Tag Archives: #memory

Researchers Shed Light On The Cellular Mechanisms Underlying Navigation And Memory in Humans (Neuroscience)

A previously unknown kind of human brain cell appears to help people center themselves in their personal maps of the world, according to a new study from neuroscientists at Columbia Engineering. This discovery sheds light on the cellular mechanisms underlying navigation and memory in humans, as well as what parts of the brain might get disrupted during the kinds of memory impairments common in neurodegenerative diseases such as Alzheimer’s.

There are two strategies with which humans and animals navigate and orient themselves. One involves locating places, distances and directions in “allocentric” or other-centered frames of reference rooted in the external world. The other strategy involves “egocentric” frames of reference that are centered on the self.

Whenever you use a mobile phone app to find driving directions, it will likely employ both these modes of navigation. When you first type in an address, it will normally show you the address on a map from an allocentric perspective, with ‘north’ at the top and ‘south’ at the bottom. When you then go to route view, it will switch to an egocentric perspective where ‘ahead’ is at the top and ‘behind’ is at the bottom.

Scientists first discovered brain cells linked with allocentric frames of reference in rats in 1971 — “place cells” that may, for example, indicate that one is located in the northeast corner of an area. Other allocentric spatial cell types include head-direction cells that may activate whenever one is navigating south, or border cells that may respond when a boundary is located to the west.

In the past decade, researchers began investigating how rat brains mapped egocentric frames of reference. Two years ago, scientists at Dartmouth College in Hanover, New Hampshire, identified a brain region in rats called the postrhinal cortex in which egocentrically tuned cells are abundant. However, it remained poorly understood what brain cells formed the basis of egocentric spatial maps in humans.

“In humans it is only rarely possible to directly record the activity of single neurons from the brain, due to ethical reasons,” said Lukas Kunz, a postdoctoral research scientist at Columbia University’s Department of Biomedical Engineering and first author of the new study. “There are techniques like fMRI or EEG, which allow us to indirectly measure neural activity from healthy human brains, but this neural activity reflects the sum activity of millions of neurons, which does not allow for direct conclusions about the working principles of single neurons.”

In the new study, neuroscientists from the United States and Germany investigated 15 epilepsy patients at the University of Freiburg’s Medical Center in Germany. These volunteers were implanted with electrodes to help doctors monitor their disorder.

The researchers asked the volunteers to perform computer tasks that explored their ability to navigate through virtual environments and to remember where many different objects were located there. At the same time, the scientists recorded the activity of more than 1,400 single neurons in multiple brain regions across all the participants.

The scientists identified more than 160 neurons that behaved like egocentric spatial cell types, activating when specific parts of the virtual environment were ahead, behind, to the left, or to the right of the patients, or when points in space were close to or far away from the patients.

“We are now the first to report egocentric spatial cell types in humans,” Kunz said. The scientists published their study, “A neural code for egocentric spatial maps in the human medial temporal lobe,” in the journal Neuron on July 14, 2021.

These “egocentric bearing cells” likely encode spatial information on a mental map centered on each person. “This is presumably important for everyday life, when humans try to orient themselves in their environments and when they navigate along routes,” said Joshua Jacobs, associate professor of biomedical engineering at Columbia Engineering and senior author of the study.

These egocentric bearing cells were particularly ample in the parahippocampal cortex, a region located deep within the brain that prior work suggested is the human equivalent of the rodent postrhinal cortex. Egocentric bearing cells comprised about 25% of all neurons in the parahippocampal cortex. “Previous studies had shown that patients with damage to this brain region are disoriented, presumably because their egocentric bearing cells were affected,” Kunz said.

The researchers also found these egocentric bearing cells showed increases in activity when the patients used their memory to successfully recall the locations of objects they had found in the virtual environments. “This suggests these cells are not only relevant for navigation, but also play a role in correctly remembering past experiences,” Kunz said.

“Memories consist of multiple different elements, such as a specific event, the place where the event happened, and the time when the event happened,” Kunz said. “We believe that there are different neural systems for the different components of these memories. Egocentric bearing cells are presumably particularly involved in processing the spatial information of the memories.”

These findings may illuminate what might go wrong in people with memory deficits, including patients with neurodegenerative diseases such as Alzheimer’s. “Their egocentric bearing cells may not function correctly, or may have been destroyed for some reason, such as a stroke, a brain tumor, or dementia,” Jacobs said.

These new findings do not answer how one might deal with such memory impairments. “There is still a lot of research to do before memory impairments can be treated successfully,” Kunz cautioned.

In the future, the researchers want to see why exactly any given egocentric bearing cell is tuned to whatever point in space it is focused on. Currently, Kunz and his colleagues assume that multiple different spatial cues, such as objects, spatial boundaries and landmarks, combine to influence the position of these reference points. The scientists can examine the influence these cues have on the location of these reference points by removing these cues from environments during experiments.

“Another important question is how egocentric bearing cells interact with allocentric spatial cell types, Kunz said. “We currently hypothesize that egocentric bearing cells provide essential input to allocentric spatial cell types. By understanding this, future studies could explain how the tuning of allocentric spatial cell types is influenced by the functioning of egocentric bearing cells.”


About the Study

  • The study is titled “A neural code for egocentric spatial maps in the human medial temporal lobe.”
  • The study appeared in the journal Neuron on July 14, 2021.
  • Authors are: Lukas Kunz, Armin Brandt, Peter C. Reinacher, Bernhard P. Staresina, Eric T. Reifenstein, Christoph T. Weidemann, Nora A. Herweg, Ansh Patel, Melina Tsitsiklis, Richard Kempter, Michael J. Kahana, Andreas Schulze-Bonhage, Joshua Jacobs.

Provided by Columbia University

Memory Making Involves Extensive DNA Breaking (Neuroscience)

To quickly express genes needed for learning and memory, brain cells snap both strands of DNA in many more places and cell types than previously realized, a new study shows

The urgency to remember a dangerous experience requires the brain to make a series of potentially dangerous moves: Neurons and other brain cells snap open their DNA in numerous locations—more than previously realized, according to a new study—to provide quick access to genetic instructions for the mechanisms of memory storage.

The extent of these DNA double-strand breaks (DSBs) in multiple key brain regions is surprising and concerning, said study senior author Li-Huei Tsai, Picower Professor of Neuroscience at MIT and director of The Picower Institute for Learning and Memory, because while the breaks are routinely repaired, that process may become more flawed and fragile with age. Tsai’s lab has shown that lingering DSBs are associated with neurodegeneration and cognitive decline and that repair mechanisms can falter.

“We wanted to understand exactly how widespread and extensive this natural activity is in the brain upon memory formation because that can give us insight into how genomic instability could undermine brain health down the road,” said Tsai, who is also a professor in the Department of Brain and Cognitive Sciences and a leader of MIT’s Aging Brain Initiative. “Clearly memory formation is an urgent priority for healthy brain function but these new results showing that several types of brain cells break their DNA in so many places to quickly express genes is still striking.”

Tracking breaks

In 2015, Tsai’s lab provided the first demonstration that neuronal activity caused DSBs and that they induced rapid gene expression. But those findings, mostly made in lab preparations of neurons, did not capture the full extent of the activity in the context of memory formation in a behaving animal and did not investigate what happened in cells other than neurons.

IIn the new study published July 1 in PLOS ONE, lead author and former graduate student Ryan Stott and co-author and former research technician Oleg Kritsky sought to investigate the full landscape of DSB activity in learning and memory. To do so, they gave mice little electrical zaps to the feet when they entered a box, to condition a fear memory of that context. They then used several methods to assess DSBs and gene expression in the brains of the mice over the next half hour, particularly among a variety of cell types in the prefrontal cortex and hippocampus, two regions essential for the formation and storage of conditioned fear memories. They also made measurements in the brains of mice who did not experience the foot shock to establish a baseline of activity for comparison.

The creation of a fear memory doubled the number of DSBs among neurons in the hippocampus and the prefrontal cortex, affecting more than 300 genes in each region. Among 206 affected genes common to both regions, the researchers then looked at what those genes do. Many were associated with the function of the connections neurons make with each other, called synapses. This makes sense because learning arises when neurons change their connections (a phenomenon called “synaptic plasticity”) and memories are formed when groups of neurons connect together into ensembles called engrams.

“Many genes essential for neuronal function and memory formation, and significantly more of them than expected based on previous observations in cultured neurons…are potentially hotspots of DSB formation,” the authors wrote in the study.

In another analysis, the researchers confirmed through measurements of RNA that the increase in DSBs indeed correlated closely with increased transcription and expression of affected genes, including ones affecting synapse function, as quickly as 10-30 minutes after the foot shock exposure.

“Overall, we find transcriptional changes are more strongly associated with [DSBs] in the brain than anticipated,” they wrote. “Previously we observed 20 gene-associated [DSB] loci following stimulation of cultured neurons, while in the hippocampus and prefrontal cortex we see more than 100-150 gene associated [DSB] loci that are transcriptionally induced.”

Snapping with stress

In the analysis of gene expression, the neuroscientists looked at not only neurons but also non-neuronal brain cells, or glia, and found that they also showed changes in expression of hundreds of genes after fear conditioning. Glia called astrocytes are known to be involved in fear learning, for instance, and they showed significant DSB and gene expression changes after fear conditioning.

Among the most important functions of genes associated with fear conditioning-related DSBs in glia was the response to hormones. The researchers therefore looked to see which hormones might be particularly involved and discovered that it was glutocortocoids, which are secreted in response to stress. Sure enough, the study data showed that in glia, many of the DSBs that occurred following fear conditioning occurred at genomic sites related to glutocortocoid receptors. Further tests revealed that directly stimulating those hormone receptors could trigger the same DSBs that fear conditioning did and that blocking the receptors could prevent transcription of key genes after fear conditioning.

Tsai said the finding that glia are so deeply involved in establishing memories from fear conditioning is an important surprise of the new study.

“The ability of glia to mount a robust transcriptional response to glutocorticoids suggest that glia may have a much larger role to play in the response to stress and its impact on the brain during learning than previously appreciated,” she and her co-authors wrote.

Damage and danger?

More research will have to be done to prove that the DSBs required for forming and storing fear memories are a threat to later brain health, but the new study only adds to evidence that it may be the case, the authors said.

“Overall we have identified sites of DSBs at genes important for neuronal and glial functions, suggesting that impaired DNA repair of these recurrent DNA breaks which are generated as part of brain activity could result in genomic instability that contribute to aging and disease in the brain,” they wrote.

The National Institutes of Health, The Glenn Foundation for Medical Research and the JPB Foundation provided funding for the research.


Reference: Stott RT, Kritsky O, Tsai L-H (2021) Profiling DNA break sites and transcriptional changes in response to contextual fear learning. PLoS ONE 16(7): e0249691. doi:10.1371/journal.pone.0249691


Provided by Picower Institute

Study Shows How Taking Short Breaks May Help Our Brains Learn New Skills (Neuroscience)

NIH scientists discover that the resting brain repeatedly replays compressed memories of what was just practiced

In a study of healthy volunteers, National Institutes of Health researchers have mapped out the brain activity that flows when we learn a new skill, such as playing a new song on the piano, and discovered why taking short breaks from practice is a key to learning. The researchers found that during rest the volunteers’ brains rapidly and repeatedly replayed faster versions of the activity seen while they practiced typing a code. The more a volunteer replayed the activity the better they performed during subsequent practice sessions, suggesting rest strengthened memories.

“Our results support the idea that wakeful rest plays just as important a role as practice in learning a new skill. It appears to be the period when our brains compress and consolidate memories of what we just practiced,” said Leonardo G. Cohen, M.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study published in Cell Reports. “Understanding this role of neural replay may not only help shape how we learn new skills but also how we help patients recover skills lost after neurological injury like stroke.”

The study was conducted at the NIH Clinical Center. Dr. Cohen’s team used a highly sensitive scanning technique, called magnetoencephalography, to record the brain waves of 33 healthy, right-handed volunteers as they learned to type a five-digit test code with their left hands. The subjects sat in a chair and under the scanner’s long, cone-shaped cap. An experiment began when a subject was shown the code “41234” on a screen and asked to type it out as many times as possible for 10 seconds and then take a 10 second break. Subjects were asked to repeat this cycle of alternating practice and rest sessions a total of 35 times.

During the first few trials, the speed at which subjects correctly typed the code improved dramatically and then leveled off around the 11th cycle. In a previous study, led by former NIH postdoctoral fellow Marlene Bönstrup, M.D., Dr. Cohen’s team showed that most of these gains happened during short rests, and not when the subjects were typing. Moreover, the gains were greater than those made after a night’s sleep and were correlated with a decrease in the size of brain waves, called beta rhythms. In this new report, the researchers searched for something different in the subjects’ brain waves.

“We wanted to explore the mechanisms behind memory strengthening seen during wakeful rest. Several forms of memory appear to rely on the replaying of neural activity, so we decided to test this idea out for procedural skill learning,” said Ethan R. Buch, Ph.D., a staff scientist on Dr. Cohen’s team and leader of the study.

To do this, Leonardo Claudino, Ph.D., a former postdoctoral fellow in Dr. Cohen’s lab, helped Dr. Buch develop a computer program which allowed the team to decipher the brain wave activity associated with typing each number in the test code.

The program helped them discover that a much faster version – about 20 times faster – of the brain activity seen during typing was replayed during the rest periods. Over the course of the first eleven practice trials, these compressed versions of the activity were replayed many times – about 25 times – per rest period. This was two to three times more often than the activity seen during later rest periods or after the experiments had ended.

Interestingly, they found that the frequency of replay during rest predicted memory strengthening. In other words, the subjects whose brains replayed the typing activity more often showed greater jumps in performance after each trial than those who replayed it less often.

“During the early part of the learning curve we saw that wakeful rest replay was compressed in time, frequent, and a good predictor of variability in learning a new skill across individuals,” said Dr. Buch. “This suggests that during wakeful rest the brain binds together the memories required to learn a new skill.”

As expected, the team discovered that the replay activity often happened in the sensorimotor regions of the brain, which are responsible for controlling movements. However, they also saw activity in other brain regions, namely the hippocampus and entorhinal cortex.

“We were a bit surprised by these last results. Traditionally, it was thought that the hippocampus and entorhinal cortex may not play such a substantive role in procedural memory. In contrast, our results suggest that these regions are rapidly chattering with the sensorimotor cortex when learning these types of skills,” said Dr. Cohen. “Overall, our results support the idea that manipulating replay activity during waking rest may be a powerful tool that researchers can use to help individuals learn new skills faster and possibly facilitate rehabilitation from stroke.”

Article:

Buch et al., Consolidation of human skill linked to waking hippocampo-neocortical replay, Cell Reports, June 8, 2021, DOI: 10.1016/j.celrep.2021.109193

This study was supported by the NIH Intramural Research Program at the NINDS.

Featured image: In a study of healthy volunteers, NIH researchers discovered that our brains may replay compressed memories of learning new skills when we rest. Above is a map of the memory replay activity observed in the study. © Courtesy of Cohen lab, NIH/NINDS.


Provided by NINDS

Memory Details Fade Over Time, With Only the Main gist Preserved (Neuroscience)

What information is retained in a memory over time, and which parts get lost? These questions have led to many scientific theories over the years, and now a team of researchers at the Universities of Glasgow and Birmingham have been able to provide some answers.

Their new study, which is published today in Nature Communications, demonstrates that our memories become less vibrant and detailed over time, with only the central gist eventually preserved. Moreover, this ‘gistification’ of our memories is boosted when we frequently recall our recent experiences.

The work could have implications in a number of areas, including the nature of memories in post-traumatic stress disorder, the repeated questioning of eye-witness testimonies and even in best practice for exam studying.

While memories are not exact carbon copies of the past – remembering is understood to be a highly reconstructive process – experts have suggested that the contents of a memory could change each time we bring it back to mind.

However, exactly how our memories differ from the original experiences, and how they are transformed over time, has until now proven difficult to measure in laboratory settings.

For this study the researchers developed a simple computerised task that measures how fast people can recover certain characteristics of visual memories when prompted to do so. Participants learned word-image pairs and were later required to recollect different elements of the image when cued with the word. For example, participants were asked to indicate, as fast as possible, if the image was coloured or greyscale (a perceptual detail), or whether it showed an animate or inanimate object (a semantic element).

These tests, probing the quality of the visual memories, happened immediately after learning and also after a two-day delay. Reaction time patterns showed that participants were faster to recollect meaningful, semantic elements than surface, perceptual ones.

Julia Lifanov, lead author of the study from the University of Birmingham, said: “Many memory theories assume that over time, and as people re-tell their stories, they tend to forget the surface details but retain the meaningful, semantic content of an event.

“Imagine reminiscing about a pre-COVID dinner with a friend – you realize that you cannot recall the table décor but know exactly what you ordered; or you remember the conversation with the bartender, but not the colour of his shirt. Memory experts call this phenomenon ‘semanticization’.”

Prof Maria Wimber, senior author on the study from the University of Glasgow, said: “The pattern towards recollection of meaningful semantic elements we demonstrate in this study indicates that memories are biased towards meaningful content in the first place – and we have shown in previous studies that this bias is clearly reflected in brain signals too.

“Our memories change with time and use and that is a good and adaptive thing. We want our memories to retain the information that is most likely to be useful in the future, when we encounter similar situations.”

The researchers found that the bias towards semantic memory content becomes significantly stronger with the passage of time, and with repeated remembering. When participants came back to the lab two days later, they were much slower at answering the perceptual-detailed questions, but they show relatively preserved memory for the semantic content of the images. However, the shift from detail-rich to more concept-based memories was far less pronounced in a group of subjects who repeatedly viewed the images, rather than being asked to actively bringing them back to mind.

The study has implications for probing the nature of memories in health and disease. It provides a tool to study maladaptive changes, for example in post-traumatic stress disorder where patients often suffer from intrusive, traumatic memories, and tend to over-generalize these experiences to novel situations. The findings are also highly relevant for understanding how eyewitness memories may be biased by frequent interviews and repeatedly recalling the same event.

The findings also demonstrate that testing yourself prior to an exam (for example, by using flashcards) will make the meaningful information stick for longer, especially when followed by periods of rest and sleep.

The study, ‘Feature-specific reaction times reveal a semanticisation of memories over time and with repeated remembering’ is published in Nature Communications. The work is funded by the European Research Council, the Economic and Social Sciences Research Council UK and the Midlands Integrative Biosciences Training Partnership.


Provided by University of Birmingham

Shootin1a – The Missing Link Underlying Learning and Memory (Neuroscience)

Researchers from Nara Institute of Science and Technology find that the shootin1a protein is crucial for allowing dendritic spines to change in size, which is an important process underlying learning and memory

In neurons, changes in the size of dendritic spines – small cellular protrusions involved in synaptic transmission – are thought to be a key mechanism underlying learning and memory. However, the specific way in which these structural changes occur remains unknown. In a study published in Cell Reports, researchers from Nara Institute of Science and Technology (NAIST) have revealed that the binding of cell adhesion molecules with actin, via an important linker protein in the structural backbone of synapses, is vital for this process of structural plasticity.

Actin proteins make up an important part of a cell’s structure, or cytoskeleton, and allow for dynamic changes in this structure by forming microfilaments when growth or movement is required. It was originally thought that the polymerization of actin was all that was needed for dendritic spines to change size in response to synaptic activation, but researchers at NAIST found that this process alone was not enough to cause structural plasticity, and decided to address this problem.

“Current models of structural plasticity in dendritic spines do not take mechanical force into account,” says Naoyuki Inagaki, corresponding author. “We had already identified the role of shootin1a, a protein involved in neuronal development, in axon growth and so we wanted to investigate whether this protein might also have a role in the structural plasticity of dendritic spines.”

To explore this question, the researchers used neurons of control and shootin1a knockout rodents to examine whether shootin1a was involved in the formation of dendritic spines. The researchers wanted to determine if mechanical force was generated in dendritic spines by the shootin1a-mediated coupling of actin and cell adhesion molecules – cell-surface proteins that bind cells together at synapses – similar to what they had observed in axons.

“The results were clear,” explains Inagaki. “We found that shootin1a mechanically linked polymerizing actin with cell adhesion molecules in dendritic spines, and revealed that synaptic activity enhanced this coupling, thus allowing the actin filaments to push against the membranes and enlarge spines.” The results of this study are the first to link mechanical force with synaptic activity-dependent dendritic spine plasticity and provide new insights into the mechanisms of structural plasticity in these spines.

Given that changes in activity-dependent dendritic spine plasticity have been implicated in multiple neuropsychiatric and neurodegenerative disorders, including autism spectrum disorder and Alzheimer’s disease, these findings are important because they suggest that shootin1a disruption may lead to the development of neurological disorders. Future studies into this mechanism of structural plasticity in dendritic spines might provide new drug targets for these disorders.

Featured image: Shootin1a Is Required for Spine Structural Plasticity. Fluorescence time-lapse images of dendritic spines (A) and time course of their volume changes (B) of hippocampal neurons in slice culture. Spines were stimulated by local application of a neurotransmitter glutamate for 30 s (red asterisks). 30-sec stimulation of control spines induced their rapid enlargement which persisted for more than 30 min (blue arrows, top). Downregulation of shootin1a significantly inhibited the spine enlargement (middle). Furthermore, re-addition of shootin1a rescued the reduction of the spine enlargement (blue arrows, bottom), thereby indicating that shootin1a plays an essential role in spine structural plasticity. © Naoyuki Inagaki


Resource

  • Title: Shootin1a-mediated actin-adhesion coupling generates force to trigger structural plasticity of dendritic spines
  • Authors: Ria Fajarwati Kastian, Takunori Minegishi, Kentarou Baba, Takeo Saneyoshi, Hiroko Katsuno-Kambe, Singh Saranpal, Yasunori Hayashi & Naoyuki Inagaki
  • JournalCell Reports
  • DOI: 10.1016/j.celrep.2021.109130

Provided by Nara Institute of Science and Technology

Could Leak in Blood-brain Barrier Cause Poor Memory? (Neuroscience)

Researchers review 150 articles to determine what happens as the blood-brain barrier ages.

Have you forgotten where you laid your keys?  Ever wondered where you had parked your car? Or having trouble remembering the name of the new neighbor? Unfortunately, these things seem to get worse as one gets older. A big question for researchers is where does benign forgetfulness end and true disease begin?

One of the keys to having a healthy brain at any age is having a healthy blood-brain barrier, a complex interface of blood vessels that run through the brain. Researchers reviewed more than 150 articles to look at what happens to the blood-brain barrier as we age. Their findings were published March 15 in Nature Aging.

Whether the changes to the blood-brain barrier alters brain function, however, is still up for debate. But research shows the blood-brain barrier leaks as we age, and we lose cells called pericytes. 

“It turns out very little is known how the blood-brain barrier ages,” said lead author William Banks, a gerontology researcher at the University of Washington School of Medicine and at the Veterans Affairs Puget Sound Health Care System. “It’s often hard to tell normal aging from early disease.”

The blood-brain barrier, discovered in the late 1800s, prevents the unregulated leakage of substances from blood into the brain. The brain is an especially sensitive organ and cannot tolerate direct exposure to many of the substances in the blood. Increasingly, scientists have realized that the blood-brain barrier also allows many substances into the brain in a regulated way to serve the nutritional needs of the brain. It also transports informational molecules from the blood to the brain and pumps toxins out of the brain. A malfunctioning blood-brain barrier can contribute to diseases such as multiple sclerosis, diabetes, and Alzheimer’s. 

Before scientists can understand how such malfunctioning can contribute to the diseases of aging, they need to understand how a healthy blood-brain barrier normally ages. 

Research shows that healthy aging individuals have a very small leak in their blood-brain barrier. This leakage is associated with some measures of the benign forgetfulness of aging, considered by most scientists to be normal. But could this leak and the difficulties in recall be the early stages of Alzheimer’s disease?

When a person carries the ApoE4 allele, the strongest genetic risk of Alzheimer’s risk, researchers said there is an acceleration of most of the blood-brain barrier age-related changes.

People with ApoE4 have a hard time getting rid of amyloid beta peptide in their brains, which causes an accumulation of plaque. With healthy aging, the pumps in the blood-brain barrier work less efficiently in getting rid of the amyloid beta peptide. The pumps work even less well in people with Alzheimer’s disease.

Another key finding in the review is that as we age, two cells begin to change in the blood-brain barrier: pericytes and astrocytes.

Recent work suggests that the leak in the blood-brain barrier that occurs with Alzheimer’s may be due to an age-related loss of pericytes. Astrocytes, by contrast, seem to be overactive. Recent work suggests that preserving pericyte function by giving the factors that they secrete or even transplanting them could lead to a healthier blood-brain barrier.

Some research suggests that pericyte health can be preserved by some of the same interventions that extend lifespan, such as regular exercise, caloric restriction, and rapamycin.

Other findings raise the question of whether the brain’s source of nutrition and its grip on control of the immune and endocrine systems could deteriorate with aging. Another finding raises the possibility that the rate at which many drugs are taken up by the brain may explain why older folks sometimes have different sensitivities to drugs than their children or grandchildren.

The research was supported by the Department of Veterans Affairs and National Institutes of Aging R01AG059088. Other researchers include May Reed, Aric Logsdon, Elizabeth Rhea, Michelle Erickson, all gerontology researchers with the UW School of Medicine and with the Geriatrics Research Education and Clinical Center at the Veterans Affairs Puget Sound Health Care System.

Featured image: Research shows that leakage in the blood-brain barrier is associated with forgetfulness in aging. © Gettyimages


Reference: Banks, W.A., Reed, M.J., Logsdon, A.F. et al. Healthy aging and the blood–brain barrier. Nat Aging 1, 243–254 (2021). https://doi.org/10.1038/s43587-021-00043-5


Provided by UW Medicine

How Sperm Remember? (Biology)

Discovery identifies non-DNA mechanism involved in transmitting paternal experience to offspring

It has long been understood that a parent’s DNA is the principal determinant of health and disease in offspring. Yet inheritance via DNA is only part of the story; a father’s lifestyle such as diet, being overweight and stress levels have been linked to health consequences for his offspring. This occurs through the epigenome – heritable biochemical marks associated with the DNA and proteins that bind it. But how the information is transmitted at fertilization along with the exact mechanisms and molecules in sperm that are involved in this process has been unclear until now.

A new study from McGill, published recently in Developmental Cellhas made a significant advance in the field by identifying how environmental information is transmitted by non-DNA molecules in the sperm. It is a discovery that advances scientific understanding of the heredity of paternal life experiences and potentially opens new avenues for studying disease transmission and prevention.

A paradigm shift in understanding of heredity

“The big breakthrough with this study is that it has identified a non-DNA based means by which sperm remember a father’s environment (diet) and transmit that information to the embryo,” says Sarah Kimmins, PhD, the senior author on the study and the Canada Research Chair in Epigenetics, Reproduction and Development. The paper builds on 15 years of research from her group. “It is remarkable, as it presents a major shift from what is known about heritability and disease from being solely DNA-based, to one that now includes sperm proteins. This study opens the door to the possibility that the key to understanding and preventing certain diseases could involve proteins in sperm.”

“When we first started seeing the results, it was exciting, because no one has been able to track how those heritable environmental signatures are transmitted from the sperm to the embryo before,” adds PhD candidate Ariane Lismer, the first author on the paper. “It was especially rewarding because it was very challenging to work at the molecular level of the embryo, just because you have so few cells available for epigenomic analysis. It is only thanks to new technology and epigenetic tools that we were able to arrive at these results.”

Changes in sperm proteins affect offspring

To determine how information that affects development gets passed on to embryos, the researchers manipulated the sperm epigenome by feeding male mice a folate deficient diet and then tracing the effects on particular groups of molecules in proteins associated with DNA.

They found that diet-induced changes to a certain group of molecules (methyl groups), associated with histone proteins, (which are critical in packing DNA into cells), led to alterations in gene expression in embryos and birth defects of the spine and skull. What was remarkable was that the changes to the methyl groups on the histones in sperm were transmitted at fertilization and remained in the developing embryo.

“Our next steps will be to determine if these harmful changes induced in the sperm proteins (histones) can be repaired. We have exciting new work that suggest that this is indeed the case,” adds Kimmins. “The hope offered by this work is that by expanding our understanding of what is inherited beyond just the DNA, there are now potentially new avenues for disease prevention which will lead to healthier children and adults.”

About this study:

“Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring” by Ariane Lismer et al in Developmental Cell

https://doi.org/10.1016/j.devcel.2021.01.01

The research was funded by the Canadian Institute of Health Research


Provided by McGill University


About McGill University

Founded in Montreal, Quebec, in 1821, McGill University is Canada’s top ranked medical doctoral university. McGill is consistently ranked as one of the top universities, both nationally and internationally. It is a world-renowned institution of higher learning with research activities spanning two campuses, 11 faculties, 13 professional schools, 300 programs of study and over 40,000 students, including more than 10,200 graduate students. McGill attracts students from over 150 countries around the world, its 12,800 international students making up 31% of the student body. Over half of McGill students claim a first language other than English, including approximately 19% of our students who say French is their mother tongue.

Signal Coupling Between Neuron-glia Super-network May Lead to Improved Memory Formation (Neuroscience)

Tohoku University scientists have shown that neuronal and glial circuits form a loosely coupled super-network within the brain. Activation of the metabotropic glutamate receptors in neurons was shown to be largely influenced by the state of the glial cells. Therefore, artificial control of the glial state could potentially be used to enhance the memory function of the brain.

The findings were detailed in the Journal of Physiology.

Although the glial cells occupy more than half of the brain, they were thought to act as glue–merely filling the gap between neurons. However, recent findings show that the concentration of intracellular ions in glia, such as calcium and proton, can fluctuate over time.

“Glial cells appear to have the capacity of coding information,” says professor Ko Matsui of the Super-network Brain Physiology lab at Tohoku University, who led the research. “However, the role of the added layer of signals encoded in the glial circuit has always been an enigma.”

Using patch clamp electrophysiology techniques in acute brain slices from mice, Dr. Kaoru Beppu, Matsui, and their team show that glial cells in the cerebellum react to excitatory transmitter glutamate released from synapses of neurons. The glial cells then release additional glutamate in return. Therefore, these glial cells effectively function as excitatory signal amplifiers.

The additional glutamate released from glial cells efficiently activate metabotropic glutamate receptors on Purkinje neurons–essential for cerebellar motor learning. The amount of feedforward excitation was controlled by the intracellular pH of the glia cells.

“Depending on the state of our mind, the same experience could become a lasting memory or could fade away,” says Matsui. “It is possible that the pH of the glial cells at the time of the experience could have a pivotal role on memory formation.”

In this study, light-sensitive proteins were genetically expressed in glial cells to control their pH at will. Such optogenetics technology would be difficult to apply in human patients. “Although it would take a long time for clinical use, it is possible to imagine a future where a therapeutic strategy is designed to target glial cells to control their pH for memory enhancement to treat dementia,” added Matsui.

Featured image: Optogenetic control of glial pH suppresses or enhances the glial release of glutamate © Ko Matsui


Publication Details: Title: Glial amplification of synaptic signals
Authors: Kaoru Beppu, Naoko Kubo, and Ko Matsui*
Journal: Journal of Physiology
DOI: 10.1113/JP280857


Provided by Tohoku University

A Memory Without a Brain (Neuroscience)

How a single cell slime mold makes smart decisions without a central nervous system

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 to 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.

The network architecture as a memory

“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 in Göttingen and professor for the 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.

“These results present an important piece of the puzzle in understanding the behavior of this ancient organism and at the same time points to universal principles underlying behavior. We envision potential applications of our findings in designing smart materials and building soft robots that navigate through complex environments”, concludes Karen Alim.

Featured image: Prof. Dr. Karen Alim in her laboratory. Image: Bilderfest / TUM


Publications:

Encoding memory in tube diameter hierarchy of living flow network
Mirna Kramar and Karen Alim
PNAS, 22.02.2021 – DOI: 10.1073/pnas.2007815118


Provided by TUM