Tag: 27/11/24

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New Insights into Sleep Uncover Mechanism for Enhancing Cognitive Function

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While it’s well known that sleep enhances cognitive performance, the underlying neural mechanisms, particularly those related to nonrapid eye movement (NREM) sleep, remain largely unexplored. A new study by a team of researchers coordinated by Rice University’s Valentin Dragoi, has nonetheless uncovered a key mechanism by which sleep enhances neuronal and behavioural performance, potentially changing our fundamental understanding of how sleep boosts brainpower.

The research, published in Science, reveals how NREM sleep – such as in a nap – fosters brain synchronisation and enhances information encoding, shedding new light on this sleep stage. The researchers replicated these effects through invasive stimulation, suggesting promising possibilities for future neuromodulation therapies in humans. The implications of this discovery potentially pave the way for innovative treatments for sleep disorders and even methods to enhance cognitive and behavioural performance.

The investigation involved an examination of the neural activity in multiple brain areas in macaques while the animals performed a visual discrimination task before and after a 30-minute period of NREM sleep. Using multielectrode arrays, the researchers recorded the activity of thousands of neurons across three brain areas: the primary and midlevel visual cortices and the dorsolateral prefrontal cortex, which are associated with visual processing and executive functions. To confirm that the macaques were in NREM sleep, researchers used polysomnography to monitor their brain and muscle activity alongside video analysis to ensure their eyes were closed and their bodies relaxed.

The findings demonstrated that sleep improved the animals’ performance in the visual task with enhanced accuracy in distinguishing rotated images. Meanwhile, the macaques that experienced quiet wakefulness without falling asleep did not show the same performance boost.

“During sleep, we observed an increase in low-frequency delta wave activity and synchronised firing among neurons across different cortical regions,” said first author Dr Natasha Kharas. “After sleep, however, neuronal activity became more desynchronised compared to before sleep, allowing neurons to fire more independently. This shift led to improved accuracy in information processing and performance in the visual tasks.”

The researchers also simulated the neural effects of sleep through low-frequency electrical stimulation of the visual cortex. They applied a 4-Hz stimulation to mimic the delta frequency observed during NREM sleep while the animals were awake. This artificial stimulation reproduced the desynchronization effect seen after sleep and similarly enhanced the animals’ task performance, suggesting that specific patterns of electrical stimulation could potentially be used to emulate the cognitive benefits of sleep.

“This finding is significant because it suggests that some of the restorative and performance-enhancing effects of sleep might be achieved without the need for actual sleep,” said Dragoi, study co-author, professor of electrical and computer engineering at Rice and professor of neuroscience at Weill Cornell. “The ability to reproduce sleeplike neural desynchronisation in an awake state opens new possibilities for enhancing cognitive and perceptual performance in situations where sleep is not feasible – such as for individuals with sleep disorders or in extenuating circumstances such as space exploration.”

The researchers further investigated their findings by building a large neural network model. They found that during sleep, both excitatory and inhibitory connections in the brain become weaker, but they do so asymmetrically, making inhibitory connections weaker than excitatory connections, which causes an increase in excitation.

“We have uncovered a surprising solution that the brain employs after sleep whereby neural populations participating in the task reduce their level of synchrony after sleep despite receiving synchronizing inputs during sleep itself,” Dragoi said.

The idea that NREM sleep effectively “boosts” the brain in this way, and that this resetting can be mimicked artificially, offers potential for developing therapeutic brain stimulation techniques to improve cognitive function and memory.

“Our study not only deepens our mechanistic understanding of sleep’s role in cognitive function but also breaks new ground by showing that specific patterns of brain stimulation could substitute for some benefits of sleep, pointing toward a future where we might boost brain function independently of sleep itself,” Dragoi said.

Source: Rice University

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Carbon Dioxide Protects Cells from Damage by Free Radicals

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A team of University of Utah chemists have found that carbon dioxide, well-known for being deadly at high concentrations, also has an important beneficial effect in preserving cell function. This is something not accounted for in most in vitro experiments of cell damage, and may have important consequences for understanding environments with high CO2 concentrations, like underground mines, submarines and spacecraft.

The cells in our bodies are like bustling cities, running on an iron-powered system that uses hydrogen peroxide (H₂O₂) not just for cleaning up messes but also for sending critical signals. Normally, this works fine, but under stress, such as inflammation or a burst of energy use, oxidative stress damages cells at the genetic level.

This is because iron and H₂O₂ react in what’s known as the Fenton reaction, producing hydroxyl radicals, destructive molecules that attack DNA and RNA indiscriminately. But there’s a catch. In the presence of carbon dioxide, our cells gain a secret weapon in the form of bicarbonate which helps keep pH levels balanced.

In this study, the researchers discovered that bicarbonate doesn’t just act as a pH buffer but also alters the Fenton reaction itself in cells. Instead of producing chaotic hydroxyl radicals, the reaction instead makes carbonate radicals, which affect DNA in a far less harmful way, according to Cynthia Burrows, a distinguished professor of chemistry and senior author of a study published this week in PNAS.

“So many diseases, so many conditions have oxidative stress as a component of disease. That would include many cancers, effectively all age-related diseases, a lot of neurological diseases,” Burrows said. “We’re trying to understand cells’ fundamental chemistry under oxidative stress. We have learned something about the protective effect of CO₂ that I think is really profound.”

Without bicarbonate or CO₂ present in experimental DNA oxidation reactions, the chemistry is also different. The free radical species generated, hydroxyl radical, is extremely reactive and hits DNA like a shotgun blast, causing damage everywhere, Burrows said.

In contrast, her team’s findings show that the presence of bicarbonate from dissolved CO₂ changes the reaction to make a milder radical striking only guanine, the G in our four-letter genetic code.

“Like throwing a dart at the bullseye where G is the center of the target,” Burrows said. “It turns out that bicarbonate is a major buffer inside your cells. Bicarbonate binds to iron, and it completely changes the Fenton reaction. You don’t make these super highly reactive radicals that everyone’s been studying for decades.”

What do these findings mean for science? Potentially a lot.

For starters, the team’s discovery shows cells are a lot smarter than previously imagined, which could reshape how we understand oxidative stress and its role in diseases like cancer or aging.

But it also raises the possibility that many scientists studying cell damage have been conducting laboratory experiments in ways that don’t reflect the real world, rendering their results suspect, Burrows said. Chemists and biologists everywhere grow cells in a tissue culture in an incubator set to 37°C. In these cultures, carbon dioxide levels are raised to 5%, or about 100 times more concentrated than what’s found in the atmosphere.

The elevated CO₂ recreates the environment the cells normally inhabit as they metabolise nutrients, however, it is lost when researchers start their experiments outside the incubator.

“Just like opening up a can of beer. You release the CO₂ when you take your cells out of the incubator. It’s like doing experiments with a day-old glass of beer. It’s pretty flat. It has lost the CO₂, its bicarbonate buffer,” Burrows said. “You no longer have the protection of CO₂ to modulate the iron-hydrogen peroxide reaction.”

She believes bicarbonate needs to be added to ensure reliable results from such experiments.

“Most people leave out bicarbonate/CO₂ when studying DNA oxidation because it is difficult to deal with the constant outgassing of CO₂,” Burrows said. “These studies suggest that to get an accurate picture of DNA damage that occurs from normal cellular processes like metabolism, researchers need to be careful to mimic the proper conditions of the cell and add bicarbonate, ie baking powder!”

Burrows anticipates her study could result in unintended outcomes that may someday benefit research in other areas. Her lab is seeking new funding from NASA, for example, to study the effect of CO₂ on people confined to enclosed spaces, such as inside of space capsules and submarines.

“You’ve got astronauts in a capsule living and breathing, and they are exhaling CO₂. The problem is how much CO₂ can they safely handle in their atmosphere? One of the things we found is that, at least in terms of tissue culture, CO₂ does have a protective effect from some of the radiation damage these astronauts might experience. So what you might want to do is push up that CO₂ level. You certainly don’t want to go very high, but having it slightly higher might actually have a protective effect against radiation, which generates hydroxyl radicals.”

Source: University of Utah

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An Experimental Drug to Prevent Post-heart Attack Heart Failure

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Scientists at UCLA have developed a first-of-its-kind experimental therapy that has the potential to enhance heart repair following a heart attack, preventing the onset of heart failure. After a heart attack, the heart’s innate ability to regenerate is limited, causing the muscle to develop scars to maintain its structural integrity. This inflexible scar tissue, however, interferes with the heart’s ability to pump blood, leading to heart failure in many patients – 50% of whom do not survive beyond five years.

The new therapeutic approach aims to improve heart function after a heart attack by blocking a protein called ENPP1, which is responsible for increasing the inflammation and scar tissue formation that exacerbate heart damage. The findings, published in Cell Reports Medicine, could represent a major advance in post-heart attack treatment.

The research was led by senior author Dr Arjun Deb, a professor of medicine and molecular, cell and developmental biology at UCLA.

“Despite the prevalence of heart attacks, therapeutic options have stagnated over the last few decades,” said Deb, who is also a member of the UCLA Broad Stem Cell Research Center. “There are currently no medications specifically designed to make the heart heal or repair better after a heart attack.”

The experimental therapy uses a therapeutic monoclonal antibody engineered by Deb and his team. This targeted drug therapy is designed to mimic human antibodies and inhibit the activity of ENPP1, which Deb had previously established increases in the aftermath of a heart attack.

The researchers found that a single dose of the antibody significantly enhanced heart repair in mice, preventing extensive tissue damage, reducing scar tissue formation and improving cardiac function. Four weeks after a simulated heart attack, only 5% of animals that received the antibody developed severe heart failure, compared with 52% of animals in the control group.

This therapeutic approach could become the first to directly enhance tissue repair in the heart following a heart attack; an advantage over current therapies that focus on preventing further damage but not actively promoting healing. This can be attributed to the way the antibody is designed to target cellular cross-talk, benefitting multiple cell types in the heart, including heart muscle cells, the endothelial cells that form blood vessels, and fibroblasts, which contribute to scar formation. 

Initial findings from preclinical studies also show that the antibody therapy safely decreased scar tissue formation without increasing the risk of heart rupture – a common concern after a heart attack. However, Deb acknowledges that more work is needed to understand potential long-term effects of inhibiting ENPP1, including potential adverse effects on bone mass or bone calcification. 

Deb’s team is now preparing to move this therapy into clinical trials. The team plans to submit an Investigational New Drug, or IND, application to the U.S. Food and Drug Administration this winter with the goal of beginning first-in-human studies in early 2025. These studies will be designed to administer a single dose of the drug in eligible individuals soon after a heart attack, helping the heart repair itself in the critical initial days after the cardiac event.

While the current focus is on heart repair after heart attacks, Deb’s team is also exploring the potential for this therapy to aid in the repair of other vital organs.

“The mechanisms of tissue repair are broadly conserved across organs, so we are examining how this therapeutic might help in other instances of tissue injury,” said Deb, who is also the director of the UCLA Cardiovascular Research Theme at the David Geffen School of Medicine. “Based on its effect on heart repair, this could represent a new class of tissue repair-enhancing drugs.”

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Cannabis Disrupts Brain Activity in Young Adults Prone to Psychosis

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Young adults at risk of psychosis show reduced brain connectivity, a deficit that cannabis use appears to worsen, a new study has found. The breakthrough paves the way for psychosis treatments targeting symptoms that current medications miss. In the first-of-its-kind study, McGill University researchers detected a marked decrease in synaptic density in individuals at risk of psychosis, compared to a healthy control group.

“Not every cannabis user will develop psychosis, but for some, the risks are high. Our research helps clarify why,” said Dr Romina Mizrahi, senior author of the study and professor in McGill’s Department of Psychiatry.

“Cannabis appears to disrupt the brain’s natural process of refining and pruning synapses, which is essential for healthy brain development.”

Hope for new treatments

Using advanced brain scanning technology, the team studied 49 participants aged 16 to 30, including individuals with recent psychotic symptoms and those considered at high risk. The results, published in JAMA Psychiatry, indicate that lower synaptic density is linked to social withdrawal and lack of motivation, symptoms the researchers say are difficult to treat.

“Current medications largely target hallucinations, but they don’t address symptoms that make it difficult to manage social relationships, work, or school,” said first author Belen Blasco, a PhD student at McGill’s Integrated Program in Neuroscience. “By focusing on synaptic density, we may eventually develop therapies that enhance social function and quality of life for those affected.”

While cannabis is a known risk factor for developing psychosis, which can progress to schizophrenia, this is the first time researchers have measured structural changes in the brains of a high-risk population in real time.

The team’s next research phase will explore whether these observed brain changes could predict psychosis development, potentially enabling earlier intervention.

Source: McGill University

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Long Ring Fingers are Associated with a Preference for Alcohol

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People’s finger lengths may hold a vital clue to their drinking habits, a new study suggests. There is evidence that alcohol consumption is influenced by prenatal sex steroids – so experts from Swansea University and colleagues from the Medical University of Lodz decided to use a sample of students for their research into the subject.

Their findings, published in the American Journal of Human Biology, revealed relationships between high alcohol consumption and long 4th  digits (ring fingers) relative to 2nd  digits (index fingers). This showed that high prenatal testosterone relative to oestrogen is linked to high student alcohol consumption.

Professor John Manning said: “Alcohol consumption is a major social and economic problem. Therefore, it is important to understand why alcohol use shows considerable differences across individuals.”

The study used a sample of 258 participants – 169 of them female  –  and it revealed consumption rates varied between the sexes. In comparison to women, men show higher alcohol consumption and higher mortality from alcohol abuse.

He said: “A pattern like this suggests an involvement of sex hormones, such as testosterone and oestrogen. Digit ratio (2D:4D: the relative lengths of the 2nd and 4th fingers) is thought to be an index of early testosterone (long 4th digit) and oestrogen (long 2nd digit).

“It is known that alcohol-dependent patients have very long 4th digits relative to their 2nd digits, suggesting high testosterone relative to oestrogen exposure before birth. As expected, the associations were stronger for men than women.”

Now the researchers hope their conclusions will bring a better understanding of the factors underlying the pattern of alcohol consumption, from abstinence to occasional use to harmful dependence. 

This is the latest paper which has highlighted Professor Manning’s work in the field of digit ratios. Previous research  has examined how digit ratio may provide vital information concerning outcomes after contracting Covid-19, as well as oxygen consumption in footballers.

Source: University of Swansea