate anxiety in people with post-traumatic stress disorder (PTSD).

The study shines a light on the role of spindles in alleviating anxiety in PTSD as well as confirms their established role in the transfer of new information to longer-term memory storage. The findings challenge recent work by other researchers that has indicated spindles may heighten intrusive and violent thoughts in people with PTSD.

The final draft of the preprint publishes in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging on May 3, 2023.

“These findings may be meaningful not only for people with PTSD, but possibly for those with anxiety disorders,” said senior author Anne Richards, MD, MPH, of the UCSF Department of Psychiatry and Behavioral Sciences, the Weill Institute for Neurosciences and the San Francisco VA Medical Center. “There are non-invasive ways that might harness the benefits of this sleep stage to provide relief from symptoms."

The researchers enrolled 45 participants who had all experienced combat or noncombat trauma; approximately half had moderate symptoms of PTSD and the other half had milder symptoms or were asymptomatic. The researchers studied the spindles during non-rapid eye movement 2 (NREM2) sleep, the phase of sleep when they mainly occur, which comprises about 50% of total sleep.

Violent Images Used to Test Brain Processing

In the study, participants attended a “stress visit” in which they were shown images of violent scenes, such as accidents, war violence, and human and animal injury or mutilation, prior to a lab-monitored nap that took place about two hours later.

Anxiety surveys were conducted immediately after exposure to the images as well as after the nap when recall of the images was tested. The researchers also compared anxiety levels in the stress visit to those in a control visit without exposure to these images.

The researchers found that spindle rate frequency was higher during the stress visit than during the control visit. “This provides compelling evidence that stress was a contributing factor in spindle-specific sleep rhythm changes,” said first author Nikhilesh Natraj, PhD, of the UCSF Department of Neurology, the Weill Institute for Neurosciences and the San Francisco VA Medical Center. Notably, in participants with greater PTSD symptoms, the increased spindle frequency after stress exposure reduced anxiety post-nap.

Sleeping Meds, Electrical Stimulation May Promote Sleep Spindles

In the study, naps took place shortly after exposure to violent images – raising a question about whether sleep occurring days or weeks after trauma will have the same therapeutic effect. The researchers think this is likely, and point to interventions that could trigger the spindles associated with NREM2 sleep and benefit patients with stress and anxiety disorders.

Prescription drugs, like Ambien, are one option that should be studied further, “but a big question is whether the spindles induced by medications can also bring about the full set of brain processes associated with naturally occurring spindles,” said Richards.

Electrical brain stimulation is another area for more study, researchers said. “Transcranial electrical stimulation in which small currents are passed through the scalp to boost spindle rhythms or so-called targeted memory reactivation, which involves a cue, like an odor or sound used during an experimental session and replayed during sleep may also induce spindles,” said Natraj.

“In lieu of such inventions, sleep hygiene is definitely a zero-cost and easy way to ensure we are entering sleep phases in an appropriate fashion, thereby maximizing the benefit of spindles in the immediate aftermath of a stressful episode,” he said.

The researchers’ next project is to study the role of spindles in the consolidation and replay of intrusive and violent memories many weeks after trauma exposure.