Tag: Cell

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Basolateral amygdala may play a larger, overarching role during naturalistic events

Study provides insights into how early life events can affect brain wiring patterns

The basolateral amygdala (BLA) is a region of the brain that has been almost exclusively studied in the context of fear and emotion. Only recently have researchers begun to question whether the BLA may play a larger, overarching role in memory and behavior. Yet almost nothing is known about the neuronal activity of the BLA during naturalistic behavior.

To address these questions, neuroscientists at the Sainsbury Wellcome Centre at UCL observed the neuronal activity in this brain region while rats freely engaged with a variety of different ethological stimuli. Interactions with ethological stimuli are relevant to the animal’s survival and to the propagation of its genes, and include food, prey and conspecifics. In a new study, published today in Cell Reports, the researchers demonstrate strong responses to these classes of events in the BLA.

The naturalistic stimuli in this study were important to the animals in their everyday life and the rats were naturally curious to interact with them. They included complex multisensory stimuli like male and female rats, food and a moving toy mouse.

Traditionally, research has focused on studying the BLA in rats during trained tasks. Instead, we wanted to observe neuronal activity while rats were freely behaving to see if we could find an overarching role for the BLA during natural behavior that might tie together the previous lines of research.” 

Cristina Mazuski, Research Fellow in the O’Keefe Lab, Sainsbury Wellcome Centre and lead author on the paper

Using Neuropixels, Mazuski and O’Keefe simultaneously recorded from hundreds of neurons in the rat BLA and correlated single-cell neural activity with complex behavior to identify different classes of cells within the BLA that respond to the ethological stimuli. They identified and described two novel categories of cells in the BLA; event-specific neurons, which responded to only one of the four classes of stimuli, and panresponsive neurons, which responded equally well to most or all of the stimuli.

Strikingly, 1/3 of the cells showed an active memory response: not only did the neural response last throughout the entire event but it continued after the end of the event for many minutes. The authors speculate that these after-responses might be acting as a memory system telling the rest of the brain that an important event had just occurred and perhaps alerting other brain regions to store information about other aspects of the event and the circumstances surrounding it.

Commenting on these aspects of the results, Prof. O’Keefe, the senior author on the paper, said “These findings position the basolateral amygdala at the center of the social/ethological brain and open up a whole research program investigating what other naturally-occurring stimuli the rest of the (normally silent) BLA cells are interested in. They also direct our attention to the memory functions of the amygdala which have not, to date, received sufficient consideration”.

As the researchers were recording from many neurons simultaneously using Neuropixels probes, they were also able to look at the circuit connectivity. By delving into the correlated activity between different single neurons, they could infer the flow of information from more-specific neurons such as those responding to female rats or food to the less-specific panresponsive neurons.

“This initial study opens up a lot of future avenues for research. The next steps are to find out what the responses are sensitive to, how robust they are and confirm whether they play a role in memory,” concluded Cristina.

This research received funding from the European Union’s Horizon 2020 research and innovation program under the Marie-Sklodowska-Curie grant agreement No. 840562 to Cristina Mazuski, the Sainsbury Wellcome Centre Core Grant from the Gatsby Charitable Foundation and Wellcome Trust (090843/F/09/Z), and Wellcome Trust Principal Research Fellowship (Wt203020/z/16/z) to John O’Keefe.

Source:

Sainsbury Wellcome Centre

Journal reference:

Mazuski, C & O’Keefe, J., (2022) Representation of Ethological Events by Basolateral Amygdala Neurons. Cell Reports. doi.org/10.1016/j.celrep.2022.110921.

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Corticosteroid exposure associated with hospitalization for severe pain event among patients with sickle cell disease

Corticosteroid exposure associated with hospitalization for severe pain event among patients with sickle cell disease

People with sickle cell disease (SCD) who were recently prescribed a corticosteroid – a medicine frequently used to treat asthma or inflammation – were found to be significantly more likely to be hospitalized for a severe pain event, according to a paper published today in the journal Blood. The research also found that older adults, women, and people who were not taking the drug hydroxyurea to manage their underlying SCD symptoms were the most likely to be hospitalized.

SCD is the most common inherited red blood cell disorder in the United States, affecting an estimated 100,000 people. According to the Centers for Disease Control and Prevention (CDC), SCD affects one out of every 365 Black or African American births and one out of every 16,300 Hispanic American births. Pain events, also known as vaso-occlusive episodes (VOE), are the most common complications of SCD and can result in intense pain and potentially irreversible organ damage.

Apart from case reports, researchers say this is the first study to systematically evaluate the association between corticosteroid exposure and hospitalization for VOE.

Individuals living with SCD often suffer crippling episodes of pain, which can greatly impair their quality of life. Based on our data, corticosteroids are commonly prescribed for conditions unrelated to their underlying SCD. Vaso-occlusive events and related hospitalization appear to follow corticosteroid prescription fairly quickly. This evidence suggests corticosteroids may be contributing to the events and should be avoided as much as possible in these patients.”


Ondine Walter, MD, Study Author, Toulouse University Hospital in France

Notably, the median time between filling a prescription for a corticosteroid and hospitalization was just five days. Also striking was the fact that nearly half (46%) of patients with SCD had been prescribed at least one systemic corticosteroid during the study period. Dr. Walter said the results underscore the need for widespread education of clinicians and patients alike about the potential risks of using corticosteroids, especially when there isn’t a clear indication to use them.

“Corticosteroids are mostly easy to avoid, and in circumstances when they are necessary, it’s important to start them in collaboration with an SCD expert and to take all appropriate precautionary measures to administer them safely,” said Dr. Walter.

The study used data from a total of 5,151 patients with SCD drawn from the French National Health Insurance Database between 2010 and 2018. Patients had to have at least one hospitalization for VOE to be included, and corticosteroid exposure was identified using outpatient prescribing records.

The study found that those who had exposure to a corticosteroid – defined in the month leading up to the event – were significantly more likely to be hospitalized for VOE. People who were also taking hydroxyurea seem to have less risk of hospitalization compared with those not taking the drug, which may signal a potential protective effect of hydroxyurea on the occurrence of VOE, Dr. Walter explained. Hydroxyurea is often prescribed to reduce the number of pain events caused by SCD as well as the need for blood transfusions. The risk of admission was also lower in men compared to women and in children compared to adults.

“Some factors such as hydroxyurea use, male gender, and younger age were associated with a lower risk of hospitalization for VOE after corticosteroid exposure in our study. Still, based on these results, we still need to think twice about using corticosteroids when treating patients with SCD,” said Dr. Walter.

This study is limited in that it can only show an association between corticosteroids and VOE-related hospitalizations and not prove causation. Because corticosteroid exposure was based on dispensing data, it is also not possible to confirm that patients took the medicine, only that the prescription was filled.

With future research, investigators aim to understand how corticosteroids may prompt VOE. Studies have shown that the cessation of corticosteroids, in particular, has been associated with rebound pain. ASH’s Clinical Practice Guidelines on SCD recommend against using corticosteroids for acute pain management in patients with SCD. This study adds important data about the association of corticosteroid use with subsequent VOE to a growing body of evidence that suggests corticosteroids should be used only when needed, and under the guidance of an SCD expert.

Source:

American Society of Hematology

Journal reference:

Walter, O., et al. (2022) Risk of vaso-occlusive episode after exposure to corticosteroids in patients with sickle cell disease. Blood. doi.org/10.1182/blood.2021014473.

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Study provides insights into how early life events can affect brain wiring patterns

Study provides insights into how early life events can affect brain wiring patterns

Mar 10 2022

A new study of brain development in mice shortly after birth may provide insights into how early life events can affect wiring patterns in the brain that manifest as disease later in life – specifically such disorders as schizophrenia, epilepsy and autism.

Researchers focused on two types of brain cells that have been linked to adult neurological disorders: neurons in a modulating system nestled deep in the brain and other neurons in the cortex, the brain’s outermost layer, that counteract excitation in other cells using inhibitory effects. The modulating cells send long-range cables to the cortex to remotely influence cortical cell activity.

The study is the first to show that these two types of cells communicate very early in brain development. A chemical released from the modulating cells initiates the branching, or arborization, of axons, the long, slender extensions of nerve cell bodies that transmit messages, on the cortical cells – and that arborization dictates how effective the cells in the cortex are at doing their job.

Though there is still a lot to learn about the impact of this cellular interaction in the postnatal brain, the researchers said the study opens the door to a better understanding of how neurological diseases in adults may relate to early-life events.

It’s known that abnormal early-life experiences can impact kids’ future sensation and behavior. This finding may help explain that kind of mechanism.”


Hiroki Taniguchi, associate professor of pathology, The Ohio State University College of Medicine and senior author of the study

“This study provides new insight into brain development and brain pathology. It’s possible that during development, depending on animals’ experiences, this modulating system activity can be changed and, accordingly, the cortical circuit wiring can be changed.”

Taniguchi completed the work with co-authors André Steinecke and McLean Bolton while he was an investigator at the Max Planck Florida Institute for Neuroscience.

The research is published today (March 9, 2022) in the journal Science Advances.

The study involved chandelier cells, a type of inhibitory neurons in the cortical section of the brain, and neurons of the cholinergic system – one of the systems that monitor the environment and the internal state, and send signals to the rest of the brain to trigger memory and appropriate behaviors.

“Both of these types of cells have been separately studied in the context of adult functions or modulations so far. The developmental role of cholinergic neurons in the brain wiring remains poorly understood,” Taniguchi said.

Chandelier cells are named for the spray of signal-transmitting synapses (called synaptic cartridges) at the branch terminals that resemble candles of a traditional chandelier, a pattern that gives them inhibitory control over hundreds of cells at a time.

“These cells have output control,” said Steinecke, first author of the study who is now working at Neuway Pharma in Germany. “Chandelier cells can put a brake on excitatory cells and tell them they’re not ready to fire. As inhibitory cells, chandelier cells are thought to regulate waves of firing – which is important, because the waves contain information that is transmitted over large distances of the brain.”

Previous post-mortem studies have shown that the synaptic terminals located at the end of chandelier cell axons appear to be reduced in the brains of patients with schizophrenia.

“This axonal ‘arbor’ being reduced suggests they don’t make as many connections to downstream targets, and the connections themselves are also altered and don’t work that well,” Steinecke said.

The team used two techniques to observe chandelier cells during early-life brain development in mice: genetically targeting and using a dye to label and detect cells that differentiate into chandelier cells, and transplanting genetically manipulated cells back into animals shortly after birth. “This enabled us to watch brain development as it happens and manipulate conditions to test what the mechanisms are,” Taniguchi said.

The researchers first observed how chandelier cell axons develop their branching structures, noting that small protrusions emerging from axons were the first signs that branches would sprout. And they identified the chemical needed to start that sprouting process – the neurotransmitter acetylcholine, which is released by cholinergic system cells.

The interaction between the distant cell types was confirmed through a series of experiments: Knocking out receptors that bind to acetylcholine and decreasing activity of cholinergic neurons lessened branch development, and making cholinergic neurons more likely to fire led to more widespread branching.

“The key is that we didn’t previously know how neuromodulatory systems regulate the cortical circuits – and both of them have been implicated in brain diseases,” Taniguchi said. “Now that we’ve found that cholinergic neurons could remotely impact cortical circuit development, especially cortical inhibitory signals, the question is what kind of environment or emotional state of change can impact cortical inhibitors’ development? We may want to see if we can find a link as a next step.”

This work was supported by funding from the Max Planck Society and the Brain Behavior and Research Foundation.

Source:

Journal reference:

Steinecke, A., et al. (2022) Neuromodulatory control of inhibitory network arborization in the developing postnatal neocortex. Science Advances. doi.org/10.1126/sciadv.abe7192.

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Apple Event 2022: New Low-End iPhone Expected to Have 5G Service

Apple Event 2022: New Low-End iPhone Expected to Have 5G Service

Apple Inc.


AAPL -0.38%

is bringing 5G cellular connectivity to cheaper iPhones, a move some on Wall Street say will continue to fuel record sales this year as concerns linger over demand for the more-expensive versions.

The Cupertino, Calif., tech giant is slated to reveal the third-generation iPhone SE on Tuesday during a virtual event on the company’s website, starting at 1 p.m. ET. Apple is also expected to unveil an updated iPad Air with a faster processor as well as 5G, and new computers with faster chips, according to a person familiar with the plans.

The iPhone SE was an early pandemic darling for Apple. Sales of the device approached 25 million, or 12% of the company’s estimated global smartphone shipments, in 2020, according to researcher IDC. Apple doesn’t break out results by iPhone model.

The low-end model, which starts at $399 and comes with the smallest display size of 4.7 inches, fared less well in the past year with the arrival of Apple’s flagship products. Those include the iPhone 12 lineup, which introduced ultrafast 5G to the company’s smartphone offerings for the first time and was given a boost with price breaks from carriers eager to get customers onto the new cellular networks.

Sales of the high-end devices helped propel iPhone sales to a record $192 billion in fiscal 2021 and contributed to the year’s record profit of almost $100 billion. At the same time, shipments of the iPhone SE that lacked 5G fell an estimated 40% in 2021 compared with 2020, according to IDC.

“Obviously, some of the phones that Apple has launched have been really expensive, for the mostly mid- to high-end consumer, so now you get an affordable phone with 5G,”

Samik Chatterjee,

an analyst for

J.P. Morgan,

said in an interview.

Mr. Chatterjee raised his earnings estimates for the fiscal year because of expectations for the iPhone lineup, including his faith in the potential of the SE model to appeal to price-conscious buyers looking for 5G. He is forecasting that the SE version could tally 30 million units sold in the first year and help boost overall iPhone shipments to a record of 250 million.

“That’s what will give investors confidence that Apple can continue to grow iPhone revenues,” he said.

Starting in February, U.S. cellular carriers will begin to shut down 3G. WSJ’s Joanna Stern got an old iPhone 3G and iPhone 4 working on the old network, in order to remember all it did to shape the smartphone revolution. Photo illustration: Preston Jessee for The Wall Street Journal

The iPhone 12—and the iterative iPhone 13 versions introduced last fall—helped fuel renewed interest among Chinese consumers. The iPhone’s strength was aided by the collapse of Huawei Technologies Co.’s smartphone business amid sanctions by the U.S. government. The sanctions stripped Huawei of the ability to use

Alphabet Inc.’s


GOOG 0.23%

Android operating system. In the final three months of last year, the iPhone retook the top spot as the bestselling smartphone in China. Mr. Chatterjee said the SE model could benefit from the China dynamics and the country’s interest in 5G phones.

Other analysts seem to be warming to Apple’s potential this year as well. As recently as late last year, the average estimate of analysts surveyed by FactSet predicted flat iPhone sales for the current fiscal year, which ends in September, amid worries that the appeal of the iPhone might have peaked during the year after the big upgrade with 5G technology.

In recent weeks, optimism about the company’s outlook has been growing, aided by stronger-than-expected results for the final three months of last year. Analysts now expect iPhone revenue to rise 5% this fiscal year—after soaring 39% in fiscal 2021.

When the first SE model made its debut in 2016, some analysts said the device could help Apple in markets outside of the U.S. where the iPhone—which can cost more than $1,500—is priced out of reach. Instead, the top three markets for the cheaper device last year were the U.S., Japan and Western Europe, according to IDC.

“‘Some of the phones that Apple has launched have been really expensive, for the mostly mid- to high-end consumer, so now you get an affordable phone with 5G.’”


— Samik Chatterjee, J.P. Morgan analyst

In China, the SE made up less than 10% of shipments, according to Chiew Le Xuan, an analyst at research firm Canalys. He said the phone struggled against budget-oriented Android rivals and expressed skepticism that the new version would do well in China.

“The iPhone SE third generation may seem like a hit in China due to Apple’s increasing market share and 5G penetration,” he said in an email. “However, according to Canalys data, Chinese consumers are inclined towards phones with a larger display.”

In the U.S., the SE has been a gateway to the Apple brand for owners of less-expensive Android phones. Last year, 26% of SE buyers previously had an Android phone, according to Consumer Intelligence Research Partners’ surveys of consumers. “IPhone SE has become a sort of entry-level iPhone, mostly because of its price point,” said

Michael Levin,

Consumer Intelligence Research co-founder.

Apple again might benefit from carriers eager to push its latest phones on customers, according to

Cliff Maldonado,

principal analyst for BayStreet Research, which tracks marketing efforts by the wireless-service providers.

The carriers are eager to move customers from 4G to the new faster networks because it is cheaper for them to deliver the same amount of data. Mr. Maldonado forecasts that carriers will reach about 95% of 5G subscribers in mid-2024. 5G has been aimed at improving connections for games and videos.

“The carriers will be happy to push the SE3 over the previous SE2 at roughly the same $400 price point because the SE3 will allow the carrier to support the phone less expensively on 5G than 4G LTE,” he said.

Write to Tim Higgins at Tim.Higgins@WSJ.com

Copyright ©2022 Dow Jones & Company, Inc. All Rights Reserved. 87990cbe856818d5eddac44c7b1cdeb8

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Study provides new understanding of the earliest molecular events in Type 1 Diabetes pathogenesis

Study provides new understanding of the earliest molecular events in Type 1 Diabetes pathogenesis

For the first time, researchers have revealed that during the development of Type 1 Diabetes (T1D), when insulin-producing cells in the pancreas are under attack from T lymphocytes, the cells lining the pancreatic duct reprogram themselves in an attempt to suppress autoimmune T cell responses. This study is published today in Nature Metabolism.

The first events that occur in a patient heading towards Type 1 Diabetes, the events that trigger autoimmunity, have been difficult for researchers to pin down because of our inability to biopsy the pancreas, and the fact that clinical diagnosis is only made once massive beta cell destruction has occurred. That is why it is so important to develop a better understanding of the earliest molecular events in T1D pathogenesis, so we can uncover more about biomarker identification and disease prevention.”


Golnaz Vahedi, PhD, senior author, associate professor of Genetics and member of the Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania

Autoimmune diseases, which affect as many as 23.5 million Americans, occur when the body’s immune system attacks and destroys healthy organs, tissues and cells. There are more than 80 types of autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, and T1D. In T1D, immune cells called T lymphocytes attack and destroy insulin-secreting pancreatic beta cells and the pancreas stops producing insulin, the hormone that controls blood sugar levels.

“Although it might be an ultimately unsuccessful attempt of the pancreas to limit the adaptive T cell response responsible for destroying beta cells, this finding that the ductal cells are capable of playing this suppressive role towards autoimmune T cell responses is unprecedented,” said co-senior author Klaus Kaestner, PhD, the Thomas and Evelyn Suor Butterworth Professor in Genetics. “Our study shows that these cells, which had never previously been linked to immunity, may change themselves to protect the pancreas.”

Established in 2016, the Human Pancreas Analysis Program (HPAP) is supported by a $28 million grant from the National Institutes of Health with major contributions from Penn, the University of Florida and Vanderbilt University. The HPAP, which is co-directed by Kaestner and Ali Naji MD, PhD, the J. William White Professor of Surgical Research, started collecting pancreatic tissues from hundreds of deceased organ donors diagnosed with T1D. Because many T1D patients harbor beta cell autoantibodies called Glutamic Acid Decarboxylase (GAD) in their bloodstream years before clinical diagnosis, HPAP also collects samples from autoantibody-positive donors, who are at risk for developing T1D but have not received that diagnosis.

“Our study took those quality tissue samples and created high-resolution measurements of millions of cells from patients at various stages of T1D progression, resulting in a single-cell atlas of pancreatic islets,” said co-senior author R. Babak Faryabi, PhD, an assistant professor of Pathology and Laboratory Medicine and a core member of Epigenetics Institute at Penn.

Blood tests to check for levels of GAD are common for patients with, or at risk for, T1D, and doctors use it as a diagnostic tool. Another finding of this study is the new understanding of what is happening on a molecular level in the pancreas and how it correlates to the findings of the GAD test.

“Our study is the first to show that even when a person is not clinically considered to have T1D, high levels detected in their GAD test indicate large-scale transcriptional remodeling of their beta cells,” said Naji, a study co-senior author. “It solidifies to clinicians to closely monitor patients with increasing levels of GAD, as we now know what cellular and molecular changes are in motion in relation to those levels.”

Although researchers do not yet know whether these transcriptional changes are contributing to or are consequences of disease pathogenesis, the discovery of molecular phenotypic changes in pancreatic cells of autoantibody-positive individuals advances the understanding of early pancreatic changes occurring in T1D, and sets the course for continued research in this area.

Source:

University of Pennsylvania School of Medicine

Journal reference:

Fasolino, M., et al. (2022) Single-cell multi-omics analysis of human pancreatic islets reveals novel cellular states in type 1 diabetes. Nature Metabolism. doi.org/10.1038/s42255-022-00531-x.

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Cell stress-related biochemical events may be partly driving Parkinson’s disease

Cell stress-related biochemical events may be partly driving Parkinson's disease

Parkinson’s disease may be driven in part by cell stress-related biochemical events that disrupt a key cellular cleanup system, leading to the spread of harmful protein aggregates in the brain, according to a new study from scientists at Scripps Research.

The discovery, published in The Journal of Neuroscience in February 2022, offers a clear and testable hypothesis about the progression of Parkinson’s disease, and may lead to treatments capable of significantly slowing or even stopping it.

We think our findings about this apparent disease-driving process are important for developing compounds that can specifically inhibit the process of disease spread in the brain.”


Stuart Lipton, MD, PhD, study senior author, Step Family Endowed Chair, founding co-director of the Neurodegeneration New Medicines Center, and professor in the Department of Molecular Medicine at Scripps Research

Parkinson’s disease affects roughly one million people in the United States. Its precise trigger is unknown, but it entails the deaths of neurons in a characteristic sequence through key brain regions. The killing of one small set of dopamine-producing neurons in the midbrain leads to the classic Parkinsonian tremor and other movement impairments. Harm to other brain regions results in various other disease signs including dementia in late stages of Parkinson’s. A closely related syndrome in which dementia occurs early in the disease course is called Lewy Body Dementia (LBD), and affects about 1.4 million people in the U.S.

In both diseases, affected neurons contain abnormal protein aggregations, known as Lewy bodies, whose predominant ingredient is a protein called alpha-synuclein. Prior studies have shown that alpha-synuclein aggregates can spread from neuron to neuron in Parkinson’s and LBD, apparently transmitting the disease process through the brain. But precisely how alpha-synuclein aggregates build up and spread in this way has been unclear.

One clue, uncovered by Lipton’s lab and others in prior research, is that the Parkinson’s/LBD disease process generates highly reactive nitrogen-containing molecules including nitric oxide. In principle, these reactive nitrogen molecules could disrupt important cellular systems, including “housekeeping” systems that normally keep protein aggregates under control.

In the new study, the Scripps Research team demonstrated the validity of this idea by showing that a type of nitrogen-molecule reaction called S-nitrosylation can affect an important cellular protein called p62, triggering the buildup and spread of alpha-synuclein aggregates.

The p62 protein normally assists in autophagy, a waste-management system that helps cells get rid of potentially harmful protein aggregates. The researchers found evidence that in cell and animal models of Parkinson’s, p62 is S-nitrosylated at abnormally high levels in affected neurons. This alteration of p62 inhibits autophagy, causing a buildup of alpha-synuclein aggregates. The buildup of aggregates, in turn, leads to the secretion of the aggregates by affected neurons, and some of these aggregates are taken up by nearby neurons.

“The process we observed seems very similar to what is seen in Parkinson’s and LBD brains,” says study first author Chang-Ki Oh, PhD, a staff scientist in the Lipton laboratory.

The researchers also tested postmortem brains of LBD patients, and again found that levels of S-nitrosylated p62 were abnormally high in affected brain areas-;supporting the idea that this process occurs in humans.

Lipton and Oh say that S-nitrosylation of proteins becomes more likely in many situations of cellular stress, including the presence of protein aggregates. Thus, this chemical modification of p62 could be a key factor in a self-reinforcing process that not only stresses brain cells beyond their limits, but also spreads the source of stress to other brain cells.

The team is now working to develop drug-like compounds that specifically inhibit the S-nitrosylation of p62. Although it would take years to develop such compounds as potential commercial drugs, they could, in principle, slow the Parkinson’s/LBD disease process or prevent its further spread in the brain after it begins, Lipton says.

Source:

Scripps Research Institute

Journal reference:

Oh, C., et al. (2022) S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson’s Disease and Lewy Body Dementia. Journal of Neuroscience. doi.org/10.1523/JNEUROSCI.1508-21.2022.