Good and bad feelings for brain stem serotonin

An illustration of the facial expression changes in mice following stimulation and inhibition of the median raphe nucleus
Image Credit: Yu Ohmura

New insights into the opposing actions of serotonin-producing nerve fibers in mice could lead to drugs for treating addictions and major depression.

Scientists in Japan have identified a nerve pathway involved in the processing of rewarding and distressing stimuli and situations in mice.

The new pathway, originating in a bundle of brain stem nerve fibers called the median raphe nucleus, acts in opposition to a previously identified reward/aversion pathway that originates in the nearby dorsal raphe nucleus. The findings, published by scientists at Hokkaido University and Kyoto University with their colleagues in the journal Nature Communications, could have implications for developing drug treatments for various mental disorders, including addictions and major depression.

Previous studies had already revealed that activating serotonin-producing nerve fibers from the dorsal raphe nucleus in the brain stem of mice leads to the pleasurable feeling associated with reward. However, selective serotonin reuptake inhibitors (SSRIs), antidepressant drugs that increase serotonin levels in the brain, fail to exert clear feelings of reward and to treat the loss of ability to feel pleasure associated with depression. This suggests that there are other serotonin-producing nerve pathways in the brain associated with the feelings of reward and aversion.

Network neuroscience theory best predictor of intelligence

U. of I. Professor Aron Barbey, pictured, and co-author Evan Anderson found that taking into account the features of the whole brain – rather than focusing on individual regions or networks – allows the most accurate predictions of intelligence.     
Photo Credit: Fred Zwicky

Scientists have labored for decades to understand how brain structure and functional connectivity drive intelligence. Researchers report a new analysis offers the clearest picture yet of how various brain regions and neural networks contribute to a person’s problem-solving ability in a variety of contexts, a trait known as general intelligence, researchers report.

They detail their findings in the journal Human Brain Mapping.

The study used “connectome-based predictive modeling” to compare five theories about how the brain gives rise to intelligence, said Aron Barbey, a professor of psychology, bioengineering and neuroscience at the University of Illinois Urbana-Champaign who led the new work with first author Evan Anderson, now a researcher for Ball Aerospace and Technologies Corp. working at the Air Force Research Laboratory.

“To understand the remarkable cognitive abilities that underlie intelligence, neuroscientists look to their biological foundations in the brain,” Barbey said. “Modern theories attempt to explain how our capacity for problem-solving is enabled by the brain’s information-processing architecture.”

Mouse pups cry for help most urgently while active

Mouse pups produce ultrasonic vocalizations, called isolation USVs, when they are separated from the nest. It’s a survival mechanism – baby mice need their parents to regulate their temperature and feed them – that diminishes with age.

But before the USV reflex peters out around 20 days after birth, the rate at which mouse pups cry varies a lot, even within the same individual at the same age, according to Katherine Tschida, the Mary Armstrong Meduski ’80 Assistant Professor of psychology in the College of Arts and Sciences. Exploring this variation, researchers in the Tschida Lab found a link between mouse pup USV rates and their activity levels; the greater amount of body movement, the higher the rate of vocalizations. The connection is important for understanding mouse neural circuitry and development and provides a richer understanding of behavioral differences in mouse models of communication disorders, including autism spectrum disorder (ASD.)

“Rates of Ultrasonic Vocalizations are More Strongly Related Than Acoustic Features to Non-vocal Behaviors in Mouse Pups” was published Dec. 19 in Frontiers in Behavioral Neuroscience. Tschida and doctoral student Nicole Pranic are first authors. Contributions were made by Thomas Cleland, professor of psychology; Chen Yang, programmer and analyst in the Cleland Lab; and by Caroline Kornbrek ’23.

Scientists from NUS and NUHS identify predictive blood biomarker for cognitive impairment and dementia

Prof Barry Halliwell (left) and Dr Irwin Cheah (right), together with their collaborators from the National University Health System, have discovered that low levels of ergothioneine in blood plasma may predict an increased risk of cognitive impairment and dementia.
Photo Credit: National University of Singapore

Identification of elderly persons at risk of developing cognitive impairment and dementia could be made possible by examining ergothioneine levels in the blood

A recent study by a team comprising researchers from the National University of Singapore (NUS) and the National University Health System (NUHS) revealed that low levels of ergothioneine (ET) in blood plasma may predict an increased risk of cognitive impairment and dementia, suggesting possible therapeutic or early screening measures for cognitive impairment and dementia in the elderly.

The research teams were led by Professor Barry Halliwell from the Department of Biochemistry under the NUS Yong Loo Lin School of Medicine and Associate Professor Christopher Chen and Dr Mitchell Lai from the Memory, Ageing and Cognition Centre under NUHS. The results of their most recent study were published in the scientific journal Antioxidants.

UCLA-developed soft brain probe could be a boon for depression research

 Illustration of the soft probe with aptamer biosensors implanted in the brain.
Illustration Credit: Zhao, et al., 2022

Anyone familiar with antidepressants like Prozac or Wellbutrin knows that these drugs boost levels of neurotransmitters in the brain like serotonin and dopamine, which are known to play an important role in mood and behavior.

It might come as a surprise, then, that scientists still have very little data about the specific relationship between neurotransmitters — chemicals that relay messages from one brain cell to others — and our psychological states. Simply put, monitoring fluctuations of these neurochemicals in living brains has proved a persistent challenge.

Now, for the first time, UCLA scientists have attached nanoscale biochemical sensors, which are tuned to identify specific neurotransmitters, to a soft, implantable brain probe in order to continuously monitor these chemicals in real time. The new brain probe, described in a paper published in ACS Sensors, would allow scientists to track neurotransmitters in laboratory animals — and, ultimately, humans — during their day-to-day activities.

Frequent genetic cause of late-onset ataxia uncovered by a Quebec-led international collaboration

Photo Credit: whitfieldink

Discovery will improve diagnosis and open treatment possibilities for thousands of people with this debilitating neurodegenerative condition worldwide

A new study published in the New England Journal of Medicine reports the identification of a previously unknown genetic cause of a late-onset cerebellar ataxia, a discovery that will improve diagnosis and open new treatment avenues for this progressive condition.

Late-onset cerebellar ataxias (LOCA) are a heterogeneous group of neurodegenerative diseases that manifest in adulthood with unsteadiness. One to three in 100,000 people worldwide will develop a late-onset ataxia. Until recently, most patients with late-onset ataxia had remained without a genetic diagnosis.

An international team led by Dr. Bernard Brais, a neurologist and researcher at The Neuro (Montreal Neurological Institute-Hospital) of McGill University and Dr. Stephan Züchner of the University of Miami’s Miller School of Medicine, in collaboration with neurologists from the Universities of Montreal and Sherbrooke, studied a group of 66 Quebec patients from different families who had late-onset ataxia for which an underlying genetic cause had not yet been found. Using the most advanced genetic technologies, the team found that 40 (61 per cent) of the patients carried the same novel disease-causing variant in the gene FGF14, making it the most common genetic cause of late-onset ataxia in Quebec. They found that a small stretch of repetitive DNA underwent a large size increase in patients, a phenomenon known as repeat expansion.

Scientists Have Created New Substance to Treat Neurological Disorders

Scientists used a set of 1,2,3-triazole derivatives and modeled the structure of the putative inhibitor.
 Photo Credit: Andrey Fomin

The international team of scientists, including chemists from the Ural Federal University, has developed a substance that may become the basis for drugs that suppress or alleviate a number of neurological disorders. These include, for example, psychosis, schizophrenia, Parkinson's and Huntington's diseases, etc. The scientists reported the development and first results of the study in the Journal of Biomolecular Structure and Dynamics. The study was supported by a grant from the Ministry of Science and Higher Education of the Russian Federation (Project No. 075-15-2020-777).

"We found that the enzyme Phosphodiesterase 10A, which is produced in the body, is directly linked to neurological disorders. If you inhibit this enzyme, you can significantly slow down or even suppress the disease. For this purpose, we used a set of derivatives of 1,2,3-triazole, a pharmacophore whose fragments are contained in many drugs, and modeled the structure of the putative TP-10 inhibitor. We hypothesize that it would have a positive effect on conditions associated with brain dysfunction by reducing the activity of the Phosphodiesterase 10A enzyme. Other inhibitors developed by foreign companies still have no reliable antipsychotic efficacy so far," notes Dhananjay Bhattacherjee, senior researcher at the Department of Organic and Biomolecular Chemistry at UrFU.

Using light to manipulate neuron excitability

MIT and Harvard University researchers have devised a way to achieve long-term changes in neuron activity. With their new strategy, they can use light exposure to change the electrical capacitance of the neurons’ membranes, which alters their excitability (how strongly or weakly they respond to electrical signals).
Photo Credit: SFLORG stock image

Nearly 20 years ago, scientists developed ways to stimulate or silence neurons by shining light on them. This technique, known as optogenetics, allows researchers to discover the functions of specific neurons and how they communicate with other neurons to form circuits.

Building on that technique, MIT and Harvard University researchers have now devised a way to achieve longer-term changes in neuron activity. With their new strategy, they can use light exposure to change the electrical capacitance of the neurons’ membranes, which alters their excitability (how strongly or weakly they respond to electrical and physiological signals).

Changes in neuron excitability have been linked to many processes in the brain, including learning and aging, and have also been observed in some brain disorders, including Alzheimer’s disease.

“This new tool is designed to tune neuron excitability up and down in a light-controllable and long-term manner, which will enable scientists to directly establish the causality between the excitability of various neuron types and animal behaviors,” says Xiao Wang, the Thomas D. and Virginia Cabot Assistant Professor of Chemistry at MIT, and a member of the Broad Institute of MIT and Harvard. “Future application of our approach in disease models will tell whether fine-tuning neuron excitability could help reset abnormal brain circuits to normal.”

New findings on neuronal activities in the sensorimotor cortex

Neurons from layer 5 of the motor cortex stained with a fluorescent dye.
Image Credit: Ilka Diester

An interdisciplinary research team at the University of Freiburg has found important clues about the functioning of the sensorimotor cortex. The new findings on neuronal activities in this brain area could be helpful for the further development and use of so-called neuroprostheses. These have an interface with the nervous system and are intended to help compensate for neuronal dysfunctions. "Our results will contribute to the improvement of neuroprosthetic approaches while shortening the training period of patients with prostheses,” says neurobiologist Prof. Dr. Ilka Diester from the Faculty of Biology at the University of Freiburg. The results have just been published in the journal Nature Communications.

Understanding the brain under more natural conditions

The research project also involved the working groups of computer scientist Prof. Dr. Thomas Brox from the University of Freiburg and neuroscientist Prof. Dr. Daniel Durstewitz from the Central Institute of Mental Health in Mannheim. The team found evidence of conserved structures of neuronal activity in the sensorimotor cortex of freely moving rats. The electrophysiological recordings across the entire bilateral sensorimotor cortex allow conclusions about the respective contributions of the premotor, motor and sensory areas. In particular, the researchers found a clear gradient for a contralateral bias, i.e. for movements of the opposite half of the body, from anterior to posterior regions.

Better Than a Hole in the Head

Just as blood pressure informs heart health, intracranial pressure (ICP) helps indicate brain health. ICP sensing is the burgeoning focus of Jana Kainerstorfer's biomedical optics lab at Carnegie Mellon University. Her team is working to modernize ICP sensing approaches, which historically have been invasive and risky. Their noninvasive alternatives will ease the risk of infection, pain and medical expenses, as well as present new monitoring capabilities for patients with an array of brain injuries and conditions, from stroke to hydrocephalus.

Investigating pressure levels in the brain is a laborious task for health professionals and hasn't progressed much since the 1960s. Current practice involves drilling a hole into a patient's skull and placing a probe inside for continuous monitoring of ICP levels. It comes with the risk of infection and damaging the brain itself, and while valuable data is to have, ICP measurement is reserved only for the most critical of situations.

"At the core of it, what we've done is build a sensor alternative that doesn't require drilling a hole into the patient's head," said Kainerstorfer, an associate professor of biomedical engineering. "We recently published two papers that explore the use of optical sensors on the forehead for noninvasive ICP monitoring, using near-infrared spectroscopy and diffuse correlation spectroscopy. Both approaches represent huge strides in improving the patient experience and providing better tools to monitor pressure levels in the brain, which can be a key variable in both diagnosis and treatment decisions."

Gut Microbes Influence Binge-Eating of Sweet Treats in Mice

Sarkis Mazmanian, Luis B. and Nelly Soux Professor of Microbiology
Photo Credit: Caltech

We have all been there. You just meant to have a single Oreo as a snack, but then you find yourself going back for another, and another, and before you know it, you have finished off the entire package even though you were not all that hungry to begin with.

But before you start feeling too guilty for your gluttony, consider this: It might not be entirely your fault. Now, new research in mice shows that specific gut bacteria may suppress binge eating behavior.

Oreos and other desserts are examples of so-called "palatable foods"—food consumed for hedonistic pleasure, not simply out of hunger or nutritional need. Humans are not alone in enjoying this kind of hedonism: Mice like to eat dessert, too. Even when they have just eaten, they will still consume sugary snacks if available.

The new Caltech study shows that the absence of certain gut bacteria causes mice to binge eat palatable foods: Mice with microbiotas disrupted by oral antibiotics consumed 50 percent more sugar pellets over two hours than mice with gut bacteria. When their microbiotas were restored through fecal transplants, the mice returned to normal feeding behavior. Further, not all bacteria in the gut are able to suppress hedonic feeding, but rather specific species appear to alter the behavior. Bingeing only applies to palatable foods; mice with or without gut microbiota both still eat the same amount of their regular diet. The findings show that the gut microbiota has important influences on behavior and that these effects can be modulated when the microbiota is manipulated.

The brain's immune cells can be triggered to slow down Alzheimer's disease

Joana B. Pereira, researcher at Lund University and Karolinska Institutet who is first author of the study.
Photo Credit: Courtesy of Lund University

The brain's big-eating immune cells can slow down the progression of Alzheimer's disease. This is shown by a study that is now published in Nature Aging.

The brain's own immune cells are called microglia and are found in the central nervous system. They are big eaters that kill viruses, damaged cells and infectious agents they come across. It has long been known that microglial cells can be activated in different ways in several neurological diseases such as Alzheimer's and Parkinson's diseases. Depending on how they are activated, they can both drive and slow disease development. Researchers from Lund University and Karolinska Institutet have now shown that a certain type of activation of the microglial cells triggers inflammatory protective mechanisms in the immune system:

“Most people probably think that inflammation in the brain is something bad and that you should inhibit the inflammatory system in case of illness. But inflammation doesn't just have to be negative”, says Joana B. Pereira, researcher at Lund University and Karolinska Institutet who is first author of the study.

A brain circuit underpinning locomotor speed control

Zebrafish Photo Credit: Petr Kuznetsov

Researchers at Karolinska have uncovered how brain circuits encode the start, duration and sudden change of speed of locomotion. The study is published in the journal Neuron.

Important findings

By exploiting the relative accessibility of adult zebrafish, combined with a broad range of techniques, the researchers can now reveal two brain circuits that encode the start, duration and sudden change in locomotor speed.

The brain circuits represent the initial step in the sequence of commands coding for the onset, duration, speed and vigor of locomotion. The two command streams revealed here, with their direct access to the spinal circuits, allow the animal to navigate through their environment by grading the speed and strength of their locomotor movements, while at the same time controlling directionality. These mechanisms in adult zebrafish can be extrapolated to mammalian model systems.

Mapping connectivity

The next step will be to map the connectivity between these brain circuits and those in the spinal cord driving locomotion.

Hopefully, the circuit revealed in the study can guide designing novel therapeutic strategies aimed at restoring motor function after traumatic spinal cord injury.

The study was financed by The Swedish Research Council, Knut and Alice Wallenberg Foundation, The Swedish Brain Foundation.

Source/Credit: Karolinska Institutet | Charlotte Brandt

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Major discovery about mammalian brains surprises researchers

Illustration shows vacuolar-type adenosine triphosphatases (V-ATPases, large blue structures) on a synaptic vesicle from a nerve cell in the mammalian brain.
Illustration Image: C. Kutzner, H. Grubmüller and R. Jahn/Max Planck Institute for Multidisciplinary Sciences.

Major discovery about mammalian brains surprises researchers, University of Copenhagen researchers have made an incredible discovery. Namely, a vital enzyme that enables brain signals is switching on/off at random, even taking hours-long “breaks from work”. These findings may have a major impact on our understanding of the brain and the development of pharmaceuticals. 

Millions of neurons are constantly messaging each other to shape thoughts and memories and let us move our bodies at will. When two neurons meet to exchange a message, neurotransmitters are transported from one neuron to another with the aid of a unique enzyme.

This process is crucial for neuronal communication and the survival of all complex organisms. Until now, researchers worldwide thought that these enzymes were active at all times to convey essential signals continuously. But this is far from the case.

Using a groundbreaking method, researchers from the University of Copenhagen’s Department of Chemistry have closely studied the enzyme and discovered that its activity is switching on and off at random intervals, which contradicts our previous understanding.

Machine learning gives nuanced view of Alzheimer’s stages

A Cornell-led collaboration used machine learning to pinpoint the most accurate means, and timelines, for anticipating the advancement of Alzheimer’s disease in people who are either cognitively normal or experiencing mild cognitive impairment.

The modeling showed that predicting the future decline into dementia for individuals with mild cognitive impairment is easier and more accurate than it is for cognitively normal, or asymptomatic, individuals. At the same time, the researchers found that the predictions for cognitively normal subjects are less accurate for longer time horizons, but for individuals with mild cognitive impairment, the opposite is true.

The modeling also demonstrated that magnetic resonance imaging (MRI) is a useful prognostic tool for people in both stages, whereas tools that track molecular biomarkers, such as positron emission tomography (PET) scans, are more useful for people experiencing mild cognitive impairment.

The team’s paper, “Machine Learning Based Multi-Modal Prediction of Future Decline Toward Alzheimer’s Disease: An Empirical Study,” published in PLOS ONE. The lead author is Batuhan Karaman, a doctoral student in the field of electrical and computer engineering.

Alzheimer’s risk gene undermines insulation of brain’s “wiring”

A new study shows how carrying the biggest genetic risk factor for Alzheimer's disease, the APOE4 gene variant, contributes to disease pathology. Here, black gold staining in postmortem brain tissue shows people with two copies of the APOE3 variant have much more myelin insulation of their neurons than people (bottom row) with a copy of APOE4.
Resized Image using AI by SFLORG
Image Credit: Tsai Lab/The Picower Institute

It’s well-known that carrying one copy of the APOE4 gene variant increases one’s risk for Alzheimer’s disease threefold and two copies about tenfold, but the fundamental reasons why, and what can be done to help patients, remain largely unknown. A study published by an MIT-based team in the journal Nature provides some new answers as part of a broader line of research that has demonstrated APOE4’s consequences, cell-type-by-cell-type, in the brain.

The new study combines evidence from postmortem human brains, lab-based human brain cell cultures, and Alzheimer’s model mice to show that when people have one or two copies of APOE4, rather than the more common and risk-neutral APOE3 version, cells called oligodendrocytes mismanage cholesterol, failing to transport the fat molecule to wrap the long vine-like axon “wiring” that neurons project to make brain circuit connections. Deficiency of this fatty insulation, called myelin, may be a significant contributor to the pathology and symptoms of Alzheimer’s disease because without proper myelination, communications among neurons are degraded.

Immune cells in ALS patients can predict the course of the disease

Solmaz Yazdani, PhD student at KI.
Photo Credit: Filip Mestanov

ALS is a disease in which nerve cells in the brain, brain stem and spinal cord die. 

By measuring immune cells in the spinal cord fluid when diagnosing ALS, it is possible to predict how the course of the disease will go, according to a study from the Karolinska Institutet published in Nature Communications.

The study shows that a high proportion of so-called effector T cells are associated with a low survival rate. At the same time, the study shows that a high proportion of activated regulatory T cells are protective against the disease. The findings provide new evidence of T-cell involvement in the course of the disease and show that certain types of effector T cells accumulate in the spinal cord fluid in ALS patients.

Zebrafish are smarter than we thought

A new study from MIT and Harvard University suggests that the brains of the seemingly simple zebrafish are more sophisticated than previously thought. The researchers found that larval zebrafish can use visual information to create three-dimensional maps of their physical surroundings.
Photo Credit: Petr Kuznetsov

A new study from MIT and Harvard University suggests that the brains of the seemingly simple zebrafish are more sophisticated than previously thought. The researchers found that larval zebrafish can use visual information to create three-dimensional maps of their physical surroundings — a feat that scientists didn’t think was possible.

In the new study, the researchers discovered that zebrafish can move around environmental barriers while escaping predators. The findings suggest that zebrafish are “much smarter than we thought,” and could be used as a model to explore many aspects of human visual perception, the researchers say.

“These results show you can study one of the most fundamental computational problems faced by animals, which is perceiving a 3D model of the environment, in larval zebrafish,” says Vikash Mansinghka, a principal research scientist in MIT’s Department of Brain and Cognitive Sciences and an author of the new study.

Andrew Bolton, an MIT research scientist and a research associate at Harvard University, is the senior author of the new study, which appears in the journal Current Biology. Hanna Zwaka, a Harvard postdoc, and Olivia McGinnis, a recent Harvard graduate who is now a graduate student at the Oxford University, are the paper’s lead authors.

Are Covid-19 “comas” signs of a protective hibernation state?

Caption:When the painted turtle hibernates it essentially sedates its brain to survive in its low-oxygen environment. Authors of a new paper in PNAS hypothesize that the same dynamic may be occurring in severe Covid-19 patients who underwent sedation and ventilation.
Photo Credit: Wayne

Many Covid-19 patients who have been treated for weeks or months with mechanical ventilation have been slow to regain consciousness even after being taken off sedation. A new article in the Proceedings of the National Academy of Sciences offers the hypothesis that this peculiar response could be the effect of a hibernation-like state invoked by the brain to protect cells from injury when oxygen is scarce.

A very similar kind of state, characterized by the same signature change of brain rhythms, is not only observed in cardiac arrest patients treated by chilling their body temperature, a method called “hypothermia,” but also by the painted turtle, which has evolved a form of self-sedation to contend with long periods of oxygen deprivation, or “anoxia,” when it overwinters underwater.

“We propose that hypoxia combined with certain therapeutic maneuvers may initiate an as-yet-unrecognized protective down-regulated state (PDS) in humans that results in prolonged recovery of consciousness in severe Covid-19 patients following cessation of mechanical ventilation and in post-cardiac arrest patients treated with hypothermia,” wrote authors Nicholas D. Schiff and Emery N. Brown. “In severe Covid-19 patients we postulate that the specific combination of intermittent hypoxia, severe metabolic stress and GABA-mediated sedation may provide a trigger for the PDS.”

Study yields clues to why Alzheimer’s disease damages certain parts of the brain

Red and orange areas on these heat maps of human brains show where the gene APOE is most active (top two brain images) and where tangles of the protein tau are most concentrated (bottom two brain images). APOE is the biggest genetic risk factor for Alzheimer’s, and tau tangles drive brain damage in the disease. The similarities in the two sets of maps suggested to researchers at Washington University School of Medicine in St. Louis that APOE plays a role in making certain brain areas particularly vulnerable to Alzheimer’s damage.
Image Credit: Diana Hobbs

Memory loss is often the first sign of Alzheimer’s disease, followed by confusion and difficulty thinking. These symptoms reflect the typical pattern of worsening damage to brain tissues. Toxic clusters of proteins first concentrate in the temporal lobes of the brain — the memory area — before spreading to parts of the brain important for thinking and planning.

A study by researchers at Washington University School of Medicine in St. Louis yields clues to why certain parts of the brain are particularly vulnerable to Alzheimer’s damage. It comes down to the gene APOE, the greatest genetic risk factor for Alzheimer’s disease. The parts of the brain where APOE is most active are the areas that sustain the most damage, they found.

The findings, published in Science Translational Medicine, help explain why symptoms of Alzheimer’s disease sometimes vary, and highlights an understudied aspect of Alzheimer’s disease that suggests yet-to-be discovered biological mechanisms may play an important role in the disease.