Tag Archives: #neurons

Mechanism That Triggers Brain Neurone Response Revealed (Neuroscience)

It is the first time it has been possible to see how neurotransmitters and proteins interact at the atomic level to trigger neuronal responses.

Researchers from the G-protein-coupled receptor-based drug development research group at the Hospital del Mar Medical Research Institute (IMIM) have been able to verify, with a degree of precision never before achieved, how the process that triggers the response of neurones in the brain occurs. This is an essential mechanism for understanding how moods or even processes such as addictions are produced, and in which neurotransmitters, molecules that help transmit information between neurones through specialised receptors, the G protein-coupled receptors (GPCRs), play a vital role.

Neurotransmission is one of the most crucial physiological processes, as its dysregulation can result in various neuropsychiatric disorders”, explains Dr. Jana Selent, principal author of the study, published in the journal Chemical Science, and coordinator of the research group that led the work. Very small changes in how information is transmitted by these molecules can trigger different reactions in the brain, some of which are linked to behaviour, addictions and moods.

Jana Selent and Tomasz Stepniewski © IMIM

Possible new treatments for psychiatric illnesses

Researchers have analysed how neurotransmitters connect to proteins in the cell membrane of neurones at the atomic level. They were able to determine which connections between the neurotransmitter and its receptor protein control how the cell will respond. They observed that evolution has naturally caused small changes in the regions where these connections occur, giving rise to different proteins capable of generating different cellular responses. This allows our body to regulate, in a very precise way, the response that the same neurotransmitter causes in the neurone and in the brain. With this information, the authors of the study were able to predict what would happen on each occasion by studying different types of proteins and modified neurotransmitters, checking their conclusions with cell experiments conducted in laboratories in Sweden and Canada.

In this way, the researchers were able to relate the small differences that receptors in these important regions may have to the neuronal response they generate when interacting with the same neurotransmitter. It also shows how modified neurotransmitters can control which regions of the protein they can bind to, to be able to cause a different neuronal response. This makes it possible to “design molecules that only bind to certain regions of the receptor and to specific types of receptors, which may allow the neuronal response to be changed”, explains Dr Tomasz Stepniewski, first author of the study. This possibility is “particularly interesting in neuropsychiatric diseases like schizophrenia, certain addictions, and behavioural patterns, such as those that regulate appetite or mood”, he adds. The signalling pathways involved in each process must now be studied in order to develop the treatments, the molecules, for addressing these pathologies.

Reference article

Stepniewski TMMancini A, Agren R, Torrens-Fontanals M, M Semache, Bouvier M, Sahlholm K, Breton BSelent J. Mechanistic insights into dopaminergic and serotonergic neurotransmission-concerted interactions with helices 5 and 6 drive the functional outcome. Chem Sci, 2021 DOI: 10.1039/D1SC00749A.


Provided by IMIM

Fruit Fly Study Reveals Function Of Taste Neurons (Neuroscience)

UC Riverside study shows food choice decisions require taste input

What can the fruit fly teach us about taste and how chemicals cause our taste buds to recognize sweet, sour, bitter, umami, and salty tastes? Quite a lot, according to University of California, Riverside, researchers who have published a study exploring the insect’s sense of taste.

“Insect feeding behavior directly impacts humans in many ways, from disease-carrying mosquitos that seek human blood to pests whose appetite can wreak havoc on the agricultural sector,” said Anupama Dahanukar, an associate professor of molecular, cell and systems biology, who led the study appearing in the Journal of Neuroscience. “How insect taste neurons are organized and how they function is critical for a deeper understanding of their feeding behavior.”

The fruit fly has multiple taste organs throughout its body to detect chemicals, called tastants, that signal whether a food is palatable or harmful. It is still unclear, however, how individual neurons in each taste organ act to control feeding. To explore this question, Dahanukar’s team used the fly pharynx as a model to study whether taste information regulates sugar and amino acid consumption at the cellular level.

Anupama Dahanukar and David Chen and Ryan Matthew Joseph
Anupama Dahanukar (left), Yu-Chieh David Chen (center) and Ryan Matthew Joseph. © University of California Riverside

Dahanukar explained animals rely heavily on the sense of taste to make feeding decisions, such as consuming nutritive foods while avoiding toxic ones. 

“In mammals, taste information is encoded by specialized cells present in taste buds of the tongue,” she said. “Taste receptors expressed in these cells can detect different chemicals. Molecular and functional differences in receptors expressed in different cells allow recognition of different tastes, such as salty, sour, sweet, bitter, or umami.”

Several new studies in flies indicate individual taste neurons can detect compounds belonging to more than one taste category, raising some questions about the distinct behavioral roles of individual taste neurons. If many classes of taste neurons are activated by sugar, for example, how does activation of just one class of taste neurons affect behavior?

Dahanukar’s team answered this question by genetically engineering a fly in which only a single defined class of pharyngeal neurons is active. The team then tested this fly in different feeding experiments to understand what the fly can or cannot do compared to animals that have all their taste neurons intact.

“We found single-taste neurons are capable of responding and activating behavioral responses to more than one tastant category — sweet and amino acids in our study,” said Yu-Chieh David Chen, the first author of the research paper. “We also found that a single tastant category — amino acids in our study — can activate multiple classes of taste neurons.” 

The team also tested flies that had no functional taste neurons. Such flies were incapable of making any proper feeding decisions, no matter the food choices — whether these were two attractive stimuli, one attractive and one aversive, or one nutritive and the other nonnutritive.

The researchers found food choice decisions cannot be made in the absence of taste input; the latter is critical for ensuring appropriate food choice and feeding behavior. Further, flies that had pharyngeal sweet taste neurons as the only source of taste input were consistently able to select more palatable food. 

“Altogether, our results argue for the existence of a combinatorial coding system, wherein multiple neurons coordinate the response to any given tastant,” Dahanukar said.

The study is the first to directly test the impact of loss of all taste neurons on behavioral responses to tastants of different categories. It is also the first to test whether a single class of taste neurons is sufficient for food choice and feeding behavior.

“Along with several other recent studies in the field, our work also invites revisiting some established ideas about how insect taste is organized,” Dahanukar said. “Rather than encoding tastes as in mammals, flies appear to encode some combination of valence — attractive versus aversive — and tastant identity.”

Her team anticipates that knowing how taste neurons work in flies will facilitate insect studies of greater health or agricultural importance. 

“We are building tools for asking the same sorts of questions in mosquitoes,” Dahanukar said. “Such studies could offer potential targets for manipulating feeding behaviors of pests or disease vectors in surveillance or control strategies.”

She acknowledged that her lab has only evaluated a single taste neuron within the system it set up, with many more remaining to be studied. 

Vaibhav Menon
Vaibhav Menon. © University of California Riverside

“We are interested in understanding what these neurons sense and how they act, individually and as part of a group, to control parameters that lead to either promotion or cessation of food intake,” said Vaibhav Menon, a graduate student in Dahanukar’s lab and a co-author on the study. 

The team plans to apply some of the same strategies to investigate how feeding behavior is controlled in mosquitoes.

Dahanukar, Chen, and Menon were joined in the study by Ryan Matthew Joseph. Chen is now at New York University; Joseph is at Riverside City College.

The study was supported by the Whitehall Foundation, National Institutes of Health, National Institute of Food and Agriculture of the U.S. Department of Agriculture, and UCR Agricultural Experimental Station. Chen was a Howard Hughes Medical Institute International Student Research Fellow at UCR.

The research paper is titled “Control of sugar and amino acid feeding via pharyngeal taste neurons.”


Provided by UCR

Scientists Discover A New Class of Neurons For Remembering Faces (Neuroscience)

Scientists have long searched in vain for a class of brain cells that could explain the visceral flash of recognition that we feel when we see a very familiar face, like that of our grandmothers. But the proposed “grandmother neuron”—a single cell at the crossroads of sensory perception and memory, capable of prioritizing an important face over the rabble—remained elusive.

Now, newresearch reveals a class of neurons in the brain’s temporal pole region that links face perception to long-term memory. It’s not quite the apocryphal grandmother neuron—rather than a single cell, it’s a population of cells that collectively remembers grandma’s face. The findings, published in Science, are the first to explain how brains inculcate the faces of loved ones.

“When I was coming up in neuroscience, if you wanted to ridicule someone’s argument you would dismiss it as ‘just another grandmother neuron’—a hypothetical that could not exist,” says Winrich Freiwald, head of Rockefeller’s Laboratory of Neural Systems.

“Now, in an obscure and understudied corner of the brain, we have found the closest thing to a grandmother neuron: cells capable of linking face perception to memory.”

Have I seen that face before?

The idea of a grandmother neuron first showed up in the 1960s as a theoretical brain cell that would code for a specific, complex concept, all by itself. One neuron for the memory of one’s grandmother, another to recall one’s mother, and so on. At its heart, the notion of a one-to-one ratio between brain cells and objects or concepts was an attempt to tackle the mystery of how the brain combines what we see with our long-term memories.

An area (red/yellow) in the brain’s temporal pole specializes in familiar face recognition. (Credit: Sofia Landi)

Scientists have since discovered plenty of sensory neurons that specialize in processing facial information, and as many memory cells dedicated to storing data from personal encounters. But a grandmother neuron—or even a hybrid cell capable of linking vision to memory—never emerged. “The expectation is that we would have had this down by now,” Freiwald says. “Far from it! We had no clear knowledge of where and how the brain processes familiar faces.”

Previously, Freiwald and colleagues discovered that a small area in the brain’s temporal pole region may be involved in facial recognition. So the team used functional magnetic resonance imaging as a guide to zoom in on the TP regions of two rhesus monkeys, and recorded the electrical signals of TP neurons as the macaques watched images of familiar faces (which they had seen in-person) and unfamiliar faces that they had only seen virtually, on a screen.

The team found that neurons in the TP region were highly selective, responding to faces that the subjects had seen before more strongly than unfamiliar ones. And the neurons were fast—discriminating between known and unknown faces immediately upon processing the image.

Interestingly, these cells responded threefold more strongly to familiar over unfamiliar faces even though the subjects had in fact seen the unfamiliar faces many times virtually, on screens. “This may point to the importance of knowing someone in person,” says neuroscientist Sofia Landi, first author on the paper. “Given the tendency nowadays to go virtual, it is important to note that faces that we have seen on a screen may not evoke the same neuronal activity as faces that we meet in-person.”

A tapestry of grandmothers

The findings constitute the first evidence of a hybrid brain cell, not unlike the fabled grandmother neuron. The cells of the TP region behave like sensory cells, with reliable and fast responses to visual stimuli. But they also act like memory cells which respond only to stimuli that the brain has seen before—in this case, familiar individuals—reflecting a change in the brain as a result of past encounters. “They’re these very visual, very sensory cells—but like memory cells,” Freiwald says. “We have discovered a connection between the sensory and memory domains.”

But the cells are not, strictly speaking, grandmother neurons. Instead of one cell coding for a single familiar face, the cells of the TP region appear to work in concert, as a collective.

“It’s a ‘grandmother face area’ of the brain,” Freiwald says.

The discovery of the TP region at the heart of facial recognition means that researchers can soon start investigating how those cells encode familiar faces. “We can now ask how this region is connected to the other parts of the brain and what happens when a new face appears,” Freiwald asks. “And of course, we can begin exploring how it works in the human brain.”

In the future, the findings may also have clinical implications for people suffering from prosopagnosia, or face blindness, a socially isolating condition that affects about one percent of the population. “Face-blind people often suffer from depression. It can be debilitating, because in the worst cases they cannot even recognize close relatives,” Freiwald says.

“This discovery could one day help us devise strategies to help them.”


Provided by Rockefeller University

Human ‘Time Neurons’ Encode Specific Moments in Time (Neuroscience)

Special neurons in the hippocampus may be involved in time-related features of memory

Neurons in the hippocampus fire during specific moments in time, according to research recently published in JNeurosci. The cells may contribute to memory by encoding information about the time and order of events.

Episodic memories involve remembering the “what, where, and when” of past experiences. The “where” may be encoded by place cells in the hippocampus, which fire in response to specific locations. Rodents have hippocampal neurons that fire in response to specific moments in time — the “when” — but until recently it was not known if the human brain contained them too.

Reddy et al. recorded the electrical activity of neurons in the hippocampus of epilepsy patients undergoing diagnostic invasive monitoring for surgery. During the recording, the participants viewed and memorized a sequence of 5 to 7 images. At random intervals, the participants were quizzed on the next image in the sequence before it resumed. Time-sensitive neurons fired during specific moments in time between quizzes, irrespective of the image. The neurons still tracked time even during 10-second gaps with no images while the participants waited. The researchers could decode different moments in time based on the activity of the entire group of neurons. These results demonstrate the human brain contains time-tracking neurons.

Featured image: Hippocampal neurons fire at successive moments of a temporal interval. This shows the firing activity of the population of time cells (N=128). Each row shows the firing activity for an individual time cell, averaged across trials. The x-axis corresponds to time of the median trial length. The neurons are sorted by the latency of the maximum firing rate. © Reddy et al., JNeurosci 2021


Paper title: Leila Reddy, Benedikt Zoefel, Jessy K. Possel, Judith C. Peters, Doris Dijksterhuis, Marlene Poncet, Elisabeth C.W. van Straaten, Johannes C. Baayen, Sander Idema and Matthew W. Self, “Human Hippocampal Neurons Track Moments in a Sequence of Events”, Journal of Neuroscience 28 June 2021, JN-RM-3157-20; DOI: https://doi.org/10.1523/JNEUROSCI.3157-20.2021


Provided by Society for Neuroscience

New Tool Activates Deep Brain Neurons by Combining Ultrasound, Genetics (Neuroscience)

It is the first work to show that sonothermogenetics can control behavior by stimulating a specific target deep in the brain

Neurological disorders such as Parkinson’s disease and epilepsy have had some treatment success with deep brain stimulation, but those require surgical device implantation. A multidisciplinary team at Washington University in St. Louis has developed a new brain stimulation technique using focused ultrasound that is able to turn specific types of neurons in the brain on and off and precisely control motor activity without surgical device implantation. 

The team, led by Hong Chen, assistant professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine, is the first to provide direct evidence showing noninvasive, cell-type-specific activation of neurons in the brain of mammal by combining ultrasound-induced heating effect and genetics, which they have named sonothermogenetics. It is also the first work to show that the ultrasound- genetics combination can robustly control behavior by stimulating a specific target deep in the brain.

Results of the three years of research, which was funded in part by the National Institutes of Health’s BRAIN Initiative, were published online in Brain Stimulation May 11, 2021.

The senior research team included renowned experts in their fields from both the McKelvey School of Engineering and the School of Medicine, including Jianmin Cui, professor of biomedical engineering; Joseph P. Culver, professor of radiology, of physics and of biomedical engineering; Mark J. Miller, associate professor of medicine in the Division of Infectious Diseases in the Department of Medicine; and Michael Bruchas, formerly of Washington University, now professor of anesthesiology and pharmacology at the University of Washington.

“Our work provided evidence that sonothermogenetics evokes behavioral responses in freely moving mice while targeting a deep brain site,” Chen said. “Sonothermogenetics has the potential to transform our approaches for neuroscience research and uncover new methods to understand and treat human brain disorders.” 

Using a mouse model, Chen and the team delivered a viral construct containing TRPV1 ion channels to genetically-selected neurons. Then, they delivered small burst of heat via low-intensity focused ultrasound to the select neurons in the brain via a wearable device. The heat, only a few degrees warmer than body temperature, activated the TRPV1 ion channel, which acted as a switch to turn the neurons on or off.

“We can move the ultrasound device worn on the head of free-moving mice around to target different locations in the whole brain,” said Yaoheng Yang, first author of the paper and a graduate student in biomedical engineering. “Because it is noninvasive, this technique has the potential to be scaled up to large animals and potentially humans in the future.”

The work builds on research conducted in Cui’s lab that was published in Scientific Reports in 2016. Cui and his team found for the first time that ultrasound alone can influence ion channel activity and could lead to new and noninvasive ways to control the activity of specific cells. In their work, they found that focused ultrasound modulated the currents flowing through the ion channels on average by up to 23%, depending on channel and stimulus intensity. Following this work, researchers found close to 10 ion channels with this capability, but all of them are mechanosensitive, not thermosensitive.

The work also builds on the concept of optogenetics, the combination of the targeted expression of light-sensitive ion channels and the precise delivery of light to stimulate neurons deep in the brain. While optogenetics has increased discovery of new neural circuits, it is limited in penetration depth due to light scattering and requires surgical implantation of optical fibers.

Sonothermogenetics has the promise to target any location in the mouse brain with millimeter-scale resolution without causing any damage to the brain, Chen said. She and the team continue to optimize the technique and further validate their findings.

This work was supported by the National Institutes of Health (NIH) BRAIN Initiative (R01MH116981) and NIBIB (R01EB027223 and R01EB030102). This work was supported by the Hope Center Viral Vectors Core at Washington University School of Medicine.


Reference: Yang Y, Pacia C, Ye D, Zhu L, Baek H, Yue Y, Yan J, Miller M, Cui J, Culver J, Bruchas M, Chen H. Sonothermogenetics for noninvasive and cell-type specific deep brain neuromodulation. Brain Stimulation, In Press, published online May 11, 2021. https://doi.org/10.1016/j.brs.2021.04.021


Provided by McKelvey School of Engineering

Team From UHN, CAMH Identify Unique Characteristics of Human Neurons (Neuroscience)

These findings may have implications for brain disease, disorders

Scientists at the Krembil Brain Institute, part of University Health Network (UHN), in collaboration with colleagues at the Centre for Addiction and Mental Health (CAMH), have used precious and rare access to live human cortical tissue to identify functionally important features that make human neurons unique.

This experimental work is among the first of its kind on live human neurons and one of the largest studies of the diversity of human cortical pyramidal cells to date.

“The goal of this study was to understand what makes human brain cells ‘human,’ and how human neuron circuitry functions as it does,” says Dr. Taufik Valiante, neurosurgeon, scientist at the Krembil Brain Institute at UHN and co-senior author on the paper.

“In our study, we wanted to understand how human pyramidal cells, the major class of neurons in the neocortex, differ between the upper and bottom layers of the neocortex,” says Dr. Shreejoy Tripathy, a scientist with the Krembil Centre for Neuroinformatics at CAMH and co-senior author on this study.

“In particular, we wanted to understand how electrical features of these neurons might support different aspects of cross-layer communication and the generation of brain rhythms, which are known to be disrupted in brain diseases like epilepsy.”

With consent, the team used brain tissue immediately after it had been removed during routine surgery from the brains of patients with epilepsy and tumours. Using state-of-the-art techniques, the team was then able to characterize properties of individual cells within slices of this tissue, including visualizations of their detailed morphologies.

“Little is known about the shapes and electrical properties of living adult human neurons because of the rarity of obtaining living human brain tissue, as there are few opportunities other than epilepsy surgery to obtain such recordings,” says Dr. Valiante.

To keep the resected tissue alive, it is immediately transferred into the modified cerebrospinal fluid in the operating room then taken directly into the laboratory where it is prepared for experimental characterization.

It is rare to study human tissue because accessing human tissue for scientific inquiries requires a tight-knit multidisciplinary community, including patients willing to participate in the studies, ethicists ensuring patient rights and safety, neurosurgeons collecting and delivering samples, and neuroscientists with necessary research facilities to study these tissues.

After initial analysis, members of the Krembil Centre for Neuroinformatics used further large-scale data analysis to identify the properties that distinguished neurons in this cohort from each other. These properties were then compared to those from other centres doing similar work with human brain tissue samples, including the Allen Institute for Brain Sciences in Seattle, Washington.

Noted in the team’s findings:

  • A massive amount of diversity among human neocortical pyramidal cells
  • Distinct electrophysiological features between neurons located at different layers in the human neocortex
  • Specific features of deeper layer neurons enabling them to support aspects of across-layer communication and the generation of functionally important brain rhythms

The teams also found notable and unexpected differences between their findings and similar experiments in pre-clinical models, which Dr. Tripathy believes is likely reflective of the massive expansion of the human neocortex over mammalian and primate evolution.

“These results showcase the notable diversity of human cortical pyramidal neurons, differences between similarly classified human and pre-clinical neurons, and a plausible hypothesis for the generation of human cortical theta rhythms driven by deep layer neurons,” says Dr. Homeira Moradi Chameh, a scientific associate in Dr. Valiante’s laboratory at Krembil Brain Institute and lead author on the study.

In total, the team was able to characterize over 200 neurons from 61 patients, reflecting the largest dataset of its kind to-date and encapsulating almost a decade’s worth of painstaking work at UHN and the Krembil Brain Institute.

“This unique data set will allow us to build computational models of the distinctly human brain, which will be invaluable for the study of distinctly human neuropathologies,” says Dr. Scott Rich, a postdoctoral research fellow in Dr. Valiante’s laboratory at the Krembil Brain Institute and co-author on this work.

“For instance, the cellular properties driving many of the unique features identified in these neurons are known to be altered in certain types of epilepsy. By implementing these features in computational models, we can study how these alterations affect dynamics at the various spatial scales of the human brain related to epilepsy, and facilitate the translation of these ‘basic science’ findings back to the clinic and potentially into motivations for new avenues in epilepsy research.”

“This effort was only possible because of the very large and active epilepsy program at the Krembil Brain Institute at UHN, one of the largest programs of its kind in the world and the largest program of its kind in Canada,” says Dr. Valiante.

Featured image credit: Science Photo Library – KTSDESIGN / Getty Images


Reference: Moradi Chameh, H., Rich, S., Wang, L. et al. Diversity amongst human cortical pyramidal neurons revealed via their sag currents and frequency preferences. Nat Commun 12, 2497 (2021). https://doi.org/10.1038/s41467-021-22741-9 (DOI: 10.1038/s41467-021-22741-9).


Provided by University Health Network

DNA Damage ‘Hot Spots’ Discovered Within Neurons (Neuroscience)

NIH labs collaborate to develop new methods for studying genome-wide DNA damage and repair

Researchers at the National Institutes of Health (NIH) have discovered specific regions within the DNA of neurons that accumulate a certain type of damage (called single-strand breaks or SSBs). This accumulation of SSBs appears to be unique to neurons, and it challenges what is generally understood about the cause of DNA damage and its potential implications in neurodegenerative diseases.

Because neurons require considerable amounts of oxygen to function properly, they are exposed to high levels of free radicals–toxic compounds that can damage DNA within cells. Normally, this damage occurs randomly. However, in this study, damage within neurons was often found within specific regions of DNA called “enhancers” that control the activity of nearby genes.

Fully mature cells like neurons do not need all of their genes to be active at any one time. One way that cells can control gene activity involves the presence or absence of a chemical tag called a methyl group on a specific building block of DNA. Closer inspection of the neurons revealed that a significant number of SSBs occurred when methyl groups were removed, which typically makes that gene available to be activated.

An explanation proposed by the researchers is that the removal of the methyl group from DNA itself creates an SSB, and neurons have multiple repair mechanisms at the ready to repair that damage as soon as it occurs. This challenges the common wisdom that DNA damage is inherently a process to be prevented. Instead, at least in neurons, it is part of the normal process of switching genes on and off. Furthermore, it implies that defects in the repair process, not the DNA damage itself, can potentially lead to developmental or neurodegenerative diseases.

This study was made possible through the collaboration between two labs at the NIH: one run by Michael E. Ward, M.D., Ph.D. at the National Institute of Neurological Disorders and Stroke (NINDS) and the other by Andre Nussenzweig, Ph.D. at the National Cancer Institute (NCI). Dr. Nussenzweig developed a method for mapping DNA errors within the genome. This highly sensitive technique requires a considerable number of cells in order to work effectively, and Dr. Ward’s lab provided the expertise in generating a large population of neurons using induced pluripotent stem cells (iPSCs) derived from one human donor. Keith Caldecott, Ph.D. at the University of Sussex also provided his expertise in single strand break repair pathways.

The two labs are now looking more closely at the repair mechanisms involved in reversing neuronal SSBs and the potential connection to neuronal dysfunction and degeneration.

Featured image: Neurons (labeled in purple) show signs of an active DNA repair process (labeled in yellow). The cells’ DNA itself is labeled in cyan (in this image, overlap between cyan and yellow appears green). Image courtesy of Ward lab, NINDS


Reference: Wu, W., Hill, S.E., Nathan, W.J. et al. Neuronal enhancers are hotspots for DNA single-strand break repair. Nature (2021). https://doi.org/10.1038/s41586-021-03468-5 https://www.nature.com/articles/s41586-021-03468-5


Provided by NIH/NINDS

New Signaling Pathway in Neurons (Neuroscience)

A new signaling pathway has been identified that can prevent the overproduction of certain RNA-protein complexes in neurons. These complexes play an important role in neurodegenerative diseases.

Neurodegenerative diseases, such as various forms of senile dementia or amyotrophic lateral sclerosis (ALS), have one thing in common: large amounts of certain RNA-protein complexes (snRNPs) are produced and deposited in the nerve cells of those affected – and this hinders the function of the cells. The overproduction is possibly caused by a malfunction in the assembly of the protein complexes.

How the production of these protein complexes is regulated was unknown until now. Researchers from Martinsried and Würzburg in Bavaria, Germany, have solved the puzzle and now report on it in the open access journal Nature Communications. They describe in detail a signaling pathway that prevents the overproduction of snRNPs when they are not needed. The results should make it possible to better understand the processes in motor neuron diseases and senile dementia.

The research group led by Professor Michael Sendtner and Dr. Michael Briese from the Institute of Clinical Neurobiology at Julius-Maximilians-Universität Würzburg (JMU) was in charge of the publication. Professor Utz Fischer and Pradhipa Ramanathan from the JMU Institute of Biochemistry were also involved, as was a team from the Max Planck Institute of Biochemistry in Martinsried.

The next steps in research

Further investigations shall now show how the synthesis and degradation of excess snRNPs are regulated in nerve cells. The scientists hope that in the end they will be able to identify new therapeutic options for neurodegenerative diseases.

This work was financially supported by the German Research Foundation and the European Research Council.

Featured image: The molecule Larp7 plays an important role in the assembly of snRNP complexes. It accumulates in nerve cells (arrow) where the complexes are formed. (Image: Changhe Ji / Universität Würzburg)


Publication

Ji, C., Bader, J., Ramanathan, P. et al. Interaction of 7SK with the Smn complex modulates snRNP production. Nature Communications 12, 1278 (24 February 2021). https://doi.org/10.1038/s41467-021-21529-1


Provided by University of Wurzburg

Reactivating Aging Stem Cells in the Brain (Neuroscience)

As people get older, their neural stem cells lose the ability to proliferate and produce new neurons, leading to a decline in memory function. Researchers at the University of Zurich have now discovered a mechanism linked to stem cell aging – and how the production of neurons can be reactivated.

The stem cells in our brain generate new neurons throughout life, for example in the hippocampus. This region of the brain plays a key role for a range of memory processes. With increasing age, and in patients suffering from Alzheimer’s disease, the hippocampus’ ability to create new neurons declines steadily – and with it, its memory functions.

Distribution of age-dependent cell damage

A study conducted by the research group of Sebastian Jessberger, a professor at the Brain Research Institute of the University of Zurich, shows how the formation of new neurons is impaired with advancing age. Protein structures in the nuclei of neural stem cells make sure that harmful proteins accumulating over time are unevenly distributed onto the two daughter cells during cell division. This seems to be an important part of the cells’ ability to proliferate over a long time in order to maintain the supply of neurons. With advancing age, however, the amounts of nucleic proteins change, resulting in defective distribution of harmful proteins between the two daughter cells. This results in a decrease in the numbers of newly generated neurons in the brains of older mice.

The central element in this process is a nuclear protein called lamin B1, the levels of which decrease as people age. When the researchers increased lamin B1 levels in experiments in aging mice, stem cell division improved and the number of new neurons grew. “As we get older, stem cells throughout the body gradually lose their ability to proliferate. Using genetic engineering and cutting-edge microscope technology, we were able to identify a mechanism that is associated with this process,” says doctoral candidate and first author Khadeesh bin Imtiaz.

Halting the aging process of stem cells

The research is part of several ongoing projects aiming to reactivate aging stem cells. The ability to regenerate damaged tissue generally declines with age, thus affecting almost all types of stem cells in the body. “While our study was limited to brain stem cells, similar mechanisms are likely to play a key role when it comes to the aging process of other stem cells,” says Sebastian Jessberger.

These latest findings are an important step towards exploring age-dependent changes in the behavior of stem cells. “We now know that we can reactivate aging stem cells in the brain. Our hope is that these findings will one day help increase levels of neurogenesis, for example in older people or those suffering from degenerative diseases such as Alzheimer’s. Even if this may still be many years in the future,” says Jessberger.

Funding

The research was funded by the European Research Council, the Swiss National Science Foundation, the Helmut Horten Foundation, the Wisconsin Partnership Program, an NIH New Innovator Award and the Neuroscience Center Zurich.

Featured image: Stem cells in the mouse hippocampus (in blue): With increasing age, their ability to form new neurons decreases as the amount of the nuclear protein lamin B1 (in red) drops. (Image: Khadeesh bin Imtiaz, UZH)


Literature:

M.K. bin Imtiaz, B.N. Jaeger, S. Bottes, R.A.C. Machado, M. Vidmar, D.L. Moore, S. Jessberger. Declining Lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity. 24 February 2021. Cell Stem Cell. DOI: 10.1016/j.stem.2021.01.015


Provided by University of Zurich