A 47-year-old man presented to the hospital with a 2-day history of weakness and fever. His blood pressure was 64/47 mm Hg, heart rate 110 beats per minute, and temperature 39.0°C. On physical examination, the patient had swelling and redness of the left thigh, which aroused concern about the presence of an abscess. Laboratory studies showed pancytopenia and extreme elevation of the d-dimer level. Promyelocytic blast cells with intracellular Auer rods — needle-shaped cytoplasmic structures specific for myeloid neoplasms — were seen on a peripheral-blood smear. Owing to concern about acute promyelocytic leukemia and sepsis, the patient was admitted to the intensive care unit. Induction chemotherapy with all-trans retinoic acid and prednisolone was initiated. A bone marrow biopsy showed promyelocytes with abundant intracellular Auer rods in formations that resembled bundles of sticks (arrows). Genetic analysis for chromosomal translocation identified a PML–RARA fusion gene. A diagnosis of acute promyelocytic leukemia was confirmed. Two days after the start of treatment, differentiation syndrome developed. The hospital course was further complicated by the presence of disseminated intravascular coagulation and Staphylococcus aureus bacteremia with leg abscesses. After molecular complete remission had been attained, consolidation chemotherapy that included arsenic trioxide was administered. On hospital day 72, the patient was discharged.
A 57-year-old woman with a history of depression and insomnia presented to the emergency department with a 3-day history of shortness of breath and dizziness. The physical examination was notable for pallor. Laboratory studies showed a hemoglobin level of 4.4 g per deciliter (reference range, 11.6 to 15.5), an elevated reticulocyte count, an elevated lactate dehydrogenase level, and a low haptoglobin level. The results of hemoglobin electrophoresis and glucose-6-phosphate dehydrogenase testing were normal, and methemoglobin and direct antiglobulin tests were negative. A peripheral-blood smear (Panel A, Giemsa staining) showed poikilocytosis, nucleated red cells (black arrows), and polychromatic cells (white arrows). The findings were also consistent with oxidative hemolysis, including the presence of bite cells (Panel A, red arrows), blister cells (Panel A, asterisks), and erythrocyte inclusions (Panel B, Giemsa staining). The erythrocyte inclusions were identified as Heinz bodies on the basis of positive staining with methyl violet (Panel C). Blood transfusions were administered. After a prolonged toxicologic investigation that involved multiple readmissions over the course of the next 7 months, the patient eventually reported having taken 10 times the recommended daily dose of zopiclone (a nonbenzodiazepine hypnotic) every night to treat insomnia since 1 month before the first presentation. Urine drug testing was positive for zopiclone. A diagnosis of drug-induced oxidative hemolysis was made. The patient was counseled to cease zopiclone use and was referred to psychiatry for treatment.
Summary: A new study aims to examine the role of napping in brain development among infants and preschoolers. By tracking changes in the hippocampus, the research aims to prove how critical naps are for memory retention and brain growth in young children.
These longitudinal studies could set new standards for nap policies in educational settings, benefiting both neurotypical and neurodiverse children. Insights from this research will provide valuable guidelines for parents and educators on the importance of napping in early childhood.
Key Facts:
Focus on the Hippocampus: The studies investigate the hippocampus’s role during nap transitions, highlighting its significance in short-term memory and overall brain development.
Longitudinal Approach: Unlike previous cross-sectional studies, these projects will observe the same children over time to better understand the developmental milestones associated with napping.
Practical Applications: Findings from the studies are expected to influence nap policies in preschool environments and offer actionable insights for parents of young children.
Source: UMass
A University of Massachusetts Amherst sleep scientist, funded with $6.7 million in grants from the National Institutes of Health (NIH), has launched two unprecedented studies that will track over time the brain development of infants and preschoolers to confirm the role of napping in early life and to identify the bioregulatory mechanisms involved.
Rebecca Spencer, a professor of psychological and brain sciences who is well-known for her groundbreaking research into napping, is testing her theories about what’s happening in the hippocampus–the short-term memory area of the brain–as babies and young children undergo nap transitions.
Naps allow children with an immature hippocampus to process memories. Credit: Neuroscience News
This new research is expected to become the gold standard of scientific evidence that emphasizes the importance of healthy sleep for young children as their brains develop.
The findings will help inform nap policies for preschool and pre-kindergarten and be useful to teachers and parents of both neurotypical and neurodiverse children.
“The work we’ve been doing has always pointed to this interaction of sleep and brain development,” says Spencer, who carries out research in her Somneurolab at UMass Amherst.
“We think that kids get ready to transition out of naps when the brain is big enough to hold all the information of the day until night-time sleep.”
The study involving preschoolers is a collaboration between Spencer at UMass Amherst; Tracy Riggins, a developmental psychologist specializing in memory development at the University of Maryland; and Gregory Hancock, a UMD professor of human development and quantitative methodology.
Previous research by Spencer and Riggins showed differences in the hippocampus of kids who nap compared to those who have transitioned out of naps.
“So far, we’ve used cross-sectional approaches,” says Spencer, referring to research that analyzes data at one point in time, as opposed to longitudinal studies that involve repeated observation over time.
“We really need to show longitudinally within a child that the point when they transition out of naps is predicted by a transition in the development of their hippocampus.”
The hippocampus is the short-term location for memories before they move to the cortex for long-term storage. Naps allow children with an immature hippocampus to process memories.
Young children give up their afternoon nap, not based on their age, but their brain development, Spencer hypothesizes.
“Naps are beneficial to everybody. Naps protect memory for everybody, no matter what age. Kids who are habitual nappers really need the nap. If they don’t nap, they get catastrophic forgetting.
“That’s the difference between habitual and non-habitual nappers – not how good is the nap, but how bad is staying awake,” Spencer explains.
Adds Riggins, “In the end, being able to tell parents that those little deviations from routine that keep their children from napping might not have these huge implications for a neurotypical child in the long run would be great.
“And, the more we know about how the brain works in a typically developing child during this nap transition, the more we will be able to know about where we could possibly intervene to help neurodiverse children–like children with autism and ADHD, whose sleep patterns tend to be disrupted–since we will have some sort of scientific basis.”
The research team is recruiting 180 children, ages 3 to 5 years. The researchers will track their brain development, memory performance and nap status over the course of one year at three checkpoints.
During the first and second sessions, the children will wear activity-tracking watches and EEG equipment to record naps and overnight sleep. They will also play memory games before and after naps. The children will undergo an MRI brain scan during the third session.
Monica and David Dumlao, of Chicopee, Mass., signed up their son Miles, 4, for the preschool study after watching the Netflix documentary series, “Babies,” which featured Spencer in the episode about sleep.
“We like learning about the neuroscience behind brain development,” Monica Dumlao said at a recent study session in Spencer’s lab.
“We thought this was a good opportunity to contribute to the science about the importance of naps.”
In the three-part infant study on nap transitions and memory, Spencer is studying the period before and after babies transition from two naps–one in the morning and one in the afternoon–to one, richer afternoon nap.
She is recruiting 140 infants 7 to 9 months old. The babies will play a memory game before and after their naps. Their brain activity will be recorded during their naps using a noninvasive electrode cap. The sessions will take place at 9, 12 and 15 months.
“We think as they are getting ready to drop the morning nap, staying awake in that morning interval will be less and less damaging to their memory,” Spencer says.
“But we don’t think that’s going to happen with the afternoon nap at this age. We think the afternoon nap stays superimportant.”
Summary: Vitamin D enhances a type of gut bacteria in mice, improving their immunity to cancer. The study shows that mice with higher levels of vitamin D resist tumor growth better and respond more effectively to immunotherapy.
This effect seems linked to the increase of Bacteroides fragilis in the gut, which somehow enhances the mice’s immune response to cancer. Further research is needed to see if this applies to humans, as earlier studies suggest a potential link between vitamin D levels and cancer risk.
Key Facts:
Vitamin D Role: Mice fed with vitamin D exhibited increased levels of Bacteroides fragilis, which helped them resist cancer better.
Human Implications: Preliminary data analysis from 1.5 million people in Denmark hints at a correlation between low vitamin D levels and higher cancer risk.
Future Research: Understanding how vitamin D can be utilized to boost the beneficial gut microbiome could open new pathways for cancer treatment and prevention.
Source: Francis Crick Institute
Researchers at the Francis Crick Institute, the National Cancer Institute (NCI) of the U.S. National Institutes of Health (NIH) and Aalborg University in Denmark, have found that vitamin D encourages the growth of a type of gut bacteria in mice which improves immunity to cancer.
Reported today in Science, the researchers found that mice given a diet rich in vitamin D had better immune resistance to experimentally transplanted cancers and improved responses to immunotherapy treatment.
This effect was also seen when gene editing was used to remove a protein that binds to vitamin D in the blood and keeps it away from tissues.
Surprisingly, the team found that vitamin D acts on epithelial cells in the intestine, which in turn increase the amount of a bacteria called Bacteroides fragilis. This microbe gave mice better immunity to cancer as the transplanted tumours didn’t grow as much, but the researchers are not yet sure how.
To test if the bacteria alone could give better cancer immunity, mice on a normal diet were given Bacteroides fragilis. These mice were also better able to resist tumour growth but not when the mice were placed on a vitamin D-deficient diet.
Previous studies have proposed a link between vitamin D deficiency and cancer risk in humans, although the evidence hasn’t been conclusive.
To investigate this, the researchers analysed a dataset from 1.5 million people in Denmark, which highlighted a link between lower vitamin D levels and a higher risk of cancer.
A separate analysis of a cancer patient population also suggested that people with higher vitamin D levels were more likely to respond well to immune-based cancer treatments.
Although Bacteroides fragilis is also found in the microbiome in humans, more research is needed to understand whether vitamin D helps provide some immune resistance to cancer through the same mechanism.
Caetano Reis e Sousa, head of the Immunobiology Laboratory at the Crick, and senior author, said: “What we’ve shown here came as a surprise – vitamin D can regulate the gut microbiome to favour a type of bacteria which gives mice better immunity to cancer.
“This could one day be important for cancer treatment in humans, but we don’t know how and why vitamin D has this effect via the microbiome. More work is needed before we can conclusively say that correcting a vitamin D deficiency has benefits for cancer prevention or treatment.”
Evangelos Giampazolias, former postdoctoral researcher at the Crick, and now Group Leader of the Cancer Immunosurveillance Group at the Cancer Research UK Manchester Institute, said: “Pinpointing the factors that distinguish a ‘good’ from a ‘bad’ microbiome is a major challenge. We found that vitamin D helps gut bacteria to elicit cancer immunity improving the response to immunotherapy in mice.
“A key question we are currently trying to answer is how exactly vitamin D supports a ‘good’ microbiome. If we can answer this, we might uncover new ways in which the microbiome influences the immune system, potentially offering exciting possibilities in preventing or treating cancer.”
Romina Goldszmid, Stadtman Investigator in NCI’s Center For Cancer Research, said: “These findings contribute to the growing body of knowledge on the role of microbiota in cancer immunity and the potential of dietary interventions to fine-tune this relationship for improved patient outcomes.
“However, further research is warranted to fully understand the underlying mechanisms and how they can be harnessed to develop personalized treatment strategies.”
This research was funded by Cancer Research UK, the UK Medical Research Council, the Wellcome Trust, an ERC Advanced Investigator grant, a Wellcome Investigator Award, a prize from the Louis-Jeantet Foundation, the Intramural Research Program of the NCI, part of the National Institutes of Health, CCR-NCI and the Danish National Research Foundation.
Research Information Manager at Cancer Research UK, Dr Nisharnthi Duggan said: “We know that vitamin D deficiency can cause health problems, however, there isn’t enough evidence to link vitamin D levels to cancer risk.
This early-stage research in mice, coupled with an analysis of Danish population data, seeks to address the evidence gap. While the findings suggest a possible link between vitamin D and immune responses to cancer, further research is needed to confirm this.
“A bit of sunlight can help our bodies make vitamin D but you don’t need to sunbathe to boost this process. Most people in the UK can make enough vitamin D by spending short periods of time in the summer sun.
“We can also get vitamin D from our diet and supplements. We know that staying safe in the sun can reduce the risk of cancer, so make sure to seek shade, cover up and apply sunscreen when the sun is strong.”
Abstract
Vitamin D regulates microbiome-dependent cancer immunity
A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies.
Similarly, in humans, vitamin D–induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival.
In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity.
Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer.
Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.
A retrospective evaluation of I-SPY2 clinical trial data indicates that in appropriately selected patients with breast cancer, sentinel lymph node surgery with adjuvant radiation may provide appropriate oncologic control without the routine use of axillary dissection. Judy C. Boughey, MD, of the Mayo Clinic, Rochester, Minnesota, and colleagues presented their results during the 2024 Society of Surgical Oncology (SSO) Annual Meeting (Abstract 3). Although follow-up in the I-SPY2 cohort thus far is fairly short (median, 3.5 years), they found that compared with selective use of sentinel lymph node surgery alone after neoadjuvant chemotherapy, axillary dissection did not improve axillary recurrence, locoregional recurrence, distant recurrence, or event-free survival—even in patients with node-positive disease.
They evaluated the outcomes of patients—those who did and did not have residual nodal disease—who underwent axillary surgery after neoadjuvant chemotherapy between 2011 and 2022. Axillary surgery was classified as sentinel lymph node surgery alone or as axillary dissection (with or without sentinel lymph node surgery).
Slightly more than 1,500 patients were included: 714 (47.1%) had clinically node-negative disease at diagnosis, of whom 104 (14.6%) had pathologically node-positive disease; 801 (52.9%) had clinically node-positive disease at diagnosis, of whom 396 (49.4%) had pathologically node-positive disease. Sentinel lymph node surgery alone was performed in 805 of 1,015 (79.3%) patients with pathologically node-negative disease and in 126 of 500 patients (25.2%) with pathologically node-positive disease.
Dr. Boughey and co-investigators found that among patients who had pathologically node-negative disease, no significant differences occurred between those who underwent sentinel lymph node surgery alone and those who had axillary dissection in the 5-year estimated rate of axillary recurrence, locoregional recurrence, distant recurrence, and event-free survival. Among patients who had pathologically node-positive disease, there was no difference between sentinel lymph node surgery alone and axillary dissection in the 5-year estimated axillary recurrence or locoregional recurrence.
BACKGROUND: Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known.
METHODS: In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients’ assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment.
RESULTS: A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and -0.013 (95% Bayesian credible interval, -0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration.
CONCLUSIONS: Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages.
Summary: Researchers discovered a critical role for the cytokine XCL1 in fetal brain development and the emotional behavior of offspring, challenging previous assumptions about its low impact due to minimal circulating levels during pregnancy. The study shows that a temporary spike in maternal XCL1 is essential for proper placental development and regulating fear behavior in male offspring.
Disruptions in this cytokine level were linked to increased anxiety and stress reactions due to neuronal abnormalities in the ventral hippocampus. These findings provide new insights into how maternal immune responses during pregnancy might influence psychiatric conditions in children.
Key Facts:
Critical XCL1 Spike: A transient increase in XCL1 during pregnancy is crucial for healthy placental development and managing offspring emotional behavior, particularly fear responses.
Neuronal Impact: Blocking or neutralizing this cytokine spike leads to neuronal abnormalities in the ventral hippocampus and increased anxiety behaviors in male offspring.
Long-Term Effects: Although the immune and neuronal abnormalities observed in offspring normalize by adulthood, the early-life inflammatory state linked to XCL1 deficiency may set the stage for adult anxious behavior.
Source: Weill Cornell University
Researchers at Weill Cornell Medicine have discovered in a preclinical model that cytokines, proteins that control immune response, circulating in maternal blood during pregnancy may mitigate an offspring’s risk for psychiatric conditions.
The findings are surprising because circulating maternal cytokines are at such low levels that they were not implicated in fetal brain development and offspring behavior before.
Dr. Toth will explore other chemokines that may regulate placenta development and impact offspring emotional behavior.
The study published online in Brain, Behavior, and Immunity on Feb. 29, reported that cytokine XCL1 produced by maternal immune cells can function as a pregnancy hormone and is required for the proper development of placenta and male offspring fear behavior.
These results support epidemiological studies which have long suggested a link between human maternal infection and inflammation during pregnancy and offspring developing psychiatric disorders later life.
“Using mouse models, we found that circulating XCL1 normally remained at the same low pre-pregnancy level throughout gestation except for a short rise and fall in the middle period,” said corresponding author Dr. Miklos Toth, professor of pharmacology at Weill Cornell Medicine.
“This temporary rise is essential for the proper development of the placenta and offspring emotional behavior.” First author Dr. Rosa Chen was a graduate student in the Toth lab during the study, which was a collaboration with Dr. Heidi Stuhlmann, acting chair of Biochemistry and also of Cell and Developmental Biology and the Harvey Klein Professor of Biomedical Sciences, Cell and Developmental Biology at Weill Cornell Medicine.
When this spike in XCL1 in maternal blood was blocked genetically or neutralized by anti-XCL1 antibodies, the researchers found increased production of factors associated with tissue damage in the fetal placenta which led to increased innate anxiety and stress reactions in male mouse offspring.
The researchers also found a neuronal abnormality in the developing brains of these offspring, specifically in the ventral hippocampus, a region that has been linked to anxiety and anxious behavior.
The immune and neuronal abnormalities observed when the cytokine spike was blocked were normalized by adulthood, suggesting that the adult anxious behavior of the offspring could be related to the early life proinflammatory state caused by the absence of elevated XCL1.
Dr. Toth will explore other chemokines that may regulate placenta development and impact offspring emotional behavior. The team plans to collaborate with researchers who have access to blood samples from pregnant women to see if the profile of XCL1, a protein also found in humans, corresponds to the observations in mouse models.
Abstract
The chemokine XCL1 functions as a pregnancy hormone to program offspring innate anxiety
Elevated levels of cytokines in maternal circulation increase the offspring’s risk for neuropsychiatric disease.
Because of their low homeostatic levels, circulating maternal cytokines during normal pregnancies have not been considered to play a role in fetal brain development and offspring behavior.
Here we report that the T/NK cell chemotactic cytokine XCL1, a local paracrine immune signal, can function as a pregnancy hormone and is required for the proper development of placenta and male offspring approach-avoidance behavior.
We found that circulating XCL1 levels were at a low pregestational level throughout pregnancy except for a midgestational rise and fall.
Blunted elevation in maternal plasma XCL1 in dams with a genetic 5HT1A receptor deficit or following neutralization by anti-XCL1 antibodies increased the expression of tissue damage associated factors in WT fetal placenta and led to increased innate anxiety and stress reactivity in the WT male offspring.
Therefore, chemokines like XCL1 may act as pregnancy hormones to regulate placenta development and offspring emotional behavior.
Summary: A new study introduces BARseq—a rapid, cost-effective method for mapping brain cells, revealing new insights into how our brains are structured at a cellular level. Researchers used BARseq to classify millions of neurons across multiple mouse brains, discovering unique ‘cellular signatures’ that define each brain region.
The study also highlighted how sensory deprivation, such as loss of sight, can significantly reorganize these neuronal structures, underscoring the importance of sensory experiences in shaping the brain. This new tool not only advances our understanding of brain architecture but also opens up possibilities for exploring brain changes associated with diseases.
Key Facts:
BARseq technology enables rapid and extensive mapping of neurons across the brain, identifying distinct cellular signatures unique to each brain region.
Sensory experiences, particularly vision, play a critical role in maintaining and shaping the distinct cellular identities of different brain areas.
The BARseq method is both more affordable and faster than previous brain mapping technologies, allowing broader accessibility for researchers to conduct advanced brain studies.
Source: Allen Institute
Scientists have long known that our brains are organized into specialized areas, each responsible for distinct tasks. The visual cortex processes what we see, for instance, while the motor cortex governs movement. But howthese regions form—and how their neural building blocks differ—remain a mystery.
A study published today in Nature sheds new light on the brain’s cellular landscape. Researchers at the Allen Institute for Brain Science used an advanced method called BARseq to swiftly classify and map millions of neurons across nine mouse brains.
They discovered that while brain regions share the same types of neurons, the specific combination of these cells gives each area a distinct ‘signature,’ akin to a cellular ID card.
The team further explored how sensory inputs influence these cellular signatures. They discovered that mice deprived of sight experienced a major reorganization of cell types within the visual cortex, which blurred the distinctions with neighboring areas.
These shifts were not confined to the visual area but occurred across half of cortical regions, though to a lesser extent.
The study underscores the pivotal role of sensory experiences in shaping and maintaining each brain region’s unique cellular identity.
“BARseq lets us see with unprecedented precision how sensory inputs affect brain development,” said Xiaoyin Chen, Ph.D., the study’s co-lead author and an Assistant Investigator at the Allen Institute.
“These broad changes illustrate how important vision is in shaping our brains, even at the most basic level.”
A powerful new brain mapping tool
Previously, capturing single-cell data across multiple brains was challenging, said Mara Rue, Ph.D., co-lead author and a Scientist at the Allen Institute. But BARseq is cheaper and less time-consuming than similar mapping technologies, she said, enabling researchers to examine and compare brain-wide molecular architecture across multiple individuals.
BARseq tags individual brain cells with unique RNA ‘barcodes’ to track their connections across the brain. This data, combined with gene expression analysis, allows scientists to pinpoint and identify vast numbers of neurons in tissue slices.
For this study, the researchers used BARseq as a standalone method to rapidly analyze gene expression in intact tissue samples. In just three weeks, the researchers mapped more than 9 million cells from eight brains.
The scale and speed of BARseq provides scientists with a powerful new tool to delve deeper into the intricacies of the brain, Chen said.
“BARseq allows us to move beyond mapping what a ‘model’ or ‘standard’ brain looks like and start to use it as a tool to understand how brains change and vary,” Chen said. “With this throughput, we can now ask these questions in a very systematic way, something unthinkable with other techniques.”
Chen and Rue emphasized that the BARseq method is freely available. They hope their study encourages other researchers to use it to investigate the brain’s organizational principles or zoom in on cell types associated with disease.
“This isn’t something that only the big labs can do,” Rue said. “Our study is a proof of principle that BARseq allows a wide range of people in the field to use spatial transcriptomics to answer their own questions.”
Abstract
Whole-cortex in situ sequencing reveals input-dependent area identity
The cerebral cortex is composed of neuronal types with diverse gene expression that are organized into specialized cortical areas. These areas, each with characteristic cytoarchitecture, connectivity and neuronal activity, are wired into modular networks.
However, it remains unclear whether these spatial organizations are reflected in neuronal transcriptomic signatures and how such signatures are established in development.
Here we used BARseq, a high-throughput in situ sequencing technique, to interrogate the expression of 104 cell-type marker genes in 10.3 million cells, including 4,194,658 cortical neurons over nine mouse forebrain hemispheres, at cellular resolution. De novo clustering of gene expression in single neurons revealed transcriptomic types consistent with previous single-cell RNA sequencing studies. The composition of transcriptomic types is highly predictive of cortical area identity.
Moreover, areas with similar compositions of transcriptomic types, which we defined as cortical modules, overlap with areas that are highly connected, suggesting that the same modular organization is reflected in both transcriptomic signatures and connectivity.
To explore how the transcriptomic profiles of cortical neurons depend on development, we assessed cell-type distributions after neonatal binocular enucleation.
Notably, binocular enucleation caused the shifting of the cell-type compositional profiles of visual areas towards neighbouring cortical areas within the same module, suggesting that peripheral inputs sharpen the distinct transcriptomic identities of areas within cortical modules.
Enabled by the high throughput, low cost and reproducibility of BARseq, our study provides a proof of principle for the use of large-scale in situ sequencing to both reveal brain-wide molecular architecture and understand its development.
Summary: A new study demonstrates how spinal cord injuries can lead to significant metabolic disruptions, including the onset of conditions such as diabetes and heart disease. The study found that abnormal neuronal activities post-injury lead to excessive breakdown of triglycerides in fat tissue, releasing harmful compounds into organs like the liver.
By administering gabapentin, a nerve pain medication, researchers successfully prevented these metabolic effects in animal models. This discovery could pave the way for new treatments that mitigate the secondary health issues caused by spinal injuries.
Key Facts:
The study identifies a link between spinal cord injuries and metabolic dysfunctions due to abnormal neuronal activity affecting fat tissue.
Gabapentin was effective in normalizing metabolic functions in mice by inhibiting problematic neural proteins and preventing the excessive breakdown of fats.
Despite its benefits, gabapentin induced insulin resistance, prompting researchers to adjust dosing strategies to retain therapeutic effects while minimizing side effects.
Source: Ohio State University
Conditions such as diabetes, heart attack and vascular diseases commonly diagnosed in people with spinal cord injuries can be traced to abnormal post-injury neuronal activity that causes abdominal fat tissue compounds to leak and pool in the liver and other organs, a new animal study has found.
After discovering the connection between dysregulated neuron function and the breakdown of triglycerides in fat tissue in mice, researchers found that a short course of the drug gabapentin, commonly prescribed for nerve pain, prevented the damaging metabolic effects of the spinal cord injury.
Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment.
Gabapentin inhibits a neural protein that, after the nervous system is damaged, becomes overactive and causes communication problems – in this case, affecting sensory neurons and the abdominal fat tissue to which they’re sending signals.
“We believe there is maladaptive reorganization of the sensory system that causes the fat to undergo changes, initiating a chain of reactions – triglycerides start breaking down into glycerol and free fatty acids that are released in circulation and taken up by the liver, the heart, the muscles, and accumulating, setting up conditions for insulin resistance,” said senior author Andrea Tedeschi, assistant professor of neuroscience in The Ohio State University College of Medicine.
“Through administration of gabapentin, we were able to normalize metabolic function.”
The study is published today (April 24, 2024) in Cell Reports Medicine.
Previous research has found that cardiometabolic diseases are among the leading causes of death in people who have experienced a spinal cord injury.
These often chronic disorders can be related to dysfunction in visceral white fat (or adipose tissue), which has a complex metabolic role of storing energy and releasing fatty acids as needed for fuel, but also helping keep blood sugar levels at an even keel.
Earlier investigations of these diseases in people with neuronal damage have focused on adipose tissue function and the role of the sympathetic nervous system – nerve activity known for its “fight or flight” response, but also a regulator of adipose tissue that surrounds the abdominal organs.
Instead, Debasish Roy – a postdoctoral researcher in the Tedeschi lab and first author on the paper – decided to focus on sensory neurons in this context. Tedeschi and colleagues have previously shown that a neuronal receptor protein called alpha2delta1 is overexpressed after spinal cord injury, and its increased activation interferes with post-injury function of axons, the long, slender extensions of nerve cell bodies that transmit messages.
In this new work, researchers first observed how sensory neurons connect to adipose tissue under healthy conditions, and created a spinal cord injury mouse model that affected only those neurons – without interrupting the sympathetic nervous system.
Experiments revealed a cascade of abnormal activity within seven days after the injury in neurons – though only in their communication function, not their regrowth or structure – and in visceral fat tissue.
Expression of the alpha2delta1 receptor in sensory neurons increased as they over-secreted a neuropeptide called CGRP, all while communicating through synaptic transmission to the fat tissue – which, in a state of dysregulation, drove up levels of a receptor protein that engaged with the CGRP.
“These are quite rapid changes. As soon as we disrupt sensory processing as a result of spinal cord injury, we see changes in the fat,” Tedeschi said. “A vicious cycle is established – it’s almost like you’re pressing the gas pedal so your car can run out of gas but someone else continues to refill the tank, so it never runs out.”
The result is the spillover of free fatty acids and glycerol from fat tissue, a process called lipolysis, that has gone out of control. Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment.
“The fat is responding to the presence of CGRP, and it’s activating lipolysis,” Tedeschi said. “CGRP is also a potent vasodilator, and we saw increased vascularization of the fat – new blood vessels forming as a result of the spinal cord injury. And the recruitment of monocytes can help set up a chronic pro-inflammatory state.”
Silencing the genes that encode the alpha2delta1 receptor restored the fat tissue to normal function, indicating that gabapentin – which targets alpha2delta1 and its partner, alpha2delta2 – was a good treatment candidate.
Tedeschi’s lab has previously shown in animal studies that gabapentin helped restore limb function after spinal cord injury and boosted functional recovery after stroke.
But in these experiments, Roy discovered something tricky about gabapentin: The drug prevented changes in abdominal fat tissue and lowered CGRP in the blood – and in turn prevented spillover of fatty acids into the liver a month later, establishing normal metabolic conditions. But paradoxically, the mice developed insulin resistance – a known side effect of gabapentin.
The team changed drug delivery tactics, starting with a high dose and tapering off – and stopping after four weeks.
“This way, we were able to normalize metabolism to a condition much more similar to control mice,” Roy said. “This suggests that as we discontinue administration of the drug, we retain beneficial action and prevent spillover of lipids in the liver. That was really exciting.”
Finally, researchers examined how genes known to regulate white fat tissue were affected by targeting alpha2delta1 genetically or with gabapentin, and found both of these interventions after spinal cord injury suppress genes responsible for disrupting metabolic functions.
Tedeschi said the combined findings suggest starting gabapentin treatment early after a spinal cord injury may protect against detrimental conditions involving fat tissue that lead to cardiometabolic disease – and could enable discontinuing the drug while retaining its benefits and lowering the risk for side effects.
Summary: Researchers developed an innovative chemical tool to explore how signals like dopamine and epinephrine interact with neurons via G protein-coupled receptors (GPCRs).
This new tool allows for precise detection of neuromodulators across various brain regions with high spatial resolution. It marks cells with a permanent fluorescent signal, facilitating the study of signal pathways and interactions at a cellular level across the entire brain.
This advancement could significantly enhance our understanding of neuronal signaling and improve targeting GPCRs in drug development.
Key Facts:
The tool enables detailed visualization of GPCR-related signals across the entire brain with high spatial resolution, a balance previously unachievable in neuroscience.
It has been tested on opioids and epinephrine, utilizing both green and red fluorescence to track multiple molecules simultaneously.
While the fluorescence takes several hours to manifest and is not suitable for real-time tracking, the tool provides valuable postmortem insights into neuronal pathways and drug targeting.
Source: University of Michigan
University of Michigan researchers have developed a new tool to better understand how chemicals like dopamine and epinephrine interact with neurons.
These chemicals are among a wide variety of signals that get processed in the brain through G protein-coupled receptors (GPCRs), proteins that sit on the surface of neurons to receive messages—in the forms of proteins, sugars, fats, even light—that inform cellular behavior.
Wang’s lab at LSI uses protein engineering to develop technologies that can detect how signaling molecules travel within the brain to reach and interact with specific neurons.
GPCRs are involved in an enormous number of biological functions, making them a prime target for treating diseases; more than one-third of FDA-approved drugs target GPCRs. But to fully understand how various molecules interact with GPCRs, researchers need to be able to detect those molecules across the whole brain with high spatial resolution.
“The challenge in our field has been achieving the right balance between a detailed view and the whole picture across the brain,” said Wenjing Wang, a neuroscientist at the U-M Life Sciences Institute.
LSI faculty member Peng Li said most existing tools can detect a neural modulator either in a small part of the brain with high spatial resolution or in the whole brain with very low resolution.
“But we need to identify the cells that respond to the neuromodulators across various brain regions, in high resolution,” he said.
In a study published in the Proceedings of the National Academy of Sciences, Wang, Li and colleagues unveiled a new chemical tool that achieves both goals for three chemicals that all target GPCRs.
Wang’s lab at LSI uses protein engineering to develop technologies that can detect how signaling molecules travel within the brain to reach and interact with specific neurons. They previously created a tool to reveal the presence of opioids, another GPCR binding partner, at a cellular level.
When the molecule is detected, the tool creates a permanent fluorescent mark in the cells. Thus, researchers can see the specific cells that are highlighted, as well as the whole picture of cells across the brain.
This latest work broadens the utility of that sensor to detect multiple types of GPCR activators, beyond just opioids. So far, the team has tested the tool with opioids and epinephrine in cultured neurons and in mouse models. The team also expanded the tool to use both green and red fluorescence, enabling the tracking of multiple molecules at once.
“Coming from detecting just opioids, we now have a tool that we can begin to easily modulate for various signals that interact with GPCRs,” said Wang, who also is an assistant professor of chemistry at the U-M College of Literature, Science, and the Arts.
“The goal is eventually to even study the interplays of different signaling pathways simultaneously.”
The team cautions that while the tool provides important visualizations of how signals travel across neurons for analysis postmortem, it cannot be used to track chemicals in real time, as it takes several hours for the fluorescence to appear. But it does offer a new path forward for improving understanding of neuronal signaling and the role of GPCRs as drug targets.
“Ideally, we aim to be able to create a brain map for multiple neuromodulators concurrently, offering a comprehensive understanding of the sites of neuromodulation,” said Li, who also is an assistant professor at the U-M School of Dentistry.
Abstract
Single-chain fluorescent integrators for mapping G-protein-coupled receptor agonists
G protein-coupled receptors (GPCRs) transduce the effects of many neuromodulators including dopamine, serotonin, epinephrine, acetylcholine, and opioids. The localization of synthetic or endogenous GPCR agonists impacts their action on specific neuronal pathways.
In this paper, we show a series of single-protein chain integrator sensors that are highly modular and could potentially be used to determine GPCR agonist localization across the brain.
We previously engineered integrator sensors for the mu- and kappa-opioid receptor agonists called M- and K-Single-chain Protein-based Opioid Transmission Indicator Tool (SPOTIT), respectively.
Here, we engineered red versions of the SPOTIT sensors for multiplexed imaging of GPCR agonists.
We also modified SPOTIT to create an integrator sensor design platform called SPOTIT for all GPCRs (SPOTall). We used the SPOTall platform to engineer sensors for the beta 2-adrenergic receptor (B2AR), the dopamine receptor D1, and the cholinergic receptor muscarinic 2 agonists.
Finally, we demonstrated the application of M-SPOTIT and B2AR-SPOTall in detecting exogenously administered morphine, isoproterenol, and epinephrine in the mouse brain via locally injected viruses.
The SPOTIT and SPOTall sensor design platform has the potential for unbiased agonist detection of many synthetic and endogenous neuromodulators across the brain.
ARYAN'S BLOG 