Human stem cells coaxed to mimic the very early central nervous system

The first stem cell culture method that produces a full model of the early stages of the human central nervous system has been developed by a team of engineers and biologists at the University of Michigan, the Weizmann Institute of Science, and the University of Pennsylvania.

"Models like this will open doors for fundamental research to understand early development of the human central nervous system and how it could go wrong in different disorders," said Jianping Fu, U-M professor of mechanical engineering and corresponding author of the study in Nature.

The system is an example of a 3D human organoid -- stem cell cultures that reflect key structural and functional properties of human organ systems but are partial or otherwise imperfect copies.

"We try to understand not only the basic biology of human brain development, but also diseases -- why we have brain-related diseases, their pathology, and how we can come up with effective strategies to treat them," said Guo-Li Ming, who along with Hongjun Song, both Perelman Professors of Neuroscience at UPenn and co-authors of the study, developed protocols for growing and guiding the cells and characterized the structural and cellular characteristics of the model.

For example, organoids developed using patient-derived stem cells may be used for identifying which drugs offer the most successful treatment. Already, human brain and spinal cord organoids are used to study neurological and neuropsychiatric diseases, but they often mimic one part of the central nervous system and are disorganized. The new model, in contrast, recapitulates the development of all three sections of embryonic brain and spinal cord simultaneously, a feat that has not been achieved in previous models.

"The system itself is really groundbreaking," said Orly Reiner, the Berstein-Mason Professorial Chair of Neurochemistry at Weizmann and co-author of the study who developed cellular tools to identify neural cell types in the model. "A model that mimics this structure and organization has not been done before, and it offers numerous possibilities for studying human brain development and especially developmental brain diseases."

While the model is faithful to many aspects of the early development of the brain and spinal cord, the team notes several important differences. For one, neural tube formation -- the very first stage of central nervous system development -- is very different. The model can't be used to simulate disorders that stem from improper closure of the neural tube such as spina bifida.

Instead, the model started with a row of stem cells roughly the size of the neural tube found in a 4-week-old embryo -- about 4 millimeters long and 0.2 millimeters in width. The team stuck the cells to a chip patterned with tiny channels that the team used to introduce materials that enabled the stem cells to grow and guided them toward building a central nervous system.

The team then added a gel that allowed the cells to grow in three dimensions and chemical signals that nudged them to become the precursors of neural cells. In response, the cells formed a tubular structure. Next, the team introduced chemical signals that helped the cells identify where they were within the structure and progress to more specialized cell types. As a result, the system organized itself to mimic the forebrain, midbrain, hindbrain and spinal cord in a way that mirrors embryonic development.

"As an engineer, the challenging part is to learn neural development and stem cell biology," said Xufeng Xue, first author of the study and a postdoctoral fellow in mechanical engineering U-M. "It was a team effort to make this happen, with amazing collaborators at UPenn and Weizmann."

The team grew the cells for 40 days, simulating development of the central nervous system to about 11 weeks post-fertilization. In this time, the team was able to demonstrate the roles of specific genes in spinal cord development and learn how certain cell types in the early human nervous system differentiate into different cells with specialized functions.

"In many cases, animal models simply do not recapitulate either the characteristics or the degree of severity seen in human brain diseases such as microcephaly," Song said. "Even nonhuman primates are not the same. So in the context of disease biology and treatment strategies, a human cell model is almost irreplaceable."

The team plans to apply the model to study different human brain diseases using patient derived stem cells.

Xue hopes to continue using this model to study the interplay among different parts of the brain during development. He is also interested in studying how the brain sends instructions for movement via the spinal cord. This line of inquiry, which could shed new light on disorders like paralysis, would require the neurons to link up into working circuits -- something that was not observed in this study.

Insoo Hyun, a bioethicist at the Museum of Science in Boston who was not part of the study, notes that experiments like these are closely scrutinized before they are allowed to move forward.

"Research groups must be clear about the scientific question they are trying to answer -- and that the degree of development they allow in the model is the minimum to answer the question," he said.

The model does not include peripheral nerves or functioning neural circuitry -- features that are critical for humans' ability to experience our environment and process that experience.

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Cracking the code that relates brain and behavior in a simple animal

To understand the full relationship between brain activity and behavior, scientists have needed a way to map this relationship for all of the neurons across a whole brain -- a so far insurmountable challenge. But after inventing new technologies and methods for the purpose, a team of scientists in The Picower Institute for Learning and Memory at MIT has produced a rigorous accounting of the neurons in the tractably tiny brain of a humble C. elegans worm, mapping out how its brain cells encode almost all of its essential behaviors, such as movement and feeding.

In the journal Cell, the team presents new brain-wide recordings and a mathematical model that accurately predicts the versatile ways that neurons represent the worm's behaviors. Applying that model specifically to each cell, the team produced an atlas of how most cells, and the circuits they take part in, encode the animal's actions. The atlas therefore reveals the underlying "logic" of how the worm's brain produces a sophisticated and flexible repertoire of behaviors, even as its environmental circumstances change.

"This study provides a global map of how the animal's nervous system is organized to control behavior," said senior author Steven Flavell, Associate Professor in MIT's Department of Brain and Cognitive Sciences. "It shows how the many defined nodes that make up the animal's nervous system encode precise behavioral features, and how this depends on factors like the animal's recent experience and current state."

Graduate students Jungsoo Kim and Adam Atanas, who each earned their PhDs this spring for the research, are the study's co-lead authors. They've also made all their data, and the findings of their model and atlas, freely available to fellow researchers at a website called the WormWideWeb.

Microscopes to models

To make the measurements needed to develop their model, Flavell's lab invented a new microscope and software system that automatically tracks almost all behaviors of the worm (movement, feeding, sleeping, egg-laying, etc.) and the activity of every neuron in its head (cells are engineered to flash when calcium ions build up). Reliably distinguishing and tracking separate neurons as the worm wriggles around and bends required writing custom software, utilizing the latest tools from machine learning. It proved to be 99.7 percent accurate in sampling individual neuron's activities with greatly improved signal-to-noise compared to previous systems, the scientists report.

The team used the system to record simultaneous behavior and neural data from more than 60 worms as they roved about their dishes, doing whatever they wanted.

Data analysis revealed three novel observations about neural activity in the worm: Neurons track behavior not only of the present moment but also the recent past; they tune their encoding of behaviors, such as motion, based on a surprising variety of factors; and many neurons simultaneously encode multiple behaviors.

For example, while the behavior of wriggling around one's little laboratory dish might seem like a very simple act, neurons represented factors such as speed, steering, and whether the worm is eating or not. In some cases they represented the animal's motion spanning back in time by about a minute. By encoding recent, rather than just current motion, these neurons could help the worm compute how its past actions influenced its current outcome. Many neurons also combined behavioral information to execute more complex maneuvers. Much like a human driver must remember to steer the car in the opposite way when going in reverse versus going forward, certain neurons in the worm's brain integrated the animal's direction of motion and steering direction.

By carefully analyzing these kinds of patterns of how neural activity correlated with behaviors the scientists developed the C. elegans Probabilistic Neural Encoding Model. The model, encapsulated in a single equation, accounts for how each neuron represents various factors to accurately predict whether and how the neural activity reflects behavior. Nearly 60 percent of the neurons in the worm's head indeed accounted for at least one behavior.

In fitting the model, the research team used a probabilistic modeling approach that allowed them to understand how certain they were about each fit model parameter, an approach pioneered by co-author Vikash Mansinghka, a principal research scientist who leads MIT's Probabilistic Computing Project.

Making an atlas

In creating a model that could quantify and predict how any brain cell would represent behavior, the team initially gathered data from neurons without tracking the cells' specific identities. But a key goal of studying the worms is to understand how each cell and circuit contributes to behavior. So to apply the model's capability to each of the worm's specific neurons, which have all been previously mapped out, the team's next step was to relate neural activity and behavior for each cell on the map. Doing that required labeling each neuron with a unique color so that its activity could be associated with its identity. The team did this in dozens of freely-moving animals, which provided them with information of how almost all of the defined neurons in the worm's head related to the animal's behavior.

The atlas resulting from this work revealed many insights, more fully mapping out the neural circuits that control each of the animal's behaviors. These new findings will enable a more holistic understanding of how these behaviors are controlled, Flavell said.

"It allowed us to complete the circuits," he said. "Our hope is that as our colleagues study aspects of neural circuit function, they can refer to this atlas to obtain a fairly complete view of the key neurons involved."

Built for flexibility

Another major outcome of the team's work was the finding that while most neurons always obeyed the predictions of the model, a smaller set of neurons in the worm's brain -- about 30 percent of those that encode behavior -- was able to flexibly remap their behavior encoding, essentially taking on new jobs. The neurons in this group were reliably similar across animals, and were well connected with one another in the worm's synaptic wiring diagram.

Theoretically these remapping events could occur for any number of reasons, so the team ran further experiments to see if they could cause neurons to remap. As the worms wriggled around their dishes, the researchers applied a quick laser zap that heated the agar around the worm's head. The heat was harmless but enough to annoy the worms for a while, inducing a change in the animal's behavior state that lasted for minutes. From these recordings the team was able to see that many neurons remapped their behavioral encoding right as animals switched behavioral states.

"Behavioral information is richly expressed across the brain in many different forms -- with distinct tunings, timescales, and levels of flexibility -- that map onto the defined neuron classes of the C. elegans connectome," the authors wrote.

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525-million-year-old fossil defies textbook explanation for brain evolution

Fossils of a tiny sea creature that died more than half a billion years ago may compel a science textbook rewrite of how brains evolved.

A study published in Science -- led by Nicholas Strausfeld,a Regents Professor in the University of Arizona Department of Neuroscience, and Frank Hirth, a reader of evolutionary neuroscience at King's College London -- provides the first detailed description of Cardiodictyon catenulum, a wormlike animal preserved in rocks in China's southern Yunnan province. Measuring barely half an inch (less than 1.5 centimeters) long and initially discovered in 1984, the fossil had hidden a crucial secret until now: a delicately preserved nervous system, including a brain.

"To our knowledge, this is the oldest fossilized brain we know of, so far," Strausfeld said.

Cardiodictyon belonged to an extinct group of animals known as armored lobopodians, which were abundant early during a period known as the Cambrian, when virtually all major animal lineages appeared over an extremely short time between 540 million and 500 million years ago. Lobopodians likely moved about on the sea floor using multiple pairs of soft, stubby legs that lacked the joints of their descendants, the euarthropods -- Greek for "real jointed foot." Today's closest living relatives of lobopodians are velvet worms that live mainly in Australia, New Zealand and South America.

A debate going back to the 1800s

Fossils of Cardiodictyon reveal an animal with a segmented trunk in which there are repeating arrangements of neural structures known as ganglia. This contrasts starkly with its head and brain, both of which lack any evidence of segmentation.

"This anatomy was completely unexpected because the heads and brains of modern arthropods, and some of their fossilized ancestors, have for over a hundred years been considered as segmented," Strausfeld said.

According to the authors, the finding resolves a long and heated debate about the origin and composition of the head in arthropods, the world's most species-rich group in the animal kingdom. Arthropods include insects, crustaceans, spiders and other arachnids, plus some other lineages such as millipedes and centipedes.

"From the 1880s, biologists noted the clearly segmented appearance of the trunk typical for arthropods, and basically extrapolated that to the head," Hirth said. "That is how the field arrived at supposing the head is an anterior extension of a segmented trunk."

"But Cardiodictyon shows that the early head wasn't segmented, nor was its brain, which suggests the brain and the trunk nervous system likely evolved separately," Strausfeld said.

Brains do fossilize

Cardiodictyon was part of the Chengjiang fauna, a famous deposit of fossils in the Yunnan Province discovered by paleontologist Xianguang Hou. The soft, delicate bodies of lobopodians have preserved well in the fossil record, but other than Cardiodictyon none have been scrutinized for their head and brain, possibly because lobopodians are generally small. The most prominent parts of Cardiodictyon were a series of triangular, saddle-shaped structures that defined each segment and served as attachment points for pairs of legs. Those had been found in even older rocks dating back to the advent of the Cambrian.

"That tells us that armored lobopodians might have been the earliest arthropods," Strausfeld said, predating even trilobites, an iconic and diverse group of marine arthropods that went extinct around 250 million years ago.

"Until very recently, the common understanding was 'brains don't fossilize,'" Hirth said. "So you would not expect to find a fossil with a preserved brain in the first place. And, second, this animal is so small you would not even dare to look at it in hopes of finding a brain."

However, work over the last 10 years, much of it done by Strausfeld, has identified several cases of preserved brains in a variety of fossilized arthropods.

A common genetic ground plan for making a brain

In their new study, the authors not only identified the brain of Cardiodictyon but also compared it with those of known fossils and of living arthropods, including spiders and centipedes. Combining detailed anatomical studies of the lobopodian fossils with analyses of gene expression patterns in their living descendants, they conclude that a shared blueprint of brain organization has been maintained from the Cambrian until today.

"By comparing known gene expression patterns in living species," Hirth said, "we identified a common signature of all brains and how they are formed."

In Cardiodictyon, three brain domains are each associated with a characteristic pair of head appendages and with one of the three parts of the anterior digestive system.

"We realized that each brain domain and its corresponding features are specified by the same combination genes, irrespective of the species we looked at," added Hirth. "This suggested a common genetic ground plan for making a brain."

Lessons for vertebrate brain evolution

Hirth and Strausfeld say the principles described in their study probably apply to other creatures outside of arthropods and their immediate relatives. This has important implications when comparing the nervous system of arthropods with those of vertebrates, which show a similar distinct architecture in which the forebrain and midbrain are genetically and developmentally distinct from the spinal cord, they said.

Strausfeld said their findings also offer a message of continuity at a time when the planet is changing dramatically under the influence of climatic shifts.

"At a time when major geological and climatic events were reshaping the planet, simple marine animals such as Cardiodictyon gave rise to the world's most diverse group of organisms -- the euarthropods -- that eventually spread to every emergent habitat on Earth, but which are now being threatened by our own ephemeral species."

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How COVID-19 causes neurological damage

It's not uncommon for people to lose their sense of taste and smell due to a Covid-19 infection. In others, the disease has had an even stronger impact on the nervous system, with effects ranging from lasting concentration problems to strokes. Now, researchers led by Professor Gregor Hutter from the Department of Biomedicine at the University of Basel and University Hospital of Basel have reported new insights into the development of "neuro-Covid" in the journal Nature Communications.

Specifically, the team investigated how different severities of neuro-COVID can be detected and predicted by analyzing the cerebrospinal fluid and blood plasma of affected individuals. Their findings also offer some indications of how to prevent neurological damage due to Covid-19.

The study included 40 Covid-19 patients with differing degrees of neurological symptoms. In order to identify typical changes associated with neuro-Covid, the team of researchers compared these individuals' cerebrospinal fluid and blood plasma with samples from a control group. They also measured the brain structures of test subjects and surveyed participants 13 months after their illness in order to identify any lasting symptoms.

Holes in the blood-brain barrier

Particularly in the group with the most serious neurological symptoms, the researchers identified a link with an excessive immune response. On the one hand, affected individuals showed indications of impairment of the blood-brain barrier, which the study's authors speculate was probably triggered by a "cytokine storm" -- a massive release of pro-inflammatory factors in response to the virus.

On the other hand, the researchers also found antibodies that targeted parts of the body's own cells -- in other words, signs of an autoimmune reaction -- as a result of the excessive immune response. "We suspect that these antibodies cross the porous blood-brain barrier into the brain, where they cause damage," explains Hutter. They also identified excessive activation of the immune cells specifically responsible for the brain -- the microglia.

Blood test as a long-term objective

In a further step, Hutter and his team investigated whether the severity of neurological symptoms is also perceptible in brain structures. Indeed, they found that people with serious neuro-Covid symptoms had a lower brain volume than healthy participants at specific locations in the brain and particularly at the olfactory cortex -- that is, the area of the brain responsible for smell.

"We were able to link the signature of certain molecules in the blood and cerebrospinal fluid to an overwhelming immune response in the brain and reduced brain volume in certain areas, as well as neurological symptoms," says Hutter, adding that it is now important to examine these biomarkers in a greater number of participants. The aim would be to develop a blood test that can already predict serious cases, including neuro-Covid and long Covid, at the start of an infection.

Targets for preventing consequential damage

These same biomarkers point to potential targets for drugs aimed at preventing consequential damage due to a Covid-19 infection. One of the biomarkers identified in blood, the factor MCP-3, plays a key role in the excessive immune response, and Hutter believes there is the potential to inhibit this factor medicinally.

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Multiple health benefits of b-type procyanidin-rich foods like chocolate and apples consumed in right amounts

B-type procyanidins, made of catechin oligomers, are a class of polyphenols found abundantly in foods like cocoa, apples, grape seeds, and red wine. Several studies have established the benefits of these micronutrients in reducing the risk of cardiovascular diseases and strokes. B-type procyanidins are also successful in controlling hypertension, dyslipidemia, and glucose intolerance. Studies attest to the physiological benefits of their intake on the central nervous system (CNS), namely an improvement in cognitive functions. These physiological changes follow a pattern of hormesis -- a phenomenon in which peak benefits of a substance are achieved at mid-range doses, becoming progressively lesser at lower and higher doses.

The dose-response relationship of most bioactive compounds follows a monotonic pattern, in which a higher dose shows a greater response. However, in some exceptional cases, a U-shaped dose-response curve is seen. This U-shaped curve signifies hormesis -- an adaptive response, in which a low dose of usually a harmful compound induces resistance in the body to its higher doses. This means that exposure to low levels of a harmful trigger can induce the activation of stress-resistant pathways, leading to greater repair and regeneration capabilities. In case of B-type procyanidins, several in vitro studies support their hormetic effects, but these results have not been demonstrated in vivo.

To address this knowledge gap, researchers from Shibaura Institute of Technology (SIT), Japan, led by Professor Naomi Osakabe from the Department of Bioscience and Engineering, reviewed the data from intervention trials supporting hormetic responses of B-type procyanidin ingestion. The team, comprising Taiki Fushimi and Yasuyuki Fujii from the Graduate School of Engineering and Science (SIT), also conducted in vivo experiments to understand possible connections between B-type procyanidin hormetic responses and CNS neurotransmitter receptor activation. Their article was made available online on June 15, 2022 and has been published in volume 9 of Frontiers of Nutrition on September 7, 2022.

The researchers noted that a single oral administration of an optimal dose of cocoa flavanol temporarily increased the blood pressure and heart rate in rats. But the hemodynamics did not change when the dose was increased or decreased. Administration of B-type procyanidin monomer and various oligomers produced similar results. According to Professor Osakabe, "These results are consistent with those of intervention studies following a single intake of food rich in B-type procyanidin, and support the U-shaped dose-response theory, or hormesis, of polyphenols."

To observe whether the sympathetic nervous system (SNS) is involved in the hemodynamic changes induced by B-type procyanidins, the team administered adrenaline blockers in test rats. This successfully decreased the temporary increase in heart rate induced by the optimal dose of cocoa flavanol. A different kind of blocker -- a1 blocker -- inhibited the transient rise in blood pressure. This suggested that the SNS, which controls the action of adrenaline blockers, is responsible for the hemodynamic and metabolic changes induced by a single oral dose of B-type procyanidin.

The researchers next ascertained why optimal doses, and not high doses, are responsible for the thermogenic and metabolic responses. They co-administered a high dose of cocoa flavanol and yohimbine (an α2 blocker) and noted a temporary but distinct increase in blood pressure in test animals. Similar observations were made with the use of B-type procyanidin oligomer and yohimbine. Professor Osakabe surmises, "Since α2 blockers are associated with the down-regulation of the SNS, the reduced metabolic and thermogenic outputs at a high dose of B-type procyanidins seen in our study may have induced α2 auto-receptor activation. Thus, SNS deactivation may be induced by a high dose of B-type procyanidins."

Previous studies have proven the role of the gut-brain axis in controlling hormetic stress-related responses. The activation of the hypothalamus-pituitary-adrenal (HPA) axis by optimal stress has a strong influence on memory, cognition, and stress tolerance. This article highlights how HPA activation occurs after a single dose of B-type procyanidin, suggesting that stimulation with an oral dose of B-type procyanidin might be a stressor for mammals and cause SNS activation.

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Into the brain of comb jellies: Scientists explore the evolution of neurons

Neurons, the specialized cells of the nervous system, are possibly the most complicated cell type ever to have evolved. In humans, these cells are capable of processing and transmitting vast sums of information. But how such complicated cells first came about remains a long-standing debate.

Now, scientists in Japan have revealed the type of messenger -- molecules that carry signals from one cell to another -- that likely functioned in the most ancestral nervous system.

The study, published 8th August in Nature Ecology and Evolution, also revealed key similarities between the nervous system of two early-diverging animal lineages -- the lineage of jellyfish and anemones (also called cnidarians) and that of comb jellies (ctenophores), reigniting an earlier hypothesis that neurons only evolved once.

Despite their supposed simplicity, very little is known about the nervous system of ancient animals. Out of the four animal lineages that branched off before the rise of more complex animals, only comb jellies (the first ancient lineage to diverge) and cnidarians (the last ancient lineage to diverge) are known to possess neurons. But the uniqueness of the comb jellies nervous system compared to that seen in cnidarians and more complex animals, and the absence of neurons in the two lineages that diverged in between, led some scientists to hypothesize that neurons evolved twice.

But Professor Watanabe, who leads the Evolutionary Neurobiology Unit at the Okinawa Institute of Science and Technology (OIST), remained unconvinced.

"Indeed, comb jellies lack a lot of neural proteins that we see in more evolved animal lineages," he said. "But for me, a lack of these proteins isn't enough evidence for two independent neuron origins."

In his study, Prof. Watanabe focused on an ancient and diverse group of neural messengers. Called neuropeptides, these short peptide chains are first synthesized in neurons as a long peptide chain, before being cleaved by digestive enzymes into many short peptides. They are the major form of messenger found in cnidarians, and also play a role in neural communication in humans, and other complex animals.

However, past research that has attempted to find similar neuropeptides in comb jellies has been unsuccessful. The main problem, explained Prof. Watanabe, is that the mature short peptides are encoded by only short sequences of DNA, and mutate frequently in these ancient lineages, making DNA comparisons too difficult. While artificial intelligence has identified potential peptides, these have not yet been experimentally validated.

So, Prof. Watanabe's research team approached the problem from a new direction. They extracted peptides from sponges, cnidarians and comb jellies and used mass spectrometry to search for short peptides. The team was able to find 28 short peptides in cnidarians and comb jellies and determine their amino acid sequences.

Now knowing their structures, the researchers visualized the short peptides under a fluorescent microscope, allowing them to see which cells they were produced in in both cnidarians and comb jellies.

In comb jellies, they found that one type of neuropeptide-expressing cell looked similar to classic neurons, with thin projections called neurites extending out from the cell.

But the short peptides were also produced in a second type of cell that lacked neurites. The researchers suspect these could be an early version of neuroendocrine cells -- cells which receive signals from neurons and then release signals, like hormones, to other organs in the body.

The researchers also compared what genes were expressed in cnidarian and comb jelly neurons. They found that as well as having some short neuropeptides in common, both neurons also expressed a similar array of other proteins essential for neuronal function.

"We already know that cnidarian peptide-expressing neurons are homologous to those seen in more complex animals. Now, comb jelly neurons have also been found to have a similar "genetic signature," suggesting that these neurons share the same evolutionary origin," said Prof. Watanabe. "In other words, it's most likely that neurons only evolved once."

This means, added Prof. Watanabe, that peptide-expressing neurons are probably the most ancestral form, with chemical neurotransmitters arising later. For Prof. Watanabe, these findings bring new, exciting questions to the forefront of his research.

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Microglial methylation 'landscape' in human brain

In the central nervous system, microglial cells play critical roles in development, aging, brain homeostasis, and pathology. Recent studies have shown variation in the gene-expression profile and phenotype of microglia across brain regions and between different age and disease states. But the molecular mechanisms that contribute to these transcriptomic changes in the human brain are not well understood. Now, a new study targets the methylation profile of microglia from human brain.

The study appears in Biological Psychiatry, published by Elsevier.

Microglia, the brain's own immune cells, were once thought of as a homogenous population that was either "activated" or "inactivated," with either pro-inflammatory or neuroprotective effects. But the cells are now recognized to have a vast array of phenotypes depending on environmental conditions with myriad functional consequences. Microglia are increasingly appreciated as critical players in neurologic and psychiatric disorders.

Fatemeh Haghighi, PhD, senior author of the new work, said: "To address this gap in knowledge, we set out to characterize the DNA methylation landscape of human primary microglia cells and factors that contribute to variations in the microglia methylome."

DNA methylation is the main form of epigenetic regulation, which determines the pattern of which genes are being turned "on" or "off" in various circumstances over time.

The researchers studied isolated microglia cells from post-mortem human brain tissue from 22 donors of various age, including 1 patient with schizophrenia, 13 with mood disorder, and 8 controls with no psychiatric disorder, taken from 4 brain regions. They analyzed the microglia using genome-scale methylation microarrays.

Unsurprisingly, microglia showed DNA methylation profiles that were distinct from other cells in the central nervous system. But less expected, said Haghighi, "we found that interindividual differences rather than brain region differences had a much larger effect on the DNA methylation variability." In addition, an exploratory analysis showed differences in the methylation profile of microglia from brains of subjects with psychiatric disorders compared to controls.

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New type of nerve cell discovered in the retina

Scientists at the John A. Moran Eye Center at the University of Utah have discovered a new type of nerve cell, or neuron, in the retina.

In the central nervous system a complex circuitry of neurons communicate with each other to relay sensory and motor information; so-called interneurons serve as intermediaries in the chain of communication. Publishing in the Proceedings of the National Academy of Sciences of the United States of America, a research team led by Ning Tian, PhD, identifies a previously unknown type of interneuron in the mammalian retina.

The discovery marks a notable development for the field as scientists work toward a better understanding of the central nervous system by identifying all classes of neurons and their connections.

"Based on its morphology, physiology, and genetic properties, this cell doesn't fit into the five classes of retinal neurons first identified more than 100 years ago," said Tian. "We propose they might belong to a new retinal neuron class by themselves."

The research team named their discovery the Campana cell after its shape, which resembles a hand bell. Campana cells relay visual signals from both types of light-sensing rod and cone photoreceptors in the retina, but their precise purpose is the subject of ongoing research. Experiments showed Campana cells remain activated for an unusually long time -- as long as 30 seconds -- in response to a 10 millisecond light flash stimulation.

"In the brain, persistent firing cells are believed to be involved in memory and learning," said Tian. "Since Campana cells have a similar behavior, we theorize they could play a role in prompting a temporal 'memory' of a recent stimulation."

The published research study is: "An uncommon neuronal class conveys visual signals from rods and cones to retinal ganglion cells." Authors are: Brent K. Young, Charu Ramakrishnan, Tushar Ganjawala, Ping Wang, Karl Deisseroth, and Ning Tian.

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Sense of smell is our most rapid warning system

The ability to detect and react to the smell of a potential threat is a precondition of our and other mammals' survival. Using a novel technique, researchers at Karolinska Institutet in Sweden have been able to study what happens in the brain when the central nervous system judges a smell to represent danger. The study, which is published in PNAS, indicates that negative smells associated with unpleasantness or unease are processed earlier than positive smells and trigger a physical avoidance response.

"The human avoidance response to unpleasant smells associated with danger has long been seen as a conscious cognitive process, but our study shows for the first time that it's unconscious and extremely rapid," says the study's first author Behzad Iravani, researcher at the Department of Clinical Neuroscience, Karolinska Institutet.

The olfactory organ takes up about five per cent of the human brain and enables us to distinguish between many million different smells. A large proportion of these smells are associated with a threat to our health and survival, such as that of chemicals and rotten food. Odour signals reach the brain within 100 to 150 milliseconds after being inhaled through the nose.

The survival of all living organisms depends on their ability to avoid danger and seek rewards. In humans, the olfactory sense seems particularly important for detecting and reacting to potentially harmful stimuli.

It has long been a mystery just which neural mechanisms are involved in the conversion of an unpleasant smell into avoidance behaviour in humans. One reason for this is the lack of non-invasive methods of measuring signals from the olfactory bulb, the first part of the rhinencephalon (literally "nose brain") with direct (monosynaptic) connections to the important central parts of the nervous system that helps us detect and remember threatening and dangerous situations and substances.

Researchers at Karolinska Institutet have now developed a method that for the first time has made it possible to measure signals from the human olfactory bulb, which processes smells and in turn can transmits signals to parts of the brain that control movement and avoidance behaviour.

Their results are based on three experiments in which participants were asked to rate their experience of six different smells, some positive, some negative, while the electrophysiological activity of the olfactory bulb when responding to each of the smells was measured.

"It was clear that the bulb reacts specifically and rapidly to negative smells and sends a direct signal to the motor cortex within about 300 ms," says the study's last author Johan Lundström, associate professor at the Department of Clinical Neuroscience, Karolinska Institutet. "The signal causes the person to unconsciously lean back and away from the source of the smell."

He continues:

"The results suggest that our sense of smell is important to our ability to detect dangers in our vicinity, and much of this ability is more unconscious than our response to danger mediated by our senses of vision and hearing."

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Reaching your life goals as a single-celled organism

How is it possible to move in the desired direction without a brain or nervous system? Single-celled organisms apparently manage this feat without any problems: for example, they can swim towards food with the help of small flagellar tails.

How these extremely simply built creatures manage to do this was not entirely clear until now. However, a research team at TU Wien (Vienna) has now been able to simulate this process on the computer: They calculated the physical interaction between a very simple model organism and its environment. This environment is a liquid with a non-uniform chemical composition, it contains food sources that are unevenly distributed.

The simulated organism was equipped with the ability to process information about food in its environment in a very simple way. With the help of a machine learning algorithm, the information processing of the virtual being was then modified and optimised in many evolutionary steps. The result was a computer organism that moves in its search for food in a very similar way to its biological counterparts.

Chemotaxis: Always going where the chemistry is right

"At first glance, it is surprising that such a simple model can solve such a difficult task," says Andras Zöttl, who led the research project, which was carried out in the "Theory of Soft Matter" group (led by Gerhard Kahl) at the Institute of Theoretical Physics at TU Wien. "Bacteria can use receptors to determine in which direction, for example, the oxygen or nutrient concentration is increasing, and this information then triggers a movement into the desired direction. This is called chemotaxis."

The behaviour of other, multicellular organisms can be explained by the interconnection of nerve cells. But a single-celled organism has no nerve cells -- in this case, only extremely simple processing steps are possible within the cell. Until now, it was not clear how such a low degree of complexity could be sufficient to connect simple sensory impressions -- for example from chemical sensors -- with targeted motor activity.

"To be able to explain this, you need a realistic, physical model for the movement of these unicellular organisms," says Andreas Zöttl. "We have chosen the simplest possible model that physically allows independent movement in a fluid in the first place. Our single-celled organism consists of three masses connected by simplified muscles. The question now arises: can these muscles be coordinated in such a way that the entire organism moves in the desired direction? And above all: can this process be realised in a simple way, or does it require complicated control?"

A small network of signals and commands

"Even if the unicellular organism does not have a network of nerve cells -- the logical steps that link its 'sensory impressions' with its movement can be described mathematically in a similar way to a neuronal network," says Benedikt Hartl, who used his expertise in artificial intelligence to implement the model on the computer. In the single-celled organism, too, there are logical connections between different elements of the cell. Chemical signals are triggered and ultimately lead to a certain movement of the organism.

"These elements and the way they influence each other were simulated on the computer and adjusted with a genetic algorithm: Generation after generation, the movement strategy of the virtual unicellular organisms was changed slightly," reports Maximilian Hübl, who did many of the calculations on this topic as part of his Master's thesis. Those unicellular organisms that succeeded best in directing their movement to where the desired chemicals were located were allowed to "reproduce," while the less successful variants "died out." In this way, after many generations, a control network emerged -- very similar to biological evolution -- that allows a virtual unicellular organism to convert chemical perceptions into targeted movement in an extremely simple way and with very basic circuits.

Random wobbling movement -- but with a concrete goal

"You shouldn't think of it as a highly developed animal that consciously perceives something and then runs towards it," says Andreas Zöttl. "It's more like a random wobbling movement. But one that ultimately leads in the right direction on average. And that's exactly what you observe with single-celled organisms in nature."

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A memory without a brain

 Having a memory of past events enables us to take smarter decisions about the future. Researchers at the Max-Planck Institute for Dynamics and Self-Organization (MPI-DS) and the Technical University of Munich (TUM) have now identified how the slime mold Physarum polycephalum saves memories -- although it has no nervous system.

The ability to store and recover information gives an organism a clear advantage when searching for food or avoiding harmful environments. Traditionally it has been attributed to organisms that have a nervous system.

A new study authored by Mirna Kramar (MPI-DS) and Prof. Karen Alim (TUM and MPI-DS) challenges this view by uncovering the surprising abilities of a highly dynamic, single-celled organism to store and retrieve information about its environment.

Window into the past

The slime mold Physarum polycephalum has been puzzling researchers for many decades. Existing at the crossroads between the kingdoms of animals, plants and fungi, this unique organism provides insight into the early evolutionary history of eukaryotes -- to which also humans belong.

Its body is a giant single cell made up of interconnected tubes that form intricate networks. This single amoeba-like cell may stretch several centimeters or even meters, featuring as the largest cell on earth in the Guinness Book of World Records.

Decision making on the most basic levels of life

The striking abilities of the slime mold to solve complex problems, such as finding the shortest path through a maze, earned it the attribute "intelligent." It intrigued the research community and kindled questions about decision making on the most basic levels of life.

The decision-making ability of Physarum is especially fascinating given that its tubular network constantly undergoes fast reorganization -- growing and disintegrating its tubes -- while completely lacking an organizing center.

The researchers discovered that the organism weaves memories of food encounters directly into the architecture of the network-like body and uses the stored information when making future decisions.

The network architecture as a memory of the past

"It is very exciting when a project develops from a simple experimental observation," says Karen Alim, head of the Biological Physics and Morphogenesis group at the MPI-DS and professor on Theory of Biological Networks at the Technical University of Munich.

When the researchers followed the migration and feeding process of the organism and observed a distinct imprint of a food source on the pattern of thicker and thinner tubes of the network long after feeding.

"Given P. polycephalum's highly dynamic network reorganization, the persistence of this imprint sparked the idea that the network architecture itself could serve as memory of the past," says Karen Alim. However, they first needed to explain the mechanism behind the imprint formation.

Decisions are guided by memories

For this purpose the researchers combined microscopic observations of the adaption of the tubular network with theoretical modeling. An encounter with food triggers the release of a chemical that travels from the location where food was found throughout the organism and softens the tubes in the network, making the whole organism reorient its migration towards the food.

"The gradual softening is where the existing imprints of previous food sources come into play and where information is stored and retrieved," says first author Mirna Kramar. "Past feeding events are embedded in the hierarchy of tube diameters, specifically in the arrangement of thick and thin tubes in the network."

"For the softening chemical that is now transported, the thick tubes in the network act as highways in traffic networks, enabling quick transport across the whole organism," adds Mirna Kramar. "Previous encounters imprinted in the network architecture thus weigh into the decision about the future direction of migration."

Design based on universal principles

"Given the simplicity of this living network, the ability of Physarum to form memories is intriguing. It is remarkable that the organism relies on such a simple mechanism and yet controls it in such a fine-tuned manner," says Karen Alim.

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