Gene-editing offers hope for people with hereditary disorder

A group of patients with a hereditary disorder have had their lives transformed by a single treatment of a breakthrough gene-editing therapy, according to the lead researcher.

The patients from New Zealand, the Netherlands and the UK have hereditary angioedema, a genetic disorder characterised by severe, painful and unpredictable swelling attacks.

These interfere with daily life and can affect airways and prove fatal.

Now researchers from the University of Auckland, Amsterdam University Medical Center and Cambridge University Hospitals have successfully treated more than ten patients with the CRISPR/Cas9 therapy, with interim results just published in a leading journal.

"It looks as if the single-dose treatment will provide a permanent cure for my hereditary angioedema patients' very disabling symptoms," says principal investigator Dr Hilary Longhurst, who is both a clinical immunologist at Auckland Hospital Te Toku Tumai and an honorary associate professor at the University of Auckland.

"Plus, of course, there is huge potential for development of similar CRISPR/Cas9 treatments for other genetic disorders."

Globally, it is estimated one in 50,000 people have hereditary angioedema, however, because it is rare, it is often not correctly diagnosed.

In the phase one study, there were no serious or lasting side-effects from the single infusion, which took place over two to four hours under clinical supervision from late 2021 and onwards.

The investigational therapy, called NTLA-2002, utilises in vivo CRISPR/Cas9 technology to target the KLKB1 gene, which is responsible for producing plasma prekallikrein.

By editing this gene, the therapy reduces the levels of total plasma kallikrein, effectively preventing angioedema (swelling) attacks.

The trial, published in the New England Journal of Medicine, demonstrated dose-dependent reduction in total plasma kallikrein protein with reductions of up to 95 percent achieved.

A mean reduction of 95 percent in angioedema attacks was observed across all patients through to the latest follow-up.

The patients from the initial study will be followed up for a further 15 years to continue to assess long-term safety and efficacy.

A larger and more robust, double-blinded, placebo-controlled phase two trial is under way and a Phase 3 trial is planned to start in the second half of 2024.

Dr Danny Cohn, from the Department of Vascular Medicine at the Amsterdam University Medical Center says these promising results are a step forward for this group of patients.

"We've never been closer to the ultimate treatment goal of normalising hereditary angioedema patients' lives and offering total control of the disease," says Dr Cohn.

Dr Padmalal Gurugama, consultant in clinical immunology and allergy at Cambridge University Hospitals, UK says the gene editing therapy has the potential to significantly improve patients' lives.

"Hereditary angioedema can cause patients severe swellings and intense pain which can be life-threatening as well as restricting normal activities, such as going to work or school.

"Because it is often misdiagnosed, many patients undergo unnecessary treatments and invasive procedures."

The therapy affects only the patient and is not passed onto their children, who still have an even chance of inheriting the disorder.

The studies have been funded by US company Intellia Therapeutics, which chose New Zealand to lead the research as, at that time -- late 2021, it had relatively fewer Covid-19 cases than other countries.

So far, the only approved CRISPR therapy, CASGEVY, is for sickle cell disease and beta thalassemia.

However, CASGEVY is an ex vivo CRISPR therapy, where the cells are taken from the patient and edited outside of the body and then reinfused, whereas NTLA-2002 is an in vivo CRISPR therapy, where the targeted gene editing occurs directly within the body.

Read more at Science Daily

Half the population to have a mental health disorder by 75

A global study co-led by researchers from The University of Queensland and Harvard Medical School has found one in two people will develop a mental health disorder in their lifetime.

Professor John McGrath from UQ's Queensland Brain Institute, Professor Ronald Kessler from Harvard Medical School, and their colleagues from 27 other countries, analysed data from more than 150,000 adults across 29 countries between 2001 and 2022, taken from the largest ever coordinated series of face-to-face interviews -- the World Health Organisation's World Mental Health Survey initiative.

Lead author Professor McGrath said the results demonstrate the high prevalence of mental health disorders, with 50 per cent of the population developing at least one disorder by the age of 75.

"The most common were mood disorders such as major depression or anxiety," Professor McGrath said.

"We also found the risk of certain mental disorders differed by sex."

The 3 most common mental health disorders among women:
 

• Depression
• Specific phobia (a disabling anxiety that interferes with daily life)
• Post-traumatic stress (PTSD)

The 3 most common mental health disorders among men:
 

• Alcohol abuse
• Depression
• Specific phobia

The research also found mental health disorders typically first emerge in childhood, adolescence or young adulthood.

"The peak age of first onset was at 15 years old, with a median age of onset of 19 for men and 20 for women," Professor McGrath said.

"This lends weight to the need to invest in basic neuroscience to understand why these disorders develop."

Professor Kessler said investment was also needed in mental health services with a particular focus on young people.

"Services need to be able to detect and treat common mental disorders promptly, and be optimised to suit patients in these critical parts of their lives," Professor Kessler said.

"By understanding the age at which these disorders commonly arise, we can tailor public health interventions and allocate resources to ensure that appropriate and timely support is available to individuals at risk."

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How does dopamine regulate both learning and motivation?

A new study from the Netherlands Institute for Neuroscience brings together two schools of thought on the function of the neurotransmitter dopamine: one saying that dopamine provides a learning signal, the other saying that dopamine drives motivation. 'But it is probably both', says Ingo Willuhn.

It is well-known that the dopamine system is implicated in signaling reward-related information as well as in actions that generate rewarding outcomes. This can be investigated using either Pavlovian and operant conditioning experiments. Pavlovian conditioning describes how your brain makes an association between two situations or stimuli that previously seemed unrelated. A famous example is Pavlov's experiment, where a dog heard a sound before receiving food. After several such pairings of the sound with food delivery, the sound alone began to cause the dog to salivate. Operant conditioning, or instrumental learning, differs from this in that the behavior of an individual is important to earn a food reward. Meaning that the individual after hearing a sound, has to perform a so-called operant action to receive the reward. In animal experiments, such a operant response is often the pressing of a lever.

Dopamine measurements in nucleus accumbens

In the final PhD paper of Jessica Goedhoop in collaboration with Tara Arbab and Ingo Willuhn from the Netherlands Institute for Neuroscience, they take a closer look at the role of dopamine signaling in learning and motivation. The team directly compared the two conditioning paradigms: male rats underwent either Pavlovian or operant conditioning while dopamine release was measured in the nucleus accumbens, a brain region central for processing this information. During the experiments a cue light was illuminated for a duration of 5 seconds. For the Pavlovian group, a food pellet was delivered into the reward magazine directly after the cue light turned off. For the operant conditioning group, turning off the cue light was followed by extension of the lever below the cue light into the operant box. The lever was retracted after one lever press, which immediately resulted in the delivery of one food pellet reward into the food magazine. If there was no lever press within 5 seconds after lever extension, the lever was retracted and no reward was delivered.

Sustained dopamine release in operant conditioning

Rats in both groups released the same quantity of dopamine at the onset of the reward-predictive cue. However, only the operant-conditioning group showed a subsequent, sustained plateau in dopamine concentration throughout the entire 5-second cue presentation (throughout cue presentation and before lever press). This dopamine sustainment was observed reliably and consistently throughout systematic manipulation of experimental parameters and behavioral training. Therefore, the researchers believe that sustained dopamine levels may be an intermediate between learning and action, conceptually related to the motivation to generate a reward-achieving action.

Ingo Willuhn: 'There have been a lot of studies on dopamine. We have a decent idea of when dopamine is released in the brain, but there is still lots of discussion on what the precise variables are that determine such dopamine signaling. Essentially discussion on what dopamine "means." To investigate this, scientists usually perform either Pavlovian or operant conditioning experiments. But they test slightly different things. Both have to do with learning an association between a neutral stimulus and a reward. But operant conditioning requires the motivation to perform an action in addition to that (to earn the reward). Therefore, we compared the two types of conditioning in the same experiment.'

Adding a piece to the puzzle

'Our results bring together the two camps of scientists that often battle with each other: one says that dopamine is a so-called reward-prediction error signal, meaning that dopamine is released when something better than expected happens, and is suppressed when something worse than expected happens. It is a learning (or teaching) signal. The other camp says that this is not true. They say that dopamine has something to do with motivation. Increased dopamine release will invigorate the subjects and they work harder to get the reward. There have been a few attempts in the past to bring these two camps together, but there is still need for more knowledge on the subject.'

'What we saw in our study is that only in the operant-learning task dopamine levels stayed high. It seems that the motivation is encoded in this plateau. Reward prediction is the initial dopamine peak, but how much the signal stays up, reflects motivation. Thus, our paper suggests that there is a possibility that dopamine is involved in both, learning and motivation. The next steps will be to get more details out of this. We need to replicate the experiments and make them more sophisticated. The more sophisticated you make it, the more precise our predictions have to be. We are going to build on it and see whether it still holds up.'

Implications

'Dopamine is not only involved in everyday life but also in disorders such as addiction, Parkinson's disease, and schizophrenia. Because of the two camps existing, there is disagreement about what happens exactly. For example, some researchers say that when addicts take drugs dopamine release increases and as a consequence all the environmental cues become more meaningful. Addicts learn that these cues are associated with the drug and they take more and more drug, because they are constantly reminded of the drug everywhere. In this view, addiction is misguided learning. Other researchers would say that motivation to take the drug intensifies with more frequent drug intake, because the drug elevates dopamine release. This study indicates that it may be both. Depending on the precise timing, both systems could be the driver, and both could be involved.'

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Researchers find genetic links between traits are often overstated

Many estimates of how strongly traits and diseases share genetic signals may be inflated, according to a new UCLA-led study that indicates current methods for assessing genetic relationships between traits fail to account for mating patterns.

Through the use of powerful genome sequencing technology, scientists in recent years have sought to understand the genetic associations between traits and disease risk, hoping that discoveries of shared genetics could point to clues for tackling diseases. However, UCLA researchers said their new study, published Nov. 17 in Science, provides caution against relying too heavily on genetic correlation estimates. They say that such estimates are confounded by non-biological factors more than has been previously appreciated.

Genetic correlation estimates typically assume that mating is random. But in the real world, partners tend to pair up because of many shared interests and social structures. As a result, some genetic correlations in previous work that have been attributed to shared biology may instead represent incorrect statistical assumptions. For example, previous estimates of genetic overlap between body mass index (BMI) and educational attainment are likely to reflect this type of population structure, induced by "cross-trait assortative mating," or how individuals of one trait tend to partner with individuals of another trait.

The study authors said genetic correlation estimates deserve more scrutiny, since these estimates been used to predict disease risk, glean for clues for potential therapies, inform diagnostic practices, and shape arguments about human behavior and societal issues. The authors said some in the scientific community have placed too much emphasis on genetic correlation estimates based on the idea that studying genes, because they are unalterable, can overcome confounding factors.

"If you just look at two traits that are elevated in a group of people, you can't conclude that they're there for the same reason," said lead author Richard Border, a postdoctoral researcher in statistical genetics at UCLA. "But there's been a kind of assumption that if you can track this back to genes, then you would have the causal story."

Based on their analysis of two large databases of spousal traits, researchers found that cross-trait assortative mating is strongly associated with genetic correlation estimates and plausibly accounts for a "substantial" portion of genetic correlation estimates.

"Cross-trait assortative mating has affected all of our genomes and caused interesting correlations between DNA you inherit from your mother and DNA you inherit from your father across the whole genome," said study co-author Noah Zaitlen, a professor of computational medicine and neurology at UCLA Health.

The researchers also examined genetic correlation estimates of psychiatric disorders, which have sparked debate in the psychiatric community because they appear to show genetic relationships among disorders that seemingly have little similarity, such as attention-deficit hyperactivity disorder and schizophrenia. The researchers found that genetic correlations for a number of unrelated traits could be plausibly attributed to cross-trait assortative mating and imperfect diagnostic practices. On the other hand, their analysis found stronger links for some pairs of traits, like anxiety disorders and major depression, suggesting that there truly is at least some shared biology.

"But even when there is a real signal there, we're still suggesting that we're overestimating the extent of that sharing," Border said.

Read more at Science Daily

Some types of stress could be good for brain functioning

It may feel like an anvil hanging over your head, but that looming deadline stressing you out at work may actually be beneficial for your brain, according to new research from the Youth Development Institute at the University of Georgia.

Published in Psychiatry Research, the study found that low to moderate levels of stress can help individuals develop resilience and reduce the risk of developing mental health disorders, like depression and antisocial behaviors. Low to moderate stress can also help individuals to cope with future stressful encounters.

"If you're in an environment where you have some level of stress, you may develop coping mechanisms that will allow you to become a more efficient and effective worker and organize yourself in a way that will help you perform," said Assaf Oshri, lead author of the study and an associate professor in the College of Family and Consumer Sciences.

The stress that comes from studying for an exam, preparing for a big meeting at work or pulling longer hours to close the deal can all potentially lead to personal growth. Being rejected by a publisher, for example, may lead a writer to rethink their style. And being fired could prompt someone to reconsider their strengths and whether they should stay in their field or branch out to something new.

But the line between the right amount of stress and too much stress is a thin one.

"It's like when you keep doing something hard and get a little callous on your skin," continued Oshri, who also directs the UGA Youth Development Institute. "You trigger your skin to adapt to this pressure you are applying to it. But if you do too much, you're going to cut your skin."

Good stress can act as a vaccine against the effect of future adversity

The researchers relied on data from the Human Connectome Project, a national project funded by the National Institutes of Health that aims to provide insight into how the human brain functions. For the present study, the researchers analyzed the project's data from more than 1,200 young adults who reported their perceived stress levels using a questionnaire commonly used in research to measure how uncontrollable and stressful people find their lives.

Participants answered questions about how frequently they experienced certain thoughts or feelings, such as "in the last month, how often have you been upset because of something that happened unexpectedly?" and "in the last month, how often have you found that you could not cope with all the things that you had to do?"

Their neurocognitive abilities were then assessed using tests that measured attention and ability to suppress automatic responses to visual stimuli; cognitive flexibility, or ability to switch between tasks; picture sequence memory, which involves remembering an increasingly long series of objects; working memory and processing speed.

The researchers compared those findings with the participants' answers from multiple measures of anxious feelings, attention problems and aggression, among other behavioral and emotional problems.

The analysis found that low to moderate levels of stress were psychologically beneficial, potentially acting as a kind of inoculation against developing mental health symptoms.

"Most of us have some adverse experiences that actually make us stronger," Oshri said. "There are specific experiences that can help you evolve or develop skills that will prepare you for the future."

But the ability to tolerate stress and adversity varies greatly according to the individual.

Things like age, genetic predispositions and having a supportive community to fall back on in times of need all play a part in how well individuals handle challenges. While a little stress can be good for cognition, Oshri warns that continued levels of high stress can be incredibly damaging, both physically and mentally.

"At a certain point, stress becomes toxic," he said. "Chronic stress, like the stress that comes from living in abject poverty or being abused, can have very bad health and psychological consequences. It affects everything from your immune system, to emotional regulation, to brain functioning. Not all stress is good stress."

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Diet plays key role in ADHD symptoms in children

 Here's a good reason for children with attention deficit hyperactivity disorder (ADHD) to eat their fruits and vegetables: It may help reduce inattention issues, a new study suggests.

As part of a larger study, researchers asked parents of 134 kids with ADHD symptoms to complete a detailed questionnaire about the typical foods the children ate, including portion sizes, over a 90-day period.

Another questionnaire asked parents to rate symptoms of inattention -- a hallmark of ADHD -- in their kids, such as having trouble staying focused, not following instructions, difficulty remembering things, and difficulty regulating emotions.

Results showed that kids who consumed more fruits and vegetables showed less severe symptoms of inattention, said Irene Hatsu, co-author of the study and associate professor of human nutrition at The Ohio State University.

"Eating a healthy diet, including fruits and vegetables, may be one way to reduce some of the symptoms of ADHD," Hatsu said.

The study was published online recently in the journal Nutritional Neuroscience.

The data for this research was collected as part of the Micronutrients for ADHD in Youth (MADDY) Study, which examined the efficacy of a 36-ingredient vitamin and mineral supplement to treat symptoms of ADHD and poor emotional control in the 134 kids aged 6 to 12.

The study that evaluated the effectiveness of the supplement showed that children who took the micronutrients were three times as likely to show significant improvement in their ADHD and emotional dysregulation symptoms than those who took a placebo. That study was published last year in the Journal of the American Academy of Child and Adolescent Psychiatry.

Another study involving the same children, published earlier this year in the journal Nutrients, showed that kids whose families had higher levels of food insecurity were more likely than others to show more severe symptoms of emotional dysregulation, such as chronic irritability, angry moods and outbursts of anger.

The three studies all paint a similar picture, Hatsu said: A healthy diet that provides all the nutrients that children require can help reduce the symptoms of ADHD in children.

"What clinicians usually do when kids with ADHD start having more severe symptoms is increase the dose of their treatment medication, if they are on one, or put them on medication," Hatsu said.

"Our studies suggest that it is worthwhile to check the children's access to food as well as the quality of their diet to see if it may be contributing to their symptom severity."

Children in the MADDY study, all of whom met the criteria for ADHD, were recruited from three sites: Columbus, Ohio; Portland, Oregon; and Lethbridge, Alberta, Canada. The study took place between 2018 and 2020. Participants were either not taking medication or stopped using it two weeks before the study began.

The studies on fruit and vegetable intake and the role of food insecurity were based on data collected when the children were first enrolled in the study, before they began taking the micronutrient supplement or placebo.

Why may diet be so important in ADHD?

Researchers believe that ADHD is related to low levels of some neurotransmitters in the brain -- and vitamins and minerals play a key role as cofactors in helping the body make those important neurochemicals and in overall brain function, Hatsu said.

Food insecurity may play an additional role.

"Everyone tends to get irritated when they're hungry and kids with ADHD are no exception. If they're not getting enough food, it could make their symptoms worse," she said.

Also, the stress of parents who are upset about not being able to provide enough food for their children can create family tension that could lead to more symptoms for children with ADHD.

The MADDY study is one of the first to look at the relationship between ADHD symptoms and diet quality among children in the United States and Canada, Hatsu said.

That's important because Western diets are more likely than many others, such as the Mediterranean diet, to fall short on fruit and vegetable intake, she said.

"We believe clinicians should assess the food security status of children with ADHD before creating or changing a treatment program," Hatsu said.

Read more at Science Daily

Key protein identified for brain stem cell longevity

A receptor that was first identified as necessary for insulin action, that also is located on the neural stem cells found deep in the brains of mice, is pivotal for brain stem cell longevity, according to a Rutgers study, a finding that has important implications for brain health and future therapies for brain disorders.

The study, appearing in the journal Stem Cell Reports, pinpoints a specific protein known as the insulin receptor (INSR), which is abundant on the neural stem cells that reside in the brain's subventricular zone. During development, neural stem cells give rise to the entire nervous system, and they persist into adulthood. Over the lifespan these neural stem cells produce new neurons and non-neuronal cells that maintain the infrastructure and functioning of the brain.

Separately, the scientists made another finding when examining brain tumors: INSR plays a crucial role in sustaining and maintaining a population of specialized brain cancer cells known as glioblastoma (GBM) stem cells. When they inactivated the INSR in the GBM stem cells they inhibited the growth of those primitive tumor forming cells.

"It's important to understand the molecular mechanisms that are critical for the growth and sustenance of the brain's stem cells under normal and abnormal growth states," said study author Steven Levison, a professor of neuroscience in the Department of Pharmacology, Physiology and Neuroscience and director of the Laboratory for Regenerative Neurobiology at Rutgers New Jersey Medical School. "Comprehending the signals that regulate these primitive cells could one day lead to new therapeutics for brain disorders."

Many neurodegenerative disorders, such as multiple sclerosis, Parkinson disease and Alzheimer's disease, are connected with the destruction of brain cells, said co-author Teresa Wood, a Distinguished Professor and Rena Warshow Endowed Chair in Multiple Sclerosis in the Department of Pharmacology, Physiology and Neuroscience at Rutgers New Jersey Medical School.

"If we could influence how brain stem cells function then we can use this knowledge to replace diseased or dead brain cells with living ones, which would advance the treatment of neurological diseases and brain injuries," said Wood, who also teaches and conducts research at the Cancer Institute of New Jersey.

Cell receptors such as INSR are protein molecules that reside on the surfaces of cells. Substances, either natural or human-made, that open the "lock" of a receptor can spur a cell to divide, differentiate or die. By identifying which receptors perform these functions on specific cell types, and by understanding their structures and functions, scientists can design substances that act as keys to receptors, to turn them "on" or "off."

Previous studies by this research team had shown that a certain "key," the signaling protein known as the insulin-like growth factor-II (IGF-II), was necessary to maintain the neural stem cells in the two places of the adult brain that harbor these primitive cells. In the current experiment, scientists were looking to identify the receptor. To do so, they used genetic tools that allowed them to both delete the INSR and introduce a fluorescent protein so they could track the neural stem cells and the cells they generate. They found that the numbers of neural stem cells in the subventricular zone in the brains of mice lacking the INSR collapsed.

Adult neurogenesis -- the idea that new cells are produced in the adult brain -- has been a burgeoning field of scientific inquiry since the late 1990s, when researchers confirmed what had only been a theory in lab studies of human, primate and bird brains. Neural stem cells in the adult are stem cells that can self-renew and produce new neurons and the supporting cells of the brain, oligodendrocytes and astrocytes.

"Given the widespread interest in stem cells as well as interest in whether alterations to adult stem cells might contribute to cancer, our research findings should be of interest," Levison said.

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A key brain region for substance use disorders now has a searchable atlas of distinct cell populations

In a work of systematic biology that advances the field, University of Alabama at Birmingham researchers have identified 16 distinct cell populations in a complex area of the midbrain called the ventral tegmental area, or VTA.

The VTA is important for its role in the dopamine neurotransmission involved in reward-directed behavior. Substance use disorders involve dysregulation of these reward circuits, leading to repeated drug-seeking despite adverse consequences. These include more than 100,000 drug overdose deaths in the United States in the most recent year. The VTA also has a role in several other neuropsychiatric disorders.

Thus, expanding knowledge of its function is a start to explaining the mechanisms for substance use disorders involving drugs like cocaine, alcohol, opioids and nicotine, or psychiatric disorders like schizophrenia and attention deficit hyperactivity, or ADHD.

Dopamine is one of the neurotransmitters used by the brain as chemical messengers to send signals between nerve cells. While decades of research have focused on dopaminergic neurotransmission in the VTA, there is also substantial evidence for the importance of two other neurotransmitters acting in the VTA in reward-related behaviors -- GABA and glutamate. There is also evidence for "combinatorial" neurons that can potentially synthesize and release multiple neurotransmitters. These suggest an additional layer of complexity in VTA cellular and synaptic function.

Systematic biology is the science of classification, and it usually refers to the classification of organisms with regard to their natural relationships. The UAB VTA study classifies cell populations to extend and deepen previous work on the different cell types in the VTA, to provide a starting point for deciphering the relationships among these cells and their broad connections to other areas of the brain. The research, published in Cell Reports, was led by co-first authors Robert A. Phillips III and Jennifer J. Tuscher, Ph.D., and corresponding author Jeremy J. Day, Ph.D.

The 16 distinct cell populations were identified by differences in gene expression after single-nucleus RNA sequencing of 21,600 cells from the rat VTA, creating a searchable online atlas of the VTA. The rat is the prime model for reward and substance use studies. This unbiased approach -- in contrast to previous studies that selected some subsets of cells for RNA sequencing -- was used to create the largest and most comprehensive single-cell transcriptomic analysis focused exclusively on the composition and molecular architecture of the VTA.

Though it was well known that the VTA is composed of heterogeneous cell types, the UAB atlas expands those studies in several key ways.

"For example, previous single-cell sequencing studies were conducted exclusively in the mouse brain and have relied primarily on sequencing a subset of fluorescence-activated cell sorting-isolated midbrain dopaminergic populations, rather than sampling all VTA cell types," Day said. "Notably, our sequencing dataset focuses exclusively on VTA sub-regions, unlike other studies that have focused on pooled cells from the mouse substantia nigra and VTA or a subset of fluorescently tagged cells from general midbrain regions."

The 16 distinct cell populations include classic dopaminergic neurons, three subsets of glutamatergic neurons and three subsets of GABAergic neurons, as well as nine other cell types, including astrocytes and glial cells.

After sub-clustering neuronal cells, the UAB researchers also identified four sub-clusters that may represent neurons capable of combinatorial neurotransmitter release. They also identified selective gene markers for classically defined dopamine neurons and for the combinatorial neurons. A selective marker allows viral targeting of distinct VTA subclasses for functional studies.

The researchers also examined sub-clusters for opioid neuropeptides and their receptors, and identified pan-neuronal increased expression for risk genes associated with schizophrenia and "smoking initiation," as well as enrichment of ADHD risk genes in two glutamatergic neuronal populations.

Read more at Science Daily

Decoding a direct dialog between the gut microbiota and the brain

Gut microbiota by-products circulate in the bloodstream, regulating host physiological processes including immunity, metabolism and brain functions. Scientists from the Institut Pasteur (a partner research organization of Université Paris Cité), Inserm and the CNRS have discovered that hypothalamic neurons in an animal model directly detect variations in bacterial activity and adapt appetite and body temperature accordingly. These findings demonstrate that a direct dialog occurs between the gut microbiota and the brain, a discovery that could lead to new therapeutic approaches for tackling metabolic disorders such as diabetes and obesity. The findings are due to be published in Science on April 15, 2022.

The gut is the body's largest reservoir of bacteria. A growing body of evidence reveals the degree of interdependence between hosts and their gut microbiota, and emphasizes the importance of the gut-brain axis. At the Institut Pasteur, neurobiologists from the Perception and Memory Unit (Institut Pasteur/CNRS), immunobiologists from the Microenvironment and Immunity Unit (Institut Pasteur/Inserm), and microbiologists from the Biology and Genetics of the Bacterial Cell Wall Unit (Institut Pasteur/CNRS/Inserm) have shared their expertise to investigate how bacteria in the gut directly control the activity of particular neurons in the brain.

The scientists focused on the NOD2 (nucleotide oligomerization domain) receptor which is found inside of mostly immune cells. This receptor detects the presence of muropeptides, which are the building blocks of the bacterial cell wall. Moreover, it has previously been established that variants of the gene coding for the NOD2 receptor are associated with digestive disorders, including Crohn's disease, as well as neurological diseases and mood disorders. However, these data were insufficient to demonstrate a direct relationship between neuronal activity in the brain and bacterial activity in the gut. This was revealed by the consortium of scientists in the new study.

Using brain imaging techniques, the scientists initially observed that the NOD2 receptor in mice is expressed by neurons in different regions of the brain, and in particular, in a region known as the hypothalamus. They subsequently discovered that these neurons' electrical activity is suppressed when they come into contact with bacterial muropeptides from the gut. "Muropeptides in the gut, blood and brain are considered to be markers of bacterial proliferation," explains Ivo G. Boneca, Head of the Biology and Genetics of the Bacterial Cell Wall Unit at the Institut Pasteur (CNRS/Inserm). Conversely, if the NOD2 receptor is absent, these neurons are no longer suppressed by muropeptides. Consequently, the brain loses control of food intake and body temperature. The mice gain weight and are more susceptible to developing type 2 diabetes, particularly in older females.

In this study, the scientists have demonstrated the astonishing fact that neurons perceive bacterial muropeptides directly, while this task was thought to be primarily assigned to immune cells. "It is extraordinary to discover that bacterial fragments act directly on a brain center as strategic as the hypothalamus, which is known to manage vital functions such as body temperature, reproduction, hunger and thirst," comments Pierre-Marie Lledo, CNRS scientist and Head of the Institut Pasteur's Perception and Memory Unit.

The neurons thus appear to detect bacterial activity (proliferation and death) as a direct gauge of the impact of food intake on the intestinal ecosystem. "Excessive intake of a specific food may stimulate the disproportionate growth of certain bacteria or pathogens, thus jeopardizing intestinal balance," says Gérard Eberl, Head of the Microenvironment and Immunity Unit at the Institut Pasteur (Inserm).

Read more at Science Daily

Newborns’ brains already organized into functional networks

Right from birth, human brains are organized into networks that support mental functions such as vision and attention, a new study shows.

Previous studies had shown that adults have seven such functional networks in the brain. This study, the first to take a fine-grained, whole-brain approach in newborns, found five of those networks are operating at birth.

Crucially, the study also found individual variability in those networks in newborns, which may have implications for how genetics affects behavior in adults.

"For centuries, humans have wondered about what makes them unique and the role of genetic programming versus our lifetime of experience," said Zeynep Saygin, senior author of the study and assistant professor of psychology at The Ohio State University.

"Our study shows variability in the brain at birth that may be related to some of the behavioral differences we see in adults."

The study, published recently in the journal NeuroImage, was led by M. Fiona Molloy, a psychology graduate student at Ohio State.

The researchers analyzed fMRI scans of the brains of 267 newborns, most less than a week old, who were part of the Developing Human Connectome Project. All infants were scanned for 15 minutes while they were asleep.

The study involved analysis of the smallest bits of brain possible with MRI -- called voxels or volumetric pixels -- to see how the signals of each voxel were related to other voxels in the brain.

"Even when we're sleeping, the brain is active and different parts are communicating with each other," Saygin said.

"We identify networks by finding which parts of the brain show similar patterns of activity at the same time -- for example when one area activates, the other does too. They are talking to each other."

Findings showed five networks in newborns that resembled those found in adults: the visual, default, sensorimotor, ventral attention and high-level vision networks.

Adults have two additional networks not found in the brains of newborns: the control and limbic networks. These are both involved with higher-level functions, Saygin explained.

The control network allows adults to make plans to meet goals. The limbic network is involved in emotional regulation.

"Babies have little cognitive control and emotional regulation, so it is not surprising that these networks aren't developed," Saygin said.

"But one possibility would have been that they are set up at birth and just need to be honed. That's not what we found, though. Those networks are not there at all yet and must develop through experience."

The researchers also examined individual differences in the brain networks of the newborns studied. Results showed that the ventral attention network showed the most variability in the newborns. This is the network involved in directing attention to important stimuli encountered in the world, especially something that may be unexpected.

"Our results suggest that the ventral attention network is a stable source of individual variability that exists at birth and perhaps persists through the lifetime," she said.

In adults, this individual variability in network organization has been linked to behavior and different disorders.

"We see individual differences in network organization as early as birth, and it could be interesting to see if these differences predict behavior or risk of psychological disorders later in life," Molloy said.

In another analysis, the researchers used tissue samples of human brains available through the Allan Human Brain Atlas to explore how differences in the brain networks in the newborns may be tied to differences in gene expression -- the process of turning on or activating genes.

They found multiple genes from the brain tissue samples that may have led to the specific brain organizations they found in individual newborns in the study.

"This might uncover a potential genetic basis for why we're seeing these differences in the networks of newborns in our study," she said.

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CRISPR gene editing reveals biological mechanism behind common blood disorder

UNSW researchers have used CRISPR gene editing -- a type of 'molecular scissors' -- to understand how deletions in one area of the genome can affect the expression of nearby genes. The work, led by UNSW Associate Professor Kate Quinlan and Professor Merlin Crossley, together with collaborators from the US, will help researchers investigate new therapeutic approaches for one of the world's most devastating genetic blood disorders -- sickle cell disease.

Asymptomatic sickle cell disease patients actually lack a tiny part of the genome, scientists have shown.

The team's findings are published today in academic journal Blood. (Just last week, A/Prof. Quinlan and Prof. Crossley received a $412,919 ARC linkage grant to fund a collaboration between UNSW Sydney and CSL that follows on from the work described in this paper.)

"Sickle cell disease and beta thalassemia, a closely related disease, are inherited genetic conditions that affect red blood cells. They are fairly common worldwide -- over 318,000 infants with these conditions are born every year, and haemoglobin disorders cause 3 per cent of deaths in children aged under five years worldwide," says co-lead author A/Prof. Quinlan.

Genetic mutations -- specifically, a defect in the adult globin gene -- are responsible for the disorders. The mutant genes affect the production of haemoglobin, the protein in red blood cells that carries oxygen around our bodies.

"Interestingly, when children are born, they don't show disease symptoms at first, even if they have the mutations, because at that stage, they're still expressing foetal globin and not yet adult globin. That's because we have different haemoglobin genes that we express at different stages of development," says A/Prof. Quinlan.

"As the foetal globin gets turned off, and adult globin gets turned on -- which happens within about the first year of life -- the symptoms start to manifest."

When that happens, the red blood cells take on unusual, sickled shapes and block small blood vessels, causing pain, organ damage, and premature death. The disease is particularly common in tropical countries, and in people from places where malaria is endemic.

"The goal of our research is finding out how we can reverse the foetal to adult globin switch, so that patients continue to express foetal globin throughout life, rather than the mutant adult globin genes that cause blood cells to become stiff and block vessels," says A/Prof. Quinlan.

Interestingly, this already happens in some people with sickle cell disease: thanks to another, beneficial genetic mutation, a rare subset of patients keeps the foetal globin gene 'on' throughout their life and are protected from sickle cell symptoms.

"In these patients, the persistent expression of foetal globin effectively compensates for the defective adult globin -- but up until this piece of research, we didn't really understand the process that led to this incredible advantage," A/Prof. Quinlan says.

'Deleting' genes with CRISPR

To get to the bottom of what's going on in these lucky people's genome, UNSW PhD student Sarah Topfer compiled data on the rare families that express foetal globin throughout life.

"As a first step, Sarah compared deletions in lots of different patients' genomes -- essentially, she looked to see if any shared element was missing in all of them. What do these patients have in common? She found one very small region was deleted in all these patients' genomes."

Sarah then used CRISPR gene editing to replicate some of these big patient deletions -- and the small deleted bit they all had in common -- in cell lines in the lab.

"CRISPR allows us to 'cut' bits of DNA out of cells grown in the lab, to modify genes and see what happens as a result -- it's essentially a tool to figure out what genes do inside living cells," A/Prof. Quinlan says.

"We found that deleting just that one little bit was sufficient to make foetal globin go up and adult globin down -- which suggests that we have found the key mechanism that can explain why foetal globin levels remains high in these asymptomatic patients," A/Prof. Quinlan says.

"Effectively, by deleting the adult globin 'on switch', we made the foetal globin 'on switch' active."

Prof. Quinlan says the results were unexpected.

"It was surprising to see the findings -- many people have studied these mutations for many years, so the idea that there'd be one unifying hypothesis that could explain them rather than them all working through different mechanisms will be surprising for the field.

"While we went in with the hypothesis that there might be one mechanism, we didn't expect it to come out so cleanly -- we thought that perhaps it would be more complicated than what we'd initially thought."

The CRISPR revolution and potential therapies

Co-lead author Prof. Crossley, who is also UNSW's Deputy Vice-Chancellor, Academic & Student Life, says it was impossible to test this model prior to the advent of CRISPR gene editing.

"Our group has specialised in using this new technology to understand globin gene switching," Prof. Crossley says. "Australia now has a significant number of people with either sickle cell disease or thalassemia.

"The work, supported by the National Health and Medical Research Council, is an important example of how the CRISPR gene editing revolution is accelerating scientific understanding and will deliver new therapies to the clinic."

The scientists say the work revealed today is improving our fundamental understanding of the mechanism behind sickle cell disease.

"What this really helps us to do is understand this process of turning off foetal globin and turning on adult globin and how we could reverse that, so that we can use this understanding of the mechanism to help us look for new therapeutic approaches -- it's a key piece of the puzzle," A/Prof. Quinlan says.

Some of Prof. Crossley's team's previous discoveries in the field are informing clinical trials already -- by using beneficial mutations they've discovered in the past that could lead to therapies for these disorders.

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Octopus-like tentacles help cancer cells invade the body

With help from the best tweezers in the world a team of researchers from the University of Copenhagen has shed new light on a fundamental mechanism in all living cells that helps them explore their surroundings and even invade tissue. Their discovery could have implications for research into cancer, neurological disorders and much else.

Using octopus-like tentacles, a cell pushes toward its target, a bacterium, like a predator tracking down its prey. The scene could be playing out in a nature programme. Instead the pursuit is being observed at the nano-scale through a microscope at the University of Copenhagen's Niels Bohr Institute. The microscope recording shows a human immune cell pursuing and then devouring a bacterium.

With their new study, a team of Danish researchers has added to the world's understanding of how cells use octopus-like tentacles called filopodia to move around in our bodies. This discovery about how cells move had never been addressed. The study is being published today in the journal, Nature Communications.

"While the cell doesn't have eyes or a sense of smell, its surface is equipped with ultra-slim filopodia that resemble entangled octopus tentacles. These filopodia help a cell move towards a bacterium, and at the same time, act as sensory feelers that identify the bacterium as a prey," explains Associate Professor Poul Martin Bendix, head of the laboratory for experimental biophysics at the Niels Bohr Institute.

The discovery is not that filopodia act as sensory devices -- which was already well established -- but rather about how they can rotate and behave mechanically, which helps a cell move, as when a cancer cell invades new tissue.

"Obviously, our results are of interest to cancer researchers. Cancer cells are noted for their being highly invasive. And, it is reasonable to believe that they are especially dependent on the efficacy of their filopodia, in terms of examining their surroundings and facilitating their spread. So, it's conceivable that by finding ways of inhibiting the filopodia of cancer cells, cancer growth can be stalled," explains Associate Professor Poul Martin Bendix.

For this reason, researchers from the Danish Cancer Society Research Center are a part of the team behind the discovery. Among other things, the cancer researchers are interested in whether switching off the production of certain proteins can inhibit the transport mechanisms which are important for the filopodia of cancer cells.

The cell's engine and cutting torch

According to Poul Martin Bendix, the mechanical function of filopodia can be compared to a rubber band. Untwisted, a rubber band has no power. But if you twist it, it contracts. This combination of twisting and contraction helps a cell move directionally and makes the filopodia very flexible.

"They're able to bend -- twist, if you will -- in a way that allows them to explore the entire space around the cell, and they can even penetrate tissues in their environment," says lead author, Natascha Leijnse.

The mechanism discovered by the Danish researchers appears to be found in all living cells. Besides cancer cells, it is also relevant to study the importance of filopodia in other types of cells, such as embryonic stem cells and brain cells, which are highly dependent on filopodia for their development.

Studying cells with the best tweezers in the world

The project involved interdisciplinary collaboration at the Niels Bohr Institute, where Associate Professor Amin Doostmohammadi, who heads a research group that simulates biologically active materials, contributed with the modelling of filopodia behaviour.

"It is very interesting that Amin Doostmohammadi could simulate the mechanical movements we witnessed through the microscope, completely independent of chemical and biological details," explains Poul Martin Bendix.

The main reason that the team succeeded in being the first to describe the mechanical behaviour of filopodia is that NBI has unique equipment for this type of experiment, as well as skilled researchers with tremendous experience working with optical tweezers. When an object is extraordinarily small, holding onto it mechanically becomes impossible. However, it can be held and moved using a laser beam with a wavelength carefully calibrated to the object being studied. This is called an optical tweezers.

"At NBI, we have some of the world's best optical tweezers for biomechanical studies. The experiments require the use of several optical tweezers and the simultaneous deployment of ultra-fine microscopy," explains Poul Martin Bendix.

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How does the brain make memories?

Researchers have discovered two types of brain cells that play a key role in dividing continuous human experience into distinct segments that can be recalled later. The discovery provides new promise as a path toward development of novel treatments for memory disorders such as dementia and Alzheimer's disease.

In a study led by Cedars-Sinai, researchers have discovered two types of brain cells that play a key role in dividing continuous human experience into distinct segments that can be recalled later. The discovery provides new promise as a path toward development of novel treatments for memory disorders such as dementia and Alzheimer's disease.

The study, part of a multi-institutional BRAIN Initiative consortium funded by the National Institutes of Health and led by Cedars-Sinai, was published in the peer-reviewed journal Nature Neuroscience. As part of ongoing research into how memory works, Ueli Rutishauser, PhD, professor of Neurosurgery, Neurology, and Biomedical Sciences at Cedars-Sinai, and co-investigators looked at how brain cells react as memories are formed.

"One of the reasons we can't offer significant help for somebody who suffers from a memory disorder is that we don't know enough about how the memory system works," said Rutishauser, senior author of the study, adding that memory is foundational to us as human beings.

Human experience is continuous, but psychologists believe, based on observations of people's behavior, that memories are divided by the brain into distinct events, a concept known as event segmentation. Working with 19 patients with drug-resistant epilepsy, Rutishauser and his team were able to study how neurons perform during this process.

Patients participating in the study had electrodes surgically inserted into their brains to help locate the focus of their epileptic seizures, allowing investigators to record the activity of individual neurons while the patients viewed film clips that included cognitive boundaries.

While these boundaries in daily life are nuanced, for research purposes, the investigators focused on "hard" and "soft" boundaries.

"An example of a soft boundary would be a scene with two people walking down a hallway and talking, and in the next scene, a third person joins them, but it is still part of the same overall narrative," said Rutishauser, interim director of the Center for Neural Science and Medicine and the Board of Governors Chair in Neurosciences at Cedars-Sinai.

In the case of a hard boundary, the second scene might involve a completely different set of people riding in a car. "The difference between hard and soft boundaries is in the size of the deviation from the ongoing narrative," Rutishauser said. "Is it a totally different story, or like a new scene from the same story?"

When study participants watched film clips, investigators noted that certain neurons in the brain, which they labeled "boundary cells," increased their activity after both hard and soft boundaries. Another group of neurons, labeled "event cells," increased their activity only in response to hard boundaries, but not soft boundaries.

Rutishauser and his co-investigators theorize that peaks in the activity of boundary and event cells -- which are highest after hard boundaries, when both types of cells fire -- send the brain into the proper state for initiating a new memory.

"A boundary response is kind of like creating a new folder on your computer," said Rutishauser. "You can then deposit files in there. And when another boundary comes around, you close the first folder and create another one."

To retrieve memories, the brain uses boundary peaks as what Rutishauser calls "anchors for mental time travel."

"When you try to remember something, it causes brain cells to fire," Rutishauser said. "The memory system then compares this pattern of activity to all the previous firing peaks that happened shortly after boundaries. If it finds one that is similar, it opens that folder. You go back for a few seconds to that point in time, and things that happened then come into focus."

To test their theory, investigators gave study participants two memory tests.

They first showed participants a series of still images and asked them whether or not they had seen them in the film clips they had viewed. Study participants were more likely to remember images that closely followed a hard or soft boundary, when a new "memory folder" would have been created.

Investigators also showed participants pairs of images from film clips they had viewed and asked which of the images appeared first. Participants had difficulty remembering the correct order of images that appeared on opposite sides of a hard boundary, possibly because the brain had segmented those images into separate memory folders.

Rutishauser said that therapies that improve event segmentation could help patients with memory disorders. Even something as simple as a change in atmosphere can amplify event boundaries, he explained.

"The effect of context is actually quite strong," Rutishauser said. "If you study in a new place, where you have never been before, instead of on your couch where everything is familiar, you will create a much stronger memory of the material."

The research team included postdoctoral fellow Jie Zheng, PhD, and neuroscientist Gabriel Kreiman, PhD, from Boston Children's Hospital; neurosurgeon Taufik A. Valiante, MD, PhD, of the University of Toronto; and Adam Mamelak, MD, professor of Neurosurgery and director of the Functional Neurosurgery Program at Cedars-Sinai.

In follow-up studies, the team plans to test the theory that boundary and event cells activate dopamine neurons when they fire, and that dopamine, a chemical that sends messages between cells, might be used as a therapy to strengthen memory formation.

Rutishauser and his team also noted during this study that when event cells fired in time with one of the brain's internal rhythms, the theta rhythm -- a repetitive pattern of activity linked to learning, memory and navigation -- subjects were better able to remember the order of images they had seen. This is an important new insight because it shows that deep brain stimulation that adjusts theta rhythms could prove therapeutic for memory disorders.

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New stem cell population provides a new way to study the awakening of the human genome

Researchers from the Babraham Institute have today published their latest work in the journal Cell Stem Cell describing a new subset of human embryonic stem cells that closely resemble the cells present at the genomic 'wake up call' of the 8-cell embryo stage in humans. This new stem cell model will allow researchers to map out the key genomic changes during early development, and help move towards a better understanding of the implications of genome activation errors in developmental disorders and embryo loss.

In all mammals, the early embryo undergoes a number of molecular events just after fertilisation that set the stage for the rest of development. During this key 'wake up call' the genome of the embryo takes over control of the cell's activities from the maternal genome. In humans, this happens at the 8-cell stage and is called zygotic genome activation (ZGA). Before the findings of this study, investigating the details of human ZGA could only be done in human embryos; existing human stem cell models represented the embryo only at later stages of the developmental process. In the UK, experiments using embryos are permitted but highly regulated, meaning that research into early development relied in part on alternative, non-human models.

In 2012, cells representing the genome activation stage of development were found in mouse embryonic stem cells (ESCs), allowing researchers to learn more about mammalian ZGA. Almost a decade later, the Reik lab at the Institute have found a human equivalent. The lab's discovery opens up a way to advance our knowledge of the earliest events during preimplantation development.

Dr Jasmin Taubenschmid-Stowers, lead author and Research Fellow in the Reik lab, part of the Institute's Epigenetics research programme , commented: "Studying mouse embryonic stem cells has allowed researchers to learn about the general process of genome activation, but we could learn even more about this important step in human development thanks to our discovery of a human stem cell counterpart."

In order to function, cells take copies of the genome in the form of an RNA code which is translated into proteins. The RNA code output is called the transcriptome and it can be used to identify different populations of cells. In this study, researchers used existing human data sets and information from mouse ESC studies to identify characteristic transcriptome marks that could be linked to genome activation. Using single cell techniques, they started the search for similar cells in their population of human ESCs.

The team found a subset of human ESCs with the right transcriptome marks to be a potential match for the 8-cell stage, when the major wave of genome activation occurs. They called these cells '8-cell like cells' or 8CLCs and used the published human data to further validate and confirm that these cells shared the same molecular outputs indicative of genome activation and could be pursued as a reliable model for future studies.

To further explore the extent of the similarities between their 8CLCs and 8-cell stage in human embryos, the team worked with Professor Jennifer Nichols from the Wellcome -- MRC Cambridge Stem Cell Institute. Together they were able to select and search for proteins present in both sets of cells that were indicative of ZGA. Their results showed that the ZGA-associated proteins of 8CLCs closely matched those seen in human 8-cell embryos.

As Jasmin explains: "The collaboration with Professor Nichols and her team was vital as we could identify selected proteins and really look at those in real, fixed human 8-cell stage embryo cells compared to our new stem cell counterparts. This work confirmed that our 8C-like cells matched at the protein level too, in additional to the transcriptomics data, providing validation that the 8-cell like cells matched embryo cells across multiple molecular layers."

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Tweaked genes borrowed from bacteria excite heart cells in live mice

Biomedical engineers at Duke University have demonstrated a gene therapy that helps heart muscle cells electrically activate in live mice. The first demonstration of its kind, the approach features engineered bacterial genes that code for sodium ion channels and could lead to therapies to treat a wide variety of electrical heart diseases and disorders.

The results appeared online February 2 in the journal Nature Communications.

"We were able to improve how well heart muscle cells can initiate and spread electrical activity, which is hard to accomplish with drugs or other tools," said Nenad Bursac, professor of biomedical engineering at Duke. "The method we used to deliver genes in heart muscle cells of mice has been previously shown to persist for a long time, which means it could effectively help hearts that struggle to beat as regularly as they should."

Sodium-ion channels are proteins in the outer membranes of electrically excitable cells, such as heart or brain cells, that transmit electrical charges into the cell. In the heart, these channels tell muscle cells when to contract and pass the instruction along so that the organ pumps blood as a cohesive unit. Damaged heart cells, however, whether from disease or trauma, often lose all or part of their ability to transmit these signals and join the effort.

One approach researchers can take to restoring this functionality is gene therapy. By delivering the genes responsible for creating sodium channel proteins, the technique can produce more ion channels in the diseased cells to help boost their activity.

In mammals, sodium channel genes are unfortunately too large to fit within the viruses currently used in modern gene therapies in humans. To skirt this issue, Bursac and his laboratory instead turned to smaller genes that code for similar sodium ion channels in bacteria. While these bacterial genes are different than their human counterparts, evolution has conserved many similarities in the channel design since multi-cellular organisms diverged from bacteria hundreds of millions of years ago.

Several years ago, Hung Nguyen, a former doctoral student in Bursac's laboratory who now works for Fujifilm Diosynth Biotechnologies, mutated these bacterial genes so that the channels they encode could become active in human cells. In the new work, current doctoral student Tianyu Wu further optimized the content of the genes and combined them with a "promoter" that exclusively restricts channel production to heart muscle cells. The researchers then tested their approach by delivering a virus loaded with the bacterial gene into veins of a mouse to spread throughout the body.

"We worked to find where the sodium ion channels were actually formed, and, as we hoped, we found that they only went into the working muscle cells of the heart within the atria and ventricles," Wu said. "We also found that they did not end up in the heart cells that originate the heartbeat, which we also wanted to avoid."

This gene therapy approach only delivers extra genes within a cell; it does not attempt to cut out, replace or rewrite the existing DNA in any way. Scientists believe these types of delivered genes make proteins while floating freely within the cell, making use of the existing biochemical machinery. Previous research with this viral gene delivery approach suggests the transplanted genes should remain active for many years.

As a proof of concept, tests on cells in a laboratory setting suggest that the treatment improves electrical excitability enough to prevent human abnormalities like arrhythmias. Within live mice, the results demonstrate that the sodium ion channels are active in the hearts, showing trends toward improved excitability. However, further tests are needed to measure how much of an improvement is made on the whole-heart level, and whether it is enough to rescue electrical function in damaged or diseased heart tissue to be used as a viable treatment.

Moving forward, the researchers have already identified different bacterial sodium channel genes that work better in preliminary benchtop studies. The team is also working with the laboratories of Craig Henriquez, professor of biomedical engineering at Duke, and Andrew Landstrom, director of the Duke Pediatric Research Scholars Program, to test the ability of these genes to restore heart functionality in mouse models that mimic human heart diseases.

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Redefining alcohol use disorder

Researchers at the University of Missouri have developed a new framework that they believe will help identify people previously overlooked for alcohol use disorder (AUD). This framework focuses on 13 risk factors, such as impulsive behavior, reward sensitivity, and punishment sensitivity, that could lead to someone developing an AUD.

"We know from decades of research that there are a lot of different pathways to alcohol use disorder," said Cassie Boness, a former graduate student at MU in the Department of Psychological Sciences. "So, we want to make sure that we are targeting people's specific pathways as accurately as possible in order to be most effective in identifying and treating AUD."

Throughout her career, Boness has been interested in the causes, diagnosis and assessment of substance use disorders, including AUD, a chronic medical condition characterized by ongoing alcohol use despite adverse consequences. For Boness, it's personal -- after seeing her loved ones stigmatized for their addiction to alcohol, and then watching them struggle to get connected with treatment, she wanted to help reduce the amount of suffering people may experience with AUD.

While today's assessment tools, such as the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) can help health care professionals diagnose someone with AUD, Boness believes the current methods are too narrowly focused on the consequences of someone's actions, rather than incorporating a broad list of potential risk factors that may lead to an AUD diagnosis.

Boness, who is now a research assistant professor at the University of New Mexico, hopes their framework can be a step forward toward a comprehensive diagnosis of AUD throughout the health care community. However, she stresses that this tool is not meant to be the only solution, but rather a way for other researchers like her to build upon and enhance the existing research on the subject.

"Eventually, we'd like to see assessment tools that more comprehensively capture the factors articulated in our framework so that we can identify individual profiles of risk and potentially intervene during earlier stages of addiction," Boness said.

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Neuroscientists explore mysterious 'events' in the brain that open new avenues for understanding brain injuries and disorders

Using a new model of brain activity, Indiana University computational neuroscientists Maria Pope, Richard Betzel and Olaf Sporns are exploring striking bursts of activity in the human brain that have not been examined before. These bursts may have potential to serve as biomarkers for brain disease and conditions such as depression, schizophrenia, dementia, and ADHD.

While analyzing human neuroimaging data, the IU research team discovered short bursts of activity that form ongoing "events" in the brain and are always taking place no matter the activity or state of the brain. In the course of a 10-minute brain scan, these events will occur roughly 10 to 20 times, each lasting for just a few seconds, the researchers found.

"What people had not seen is that how brain regions talk to each other is punctuated by these brief moments that are just a few seconds long during which there's a lot happening," said Olaf Sporns, who is Distinguished Professor and Robert H. Shaffer Chair in the College of Arts and Sciences Department of Psychological and Brain Sciences at IU Bloomington.

"Now that we see them, we've focused on those moments to get a picture of how specific brain regions link up and talk to each other during these events."

To begin investigating the workings of these mysterious events, the team built a computational model. Led by Maria Pope, a graduate student in Sporns' lab and a dual Ph.D. candidate in neuroscience and informatics, the group used neuroimaging data of a human brain to build a model replicating its connections. The model was then simulated in a state similar to the resting brain to create synthetic MRI signals, using mathematical equations that reenact neuronal activity.

The model showed burst-like events just like those seen in human brain recordings.

The paper outlining the model and describing how it compares to the real brain was published in the November 16 issue of the Proceedings of the National Academy of Sciences.

"The model shows us that these events are guided by the brain's structural network," Pope said. "They are tied to the physical structure of brain."

More specifically, the events originate in clusters of neurons and brain regions that are densely interconnected and momentarily light up together. Sporns compared the pattern to an orchestra playing a piece of music.

"There are moments when the orchestra comes together and there's a theme. They are not just playing a single note for 10 minutes. There are brief moments in which coordinated activity dominates and at other times there might be much less," Sporns said. "This ebb and flow of coordination is something we also see in the brain, and our model can reproduce it. Clusters of brain regions combine in different ways. It's not just one pattern, but multiple variations on a theme."

The new model's outcome, Sporns suggested, is a potential game changer.

"Functional connectivity has been a strong focus in research as a potential biomarker for brain disorders and has been related to conditions such as depression, schizophrenia, dementia, and ADHD. And researchers have tried for years to use brain simulations in clinical applications for modeling lesions or diseases," Sporns said. "This new model gives us a better lens through which to look at the brain, to see more clearly what goes on under both normal and abnormal conditions."

The researchers are now delving further into why the human brain employs these brief bursts of activity.

"Perhaps the brain has developed this type of activity because it's beneficial. Something about the structure of events may be useful to the brain," Pope said. "For example, many kinds of networked systems have to do occasional system updates or resets, taking some kind of globally useful information and communicating it to the rest of the system."

Answers to these questions may have implications not only for understanding the brain, but also for the study of neural networks and artificial intelligence.

"A clearer mapping of structure and function at the individual level could have implications for how we diagnose neurological disease and lead to personalized treatment and intervention," said Betzel, professor in the College of Arts and Sciences Department of Psychological and Brain Sciences.

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Anxiety cues found in the brain despite safe environment

Imagine you are in a meadow picking flowers. You know that some flowers are safe, while others have a bee inside that will sting you. How would you react to this environment and, more importantly, how would your brain react? This is the scene in a virtual-reality environment used by researchers to understand the impact anxiety has on the brain and how brain regions interact with one another to shape behavior.

"These findings tell us that anxiety disorders might be more than a lack of awareness of the environment or ignorance of safety, but rather that individuals suffering from an anxiety disorder cannot control their feelings and behavior even if they wanted to," said Benjamin Suarez-Jimenez, Ph.D., assistant professor in the Del Monte Institute for Neuroscience at the University of Rochester and first author of the study published in Communications Biology. "The patients with an anxiety disorder could rationally say -- I'm in a safe space -- but we found their brain was behaving as if it was not."

Watching anxiety in the brain

Using fMRI, the researchers observed the brain activity of volunteers with general and social anxiety as they navigated a virtual reality game of picking flowers. Half of the meadow had flowers without bees, the other half had flowers with bees that would sting them -- as simulated by a mild electrical stimulation to the hand. Researchers found all study participants could distinguish between the safe and dangerous areas, however, brain scans revealed volunteers with anxiety had increased insula and dorsomedial prefrontal cortex activation -- indicating their brain was associating a known safe area to danger or threat.

"This is the first time we've looked at discrimination learning in this way. We know what brain areas to look at, but this is the first time we show this concert of activity in such a complex 'real-world-like' environment," said Suarez-Jimenez. "These findings point towards the need for treatments that focus on helping patients take back control of their body."

The brain differences were the only differences seen in these patients. For example, sweat responses, a proxy for anxiety, which was also measured, failed to reveal any clear differences.

Suarez-Jimenez's research

Understanding the neural mechanisms by which the brain learns about the environment is the focus of Suarez-Jimenez's research, particularly how the brain predicts what is threatening and what is safe. He uses virtual reality environments to investigate neural signatures of anxiety disorders and post-traumatic stress disorder (PTSD). His goal is to understand how people build maps in the brain that are based on experience, and the role of those maps in psychopathologies of stress and anxiety.

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Anxiety effectively treated with exercise

Both moderate and strenuous exercise alleviate symptoms of anxiety, even when the disorder is chronic, a study led by researchers at the University of Gothenburg shows.

The study, now published in the Journal of Affective Disorders, is based on 286 patients with anxiety syndrome, recruited from primary care services in Gothenburg and the northern part of Halland County. Half of the patients had lived with anxiety for at least ten years. Their average age was 39 years, and 70 percent were women.

Through drawing of lots, participants were assigned to group exercise sessions, either moderate or strenuous, for 12 weeks. The results show that their anxiety symptoms were significantly alleviated even when the anxiety was a chronic condition, compared with a control group who received advice on physical activity according to public health recommendations.

Most individuals in the treatment groups went from a baseline level of moderate to high anxiety to a low anxiety level after the 12-week program. For those who exercised at relatively low intensity, the chance of improvement in terms of anxiety symptoms rose by a factor of 3.62. The corresponding factor for those who exercised at higher intensity was 4.88. Participants had no knowledge of the physical training or counseling people outside their own group were receiving.

"There was a significant intensity trend for improvement -- that is, the more intensely they exercised, the more their anxiety symptoms improved," states Malin Henriksson, doctoral student at Sahlgrenska Academy at the University of Gothenburg, specialist in general medicine in the Halland Region, and the study's first author.

Importance of strenuous exercise

Previous studies of physical exercise in depression have shown clear symptom improvements. However, a clear picture of how people with anxiety are affected by exercise has been lacking up to now. The present study is described as one of the largest to date.

Both treatment groups had 60-minute training sessions three times a week, under a physical therapist's guidance. The sessions included both cardio (aerobic) and strength training. A warmup was followed by circle training around 12 stations for 45 minutes, and sessions ended with cooldown and stretching.

Members of the group that exercised at a moderate level were intended to reach some 60 percent of their maximum heart rate -- a degree of exertion rated as light or moderate. In the group that trained more intensively, the aim was to attain 75 percent of maximum heart rate, and this degree of exertion was perceived as high.

The levels were regularly validated using the Borg scale, an established rating scale for perceived physical exertion, and confirmed with heart rate monitors.

New, simple treatments needed

Today's standard treatments for anxiety are cognitive behavioral therapy (CBT) and psychotropic drugs. However, these drugs commonly have side effects, and patients with anxiety disorders frequently do not respond to medical treatment. Long waiting times for CBT can also worsen the prognosis.

The present study was led by Maria Åberg, associate professor at the University of Gothenburg's Sahlgrenska Academy, specialist in general medicine in Region Västra Götaland's primary healthcare organization, and corresponding author.

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Brain-circuit discovery may help explain sex differences in binge drinking

A brain circuit that works as a "brake" on binge alcohol drinking may help explain male-female differences invulnerability to alcohol use disorders, according to a preclinical study led by scientists at Weill Cornell Medicine.

In the study, which appeared August 23 in Nature Communications, the researchers examined a brain region in mice called the bed nucleus of the stria terminalis (BNST) -- a major node in a stress-response network whose activity in humans has been linked to binge drinking behaviors. The researchers found that one important population of BNST neurons is more excitable in female mice than in males, helping to account for female mice's greater susceptibility to binge drinking.

The researchers also found that a distant cluster of neurons called the paraventricular nucleus of the thalamus (PVT), which is wired into the BNST, acts as a brake on its activity and has a stronger influence on the female BNST compared with the male BNST. Thus, the PVT is able to curb excessive alcohol consumption through this circuit brake in female mice but not males. While females may be offered more protection through this mechanism, they may also be more vulnerable to disease when this brake is disrupted.

"This study highlights that there are sex differences in the brain biology that controls alcohol drinking behaviors, and we really need to understand those differences if we're going to develop optimal treatments for alcohol use disorder," said senior author Dr. Kristen Pleil, assistant professor of pharmacology at Weill Cornell Medicine.

Women tend to consume less alcohol than men do, but researchers believe that is due mostly to cultural factors, and in recent decades that gender gap has narrowed significantly, especially among younger women. Women may in fact have an inherently greater vulnerability to alcohol use disorders, for reasons that lie deep within mammalian biology.

"Females across mammalian species, compared to males, display greater binge drinking and progress from first alcohol use to disease states more quickly," Dr. Pleil said. "But there has been hardly any research on the neural details that underlie this sex difference."

For the study, she and her team showed that BNST neurons, whose activity enhances binge-drinking behavior in mice, are more excitable and likely to fire spontaneously in female mice compared to males, apparently due to greater stimulation from other brain regions wired into the BNST. This higher excitability in females means that more inhibition of the female BNST is needed to prevent or reduce binge-drinking behavior.

The researchers found that the brain region with the densest projection to the BNST is the PVT -- which works as a natural inhibitor of BNST activity, more so in female mice. They found that reducing the strength of this PVT projection promotes binge alcohol drinking behavior in female mice, but not in male mice, whose BNST activity is lower to begin with.

The results, Dr. Pleil said, indicate that although this BNST-driven stress response circuit is tuned to be more excitable in females, it is also more heavily regulated in females, perhaps as an adaptation for more female-specific behaviors.

What behaviors? That is still unclear, although the researchers found that altering BNST activity via the PVT had no effect on the mice's intake of sweet-tasting sucrose -- suggesting that the PVT-BNST circuit, with its greater sensitivity and tighter regulation in females, evolved for something more specific than guiding general reward-seeking behaviors.

"Female mammals have a different set of goals compared to males, and may need to be more sensitive to different types of reward," Dr. Pleil said.

She added that sex differences in the PVT-BNST circuit may be relevant to sex differences not only in alcohol-use disorders but also in anxiety disorders -- which are much more common in women and frequently co-occur with binge drinking. The researchers found that enhancing PVT inhibition of the BNST led to reduced avoidance behaviors -- a proxy for reduced anxiety in humans -- in both male and female mice.

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