TL;DR

• Researchers have identified a vulnerability in glioblastoma, an aggressive form of brain cancer, which could lead to new treatment options. The CSHL team recently solved a decades-old mystery surrounding glioblastoma’s aggressiveness by linking the BRD8 protein to another protein, named P53. A staple in the body’s natural cancer defenses, P53 prevents cells from overgrowing and turning into tumors. Almost all cancers depend on P53 becoming mutated and thus disabled. But weirdly, in the majority of glioblastoma cases, P53 is unscathed. “So why does this cancer act like P53 is broken?” asked CSHL postdoctoral fellow Xueqin Sun. This critical question led Mills’ team to discover that BRD8 had gone rogue in glioblastoma, crippling P53 in a completely new way.
• Kickstarting the brain’s natural ability to adjust to new circumstances, or neuroplasticity, improves how effectively a cochlear implant can restore hearing loss, a new study in deaf rats shows. The investigation, researchers say, may help explain the extreme variation in hearing improvements experienced by implant recipients.
• The reason some people fail to recover their sense of smell after COVID-19 is linked to an ongoing immune assault on olfactory nerve cells and an associated decline in the number of those cells, scientists report.
• When the Golden State Warriors’ Steph Curry makes a free throw, his brain draws on motor memory. Now researchers have shown how this type of memory is consolidated during sleep when the brain processes the day’s learning to make the physical act of doing something subconsciously.
• Middle-aged smokers are far more likely to report having memory loss and confusion than nonsmokers, and the likelihood of cognitive decline is lower for those who have quit, even recently, a new study has found.
• Scientists have labored for decades to understand how brain structure and functional connectivity drive intelligence. 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.
• Craving is known to be a key factor in substance use disorders and can increase the likelihood of future drug use or relapse. Yet its neural basis — or, how the brain gives rise to craving — is not well understood. In a new study, researchers have identified a stable brain pattern, or neuromarker, for drug and food craving.
• People with chronic epilepsy often experience impaired memory. Researchers have now found a mechanism in mice that could explain these deficits.
• Psychologists had people learn words from two phonetically similar languages in virtual reality environments. Those who learned each language in its own unique context mixed up fewer words and were able to recall 92% of the words they had learned. In contrast, participants who had learned both sets of words in the same VR context were more likely to confuse terms between the two languages and retained only 76% of the words. Regardless of group, those participants who felt immersed in the VR world remembered more than those who did not feel immersed.
• After an intrepid, decade-long search, scientists say they have found a new role for a pair of enzymes that regulate genome function and, when missing or mutated, are linked to diseases such as brain tumors, blood cancers and Kleefstra syndrome — a rare genetic, neurocognitive disorder.
• And more!

Neuroscience market

The global neuroscience market size was valued at USD 28.4 billion in 2016 and it is expected to reach USD 38.9 billion by 2027.

The latest news and research

BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network

by Sun X, Klingbeil O, Lu B, et al. in Nature

The brain cancer, glioblastoma, is a fierce and formidable opponent. Its millions of victims include Senator John McCain, President Biden’s son, Beau, and famed film critic Gene Siskel, to name just a few. Most patients succumb within two years and few make it past five, a statistic that hasn’t improved in decades due to lack of effective treatment options.

“The aggressiveness of glioblastoma is notorious,” says Cold Spring Harbor Laboratory (CSHL) Professor Alea Mills. “The norm is to do surgery, treat with harsh drugs, and just hope for the best.”

But now, Mills and her colleagues have discovered in this deadly cancer a vulnerability, known as BRD8, that may finally lead to new treatment options and better patient outcomes.

The CSHL team recently solved a decades-old mystery surrounding glioblastoma’s aggressiveness by linking the BRD8 protein to another protein, named P53. A staple in the body’s natural cancer defenses, P53 prevents cells from overgrowing and turning into tumors. Almost all cancers depend on P53 becoming mutated and thus disabled. But weirdly, in the majority of glioblastoma cases, P53 is unscathed.

“So why does this cancer act like P53 is broken?” asked CSHL postdoctoral fellow Xueqin Sun. This critical question led Mills’ team to discover that BRD8 had gone rogue in glioblastoma, crippling P53 in a completely new way.

BRD8 shuts down access to genes in chromosomes. If a gene is wound up tightly, it cannot be used — it’s as if it were “asleep.” Mills and her team revealed that BRD8 was inappropriately active in glioblastoma, keeping many of P53’s critical anticancer defenses at rest. When the researchers inactivated BRD8 via genome editing, P53’s “arsenal” suddenly woke up and began blocking tumor growth.

“It’s like BRD8 is saying ‘NO ENTRY’ to P53’s tumor-preventing power, but when we hit BRD8 in the right way — go in there almost like a scalpel, but molecularly — the tumor is annihilated,” Mills explains.

She and her team implanted tumor cells from glioblastoma patients into mice and watched the tumors grow in the brain. When BRD8 was inactivated, P53 was unlocked — the tumors stopped growing and the mice lived longer.

The finding suggests that drugs targeting the heart of BRD8 could work against glioblastoma. Mills hopes her team’s discovery will help turn this deadly brain cancer into a treatable disease and for the first time in a generation, extend the life expectancy of patients who are diagnosed with it.

Locus coeruleus activity improves cochlear implant performance

by Erin Glennon, Silvana Valtcheva, Angela Zhu, Youssef Z. Wadghiri, Mario A. Svirsky, Robert C. Froemke in Nature

Kickstarting the brain’s natural ability to adjust to new circumstances, or neuroplasticity, improves how effectively a cochlear implant can restore hearing loss, a new study in deaf rats shows. The investigation, researchers say, may help explain the extreme variation in hearing improvements experienced by implant recipients.

Unlike hearing aids, which amplify, balance, and sharpen incoming sound, cochlear implants send electrical signals that represent sounds directly to the brain. Unfortunately, experts say, it can take time to understand the meaning of the signals. Past studies had shown that, while some cochlear implant users understand some speech hours after receiving their device, others required months or years to do so. However, the mechanisms that determine how quickly the brain can adjust to an implant have been unclear.

Led by researchers at NYU Langone Health, the new investigation in rats evaluated whether stimulating the locus coeruleus, a major site of neuroplasticity deep in the brainstem of mammals, improved how quickly they learned to use their devices. It showed that within just three days of receiving their implants, rodents given the extra boost could effectively complete tasks that required accurate hearing. By contrast, those without the stimulation needed up to 16 days to do so.

“Our findings suggest that differences in neuroplasticity, particularly in parts of the brain such as the locus coeruleus, may help explain why some cochlear implant users improve faster than others,” says study lead author and neuroscientist Erin Glennon, PhD, a medical student at NYU Grossman School of Medicine.

In an earlier investigation, the research team found that electrically stimulating the locus coeruleus in rodents increases neuroplasticity and changes how the brain’s hearing system represents sound. However, the new study in the journal Nature, is the first to demonstrate that stimulating this brain region hastens hearing among cochlear implant recipients, according to Glennon.

For the investigation, the study authors trained normal hearing rats to press a button after they heard a particular sound and to ignore the button if they heard a different tone. Once deafened, the rats were unable to complete the task. Then they were given cochlear implants and retrained to perform the same challenge by relying on the device.

Among the findings, the study showed that locus coeruleus activity changed dramatically as the rats learned to use their implants. At first, the brain region was most active when the animals received food after hearing the tone and pressing the correct button. As they learned to associate pressing the button with receiving the reward, activity instead peaked when they just heard the tones. Notably, the faster this change occurred, the faster the rats consistently succeeded at the task.

“Our results suggest that improving neuroplasticity in the locus coeruleus may speed up and bolster the effectiveness of cochlear implants,” says study co-senior author and neuroscientist Robert Froemke, PhD, the Skirball Foundation Professor of Genetics in the Department of Neuroscience and Physiology at NYU Langone.

Froemke says the team next plans to explore ways of stimulating the brain region in humans that do not require invasive surgery. Froemke also serves as a professor in Department of Otolaryngology — Head and Neck Surgery at NYU Langone.

“Since our goal is to activate the locus coeruleus, we need to determine what noninvasive mechanisms may be used to trigger the brain region,” says study co-senior author Mario Svirsky, PhD. Svirsky is the Noel L. Cohen Professor of Hearing Science in the Department of Otolaryngology — Head and Neck Surgery at NYU Langone.

Persistent post–COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium

by John B. Finlay, David H. Brann, Ralph Abi Hachem, David W. Jang, Allison D. Oliva, Tiffany Ko, Rupali Gupta, Sebastian A. Wellford, E. Ashley Moseman, Sophie S. Jang, Carol H. Yan, Hiroaki Matsunami, Tatsuya Tsukahara, Sandeep Robert Datta, Bradley J. Goldstein in Science Translational Medicine

The reason some people fail to recover their sense of smell after COVID-19 is linked to an ongoing immune assault on olfactory nerve cells and an associated decline in the number of those cells, a team of scientists led by Duke Health report.

The finding in the journal Science Translational Medicine, provides an important insight into a vexing problem that has plagued millions who have not fully recovered their sense of smell after COVID-19.

While focusing on the loss smell, the finding also sheds light on the possible underlying causes of other long COVID-19 symptoms — including generalized fatigue, shortness of breath, and brain fog — that might be triggered by similar biological mechanisms.

“One of the first symptoms that has typically been associated with COVID-19 infection is loss of smell,” said senior author Bradley Goldstein, M.D., Ph.D., associate professor in Duke’s Department of Head and Neck Surgery and Communication Sciences and the Department of Neurobiology.

“Fortunately, many people who have an altered sense of smell during the acute phase of viral infection will recover smell within the next one to two weeks, but some do not,” Goldstein said. “We need to better understand why this subset of people will go on to have persistent smell loss for months to years after being infected with SARS-CoV2.”

In the study, Goldstein and colleagues at Duke, Harvard and the University of California-San Diego analyzed olfactory epithelial samples collected from 24 biopsies, including nine patients suffering from long-term smell loss following COVID-19.

This biopsy-based approach — using sophisticated single-cell analyses in collaboration with Sandeep Datta, M.D., Ph.D., at Harvard University — revealed widespread infiltration of T-cells engaged in an inflammatory response in the olfactory epithelium, the tissue in the nose where smell nerve cells are located. This unique inflammation process persisted despite the absence of detectable SARS-CoV-2 levels.

Additionally, the number of olfactory sensory neurons were diminished, possibly due to damage of the delicate tissue from the ongoing inflammation.

“The findings are striking,” Goldstein said. “It’s almost resembling a sort of autoimmune-like process in the nose.”

T cell infiltrates in nasal olfactory epithelial biopsies from PASC hyposmic patients. (A) Representative immunohistochemistry images of nasal biopsy tissue from normosmic non–COVID-19, normosmic post–COVID-19, or PASC hyposmic individuals. Tissue sections were immunostained for the TUJ1 neuronal marker, CD45 pan-immune cell marker, CD3 T cell marker, and CD68 myeloid cell marker. PASC hyposmic tissue showed dense CD45+ immune cell infiltration, including prominent CD3+ lymphocytic infiltration, which was absent in the normosmic groups; scattered CD68+ cells were present in all conditions. (B) Enlarged area (yellow box) from (A) shows CD3+ lymphocytes, with prominent infiltration into the olfactory epithelium (white arrows); dashed white line marks the basal lamina. Scale bar, 50 μm. © Additional nasal biopsies were processed for scRNA-seq to permit quantitative analyses. Uniform manifold approximation projection (UMAP) visualization of combined PASC hyposmic and control normosmic scRNA-seq datasets integrating 16 human nasal biopsies permitted robust cell cluster analysis and annotation. RBCs, red blood cells; pDC, plasmacytoid DCs.

Goldstein said learning what sites are damaged and what cell types are involved is a key step toward beginning to design treatments. He said the researchers were encouraged that neurons appeared to maintain some ability to repair even after the long-term immune onslaught.

“We are hopeful that modulating the abnormal immune response or repair processes within the nose of these patients could help to at least partially restore a sense of smell,” Goldstein said, noting this work is currently underway in his lab.

He said the findings from this study could also inform additional research into other long-COVID-19 symptoms that might be undergoing similar inflammatory processes.

Cortical–hippocampal coupling during manifold exploration in motor cortex

by Jaekyung Kim, Abhilasha Joshi, Loren Frank, Karunesh Ganguly in Nature

When the Golden State Warriors’ Steph Curry makes a free throw, his brain draws on motor memory. Now researchers at UC San Francisco (UCSF) have shown how this type of memory is consolidated during sleep, when the brain processes the day’s learning to make the physical act of doing something subconscious.

The study shows the brain does this by reviewing the trials and errors of a given action. In the analogy, that means sorting through all the free throws Curry has ever thrown, weeding out the memory of all the actions except those that hit the mark, or that the brain decided were “good enough.” The result is the ability to make the free throw with a high degree of accuracy without having to think about the physical movements involved.

“Even elite athletes makes errors, and that’s what makes the game interesting,” said Karunesh Ganguly, MD, PhD, a professor of neurology and member of the UCSF Weill Institute for Neurosciences. “Motor memory isn’t about perfect performance. It’s about predictable errors and predictable successes. As long as the errors are stable from day to day, the brain says, ‘Let’s just lock this memory in.’”

Ganguly and his team found that the “locking in” process involves some surprisingly complex communication between different parts of the brain and takes place during the deep restorative slumber known as non-REM sleep.

Sleep is important because our conscious brains tend to focus on the failures, said Ganguly, who previously identified the sleep-associated brain waves that influence skill retention.

“During sleep, the brain is able to sift through all the instances it’s taken in and bring forward the patterns that were successful,” he said.

It was once thought that learning motor skills only required the motor cortex. But in recent years a more complex picture has emerged.

To look into this process more closely, Ganguly set rats on a task to reach for pellets. Then, the team looked at their brain activity in three regions during NREM sleep: the hippocampus, which is the region responsible for memory and navigation, the motor cortex and the prefrontal cortex (PFC).

Over the course of 13 days, a pattern emerged.

First, in a process called “fast learning,” the PFC coordinated with the hippocampus, likely enabling the animal to perceive its motion with respect to the space around it and its location in that space. In this phase, the brain seemed to be exploring and comparing all the actions and patterns created while practicing the task.

Second, in a process called slow learning, the PFC appeared to make value judgements, likely driven by reward centers that were activated when the task was successful. It engaged in crosstalk with the motor cortex and the hippocampus, turning down the signals related to failures and turning up the ones related to successes.

Finally, as the electrical activity of the regions became synchronized, the role of the hippocampus diminished and the instances the brain had noted as rewarding came to the fore, where they were stored in what we call “motor memory.”

Changes in performance inversely correlated with increase in PFC–M1 SO coupling. a, Flow chart of reach-to-grasp task training experiment. b, Examples of the broadband (0.1–500 Hz) and the filtered local-field potential (LFP) trace in M1 for SOs (0.1–4 Hz) and in hippocampus (HPC) for SWRs (150–250 Hz) during sleep. SOs and SWRs are marked by grey and blue boxes, respectively. Horizontal dashed lines indicate the threshold detecting SOs up-/down-states and SWRs onset. c, Schematic showing measurement of temporal coupling of M1 SOs from PFC SOs, that is, PFC–M1 SO coupling. d, Time courses of PFC–M1 SO coupling. Lines represent piecewise linear regression fits. Piecewise linear regression fits are shown with dashed lines for the fits in a single animal (n = 6 animals) and with the solid line using all six animals. In each animal, scale of minimum-to-maximum was normalized to range from 0 to 1; same as f (details in Methods). e, Comparison of linear slopes across three periods (n = 6 animals); one-way analysis of variance (ANOVA), F12,15 = 33.39, P = 3.0 × 10−6; post hoc two-sided paired t-test, corrected for multiple comparison, days 1–5 versus days 6–7: P = 4.8 × 10−3, days 6–7 versus days 8–13: P = 2.6 × 10−3. Mean ± s.e.m. f, Time courses of changes in success rate (based on 2 d history; Extended Data Fig. 2e). Piecewise linear regression fits are shown with dashed lines for the fits in a single animal (n = 6 animals) and with the solid line using all six animals. Inset: linear slopes comparison (n = 6 animals); two-sided paired t-test, t5 = −10.93, P = 1.1 × 10−4. Mean ± s.e.m. g, Relationship between changes in success rate and PFC–M1 SO coupling. Across six rats, PFC–M1 SO coupling was well predicted by changes in success rate using a linear regression fit. Norm., normalized.

While the rats were initially learning the task, their brain signals were noisy and disorganized. As time went on, Ganguly could see the signals synchronizing, until the rats were succeeding about 70 percent of the time. After that point, the brain seemed to ignore mistakes and maintained the motor memory as long as the level of success was stable. In other words, the brain starts to expect a certain level of error and does not update the motor memory.

Just like NBA players, the rats mastered a skill based on a mental model of how the world works, which they created from their physical experience with gravity, space and other cues. But this kind of motor learning wouldn’t easily transfer to a situation where the cues and physical environment were different.

“If all that changed, for example, if Steph Curry was in the world of Avatar, he might not look as skilled initially,” Ganguly said.

What if Curry hurt a finger and had to learn to shoot baskets a little differently? The study offered an answer.

“It’s possible to unlearn a task, but to do that, you have to stress the situation to a point where you’re making mistakes,” Ganguly said.

When the researchers made a slight change to the rats’ pellet procurement task, the rats would make more mistakes and the researchers saw more noise in the rats’ brain activity.

The change was small enough that the rats didn’t have to go all the way back to the beginning of their learning, only to the “breaking point,” and relearn the task from there.

But because motor memory gets ingrained as a set of motions that follow each other in time, Ganguly said, changing motor memory in a complex motion like free throwing a basketball might require changing a motion that is used to initiate the whole sequence.

If Curry usually bounces a basketball twice before he throws, Ganguly said, “It might be best to retrain the brain by bouncing it only once, or three times. That way, you’d start with a clean slate.”

Relation Between Smoking Status and Subjective Cognitive Decline in Middle Age and Older Adults: A Cross-Sectional Analysis of 2019 Behavioral Risk Factor Surveillance System Data

by Jenna I. Rajczyk, Amy Ferketich, Jeffrey J. Wing in Journal of Alzheimer’s Disease

Middle-aged smokers are far more likely to report having memory loss and confusion than nonsmokers, and the likelihood of cognitive decline is lower for those who have quit, even recently, a new study has found.

The research from The Ohio State University is the first to examine the relationship between smoking and cognitive decline using a one-question self-assessment asking people if they’ve experienced worsening or more frequent memory loss and/or confusion.

The findings build on previous research that established relationships between smoking and Alzheimer’s Disease and other forms of dementia, and could point to an opportunity to identify signs of trouble earlier in life, said Jenna Rajczyk, lead author of the study, which appears in the Journal of Alzheimer’s Disease.

It’s also one more piece of evidence that quitting smoking is good not just for respiratory and cardiovascular reasons — but to preserve neurological health, said Rajczyk, a PhD student in Ohio State’s College of Public Health, and senior author Jeffrey Wing, assistant professor of epidemiology.

“The association we saw was most significant in the 45–59 age group, suggesting that quitting at that stage of life may have a benefit for cognitive health,” Wing said. A similar difference wasn’t found in the oldest group in the study, which could mean that quitting earlier affords people greater benefits, he said.

Data for the study came from the national 2019 Behavioral Risk Factor Surveillance System

Survey and allowed the research team to compare subjective cognitive decline (SCD) measures for current smokers, recent former smokers, and those who had quit years earlier. The analysis included 136,018 people 45 and older, and about 11% reported SCD.

The prevalence of SCD among smokers in the study was almost 1.9 times that of nonsmokers. The prevalence among those who had quit less than 10 years ago was 1.5 times that of nonsmokers. Those who quit more than a decade before the survey had an SCD prevalence just slightly above the nonsmoking group.

“These findings could imply that the time since smoking cessation does matter, and may be linked to cognitive outcomes,” Rajczyk said.

The simplicity of SCD, a relatively new measure, could lend itself to wider applications, she said.

“This is a simple assessment that could be easily done routinely, and at younger ages than we typically start to see cognitive declines that rise to the level of a diagnosis of Alzheimer’s Disease or dementia,” Rajczyk said. “It’s not an intensive battery of questions. It’s more a personal reflection of your cognitive status to determine if you’re feeling like you’re not as sharp as you once were.”

Many people don’t have access to more in-depth screenings, or to specialists — making the potential applications for measuring SCD even greater, she said.

Wing said it’s important to note that these self-reported experiences don’t amount to a diagnosis, nor do they confirm independently that a person is experiencing decline out of the normal aging process. But, he said, they could be a low-cost, simple tool to consider employing more broadly.

Investigating cognitive neuroscience theories of human intelligence: A connectome‐based predictive modeling approach

by Evan D. Anderson, Aron K. Barbey in Human Brain Mapping

Scientists have labored for decades to understand how brain structure and functional connectivity drive intelligence. 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.

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.”

A biological understanding of these cognitive abilities requires “characterizing how individual differences in intelligence and problem-solving ability relate to the underlying architecture and neural mechanisms of brain networks,” Anderson said.

Historically, theories of intelligence focused on localized brain regions such as the prefrontal cortex, which plays a key role in cognitive processes such as planning, problem-solving and decision-making. More recent theories emphasize specific brain networks, while others examine how different networks overlap and interact with one another, Barbey said. He and Anderson tested these established theories against their own “network neuroscience theory,” which posits that intelligence emerges from the global architecture of the brain, including both strong and weak connections.

“Strong connections involve highly connected hubs of information-processing that are established when we learn about the world and become adept at solving familiar problems,” Anderson said. “Weak connections have fewer neural linkages but enable flexibility and adaptive problem-solving.” Together, these connections “provide the network architecture that is necessary for solving the diverse problems we encounter in life.”

To test their ideas, the team recruited a demographically diverse pool of 297 undergraduate students, first asking each participant to undergo a comprehensive battery of tests designed to measure problem-solving skills and adaptability in various contexts. These and similarly diverse tests are routinely used to measure general intelligence, Barbey said.

The researchers next collected resting-state functional MRI scans of each participant.

“One of the really interesting properties of the human brain is how it embodies a rich constellation of networks that are active even when we are at rest,” Barbey said. “These networks create the biological infrastructure of the mind and are thought to be intrinsic properties of the brain.”

These include the frontoparietal network, which enables cognitive control and goal-directed decision-making; the dorsal attention network, which aids in visual and spatial awareness; and the salience network, which directs attention to the most relevant stimuli. Previous studies have shown that the activity of these and other networks when a person is awake but not engaged in a task or paying attention to external events “reliably predicts our cognitive skills and abilities,” Barbey said.

With the cognitive tests and fMRI data, the researchers were able to evaluate which theories best predicted how participants performed on the intelligence tests.

“We can systematically investigate how well a theory predicts general intelligence based on the connectivity of brain regions or networks that theory entails,” Anderson said. “This approach allowed us to directly compare evidence for the neuroscience predictions made by current theories.”

The researchers found that taking into account the features of the whole brain produced the most accurate predictions of a person’s problem-solving aptitude and adaptability. This held true even when accounting for the number of brain regions included in the analysis.

The other theories also were predictive of intelligence, the researchers said, but the network neuroscience theory outperformed those limited to localized brain regions or networks in a number of respects.

The findings reveal that “global information processing” in the brain is fundamental to how well an individual overcomes cognitive challenges, Barbey said.

“Rather than originate from a specific region or network, intelligence appears to emerge from the global architecture of the brain and to reflect the efficiency and flexibility of systemwide network function,” he said.

A neuromarker for drug and food craving distinguishes drug users from non-users

by Leonie Koban, Tor D. Wager, Hedy Kober in Nature Neuroscience

Craving is known to be a key factor in substance use disorders and can increase the likelihood of future drug use or relapse. Yet its neural basis — or, how the brain gives rise to craving — is not well understood.

In a new study, researchers from Yale, Dartmouth, and the French National Centre for Scientific Research (CNRS) have identified a stable brain pattern, or neuromarker, for drug and food craving.

The discovery may be an important step toward understanding the brain basis of craving, addiction as a brain disorder, and how to better treat addiction in the future, researchers say. Importantly, this neuromarker may also be used to differentiate drug users from non-users, making it not only a neuromarker for craving, but also a potential neuromarker that may one day be used in diagnosis of substance use disorders.

For many diseases there are biological markers that doctors can use to diagnose and treat patients. To diagnose diabetes, for example, physicians test a blood marker called A1C.

“One benefit of having a stable biological indicator for a disease is that you can then give the test to any person and say that they do or do not have that disease,” said Hedy Kober, an associate professor of psychiatry at Yale School of Medicine and an author of the study. “And we don’t have that for psychopathology and certainly not for addiction.”

To determine if such a marker could be established for craving, Kober and her colleagues — Leonie Koban from CRNS and Tor Wager from Dartmouth College — used a machine learning algorithm. Their idea was that if many individuals experiencing similar levels of craving share a pattern of brain activity, then a machine learning algorithm might be able to detect that pattern and use it to predict craving levels based on brain images.

For the study, they used functional magnetic resonance imaging (fMRI) data — which offer insight into brain activity — and self-reported assessments of craving from 99 people to train and test the machine learning algorithm. The fMRI data was collected while the individuals — who identified themselves as either drug users or non-users — viewed images of drugs and highly palatable food. The participants then rated how strongly they craved the items they saw.

The algorithm identified a pattern of brain activity that could be used to predict the intensity of drug and food craving from fMRI images alone, the researchers said. The pattern they observed — which they dubbed “Neurobiological Craving Signature (NCS)” — includes activity in several brain areas, some of which previous studies have linked to substance use and craving. However, the NCS also provides a new level of detail, showing how neural activity within subregions of these brain areas can predict craving.

“It gives us a really granular understanding of how these regions interact with and predict the subjective experience of craving,” said Kober.

The NCS also revealed that brain responses to both drug and food cues were similar, suggesting that drug craving arises from the same neural systems that generate food craving. Importantly, the marker was able to differentiate drug users from non-users based on their brain responses to drug cues, but not to food cues.

“And these findings are not specific to one substance because we included participants who used cocaine, alcohol, and cigarettes, and the NCS predicts craving across all of them,” said Kober. “So, it’s really a biomarker for craving and addiction. There’s something common across all of these substance use disorders that is captured in a moment of craving.”

Wager also points out that emotional and motivational processes that might seem similar actually involve different brain pathways and can be measured in different ways.

“What we’re seeing here is likely not a general signature for ‘reward,’” he said, “but something more selective for craving food and drugs.”

In addition, the NCS also offers a novel brain target to better understand how food and drug craving might be influenced by context or by emotional states.

“For example,” said Koban, “we can use the NCS in future studies to measure how stress or negative emotions increase the urge to use drugs or to indulge in our favorite chocolate.”

Kober notes that while the NCS is promising, it needs further validation and is not yet ready for clinical use. That is likely a few years down the road. Now, she — along with her team and collaborators — are working to understand this network of brain regions more deeply and see if the NCS can predict how those with substance use disorders will respond to treatment.

That, she said, would make this neuromarker a powerful tool for informing treatment strategies.

“Our hope,” said Kober, “is that the brain, and specifically the NCS as a stable biological indicator, might allow us to not only to identify who has a substance use disorder and to understand the variance in people’s outcomes, but also who will respond to particular treatments.”

Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy

by Nicola Masala, Martin Pofahl, André N Haubrich, Khondker Ushna Sameen Islam, Negar Nikbakht, Maryam Pasdarnavab, Kirsten Bohmbach, Kunihiko Araki, Fateme Kamali, Christian Henneberger, Kurtulus Golcuk, Laura A Ewell, Sandra Blaess, Tony Kelly, Heinz Beck in Brain

Suppose you go to visit an acquaintance you have not been to see in a long time. Nevertheless, you ring the correct doorbell without hesitation: The apple tree in the front yard with the wooden birdhouse next to it, the bright red painted fence, the clinkered facade — all these signals that you are in the right place.

Each place has numerous characteristics that distinguish it and make it unmistakable as a whole. In order to remember a place, we therefore need to store the combination of these features (this can also include sounds or smells). Because only then can we confidently recognize it when we visit it again, and tell it apart from similar places.

It is possible that this retention of the exact combination of features is impaired in people with chronic epilepsy. At least the findings of the current study point in this direction.

“In the study, we looked at neurons in the hippocampus of mice,” explains neuroscientist Dr. Nicola Masala of the Institute of Experimental Epileptology and Cognitive Sciences at the University Hospital Bonn.

The hippocampus is a region in the brain that plays a central role in memory processes. This is especially true for spatial memory: “In the hippocampus there are so-called place cells,” Masala says. “These help us remember places we have visited.” There are about one million different place cells in the mouse hippocampus. And each responds to a combination of specific environmental characteristics. So, to put it simply, there is also a place cell for “apple tree/birdhouse/fence.”

But how is it ensured that the place cell only responds to a combination of these three features? This is ensured by a mechanism known as “dendritic integration.” Because place cells have long extensions, the dendrites. These are dotted with numerous contact points where the information that the senses convey to us about a place is received (de facto, there are often hundreds or thousands of them). These contacts are called synapses. When signals arrive at many neighboring synapses at the same time, a strong voltage pulse may form in the dendrite — a so-called dendritic spike.

In this way, the dendrite integrates different types of location information. Only when they all come together it may generate a spike. And only then is this combination stored, so that we recognize the house of our acquaintance the next time we visit it.

“In mice with epilepsy, however, this process is impaired,” explains Prof. Dr. Heinz Beck, in whose research group Dr. Masala did her doctorate and who is also speaker of the Transdisciplinary Research Area “Life and Health” at the University of Bonn. “In them, the spikes already occur when only a few synapses are stimulated. Nor does the stimulation have to occur at exactly the same time.” One might say: The place cells of the sick rodents do not look so carefully. They fire at all the houses with an apple tree in the front yard. As a result, the information stored is less specific. “We were able to show in our experiments that the affected animals had significantly greater problems distinguishing familiar places from unfamiliar ones,” Masala points out.

But what is the reason for this? For a spike to form, large amounts of electrically charged particles (the ions) must flow into the cell. For this purpose, pores open in the membrane that surrounds the dendrite — the ion channels.

“In our lab animals, a special channel for sodium ions was significantly more prevalent than normal in the dendrite membrane,” Dr. Tony Kelly of the Institute of Experimental Epileptology and Cognitive Sciences, who co-supervised the study, explains. “This means that just a few poorly synchronized stimuli at the synapses are enough to open many channels and elicit a spike.”

There are inhibitors that very specifically block the affected channel, preventing the influx of sodium ions.

“We administered such a substance to the animals,” Masala says. “This normalized the firing behavior of their dendrites. They were also better able to remember places they had visited.”

The study thus provides insight into the processes involved in memory retrieval. In addition, in the medium term it gives rise to hopes of producing new drugs that can be used to improve the memory of epilepsy patients. These promising results are also the result of fruitful cooperation, Masala emphasizes:

“Without the collaboration especially with the laboratories of Prof. Dr. Sandra Blaess, Prof. Dr. Laura Ewell and Prof. Dr. Christian Henneberger at the University of Bonn, this success would not have been possible.”

Enhancing learning and retention with distinctive virtual reality environments and mental context reinstatement

by Joey Ka-Yee Essoe, Nicco Reggente, Ai Aileen Ohno, Younji Hera Baek, John Dell’Italia, Jesse Rissman in npj Science of Learning

A new study by UCLA psychologists reveals that when VR is used to teach language, context and realism matter.

a Encoding tasks in VR-based contexts across Days 1 and 2. a1, In an underwater practice context, participants learnt VR navigation and received tasks instructions from “the teacher.” a2, Task Practice (under experimenter supervision). a3, Context A Encoding. In each of Context A’s nine named “rooms”, participants stood on a location marker and performed two clock-wise rotations (720°), while imagining themselves as tourists who forgot their camera, trying to remember what it felt like to be there. a4, Language 1 Encoding. Participants remained in Context A to encode Language 1 (Rounds 1–3, 40 words per round). a5, Context B Encoding. a6, Language 2 Encoding (Rounds 1–3). All participants experienced the same procedures except for the context in which Language 2 was encoded. Single-context participants returned to Context A to encode Language 2, while dual-context participants remained in Context B to encode Language 2. On Day 2 participants performed Rounds 4 of Language 1 and Language 2 Encoding. b Day 2: short-delay recall (T4). After a short delay, participants were tested outside of the VR contexts, in the laboratory or MRI scanner. In each of 80 trials, participants first mentally reinstated an auditorily cued room from one context before recalling the foreign translation of a cued word. In congruent reinstatement trials, the mentally reinstated room was the learning context of the cued word. In incongruent reinstatement trials, the mentally reinstated room was in the opposite context. c Day 8: one-week-delayed recall (T5). Participants were telephoned, ostensibly for an interview; experimenters then cued recall for all 80 foreign words. Image attribution: The VR environments and content depicted here were created by J.K.-Y.E or by Forde Davidson as commissioned by the research team, or were from the OpenSim community shared under the Creative Commons 0 License. The image of the telephone and computer monitor were modified from public domain images, and the image of the MRI scanner was provided by the UCLA Brain Mapping Center.

“The context in which we learn things can help us remember them better,” said Jesse Rissman, the paper’s corresponding author and a UCLA associate professor of psychology. “We wanted to know if learning foreign languages in virtual reality environments could improve recall, especially when there was the potential for two sets of words to interfere with each other.”

Researchers asked 48 English-speaking participants to try to learn 80 words in two phonetically similar African languages, Swahili and Chinyanja, as they navigated virtual reality settings.

Wearing VR headsets, participants explored one of two environments — a fantasy fairyland or a science fiction landscape — where they could click to learn the Swahili or Chinyanja names for the objects they encountered. Some participants learned both languages in the same VR environment; others learned one language in each environment.

Participants navigated through the virtual worlds four times over the course of two days, saying the translations aloud each time. One week later, the researchers followed up with a pop quiz to see how well the participants remembered what they had learned.

The results were striking: Subjects who had learned each language in its own unique context mixed up fewer words and were able to recall 92% of the words they had learned. In contrast, participants who had learned both sets of words in the same VR context were more likely to confuse terms between the two languages and retained only 76% of the words.

The study is particularly timely because so many K-12 schools, colleges and universities moved to develop online learning platforms during the COVID-19 pandemic.

“Apps like Zoom provide a rather bland context for learning,” Rissman said. “As VR technology becomes more ubiquitous and affordable, remote learners could be instantly teleported into unique and richly featured contexts for each class.”

The experiment was designed by Rissman and Joey Ka-Yee Essoe, the study’s first author who was a UCLA doctoral student at the time.

Rissman said a key predictor of the subjects’ ability to retain what they had learned was how immersed in the VR world they felt. The less a participant felt like a subject in a psychology experiment — and the more “at one” they felt with their avatar — the more the virtual contexts were able to positively affect their learning.

“The more a person’s brain was able to reconstruct the unique activity pattern associated with the learning context, the better able they were to recall the foreign words they had learned there,” Rissman said.

Psychologists have long understood that people tend to recall things more readily if they can remember something about the surrounding context in which they learned it — the so-called “context crutch” phenomenon. But when information is tied to contextual cues, people can have trouble recalling it later in the absence of those cues.

For example, students might learn Spanish in the same kind of classroom where they learn other subjects. When that happens, their Spanish vocabulary can be tied to the same contextual cues that are tied to other material they’ve been taught, like the Pythagorean theorem or a Shakespeare play. Not only does that similar context make it easier to mix up or forget what they have learned, but it also can make it harder to remember any of the information outside of a classroom setting.

“A key takeaway is that if you learn the same thing in same environment, you’ll learn it really fast,” said Essoe, who is now a postdoctoral scholar at Johns Hopkins University. “But even though you learn fast, you might have trouble with recall. What we were able to harness in this research takes advantage of both learning fast and improving recall in new environment.”

To understand the brain mechanisms that support context-dependent learning, the researchers recruited a separate group of participants and scanned their brains with functional magnetic resonance imaging, or fMRI. As the subjects attempted to recall foreign words while in the scanner, their brain activity indicated that they were thinking about the context in which they had learned each word.

That finding suggests that virtual reality can enhance learning if it is convincingly produced and if different languages or scholastic subjects are taught in highly distinctive environments.

Rissman said although the study only assessed how people learned a foreign language, the results indicate that VR could be useful for teaching other subjects as well. Similar approaches could also be used for mental and behavioral health therapies and to help patients adhere to doctors’ instructions after medical visits: Patients might be able to remember such guidance better if they’re in their own homes while chatting online with their doctors, for example.

Said Essoe: “Variable contexts can ground information in more environmental cues.”

De novo methylation of histone H3K23 by the methyltransferases EHMT1/GLP and EHMT2/G9a

by David A. Vinson, Kimberly E. Stephens, Robert N. O’Meally, Shri Bhat, Blair C. R. Dancy, Robert N. Cole, Srinivasan Yegnasubramanian, Sean D. Taverna in Epigenetics & Chromatin

After an intrepid, decade-long search, Johns Hopkins Medicine scientists say they have found a new role for a pair of enzymes that regulate genome function and, when missing or mutated, are linked to diseases such as brain tumors, blood cancers and Kleefstra syndrome — a rare genetic, neurocognitive disorder.

The new findings, published in Epigenetics & Chromatin, could eventually help scientists understand diseases caused by disruption of these enzymes and develop new treatments for them.

“Developing a better understanding of how enzymes impact the activity of our genomes offers valuable insights into biology and can help researchers design new therapeutic approaches for disease,” says Sean Taverna, Ph.D., associate professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine.

The search began more than a decade ago, when Taverna was looking for factors that influence DNA activity in Tetrahymena thermophila — a one-celled, fresh water dwelling organism. During the original study, the research team found a previously unknown signal that the single-celled creature uses to “mark” genes it has turned off.

The location of the mark is on histone proteins, which act as spools that tightly wind DNA, often turning off genes and protecting DNA from damage. If Tetrahymena are not able to add the marks — a process called methylation, which adds chemical tags to a part of histones called H3K23 — the DNA becomes damaged and the cells grow poorly.

In a follow up study published in 2016, Taverna found that the H3K23 location is conserved between Tetrahymena and mammals, including humans. However, the enzymes that control how the chemical tags are placed on H3K23 differ between the species.

Without the identity of these enzymatic H3K23 “writers” of methylation, the researchers found it difficult to study H3K23’s role in human biology and disease.

So, Taverna, recent Ph.D. graduate David Vinson and Srinivasan Yegnasubramanian, M.D., Ph.D., professor of oncology and pathology at the Johns Hopkins Kimmel Cancer Center, led a new study to search for the mammalian enzymes that add the chemical tags to H3K23.

After screening many enzymes that write methylation, Vinson found just one pair of enzymes, EHMT1/GLP and EHMT2/G9a, which placed chemical tags on the H3K23 histone location.

When the researchers used drug inhibitors and genetic mutations directed against the enzyme pair in human brain cells (neurons) grown in the laboratory, the ability of the enzymes to place methylation tags on the H3K23 histone location reduced significantly.

EHMT1/GLP and EHMT2/G9a can de novo methylate histone H3K9 and H3K23 in vitro. A Recombinant histone H3.1 was incubated with SAM and either recombinant EHMT1/GLP or EHMT2/G9a for 24 h, and these in vitro HMT reactions were subjected to western blotting to detect the abundance of various H3K9 and H3K23 methylation states. B Mass spectrometry was used to validate the presence of specific methylation states catalyzed by EHMT1/GLP or EHMT2/G9a in the in vitro HMT assays. Representative spectra for H3K23me3 in the EHMT1/GLP HMT reactions and H3K23me2 in the EHMT2/G9a reactions are shown in panel B. Please also see Additional file 1: Fig. S1, which contains ions and mass error tables that correspond to this spectra, and contains spectra of additional methylation states detected in the in vitro HMT assays.

“With this initial precedent established in human neuronal cells, the door is now wide open to study the role of these enzymes and the H3K23 modification in numerous contexts of health and disease, including human cancer,” says Yegnasubramanian.

Now that the researchers know that EHMT1/GLP and EHMT2/G9a place chemical tags on the H3K23 histone location, they are aiming to understand the precise mechanism of how they do so and develop drugs that target this activity.

“We want to better understand why diseases occur when these enzymes aren’t working correctly, and what their connections are to H3K23,” says Taverna.

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