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Using human brain organoids, an international team of researchers, led by scientists at University of California San Diego School of Medicine and Sanford Consortium, has shown how the SARS-CoV-2 virus that causes COVID-19 infects cortical neurons and specifically destroys their synapses — the connections between brain cells that allow them to communicate with each other.
The findings, published in the November 3, 2022 issue of PLOS Biology, also report that the antiviral drug sofosbuvir, already an approved treatment for hepatitis C, effectively inhibited SARS-CoV-2 replication and reversed neuronal alterations in infected brain organoids.
“Vaccines and emerging treatments have reduced the health consequences of COVID-19 in most patients,” said senior study author Alysson R. Muotri, PhD, professor in departments of Pediatrics and Cellular and Molecular at UC San Diego School of Medicine. “But the phenomenon of Long COVID, characterized by persisting symptoms that include neurological impairment, remains poorly understood and without any specific remedy.
“This work helps explain some of the neurological symptoms of COVID-19 and, more importantly, it suggests that an FDA-approved antiviral drug might be repurposed to restore infected brain cells to health and address long-term neurological outcomes of COVID-19.”
Though primarily considered to be a respiratory disease, COVID-19 can cause temporary or long-lasting neurological symptoms in some patients, ranging from loss of taste and smell, impaired concentration (brain fog), and psychological effects such as depression to stroke, epilepsy, and encephalopathy (a change in brain function or structure).
With evidence accumulating that the SARS-CoV-2 virus can infect and alter brain cells (including in developing fetuses), the research team focused on using organoids — self-organizing, three-dimensional tissues derived from cultured stem cells that can mimic some organ functions.
Researchers exposed the brain organoids to SARS-CoV-2, observed viral infection and replication and noted that the virus rapidly decreased the number of excitatory synapses in neurons within seven days post-infection. Excitatory synapses increase the firing action potential of a neuron, while their counterparts, called inhibitory synapses, decrease that potential.
However, when infected organoids were treated with sofosbuvir, viral replication was inhibited, and observed neurological impairments rescued or restored. The findings echo earlier computational models that suggested sofosbuvir could be a treatment and previous research by Muotri and colleagues that found sofosbuvir effectively protected and rescued neural cells infected by the Zika virus.
“The bottom line is that sofosbuvir appears to have the potential to arrest or prevent the development of neurological symptoms in COVID-19 patients,” Muotri said. “And because it has been shown to present no safety concerns in pregnant women, it might also be an option for preventing SARS-CoV-2 transmission to their unborn children.
“Further studies and clinical trials are needed, of course, but these findings offer a path forward for treating a condition (Long COVID) that has so far stymied remedy for millions of people wordwide.”
Co-authors include: Pinar Mesci, Janaina S. de Souza, Angela Macia, Aurian Saleh, Cedric Snethlage, Jason W. Adams, Angels Almenar-Queralt, Ryan A. Szeto, Gabriela Goldberg and Patrick T. Bruck, all at UC San Diego and Rady Children’s Hospital-San Diego; Laura Martin-Sancho, Yuan Pu and Sumit K. Chandra, Sanford Burnham Prebys Medical Discovery Institute; Simoni H. Avansini and Fabio Papes, UC San Diego and University of Campinas, Brazil; and Roberto H. Herai, Pontificia Universidade Catolica do Parana, Brazil and Lico Kaesemodel Institute, Brazil.

A longstanding question in neuroscience is how mammalian brains (including ours) adapt to external environments, information, and experiences. In a paradigm-shifting study published in Nature, researchers at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and Baylor College of Medicine have discovered the mechanistic steps underlying a new type of synaptic plasticity called behavioral timescale synaptic plasticity (BTSP). The study, led by Dr. Jeffrey Magee, professor at Baylor, who is also a Howard Hughes Medical Institute, and Duncan NRI investigator, reveals how the entorhinal cortex (EC) sends instructive signals to the hippocampus — the brain region critical for spatial navigation, memory encoding, and consolidation — and directs it to specifically re-organize the location and activity of a specific subset of its neurons to achieve altered behavior in response to its changing environment and spatial cues.
Neurons communicate with one another by transmitting electrical signals or chemicals through junctions called synapses. Synaptic plasticity refers to the adaptive ability of these neuronal connections to become stronger or weaker over time, as a direct response to changes in their external environment. This adaptive ability of our neurons to respond quickly and accurately to external cues is critical for our survival and growth and forms the neurochemical foundation for learning and memory.
An animal’s brain activity and behavior adapt quickly in response to spatial changes
To identify the mechanism that underlies the mammalian brain’s capacity for adaptive learning, a postdoctoral fellow in the Magee lab and lead author of the study, Dr. Christine Grienberger, measured the activity of a specific group of place cells, which are specialized hippocampal neurons that build and update ‘maps’ of external environments. She attached a powerful microscope to the brains of these mice and measured the activity of these cells as the mice were running on a linear track treadmill.
In the initial phase, the mice were acclimated to this experimental setup and the position of the reward (sugar water) was altered at each lap. “In this phase, the mice ran continuously at the same speed while licking the track continuously. This meant the place cells in these mice formed a uniform tiling pattern,” said Dr. Grienberger who is currently an assistant professor at Brandeis University.
In the next phase, she fixed the reward at a specific location on the track along with a few visual cues to orient the mice and measured the activity of the same group of neurons. “I saw that changing the reward location altered the behavior of these animals. The mice now slowed down briefly before the reward site to taste the sugar water. And more interestingly, this change in behavior was accompanied by increased density and activity of place cells around the reward site. This indicated that changes in spatial cues can lead to adaptive reorganization and activity of hippocampal neurons,” Dr. Grienberger added.

Scientists at the UNC School of Medicineand UNC Eshelman School of Pharmacy, in collaboration with a team from Queen Mary University of London, have illuminated the molecular events underlying an inherited movement and neurodegenerative disorder known as ARSACS — Autosomal recessive spastic ataxia of Charlevoix-Saguenay, named for two Quebec valleys where the first cases were found.
Children with ARSACS typically display difficulties with walking in the second year of life and an expanding array of neurological problems thereafter. In the cerebellum — an area of the brain which coordinates movement and balance — neurons called Purkinje cells die in individuals with ARSACS. Most patients are wheelchair-bound by their 30s-40s, and have a shortened lifespan averaging in the mid-50s.
The disorder is caused by the mutation and functional loss of a gene called SACS that encodes a very large protein called sacsin, which has been hard to study directly in part because of its unwieldy size. Relatively little has been known about its normal functions, and how its absence leads to disease. But in a study published in Cell Reports, the collaborating researchers performed the most comprehensive analysis of what happens in cells when sacsin is missing.
“We tried to take an unbiased approach to understand what goes wrong when cells lose sacsin. Our results suggest that the death of Purkinje cells in ARSACS may possibly result from changes in neuronal connectivity and synaptic structure,” said study co-senior author Justin Wolter, PhD, a postdoctoral researcher at the UNC Neuroscience Center.
The other co-senior author of the study was Paul Chapple, PhD, a professor of molecular cell biology at Queen Mary University of London.
The study began with Chapple lab and the UNC-Chapel Hill team working without knowledge of the other. “This project was started by Tammy Havener in the UNC Eshelman School of Pharmacy, then three postdoctoral researchers from different UNC departments jumped on board — Wen Aw, Katherine Hixson, and myself,” Wolter said. “When we realized that Lisa Romano in the Chapple lab had made similar discoveries using different approaches we all decided to join forces and move forward together. I think it’s a beautiful example of how open science and collaboration pays off for the community.”
For this study, the researchers used several -omics based techniques in cultured human cells to examine how the loss of sacsin changes protein levels and cellular organization. They confirmed the presence of defects that had been noted in prior studies, such as the abnormal aggregation of filament-forming structural proteins, and defects in the numbers and dynamics of mitochondria, both of which are frequently observed in many neurodegenerative diseases.
But they also found many abnormalities that hadn’t been identified before. These included the overabundance of a protein called tau and altered dynamics of microtubules, which are intracellular transport tracks regulated by tau. The researchers found that the consequence of this change in trafficking was that many proteins did not get to the proper location in the cell. Particularly affected were “synaptic adhesion” proteins, which help neurons form and maintain synapses — connections neurons use to send signals to each other. In line with these observations, the team found changes in synaptic structure in the ARSACS mouse model. Importantly, these changes occur before the onset of neurodegeneration.
These discoveries expand the picture of how sacsin regulates multiple cellular processes. They also suggest the possibility that Purkinje cells — the neurons that seem most affected in ARSACS — might die because they lack connections with other neurons. The researchers will follow up with more in-depth studies of these changes in the brain to understand whether or not this neurodegenerative disease is rooted in processes that unfold during brain development.
Although ARSACS affects probably only a few thousand individuals worldwide, this kind of research could have much broader implications, the researchers noted.
“There appear to be multiple overlaps between ARSACS and other brain disorders,” Chapple said. “We showed for example that there’s disruption of tau biology in cells lacking sacsin, and of course abnormalities in tau are also a well-known feature of Alzheimer’s disease. So we think studying this rare neurological condition could provide insights into much more common ones.”
“Much work remains to be done to understand the mechanisms by which synaptic connectivity is affected and whether it is contributing to neuronal death,” Wolter said. “But, if it is, it could inform future therapeutic approaches.”

Maternal consumption of a Western-style diet alters the transcriptional landscape of fetal blood stem cells in rhesus macaques, researchers report November 3rd in the journal Stem Cell Reports.
“This discovery is the first demonstration in primates that maternal unhealthy diet and obesity disrupt the immune system in the developing fetus,” says Oleg Varlamov of the Oregon National Primate Research Center. “The main implication of this study is that maternal obesity may influence the development of the fetal bone marrow and fetal immune system.”
Pre-pregnancy obesity is associated with an increased risk of infection and aberrant inflammatory responses in the offspring, but the underlying mechanisms remain largely unknown. In particular, very little is known about the effect of a Western-style diet on fetal hematopoiesis — the formation of blood cellular components — in animal models that resemble human development.
During late development, the fetal bone marrow becomes the major site where immune cells called macrophages and B-lymphocytes are produced via differentiation of hematopoietic stem and progenitor cells (HSPCs). In the new study, Varlamov and his collaborators analyzed the transcriptional landscape of fetal bone marrow HSPCs at single-cell resolution in fetal macaques exposed to a maternal high-fat, Western-style diet or a low-fat control diet.
“We were motivated to investigate how maternal obesity impacts the fetal immune system during pregnancy in nonhuman primates, representing the most relevant animal model for studying human development,” Varlamov says.
The results demonstrated that a Western-style diet induced a hyperinflammatory response in HSPCs and fetal macrophages and suppressed the expression of B-cell development genes. Moreover, the unhealthy diet led to poor engraftment of fetal HSPCs in immunodeficient mice.
“Maternal obesity greatly impacted the ability of fetal blood stem cells to produce B-lymphocytes — immune cells that make antibodies in response to infection — and made fetal blood stem cells more inflamed,” Varlamov says.
Study limitations included the small sample size, which might limit the ability to detect weaker effects of maternal diet on fetal outcomes. In addition, the researchers didn’t explore the effects of maternal obesity on postnatal development and only focused on prenatal development. Further studies are also needed to test whether maternal obesity disrupts offspring responses to infection and inflammation.
“This study sets the stage for understanding the link between maternal obesity, prenatal nutrition, and diseases involving immune progeny of the HSPC compartment in children and highlights the need to better understand the susceptibility of the developing hematopoietic system to metabolic dysregulation over the lifetime,” Varlamov says.
This study was supported by the National Institutes of Health.
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When neurons involved in movement — called motor neurons — form, they must build connections that reach from the brain, brainstem, or spinal cord all the way to the head, arms, or the tips of the toes. How neurons navigate these systems and “decide” where and how to grow has largely been a mystery.
Now, a new collaborative study between Salk Institute scientists and colleagues at the San Raffaele Scientific Institute in Italy show how blood vessel genes play a critical role in motor neuron development by telling blood vessels to get out of the way.
The findings, published October 7, 2022 in the journal Neuron, provide a new understanding of how a “push-pull” relationship with blood vessels — in which growing neurons both attract blood vessels to them while also pushing them out of the way — guides the growth and development of motor neurons and, potentially, a wide variety of cell types throughout the body. The discovery also has implications for understanding diseases in which motor neuron connections are destroyed, such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy (SMA).
“This discovery reveals a set of molecular and cellular interactions that had not been understood before,” says co-corresponding author Samuel Pfaff, professor in the Gene Expression Laboratory and holder of the Benjamin H. Lewis Chair at Salk. “Our discovery of how these genes regulate blood vessel growth and neuron development has implications that range from understanding how other brain circuits form to even understanding how cancer cells interact with their environment.”
Motor neuron connections are formed during fetal development. This process of wiring the nervous system is exquisitely precise, with cells making trillions of connections that reach throughout the body. And yet the genetic process that directs this development is still poorly understood.
Prior research has focused on the role of specific genes directly related to motor neurons and how they grow. But for this study, scientists took a bigger-picture approach, looking at genes both within and outside of the nervous system.

SARS-CoV-2 continues to circulate among us. Although some governments have moved on, a new study published today in the journal Nature says that specific efforts and resources are still required to save lives. This is one of six main themes for action identified by a large panel of experts from different disciplines and over 100 countries to recommend actions to end COVID-19 as a public health threat. Worldwide, over 180 organizations from 72 countries have already endorsed the findings of the consensus study, which was led by the Barcelona Institute for Global Health (ISGlobal), an institution supported by “la Caixa” Foundation.
As of October 2022, more than 630 million COVID-19 cases and over 6.5 million deaths were reported (although the real death toll has been estimated to be upwards of 20 million). In addition, millions of patients with cancer and chronic disease have experienced dangerous healthcare delays, and Long COVID continues to elude definitive treatment, posing an ongoing threat to survivors. In addition, the virus also continues to accumulate mutations that can make it better at evading previous immunity. This is why many public health leaders, including the authors of this study, continue to regard COVID-19 as a persistent and dangerous global health threat.
Despite notable scientific and medical advances, the world’s response to COVID-19 has been hindered by broader political, social, and behavioural factors such as false information, vaccine hesitancy, inconsistent global coordination, and the inequitable distribution of equipment, vaccines and treatments. “Each country has responded differently, and often inadequately, which is partly due to a serious lack of coordination and clear goals,” says Jeffrey V Lazarus, head of the Health Systems Research Group and co-director of the Viral and Bacterial Infections Programme at ISGlobal, Associate Professor at the University of Barcelona, and coordinator of the study.
To develop global consensus on how to address these issues going forward, Lazarus and colleagues carried out a Delphi study, a well-established research methodology that challenges experts to garner consensus on answers to complex research questions. A multidisciplinary panel of 386 academic, health, NGO, government and other experts from 112 countries and territories took part in three rounds of structured consultation. The result is a set of 41 statements and 57 recommendations across six major areas: communication; health systems; vaccination; prevention; treatment and care; and inequities.
Three of the highest-ranked recommendations are: i) adopt a whole-of-society strategy that involves multiple disciplines, sectors and actors to avoid fragmented efforts; ii) whole-of-government approaches (e.g. coordination between ministries) to identify, review, and address resilience in health systems and make them more responsive to people’s needs; and iii) maintain a vaccines-plus approach, which includes a combination of COVID-19 vaccination, other structural and behavioural prevention measures, treatment, and financial support measures. The panellists also prioritised recommendations for developing technologies (vaccines, therapies and services) that can reach target populations.
Other recommendations with at least 99% agreement were: communicating effectively with the public, rebuilding public trust, and engaging communities in managing the pandemic response.
Only six recommendations had more than 5% disagreement, including that which considers further economic incentives to address vaccine hesitancy or a symptoms approach to diagnose COVID-19 in settings with low access to testing.
The 57 recommendations are directed at governments, health systems, industry, and other key stakeholders. “To the greatest degree possible, our results place emphasis on health and social policy recommendations that can be implemented in months, not years, to help bring this public health threat to an end,” says Quique Bassat, ICREA professor at ISGlobal, co-author of the study and member of the University of Barcelona.
“Our study does echo some earlier recommendations, such as the Independent Panel for Pandemic Preparedness and Response and WHO’s 2022 plan on Strategic Preparedness,” says Lazarus, “but what makes this work unique is the very large number of experts consulted, the wide geographical representation, and the study design, which emphasises consensus building and identifies areas of disagreement. It may prove to be a model for developing responses to future global health emergencies.”

West syndrome, the most prevalent type of syndromic epileptic encephalopathy affecting infants, is a devastating and often fatal condition. It is characterized by a triad of symptoms — seizures/spasms, a signature brain activity between seizure events, and intellectual disabilities. Researchers in the laboratory of Dr. John Swann, professor at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, have provided the first demonstration of a progressive increase in epileptic spasms along with learning and memory deficits in an animal model of this disorder. In addition, the study published in Epilepsia, establishes this as an ‘ideal’ model to identify the underlying molecular mechanisms and to discover targeted therapies for this condition.
IS animals have a progressive increase in seizure duration
In 2008, members of Dr Swann’s lab and their collaborators infused tetrodotoxin (TTX) — a sodium channel blocker — into the neocortex of rats to model human infantile spasms (IS). Since then, this method has been used extensively to study this condition.
To evaluate how seizure activity progresses in the IS rodent model, researchers in the Swann lab performed continuous long-term electroencephalogram (EEG) recordings of the brain of these rats for almost two months. “Although these studies were labor-intensive and time-consuming, they gave us unexpected critical insights into how epileptic spasms evolve over time,” Dr. Swann said. “We noticed that the duration of the seizure events increased over this time course and then plateaued. However, unlike other epileptic syndromes (e.g., temporal lobe epilepsy), the frequency of the spasms did not change.
IS animals exhibit learning and memory deficits
Cognitive and behavioral impairments are common in children suffering from seizure disorders. In syndromic epileptic encephalopathies, developmental delays and intellectual disabilities are profound. A review of 67 studies found only 16% of patients with West syndrome have normal intellectual development. However, the cause behind this cognitive decline has remained a mystery.
Over last few decades, several factors like brain abnormalities, injury, infections, genetic mutations, have been attributed to contribute in varying degrees to the cognitive decline in IS patients. However, recurrent seizures are among the most common etiology shared by a majority of these patients. In fact, parents of these infants often report regression or stagnation of intellectual and behavioral skills following seizures. The growing consensus among experts is frequent seizures/spasms and the unique disruptive brain activity (termed hypsarrhythmia) that continues in between seizure events may be the major contributors to the cognitive decline seen in these patients.
To test this hypothesis, the Swann team performed several learning and memory tests such as object recognition, object location, and Matching to Place Water Maze test (which measures working memory i.e., the cognitive skill that allows a person to leverage newly acquired skill or knowledge to solve a problem) on the same animals that had undergone continuous video recordings. “We found a significant reduction in learning and memory skills in all three tests in these animals,” Swann said. “These findings point towards a likely association between seizure progression and cognitive decline in this model of epileptic spasms and underscore the critical importance of early diagnosis and intervention in IS infants.”
Others involved in the study were John T. Le, Carlos Ballester-Rosado, and James D. Frost. They are affiliated with the Cain Foundations Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, and Baylor College of Medicine. This study was funded by grants from the National Institutes of Health, CURE Epilepsy’s Infantile Spasms Initiative, and the National Institute of Health’s Intellectual Developmental Disabilities Research Centers.
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Some genetic variants may put people at risk of autoimmune diseases while conferring protection against the outcome of viral infection. A study publishing November 3 in the open access journal PLOS Genetics by David Morris and Timothy Vyse at King’s College London, UK and colleagues suggests that genetic predisposition for systemic lupus erythematosus (SLE) may be protective against severe COVID-19 infection.
Scientists have observed a correlation between the genes associated with severe COVID-19 and those with SLE. In order to locate associated genes and gain insight into the shared genetic effects, researchers compared the genetics of severe COVID-19 with those of SLE using multiple analyses, including an approach that can focus on specific areas of the genome. The authors then accessed data on genes and the structure of the genome obtained from several biomedical databases to understand the biology of the shared genetics.
The researchers found that TYK2, a gene associated with both SLE and severe COVID-19 provides protection against viral infection, but increases risk for autoimmune disease. Future studies will be needed to fully understand the genetic relationships between COVID-19 and other diseases. The study has its limitations, such as the overrepresentation of European ancestry in the datasets used to perform the analyses.
According to the authors, “Our results indicate that there are shared genetic effects between the autoimmune disease SLE and the clinical consequences of COVID-19. The locus with the most evidence of shared association (TYK2) is involved in interferon production, a process that is important in response to viral infection and known to be dysregulated in SLE patients. In seeking to uncover the mechanisms underlying these relationships it was apparent that the functional effects of the risk and protective genotypes are complex.”
Dr. David Morris and Professor Timothy Vyse, who led the study, add that “this is an exciting result made possible by the large genetic studies in COVID-19 and Lupus, and opens the door to our understanding of how the biology of the immune system is calibrated to protect us against infection from viruses and other infectious agents, but at the risk of developing autoimmune disease.”
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A new treatment for neurological and psychiatric diseases, that works by reducing the excitability of overactive brain cells, has been developed by UCL researchers.
Many brain diseases, such as epilepsy, are caused by excessive activity of a small number of brain cells. These conditions often don’t respond well to drug treatment, mainly because drugs affect the whole brain.
Whilst genetic therapies could be a promising way to treat these conditions, current methods do not distinguish between overactive and normal brain cells.
However, the new treatment, outlined in Science and tested in mice, uses a technique that only alters overactive cells and spares those that are acting normally.
Corresponding author, Dr Gabriele Lignani (UCL Queen Square Institute of Neurology), said: “We invented a gene therapy that switches on only in overactive cells, and switches itself off if activity returns to normal.
“We harnessed the ability of certain DNA sequences to control gene expression in response to metabolic signals. By re-directing this activity-sensing mechanism to drive the production of molecules that stop brain cells from firing, we showed that epileptic seizures can be suppressed.”
To create the gene therapy, the team screened several genes known to ‘switch on’ in response to stimulation, and coupled their promoters (DNA sequences that determine whether the DNA is copied to RNA) to potassium channels chosen for their ability to reduce the firing of nerve cells. The promoter-potassium channel combinations were tested both in mice and in miniature brain-like structures grown in dishes — which were created using skin-derived human stem cells.

Scientists at Scripps Research have uncovered a critical feature that a promising new class of cancer drugs, known as CELMoDs, needs to be effective.
CELMoDs are designed to attack cancer in a novel way, by binding to a regulatory protein called cereblon, which then triggers the degradation of key cancer-driving proteins. In the study, reported on November 3 in Science, researchers discovered that these drugs, in order to work, need to cause a critical shape-change in cereblon when they bind to it. The finding enables researchers to reliably design effective CELMoDs.
“There are a lot of research groups that have spent considerable time making drugs that bind very tightly to cereblon, but have then scratched their heads in puzzlement that these drugs fail to work,” says study senior author Gabriel Lander, PhD, professor in the Department of Integrative Structural and Computational Biology at Scripps Research.
The study’s first author was Randy Watson, PhD, a postdoctoral researcher in the Lander lab.
Cereblon works as part of a major protein-disposal system in cells. This system tags targeted proteins with molecules called ubiquitin, which mark the proteins for destruction by roving protein-breaking complexes known as proteasomes. The ubiquitin-proteasome system is used not only to destroy abnormal or damaged proteins, but also to help regulate the levels of some normal proteins. Cereblon is one of hundreds of “adaptors” used by the ubiquitin-proteasome system to guide the ubiquitin-tagging process towards specific sets of target proteins.
Scientists now recognize that some cancer drugs, including the best-selling myeloma drug lenalidomide (Revlimid), happen to work by binding to cereblon. They do so in a way that forces the ubiquitin-tagging, and consequent destruction, of key proteins that promote cell division — proteins that couldn’t be targeted easily with traditional drugs. Inspired in part by that recognition, drug companies have begun developing cereblon-binding drugs — CELMoDs, also called protein-degradation drugs — that will work even better against myeloma and other cancers.