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“We know eating avocados helps you feel full and reduces blood cholesterol concentration, but we did not know how it influences the gut microbes, and the metabolites the microbes produce,” says Sharon Thompson, graduate student in the Division of Nutritional Sciences at U of I and lead author on the paper, published in the Journal of Nutrition.

The researchers found that people who ate avocado every day as part of a meal had a greater abundance of gut microbes that break down fiber and produce metabolites that support gut health. They also had greater microbial diversity compared to people who did not receive the avocado meals in the study.

“Microbial metabolites are compounds the microbes produce that influence health,” Thompson says. “Avocado consumption reduced bile acids and increased short chain fatty acids. These changes correlate with beneficial health outcomes.”

The study included 163 adults between 25 and 45 years of age with overweight or obesity — defined as a BMI of at least 25 kg/m2 — but otherwise healthy. They received one meal per day to consume as a replacement for either breakfast, lunch, or dinner. One group consumed an avocado with each meal, while the control group consumed a similar meal but without the avocado. The participants provided blood, urine, and fecal samples throughout the 12-week study. They also reported how much of the provided meals they consumed, and every four weeks recorded everything they ate.

While other research on avocado consumption has focused on weight loss, participants in this study were not advised to restrict or change what they ate. Instead they consumed their normal diets with the exception of replacing one meal per day with the meal the researchers provided.

The purpose of this study was to explore the effects of avocado consumption on the gastrointestinal microbiota, says Hannah Holscher, assistant professor of nutrition in the Department of Food Science and Human Nutrition at U of I and senior author of the study.

“Our goal was to test the hypothesis that the fats and the fiber in avocados positively affect the gut microbiota. We also wanted to explore the relationships between gut microbes and health outcomes,” Holscher says.

Avocados are rich in fat; however, the researchers found that while the avocado group consumed slightly more calories than the control group, slightly more fat was excreted in their stool.

“Greater fat excretion means the research participants were absorbing less energy from the foods that they were eating. This was likely because of reductions in bile acids, which are molecules our digestion system secretes that allow us to absorb fat. We found that the amount of bile acids in stool was lower and the amount of fat in the stool was higher in the avocado group,” Holscher explains.

Different types of fats have differential effects on the microbiome. The fats in avocados are monounsaturated, which are heart-healthy fats.

Soluble fiber content is also very important, Holscher notes. A medium avocado provides around 12 grams of fiber, which goes a long way toward meeting the recommended amount of 28 to 34 grams of fiber per day.

“Less than 5% of Americans eat enough fiber. Most people consume around 12 to 16 grams of fiber per day. Thus, incorporating avocados in your diet can help get you closer to meeting the fiber recommendation,” she notes.

Eating fiber isn’t just good for us; it’s important for the microbiome, too, Holscher states. “We can’t break down dietary fibers, but certain gut microbes can. When we consume dietary fiber, it’s a win-win for gut microbes and for us.”

Holscher’s research lab specializes in dietary modulation of the microbiome and its connections to health. “Just like we think about heart-healthy meals, we need to also be thinking about gut healthy meals and how to feed the microbiota,” she explains.

Avocado is an energy-dense food, but it is also nutrient dense, and it contains important micronutrients that Americans don’t eat enough of, like potassium and fiber.

“It’s just a really nicely packaged fruit that contains nutrients that are important for health. Our work shows we can add benefits to gut health to that list,” Holscher says.

The paper, “Avocado consumption alters gastrointestinal bacteria abundance and microbial metabolite concentrations among adults with overweight or obesity: a randomized controlled trial” is published in the Journal of Nutrition.

Authors are Sharon Thompson, Melisa Bailey, Andrew Taylor, Jennifer Kaczmarek, Annemarie Mysonhimer, Caitlyn Edwards, Ginger Reeser, Nicholas Burd, Naiman Khan, and Hannah Holscher.

Funding for the research was provided by the Hass Avocado Board and the USDA National Institute of Food and Agriculture, Hatch project 1009249. Sharon Thompson was supported by the USDA National Institute of Food and Agriculture AFRI Predoctoral Fellowship, project 2018-07785, and the Illinois College of ACES Jonathan Baldwin Turner Fellowship. Jennifer Kaczmarek was supported by a Division of Nutrition Sciences Excellence Fellowship. Andrew Taylor was supported by a Department of Food Science and Human Nutrition Fellowship. The Division of Nutritional Sciences provided seed funding through the Margin of Excellence endowment.

The Division of Nutritional Sciences and the Department of Food Science and Human Nutrition are in the College of Agricultural, Consumer and Environmental Sciences, University of Illinois.

Frontotemporal dementia is a significant cause of dementia among younger people. It is often diagnosed between the ages of 45 and 65. It changes behaviour, language and personality, leading to impulsivity, socially inappropriate behaviour, and repetitive or compulsive behaviours.

A common feature of frontotemporal dementia is apathy, with a loss of motivation, initiative and interest in things. It is not depression, or laziness, but it can be mistaken for them. Brain scanning studies have shown that in people with frontotemporal dementia it is caused by shrinkage in special parts at the front of the brain — and the more severe the shrinkage, the worse the apathy. But, apathy can begin decades before other symptoms, and be a sign of problems to come.

“Apathy is one of the most common symptoms in patients with frontotemporal dementia. It is linked to functional decline, decreased quality of life, loss of independence and poorer survival,” said Maura Malpetti, a cognitive scientist at the Department of Clinical Neurosciences, University of Cambridge.

“The more we discover about the earliest effects of frontotemporal dementia, when people still feel well in themselves, the better we can treat symptoms and delay or even prevent the dementia.”

Frontotemporal dementia can be genetic. About a third of patients have a family history of the condition. The new discovery about the importance of early apathy comes from the Genetic Frontotemporal dementia Initiative (GENFI), a collaboration between scientists across Europe and Canada. Over 1,000 people are taking part in GENFI, from families where there is a genetic cause of Frontotemporal dementia.

Now, in a study published today in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, Professor Rowe and colleagues have shown how apathy predicts cognitive decline even before the dementia symptoms emerge.

The new study involved 304 healthy people who carry a faulty gene that causes frontotemporal dementia, and 296 of their relatives who have normal genes. The participants were followed over several years. None had dementia, and most people in the study did not know whether they carry a faulty gene or not. The researchers looked for changes in apathy, memory tests and MRI scans of the brain.

“By studying people over time, rather than just taking a snapshot, we revealed how even subtle changes in apathy predicted a change in cognition, but not the other way around,” explained Malpetti, the study’s first author. “We also saw local brain shrinkage in areas that support motivation and initiative, many years before the expected onset of symptoms.”

People with the genetic mutations had more apathy than other members of their family, which over two years increased much more than in people with normal genetics. The apathy predicted cognitive decline, and this accelerated as they approached the estimated age of onset of symptoms.

Professor Rogier Kievit from the Donders Institute, Radboud University Medical Center at Nijmegen and MRC Cognition and Brain Sciences Unit at Cambridge, said: “Apathy progresses much faster for those individuals who we know are at greater risk of developing frontotemporal dementia, and this is linked to greater atrophy in the brain. At the start, even though the participants with a genetic mutation felt well and had no symptoms, they were showing greater levels of apathy. The amount of apathy predicted cognitive problems in the years ahead.”

“From other research, we know that in patients with frontotemporal dementia, apathy is a bad sign in terms of independent living and survival. Here we show its importance in the decades before symptoms begin,” said Professor James Rowe from the Department of Clinical Neurosciences, joint senior author.

Professor Rowe said the study highlights the importance of investigating why someone has apathy. “There are many reasons why someone feels apathetic. It may well be an easy to treat medical condition, such as low levels of thyroid hormone, or a psychiatric illness such as depression. But doctors need to keep in mind the possibility of apathy heralding a dementia, and increasing the chance of dementia if left unaddressed, particularly if someone has a family history of dementia.

“Treating dementia is a challenge, but the sooner we can diagnose the disease, the greater our window of opportunity to try and intervene and slow or stop its progress.”

The research was largely funded by the Medical Research Council, Wellcome, and the National Institute for Health Research.

Usually, each cell has exactly one nucleus. But the cells of our skeletal muscles are different: These long, fibrous cells have a comparatively large cytoplasm that contains hundreds of nuclei. But up to now, we have known very little about the extent to which the nuclei of a single muscle fiber differ from each other in terms of their gene activity, and what effect this has on the function of the muscle.

A team led by Professor Carmen Birchmeier, head of the research group on Developmental Biology / Signal Transduction at the Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), has now unlocked some of the secrets contained in these muscle cell nuclei. As the researchers report in the journal Nature Communications, the team investigated the gene expression of cell nuclei using a still quite novel technique called single-nucleus RNA sequencing — and in the process, they came across an unexpectedly high variety of genetic activity.

Muscle fibers resemble entire tissues

“Due to the heterogeneity of its nuclei, a single muscle cell can act almost like a tissue, which consists of a variety of very different cell types,” explains Dr. Minchul Kim, a postdoctoral researcher in Birchmeier’s team and one of the two lead authors of the study. “This enables the cell to fulfill its numerous tasks, like communicating with neurons or producing certain muscle proteins.”

Kim undertook the majority of the experimental work in the study, and his data was also evaluated at the MDC. The bioinformatics analyses were performed by Dr. Altuna Akalin, head of the Bioinformatics and Omics Data Science Platform at the MDC’s Berlin Institute of Medical Systems Biology (BIMSB), and Dr. Vedran Franke, a postdoctoral fellow in Akalin’s team and the study’s co-lead author. “It was only thanks to the constant dialogue between the experiment-based and theory-based teams that we were we able to arrive at our results, which offer important insight for research into muscle diseases,” emphasizes Birchmeier. “New techniques in molecular biology such as single cell sequencing create large amounts of data. It is essential that computational labs are part of the process early on as analysis is as important as data generation,” adds Akalin.

Injured muscles contain activated growth-promoting genes

The researchers began by studying the gene expression of several thousand nuclei from ordinary muscle fibers of mice, as well as nuclei from muscle fibers that were regenerating after an injury. The team genetically labeled the nuclei and isolated them from the cells. “We wanted to find out whether a difference in gene activity could be observed between the resting and the growing muscle,” says Birchmeier.

And they did indeed find such differences. For example, the researchers observed that the regenerating muscle contained more active genes responsible for triggering muscle growth. “What really astonished us, however, was the fact that, in both muscle fiber types, we found a huge variety of different types of nuclei, each with different patterns of gene activity,” explains Birchmeier.

Stumbling across unknown nuclei types

Before the study, it was already known that different genes are active in nuclei located in the vicinity of a site of neuronal innervation than in the other nuclei. “However, we have now discovered many new types of specialized nuclei, all of which have very specific gene expression patterns,” says Kim. Some of these nuclei are located in clusters close to other cells adjacent to the muscle fiber: for example, cells of the tendon or perimysium — a connective tissue sheath that surrounds a bundle of muscle fibers.

“Other specialized nuclei seem to control local metabolism or protein synthesis and are distributed throughout the muscle fiber,” Kim explains. However, it is not yet clear what exactly the active genes in the nuclei do: “We have come across hundreds of genes in previously unknown small groups of nuclei in the muscle fiber that appear to be activated,” reports Birchmeier.

Muscle dystrophy seemingly causes many nuclei types to be lost

In a next step, the team studied the muscle fiber nuclei of mice with Duchenne muscular dystrophy. This disease is the most common form of hereditary muscular dystrophy (muscle wasting) in humans. It is caused by a mutation on the X chromosome, which is why it mainly affects boys. Patients with this disease lack the protein dystrophin, which stabilizes the muscle fibers. This results in the cells gradually dying off.

“In this mouse model, we observed the loss of many types of cell nuclei in the muscle fibers,” reports Birchmeier. Other types were no longer organized into clusters, as the team had previously observed, but scattered throughout the cell. “I couldn’t believe this when I first saw it,” she recounts. “I asked my team to repeat the single-nucleus sequencing immediately before we investigated the finding any further.” But the results remained the same.

The mouse nuclei resemble those of human patients

“We also found some disease-specific nuclear subtypes,” reports Birchmeier. Some of these are nuclei that only transcribe genes to a small extent and are in the process of dying off. Others are nuclei that contain genes that actively repair damaged myofibers. “Interestingly, we also observed this increase in gene activity in muscle biopsies of patients with muscle diseases provided by Professor Simone Spuler’s Myology Lab at the MDC,” says Birchmeier. “It seems this is how the muscle tries to counteract the disease-related damage.”

“With our study, we are presenting a powerful method for investigating pathological mechanisms in the muscle and for testing the success of new therapeutic approaches,” concludes Birchmeier. As muscular malfunction is also observed in a variety of other diseases, such as diabetes and age- or cancer-related muscle atrophy, the approach can be used to better research these changes too. “We are already planning further studies with other disease models,” Kim confirms.

The bacterial population in the gut, known as the gut microbiota, is the largest reservoir of bacteria in the body. Research has increasingly shown that the host and the gut microbiota are an excellent example of systems with mutually beneficial interactions. Recent observations also revealed a link between mood disorders and damage to the gut microbiota. This was demonstrated by a consortium of scientists from the Institut Pasteur, the CNRS and Inserm, who identified a correlation between the gut microbiota and the efficacy of fluoxetine, a molecule frequently used as an antidepressant. But some of the mechanisms governing depression, the leading cause of disability worldwide, remained unknown.

Using animal models, scientists recently discovered that a change to the gut microbiota brought about by chronic stress can lead to depressive-like behaviors, in particular by causing a reduction in lipid metabolites (small molecules resulting from metabolism) in the blood and the brain.

These lipid metabolites, known as endogenous cannabinoids (or endocannabinoids), coordinate a communication system in the body which is significantly hindered by the reduction in metabolites. Gut microbiota plays a role in brain function and mood regulation

Endocannabinoids bind to receptors that are also the main target of THC, the most widely known active component of cannabis. The scientists discovered that an absence of endocannabinoids in the hippocampus, a key brain region involved in the formation of memories and emotions, resulted in depressive-like behaviors.

The scientists obtained these results by studying the microbiotas of healthy animals and animals with mood disorders. As Pierre-Marie Lledo, Head of the Perception and Memory Unit at the Institut Pasteur (CNRS/Institut Pasteur) and joint last author of the study, explains: “Surprisingly, simply transferring the microbiota from an animal with mood disorders to an animal in good health was enough to bring about biochemical changes and confer depressive-like behaviors in the latter.”

The scientists identified some bacterial species that are significantly reduced in animals with mood disorders. They then demonstrated that an oral treatment with the same bacteria restored normal levels of lipid derivatives, thereby alleviating the depressive-like behaviors. These bacteria could therefore serve as an antidepressant. Such treatments are known as “psychobiotics.”

“This discovery shows the role played by the gut microbiota in normal brain function,” continues Gérard Eberl, Head of the Microenvironment and Immunity Unit (Institut Pasteur/Inserm) and joint last author of the study. If there is an imbalance in the gut bacterial community, some lipids that are vital for brain function disappear, encouraging the emergence of depressive-like behaviors. In this particular case, the use of specific bacteria could be a promising method for restoring a healthy microbiota and treating mood disorders more effectively.

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“Our research on rats with heart failure shows that exercise reduces the severity of the disease, improves heart function and increases work capacity. And the intensity of the training is really importance to achieve this effect,” says Thomas Stølen, a researcher at the Norwegian University of Science and Technology (NTNU).

Stølen and his colleague Morten Høydal are the main authors of a comprehensive study published in the Journal of Molecular and Cellular Cardiology. The researchers went to great lengths to investigate what happens inside tiny heart muscle cells after regular exercise.

“We found that exercise improves important properties both in the way heart muscle cells handle calcium and in conducting electrical signals in the heart. These improvements enable the heart to beat more vigorously and can counteract life-threatening heart rhythm disorders,” says Stølen.

For a heart to be able to beat powerfully, regularly and synchronously, a lot of functions have to work together. Each time the heart beats, the sinus node — the heart’s own pacemaker — sends out electrical impulses to the rest of the heart. These electrical impulses are called action potentials.

All the heart muscle cells are enclosed by a membrane. At rest, the electrical voltage on the inside of the cell membrane is negative compared to the voltage on the outside. The difference between the voltage on the outside and the inside of the cell membrane is called the resting membrane potential.

When the action potentials reach the heart muscle cells, they need to overcome the resting membrane potential of each cell to depolarize the cell wall. When this happens, calcium can flow into the cell through channels in the cell membrane.

Calcium initiates the actual contraction of the heart muscle cells. When this process is complete, calcium is transported out of the cell or back to its storage site inside each heart muscle cell. From there, the calcium is ready to contribute to a new contraction the next time an action potential comes rushing by.

If the heart’s electrical conduction or calcium management system fails, the risk is that fewer heart muscle cells will contract, the contraction in each cell will be weak, and the electrical signals will become chaotic so that the heart chambers begin to flutter.

“All these processes are dysfunctional when someone has heart failure. The action potentials last too long, the resting potential of the cells is too high, and the transport function of the calcium channels in the cell wall is disturbed. Calcium then constantly leaks from its storage places inside every heart muscle cell,” Stølen says.

Before Stølen gives us the rest of the good news, he notes, “Our results show that intensive training can completely or partially reverse all these dysfunctions.”

Normally, the sinus node causes a human heart to beat between 50 and 80 beats every minute when at rest. This is enough to supply all the organ systems and cells in the body with as much oxygen-rich blood as they need to function properly.

When we get up to take a walk, our heart automatically starts beating a little faster and pumping a little harder so that the blood supply is adapted to the increased level of activity. The higher the intensity of the activity, the harder the heart has to work.

Exercise strengthens the heart so it can pump more blood out to the rest of the body with each beat. Thus, the sinus node can take it a little easier, and well-trained people have a lower resting heart rate than people who have not done regular endurance training.

At the other end of the continuum are people with heart failure. Here the pumping capacity of the heart is so weak that the organs no longer receive enough blood to maintain good functioning. People with heart failure have a low tolerance for exercise and often get out of breath with minimal effort.

In other words, increasing the pumping power to the heart is absolutely crucial for the quality of life and health of people with heart failure.

Many of the more than 100,000 Norwegians who live with heart failure have developed the condition after suffering a major heart attack — just like the rats in Stølen and Høydal’s study.

In the healthy rats, the heart pumped 75 percent of the blood with each contraction. In rats with heart failure, this measure of pump capacity, called ejection fraction, was reduced to 20 per cent, Stølen says.

The ejection fraction increased to 35 percent after six to eight weeks with almost daily interval training sessions on a treadmill. The rats did four-minute intervals at about 90 percent of their maximum capacity, quite similar to the 4 × 4 method that has been advocated by several research groups at NTNU for many years.

“The interval training also significantly improved the rats’ conditioning. After the training period, their fitness level was actually better than that of the untrained rats that hadn’t had a heart attack,” says Stølen.

Impaired calcium handling in a heart muscle cell not only causes the cell to contract with reduced force every time there is an action potential. It also causes the calcium to accumulate inside the fluid-filled area of the cell — the cytosol — where each contraction begins.

The calcium stores inside the cells are only supposed to release calcium when the heart is preparing to beat. Heart failure, however, causes a constant leakage of calcium out of these stores. After each contraction, calcium needs to be efficiently transported back into the calcium stores — or out of the heart muscle cell — via specialized pumps. In heart failure patients, these pumps work poorly.

When a lot of calcium builds up inside the cytosol, the heart muscle cells can initiate new contractions when they’re actually supposed to be at rest. An electrical gradient develops which causes the heart to send electrical signals when it shouldn’t. This can cause fibrillation in the heart chambers. This ventricular fibrillation is fatal and a common cause of cardiac arrest.

“We found that interval training improves a number of mechanisms that allow calcium to be pumped out of the cells and stored more efficiently inside the cells. The leakage from the calcium stores inside the cells also stopped in the interval-trained rats,” says Stølen.

The effect was clear when the researchers tried to induce ventricular fibrillation in the diseased rat hearts: they only succeeded at this in one of nine animals that had completed interval training. By comparison, they had no problems inducing fibrillation in all the rats with heart failure who had not exercised.

So far, the research group had shown that exercise improves calcium management in diseased heart muscle cells in several ways. The training also makes the electrical wiring system of the heart more functional.

In addition, they showed that exercise counteracted processes that cause the heart to become big and stiff.

Taken together, these improvements make each heartbeat more powerful and reduce the severity of heart failure. The risk of dangerous ventricular fibrillation was also reduced.

But Stølen and team still lacked an answer to why exercise corrects slow action potentials and ensures that the heart muscle cells are able to take care of calcium in the right way.

Therefore, they investigated whether the training had altered the genetic activity inside the rat cells. Thousands of different types of micromolecules called micro-RNA probably control most of this activity through direct interaction with genes.

“It turned out that 55 of the micro-RNA variants we examined were altered in rats with heart failure compared to the healthy rats. Interval training changed 18 of these back towards healthy levels. Several of the relevant micromolecules are known to play a role in both calcium management and the electrical conduction system of the heart, but the most interesting thing is that we discovered new micro-RNAs that can play an important role in heart failure,” says Stølen.

This article has mostly considered the effects of high-intensity interval training. But the study also includes a group of rats that trained more sedately.

The rats in this group ran the same distance and thus did as much total training work as the rats in the interval training group. However, they had to exercise longer each time since they trained at a lower intensity. Stolen notes that this form of training also resulted in several health improvements.

But, he emphasizes, the vast majority of improvements were greater with interval training. “For example, we were able to induce cardiac fibrillation in five of eight rats after a period of moderate exercise, and their pumping capacity had only improved half as much as in the interval training group.”

The study was spearheaded by principal investigator, Auriel Willette, an assistant professor in Food Science and Human Nutrition, and Brandon Klinedinst, a Neuroscience PhD candidate working in the Food Science and Human Nutrition department at Iowa State. The study is a first-of-its-kind large scale analysis that connects specific foods to later-in-life cognitive acuity.

Willette, Klinedinst and their team analyzed data collected from 1,787 aging adults (from 46 to 77 years of age, at the completion of the study) in the United Kingdom through the UK Biobank, a large-scale biomedical database and research resource containing in-depth genetic and health information from half-a-million UK participants. The database is globally accessible to approved researchers undertaking vital research into the world’s most common and life-threatening diseases.

Participants completed a Fluid Intelligence Test (FIT) as part of touchscreen questionnaire at baseline (compiled between 2006 and 2010) and then in two follow-up assessments (conducted from 2012 through 2013 and again between 2015 and 2016). The FIT analysis provides an in-time snapshot of an individual’s ability to “think on the fly.”

Participants also answered questions about their food and alcohol consumption at baseline and through two follow-up assessments. The Food Frequency Questionnaire asked participants about their intake of fresh fruit, dried fruit, raw vegetables and salad, cooked vegetables, oily fish, lean fish, processed meat, poultry, beef, lamb, pork, cheese, bread, cereal, tea and coffee, beer and cider, red wine, white wine and champaign and liquor.

Here are four of the most significant findings from the study:

1. Cheese, by far, was shown to be the most protective food against age-related cognitive problems, even late into life;
2. The daily consumption of alchohol, particularly red wine, was related to improvements in cognitive function;
3. Weekly consumption of lamb, but not other red meats, was shown to improve long-term cognitive prowess; and
4. Excessive consumption of salt is bad, but only individuals already at risk for Alzheimer’s Disease may need to watch their intake to avoid cognitive problems over time.

“I was pleasantly surprised that our results suggest that responsibly eating cheese and drinking red wine daily are not just good for helping us cope with our current COVID-19 pandemic, but perhaps also dealing with an increasingly complex world that never seems to slow down,” Willette said. “While we took into account whether this was just due to what well-off people eat and drink, randomized clinical trials are needed to determine if making easy changes in our diet could help our brains in significant ways.”

Klinedinst added, “Depending on the genetic factors you carry, some individuals seem to be more protected from the effects of Alzheimers, while other seem to be at greater risk. That said, I believe the right food choices can prevent the disease and cognitive decline altogether. Perhaps the silver bullet we’re looking for is upgrading how we eat. Knowing what that entails contributes to a better understanding of Alzheimer’s and putting this disease in a reverse trajectory.”

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Unfortunately, for patient H.M., so too did time. When he woke up after surgery, he could no longer form new long-term memories, despite retaining normal cognitive abilities, language and short-term working memory. Patient H.M.’s condition ultimately revealed that the brain’s ability to create long-term memories is a distinct process that depends on the hippocampus.

Scientists had discovered where memories are made. But how they are made remained unknown.

Now, neuroscientists at Harvard Medical School have taken a decisive step in the quest to understand the biology of long-term memory and find ways to intervene when memory deficits occur with age or disease.

Reporting in Nature on Dec. 9, they describe a newly identified mechanism that neurons in the adult mouse hippocampus use to regulate signals they receive from other neurons, in a process that appears critical for memory consolidation and recall.

The study was led by Lynn Yap, HMS graduate student in neurobiology, and Michael Greenberg, chair of neurobiology in the Blavatnik Institute at HMS.

“Memory is essential to all aspects of human existence. The question of how we encode memories that last a lifetime is a fundamental one, and our study gets to the very heart of this phenomenon,” said Greenberg, the HMS Nathan Marsh Pusey Professor of Neurobiology at HMS and study corresponding author.

The researchers observed that new experiences activate sparse populations of neurons in the hippocampus that express two genes, Fos and Scg2. These genes allow neurons to fine-tune inputs from so-called inhibitory interneurons, cells that dampen neuronal excitation. In this way, small groups of disparate neurons may form persistent networks with coordinated activity in response to an experience.

“This mechanism likely allows neurons to better talk to each other so that the next time a memory needs to be recalled, the neurons fire more synchronously,” Yap said. “We think coincident activation of this Fos-mediated circuit is potentially a necessary feature for memory consolidation, for example, during sleep, and also memory recall in the brain.”

Circuit orchestration

In order to form memories, the brain must somehow wire an experience into neurons so that when these neurons are reactivated, the initial experience can be recalled. In their study, Greenberg, Yap and team set out to explore this process by looking at the gene Fos.

First described in neuronal cells by Greenberg and colleagues in 1986, Fos is expressed within minutes after a neuron is activated. Scientists have taken advantage of this property, using Fos as a marker of recent neuronal activity to identify brain cells that regulate thirst, torpor and many other behaviors.

Scientists hypothesized that Fos might play a critical role in learning and memory, but for decades, the precise function of the gene has remained a mystery.

To investigate, the researchers exposed mice to new environments and looked at pyramidal neurons, the principal cells of the hippocampus. They found that relatively sparse populations of neurons expressed Fos after exposure to a new experience. Next, they prevented these neurons from expressing Fos, using a virus-based tool delivered to a specific area of the hippocampus, which left other cells unaffected.

Mice that had Fos blocked in this manner showed significant memory deficits when assessed in a maze that required them to recall spatial details, indicating that the gene plays a critical role in memory formation.

The researchers studied the differences between neurons that expressed Fos and those that did not. Using optogenetics to turn inputs from different nearby neurons on or off, they discovered that the activity of Fos-expressing neurons was most strongly affected by two types of interneurons.

Neurons expressing Fos were found to receive increased activity-dampening, or inhibitory, signals from one distinct type of interneuron and decreased inhibitory signals from another type. These signaling patterns disappeared in neurons with blocked Fos expression.

“What’s critical about these interneurons is that they can regulate when and how much individual Fos-activated neurons fire, and also when they fire relative to other neurons in the circuit,” Yap said. “We think that at long last we have a handle on how Fos may in fact support memory processes, specifically by orchestrating this type of circuit plasticity in the hippocampus.”

Imagine the day

The researchers further probed the function of Fos, which codes for a transcription factor protein that regulates other genes. They used single-cell sequencing and additional genomic screens to identify genes activated by Fos and found that one gene in particular, Scg2, played a critical role in regulating inhibitory signals.

In mice with experimentally silenced Scg2, Fos-activated neurons in the hippocampus displayed a defect in signaling from both types of interneurons. These mice also had defects in theta and gamma rhythms, brain properties thought to be critical features of learning and memory.

Previous studies had shown that Scg2 codes for a neuropeptide protein that can be cleaved into four distinct forms, which are then secreted. In the current study, Yap and colleagues discovered that neurons appear to use these neuropeptides to fine-tune inputs they receive from interneurons.

Together, the team’s experiments suggest that after a new experience, a small group of neurons simultaneously express Fos, activating Scg2 and its derived neuropeptides, in order to establish a coordinated network with its activity regulated by interneurons.

“When neurons are activated in the hippocampus after a new experience, they aren’t necessarily linked together in any particular way in advance,” Greenberg said. “But interneurons have very broad axonal arbors, meaning they can connect with and signal to many cells at once. This may be how a sparse group of neurons can be linked together to ultimately encode a memory.”

The study findings represent a possible molecular- and circuit-level mechanism for long-term memory. They shed new light on the fundamental biology of memory formation and have broad implications for diseases of memory dysfunction.

The researchers note, however, that while the results are an important step in our understanding of the inner workings of memory, numerous unanswered questions about the newly identified mechanisms remain.

“We’re not quite at the answer yet, but we can now see many of the next steps that need to be taken,” Greenberg said. “If we can better understand this process, we will have new handles on memory and how to intervene when things go wrong, whether in age-related memory loss or neurodegenerative disorders such as Alzheimer’s disease.”

The findings also represent the culmination of decades of research, even as they open new avenues of study that will likely take decades more to explore, Greenberg added.

“I arrived at Harvard in 1986, just as my paper describing the discovery that neuronal activity can turn on genes was published,” he said. “Since that time, I’ve been imagining the day when we would figure out how genes like Fos might contribute to long-term memory.”

Additional authors include Noah Pettit, Christopher Davis, M. Aurel Nagy, David Harmin, Emily Golden, Onur Dagliyan, Cindy Lin, Stephanie Rudolph, Nikhil Sharma, Eric Griffith and Christopher Harvey.

The study was supported by the National Institutes of Health (grants R01NS028829, R01NS115965, R01NS089521, T32NS007473 and F32NS112455), a Stuart H.Q. and Victoria Quan fellowship, a Harvard Department of Neurobiology graduate fellowship, an Aramont Fund for Emerging Science Research fellowship and the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation.

About a decade ago, a group of neurons known as “time cells” was discovered in rats. These cells appear to play a unique role in recording when events take place, allowing the brain to correctly mark the order of what happens in an episodic memory.

Located in the brain’s hippocampus, these cells show a characteristic activity pattern while the animals are encoding and recalling events, explains Bradley Lega, M.D., associate professor of neurological surgery at UTSW and senior author of the PNAS study. By firing in a reproducible sequence, they allow the brain to organize when events happen, Lega says. The timing of their firing is controlled by 5 Hz brain waves, called theta oscillations, in a process known as precession.

Lega investigated whether humans also have time cells by using a memory task that makes strong demands on time-related information. Lega and his colleagues recruited volunteers from the Epilepsy Monitoring Unit at UT Southwestern’s Peter O’Donnell Jr. Brain Institute, where epilepsy patients stay for several days before surgery to remove damaged parts of their brains that spark seizures. Electrodes implanted in these patients’ brains help their surgeons precisely identify the seizure foci and also provide valuable information on the brain’s inner workings, Lega says.

While recording electrical activity from the hippocampus in 27 volunteers’ brains, the researchers had them do “free recall” tasks that involved reading a list of 12 words for 30 seconds, doing a short math problem to distract them from rehearsing the lists, and then recalling as many words from the list as possible for the next 30 seconds. This task requires associating each word with a segment of time (the list it was on), which allowed Lega and his team to look for time cells. What the team found was exciting: Not only did they identify a robust population of time cells, but the firing of these cells predicted how well individuals were able to link words together in time (a phenomenon called temporal clustering). Finally, these cells appear to exhibit phase precession in humans, as predicted.

“For years scientists have proposed that time cells are like the glue that holds together memories of events in our lives,” according to Lega. “This finding specifically supports that idea in an elegant way.”

In the second study in Science, Brad Pfeiffer, Ph.D., assistant professor of neuroscience, led a team investigating place cells — a population of hippocampal cells in both animals and humans that records where events occur. Researchers have long known that as animals travel a path they’ve been on before, neurons encoding different locations along the path will fire in sequence much like time cells fire in the order of temporal events, Pfeiffer explains. In addition, while rats are actively exploring an environment, place cells are further organized into “mini-sequences” that represent a virtual sweep of locations ahead of the rat. These radar-like sweeps happen roughly 8-10 times per second and are thought to be a brain mechanism for predicting immediately upcoming events or outcomes.

Prior to this study, it was known that when rats stopped running, place cells would often reactivate in long sequences that appeared to replay the rat’s prior experience in the reverse. While these “reverse replay” events were known to be important for memory formation, it was unclear how the hippocampus was able to produce such sequences. Indeed, considerable work had indicated that experience should strengthen forward, “look ahead” sequences but weaken reverse replay events.

To determine how these backward and forward memories work together, Pfeiffer and his colleagues placed electrodes in the hippocampi of rats, then allowed them to explore two different places: a square arena and a long, straight track. To encourage them to move through these spaces, they placed wells with chocolate milk at various places. They then analyzed the animals’ place cell activity to see how it corresponded to their locations.

Particular neurons fired as the rats wandered through these spaces, encoding information on place. These same neurons fired in the same sequence as the rats retraced their paths, and periodically fired in reverse as they completed different legs of their journeys. However, taking a closer look at the data, the researchers found something new: As the rats moved through these spaces, their neurons not only exhibited forward, predictive mini-sequences, but also backward, retrospective mini-sequences. The forward and backward sequences alternated with each other, each taking only a few dozen milliseconds to complete.

“While these animals were moving forward, their brains were constantly switching between expecting what would happen next and recalling what just happened, all within fraction-of-a-second timeframes,” Pfeiffer says.

Pfeiffer and his team are currently studying what inputs these cells are receiving from other parts of the brain that cause them to act in these forward or reverse patterns. In theory, he says, it might be possible to hijack this system to help the brain recall where an event happened with more fidelity. Similarly, adds Lega, stimulation techniques might eventually be able to mimic the precise patterning of time cells to help people more accurately remember temporal sequences of events. Further studies with “In the past few decades, there’s been an explosion in new findings about memory,” he adds. “The distance between fundamental discoveries in animals and how they can help people is becoming much shorter now.”

The researchers have also designed and validated a PCR test that can detect these mutations.

“We found that non-coding RNA mutations within the bacterium N. meningitidis are almost twice as likely to be associated with serious meningococcal disease, an uncommon but serious infection that can lead to death,” says Edmund Loh, corresponding author and assistant professor at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet. “This is also the first time a non-coding RNA in a bacterium has been associated with the development of a disease in humans.”

N. meningitidis is a bacterium that is often found in the nose of 10 to 15 percent of the human population. In general, the bacteria do not cause any disease. However, when it does, people can become very ill rapidly and die within a few hours if left untreated.

The research work began in 2017 after a strain of the N. meningitidis bacterium was isolated from a Swedish teenager who succumbed to meningococcal meningitis. When compared with another strain of the same bacterium isolated from an asymptomatic individual, the researchers discovered mutation in a regulatory non-coding RNA molecule, known as RNA thermosensor, or RNAT, within the strain from the deceased teenager.

This finding prompted the researchers to embark on a quest to collect and investigate more than 7,000 RNAT configurations of N. meningitidis from around Europe. In total, the researchers discovered five new variants of RNATs that could be linked to illness, that is they were more likely to appear in individuals who had become ill from the bacterium.

These variants shared a common trait in that they produced more and bigger capsules that insulated the bacterium and thus helped it evade the body’s immune system.

“This is the first time we have been able to associate an RNAT’s effect on meningitis disease progression,” says the paper’s first author Jens Karlsson, PhD student at the same department. “This supports further research into this and other non-coding RNAs’ potential involvement in the development of bacterial diseases.”

As part of the study, the researchers also developed a quick PCR test that is capable of distinguishing these RNAT mutations.

“In the future, this PCR test may be coupled with a simple nose swab at a clinic, and in doing so, facilitate a speedy identification of these mutations, and subsequent treatment,” Edmund Loh concludes.

The study was funded by the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation and the Swedish Research Council.

Facts about RNAs:

• RNAs (ribonucleic acids) are molecules that perform a range of functions within the cells. There are many kinds of RNAs, for example RNAs that carry protein-coding messages from DNA and RNAs that regulate the expression of different genes.
• Non-coding RNAs are molecules that are not translated into proteins. There are believed to be thousands of them in the human genome, many whose functions are not yet understood. Some have been linked to the development of diseases such as cancer and Alzheimer’s.
• Non-coding RNAs in bacteria help regulate several physiological processes. For example, the Nobel prize winning CRISPR/Cas9 gene editing tool partly originated from the discovery of the non-coding RNA molecule, tracrRNA, which helps disarm viruses by cleaving their DNA.
• In this study, the researchers link the non-coding RNA molecule, RNA thermosensor, or RNAT, in the bacterium Neisseria meningitidis to the progression of invasive meningococcal disease. It is the first time a non-coding RNA molecule in a bacterium has been linked to the progression of a disease in humans.

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