Tag: astrocytes

Categories : Mental Health NeurologyTags :

Astrocytes Identified as Hidden Culprit Behind PTSD

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Excessive astrocytic GABA impairs fear extinction in PTSD, new drug target offers hope for treatment

Figure 1. Astrocyte-Derived GABA and Therapeutic Effects of KDS2010 in PTSD. Brain imaging of PTSD patients revealed unusually high levels of GABA and reduced cerebral blood flow in the prefrontal cortex, showing that changes strongly correlated with symptom severity. In animal models, this excess GABA was traced to reactive astrocytes producing it abnormally due to increased MAOB and reduced levels of the GABA-degrading enzyme ABAT. This disrupted normal brain function and impaired the ability to extinguish fear. Treatment with KDS2010, a selective MAOB inhibitor, successfully lowered astrocytic GABA, restored brain activity, and rescued fear extinction, highlighting its potential as a therapeutic option. Credit: Institute for Basic Science

Why do patients with post traumatic stress disorder (PTSD) often struggle to forget traumatic memories, even long after the danger has passed? This failure to extinguish fear memories has long puzzled scientists and posed a major hurdle for treatment, especially since current medications targeting serotonin receptors offer limited relief for only a subset of patients.

In a new discovery, scientists at the Institute for Basic Science (IBS) and Ewha Womans University have uncovered a new brain mechanism driving PTSD – and a promising drug that may counteract its effects. The research is reported in Signal Transduction and Target Therapy.

Led by Dr C. Justin Lee at the IBS Center for Cognition and Sociality and Professor Lyoo In Kyoon at Ewha Womans University, the team has shown that excessive GABA (gamma-aminobutyric acid) produced by astrocytes, which are star-shaped support cells in the brain, impairs the brain’s ability to extinguish fear memories. This deficit is a core feature of PTSD and helps explain why traumatic memories can persist long after the threat has passed.

Crucially, the researchers found that a brain-permeable drug called KDS2010, which selectively blocks the monoamine oxidase B enzyme responsible for this abnormal GABA production, can reverse PTSD-like symptoms in mice. The drug has already passed Phase 1 safety trials in humans, making it a strong candidate for future PTSD treatments.

PTSD remains difficult to treat, with current medications targeting serotonin pathways providing limited relief for many patients. The new study focused on the medial prefrontal cortex (mPFC), a region of the brain critical for regulating fear, and found that PTSD patients had unusually high levels of GABA and reduced cerebral blood flow in this area. These findings emerged from brain imaging studies of more than 380 participants. Importantly, GABA levels decreased in patients who showed clinical improvement, pointing to the chemical’s central role in recovery.

To uncover the origin of this excess GABA, the researchers examined postmortem human brain tissue and used PTSD-like mouse models. They discovered that astrocytes, not neurons, were producing abnormal amounts of GABA via the enzyme monoamine oxidase B (MAOB). This astrocyte-derived GABA impaired neural activity, blocking the brain’s ability to forget traumatic memories.

When the researchers administered KDS2010, a highly selective, reversible MAOB inhibitor developed at IBS, the mice showed normalized brain activity and were able to extinguish fear responses. The drug reduced GABA levels, restored blood flow in the mPFC, and re-enabled memory extinction mechanisms. The study thus confirms astrocytic MAOB as a central driver of PTSD symptoms, and MAOB inhibition as a viable therapeutic path.

A major challenge of the study was linking clinical findings in humans with cellular mechanisms in the lab. The researchers addressed this by applying a “reverse translational” strategy: they began with clinical brain scans and moved backward to identify the cellular source of dysfunction, then confirmed the mechanism and tested drug effects in animal models. This approach led to a new understanding of how glial cells – long thought to be passive – actively shape psychiatric symptoms.

“This study is the first to identify astrocyte-derived GABA as a key pathological driver of fear extinction deficit in PTSD,” said Dr Won Woojin, a postdoctoral researcher and co-first author of the study. “Our findings not only uncover a novel astrocyte-based mechanism underlying PTSD, but also provide preclinical evidence for a new therapeutic approach using an MAOB inhibitor.”

Director C. Justin LEE, who led the study, emphasized that “This work represents a successful example of reverse translational research, where clinical findings in human guided the discovery of underlying mechanisms in animal models. By identifying astrocytic GABA as a pathological driver in PTSD and targeting it via MAOB inhibition, the study opens a completely new therapeutic paradigm not only for PTSD but also for other neuropsychiatric disorders such as panic disorder, depression, and schizophrenia.”

The researchers plan to further investigate astrocyte-targeted therapies for various neuropsychiatric disorders. With KDS2010 currently undergoing Phase 2 clinical trials, this discovery may soon lead to new options for patients whose symptoms have not responded to conventional treatments.

Source: Institute for Basic Science

Categories : NeurologyTags :

How the Brain Controls Its Blood Volume

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Inhibitory neurons and astrocytes hold the key to sharper functional brain imaging –

Image of an astrocyte, a subtype of glial cells. Glial cells are the most common cell in the brain. Credit: Pasca Lab, Stanford University NIH support from: NINDS, NIMH, NIGMS, NCATS

Researchers at the Center for Neuroscience Imaging Research within the Institute for Basic Science (IBS) have uncovered a two-step mechanism by which the brain regulates blood volume – a breakthrough with significant implications for how scientists understand and interpret functional magnetic resonance imaging (fMRI).

At the core of this study are somatostatin-expressing interneurons (SST neurons), a specialised type of inhibitory neuron. Among all neurons in the brain, approximately 15% are inhibitory neurons, but the role of these neurons in regulating cerebral blood volume has not been clearly elucidated in previous studies, with most of earlier research mainly focusing on the excitatory neurons. The new study by the IBS team sheds light on how inhibitory neurons interact with astrocytes, a type of support cell, to precisely control blood vessel dilation in the brain.

To unravel this complex process, the research team developed mouse models (e.g., SST-ChR2, SST-hM4Di) that allowed selective activation or inhibition of SST neurons. The researchers also used advanced neuroscience techniques in these mice. Specifically, they applied optogenetics and chemogenetics to precisely control the activity of these neurons. To observe the cellular and vascular responses, the team employed calcium imaging to visualise astrocyte activity, electrophysiology to measure neural signals, and intrinsic optical imaging (OIS) alongside ultra-high-field functional MRI (fMRI) to track blood volume dynamics with high spatial and temporal resolution.

Through these experiments, the team uncovered a two-step mechanism of vasodilation. In the early phase, SST neurons, when activated, released nitric oxide (NO) – a powerful vasodilator that triggered rapid and widespread expansion of nearby blood vessels. This was followed by a late phase, in which astrocytes became activated and induced slower, more localised vasodilation, especially during periods of prolonged sensory stimulation.

Figure 1. Somatostatin neurons regulate astrocytes surrounding cerebral blood vessels, enabling more precise delivery of blood volume to specific brain regions, thereby enhancing the spatial accuracy of neurovascular responses. Credit: Institute for Basic Science

Notably, when SST neurons were silenced, the layer-specific precision of blood volume signals observed in fMRI was lost – a finding that links cellular activity directly to spatial specificity in imaging data.

“This two-step mechanism involving inhibitory neurons and astrocytes helps explain why high-resolution fMRI can distinguish activity between different layers of the brain cortex,” the researchers explained. “Our study fills a major gap in understanding how neural signals are translated into the blood volume changes we measure in brain imaging.”

The team also overcame several technical challenges – including distinguishing overlapping signals and timing differences – by integrating multiple imaging techniques and running extensive repeat experiments to validate the causal link between SST neuron activity and vascular responses.

Their findings not only advance basic knowledge of neurovascular coupling, but also open new avenues for investigating neurological and psychiatric conditions in which SST neuron function is impaired, such as Alzheimer’s disease, depression, and autism. The group plans to study disease-model mice to identify how disruptions in this neuron–astrocyte–vascular pathway affect blood volume, brain function, and fMRI signals.

Ultimately, this research lays the groundwork for improving the accuracy of brain imaging interpretation and may lead to better diagnostic and therapeutic strategies for brain disorders.

Source: Institute for Basic Science

Categories : Exercise Neurodegenerative DiseasesTags :

Exercise Activates Cells that Protect Against Alzheimer’s

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Photo by Barbara Olsen on Pexels

Using advanced single-nuclei RNA sequencing (snRNA-seq) and a widely used preclinical model for Alzheimer’s disease, researchers from Mass General Brigham and collaborators at SUNY Upstate Medical University have identified specific brain cell types that responded most to exercise. These findings, which were validated in samples from humans, shed light on the connection between exercise and brain health and point to future drug targets. Results are published in Nature Neuroscience.

“While we’ve long known that exercise helps protect the brain, we didn’t fully understand which cells were responsible or how it worked at a molecular level,” said senior author Christiane Wrann, DVM, PhD, a neuroscientist at Massachusetts General Hospital. “Now, we have a detailed map of how exercise impacts each major cell type in the memory centre of the brain in Alzheimer’s disease.”

Brain support cells—astrocytes enriched in the protein cadherin-4 (CDH4)
Scientists identified a distinct subtype of brain support cells—astrocytes enriched in the protein cadherin-4 (CDH4), shown in magenta, that seem to protect nerve cells against cell death. In Alzheimer’s disease, these cells become less abundant, but exercise seems to strengthen them. (Image credit: Luis Moreira)

The study focused on a part of the hippocampus – a critical region for memory and learning that is damaged early in Alzheimer’s disease. The research team leveraged single-nuclei RNA sequencing, a relatively new technologies that allow researchers to look at activity at the molecular level in single cells for an in-depth understanding of diseases like Alzheimer’s.

The researchers exercised a common mouse model for Alzheimer’s disease using running wheels, which improved their memory compared to the sedentary counterparts. They then analysed gene activity across thousands of individual brain cells, finding that exercise changed activity both in microglia, a disease-associated population of brain cells, and in a specific type of neurovascular-associated astrocyte (NVA), newly discovered by the team, which are cells associated with blood vessels in the brain. Furthermore, the scientist identified the metabolic gene Atpif1 as an important regulator to create new neurons in the brain. “That we were able to modulate newborn neurons using our new target genes set underscores the promise our study,” said lead author Joana Da Rocha, PhD, a postdoctoral fellow working in Dr Wrann’s lab.

To ensure the findings were relevant to humans, the team validated their discoveries in a large dataset of human Alzheimer’s brain tissue, finding striking similarities.

“This work not only sheds light on how exercise benefits the brain but also uncovers potential cell-specific targets for future Alzheimer’s therapies,” said Nathan Tucker, a biostatistician at SUNY Upstate Medical University and co-senior of the study. “Our study offers a valuable resource for the scientific community investigating Alzheimer’s prevention and treatment.”

Source: Mass General Brigham

Categories : Neurodegenerative DiseasesTags :

How Astrocytes Know to Give the Brain an Energy Boost

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Image of an astrocyte, a subtype of glial cells. Glial cells are the most common cell in the brain. Credit: Pasca Lab, Stanford University

A key mechanism by which astrocytes detect when an energy boost is needed for the brain has been elucidated by University College of London researchers using mouse-based and in vitro studies.

The findings, published in Nature, could inform new therapies to maintain brain health and longevity, the researchers say, since other studies have found that brain energy metabolism can become impaired late in life and contribute to cognitive decline and the development of neurodegenerative disease.

Lead author Professor Alexander Gourine (UCL Neuroscience, Physiology & Pharmacology) said: “When our brain is more active, such as when we’re performing a mentally taxing task, our brain needs an immediate boost of energy, but the exact mechanisms that ensure on-demand local supply of metabolic energy to active brain regions are not fully understood.”

First and co-corresponding author Dr Shefeeq Theparambil, who began the study at UCL before moving to Lancaster University, said: “The normal activities of the brain require enormous amounts of energy, comparable to that of a human leg muscle running a marathon. This energy is primarily derived from blood glucose. Neurons in the brain consume more than 75% of this energy.”

Prior research has shown that numerous brain cells called astrocytes appear to play a role in providing the brain neurons with energy they need. Astrocytes, shaped like stars, are a type of glial cell, which are non-neuronal cells found in the central nervous system. When neighbouring neurons need an increase in energy supply, astrocytes jump into action by rapidly activating their own glucose stores and metabolism, leading to the increased production and release of lactate. Lactate supplements the pool of energy that is readily available for use by neurons in the brain.

Professor Gourine explained: “In our study, we have figured out how exactly astrocytes are able to monitor the energy use by their neighbouring nerve cells, and kick-start this process that delivers additional chemical energy to busy brain regions.”

In a series of experiments using mouse models and cell samples, the researchers identified a set of specific receptors in astrocytes that can detect and monitor neuronal activity, and trigger a signalling pathway involving an essential molecule called adenosine. The researchers found that the metabolic signalling pathway activated by adenosine in astrocytes is exactly the same as the pathway that recruits energy stores in the muscle and the liver, for example when we exercise.

Adenosine activates astrocyte glucose metabolism and supply of energy to neurons to ensure that synaptic function (neurotransmitters passing communication signals between cells) continues apace under conditions of high energy demand or reduced energy supply.

The researchers found that when they deactivated the key astrocyte receptors in mice, the animal’s brain activity was less effective, including significant impairments in global brain metabolism, memory and disruption of sleep, thus demonstrating that the signalling pathway they identified is vital for processes such as learning, memory and sleep.

Dr Theparambil said: “Identification of this mechanism may have broader implications as it could be a way of treating brain diseases where brain energetics are downregulated, such as neurodegeneration and dementia.”

Professor Gourine added: “We know that brain energy homeostasis is progressively impaired in ageing and this process is accelerated during the development of neurodegenerative diseases such as Alzheimer’s disease. Our study identifies an attractive readily druggable target and therapeutic opportunity for brain energy rescue for the purpose of protecting brain function, maintaining cognitive health, and promoting brain longevity.”

Categories : Cancer NeurologyTags :

Lung Cancer Metastases in the Brain Trick Astrocytes for Protection

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Small cell lung cancer cells (green and blue) that metastasised to the brain in a laboratory mouse recruit brain cells called astrocytes (red) for their protection. Credit: Fangfei Qu

Lung cancer cells that metastasise to the brain survive by convincing brain cells called astrocytes that they are baby neurons in need of protection, according to a study by researchers at Stanford Medicine published in Nature Cell Biology.

The cancer cells carry out their subterfuge by secreting a chemical signal prevalent in the developing human brain, the researchers found. This signal draws astrocytes to the tumour, encouraging them to secrete other factors that promote the cancer cells’ survival. Blocking that signal may be one way to slow or stop the growth of brain metastases of small cell lung cancer, which account for about 10% to 15% of all lung cancers, the researchers believe.

In the adult brain, astrocytes play a critical role in maintaining nerve function and connectivity. They are also important during brain development, when they facilitate connections between developing neurons.

The researchers studied laboratory mice, human tissue samples and human mini-brains, or organoids, grown in a lab dish to dissect the unique relationship between the cancer cells and their ‘big sister’ astrocytes, which hover nearby and shower them with protective factors.

“Small cell lung cancers are known for their ability to metastasise to the brain and thrive in an environment that is not normally conducive to tumour growth,” said professor of paediatrics and of genetics Julien Sage, PhD. “Our study suggests that these cancer cells reprogram the brain microenvironment by recruiting astrocytes for their protection.”

Professor Sage is the senior author of the study, while postdoctoral scholar Fangfei Qu, PhD, is the lead author.

Invasion of the brain

Small cell lung cancer excels at metastasising to the brain – about 15% to 20% of people already have clusters of cancer cells in their brains when their lung tumours are first diagnosed. As the cancer progresses, about 40% to 50% of patients will develop brain metastases. The problem is so prevalent, and the clinical outcome so dire, that clinicians recommend cranial radiation even before brain metastases have been found.

How and why small cell lung cancer has such an affinity for the brain has been something of a mystery. Brain metastases are rarely biopsied or removed because doing so has not been shown to affect a patient’s survival, and brain surgery is so invasive. Using laboratory mice is also of little help since small cell lung cancers in those animals rarely develop metastases in the brain, perhaps due to subtle biological differences between species.

Small cell lung cancers have another distinguishing feature – they are neuroendocrine cancers, meaning they arise from cells with similarities to both neurons and hormone-producing cells. Neuroendocrine cells link the nervous system with the endocrine system throughout the body, including in the lung.

Sage and his colleagues wondered whether neuronal-associated proteins on the surface of small cell lung cancer cells give them a leg up when the cells first begin to infiltrate the brain.

“We know the brain is full of neurons,” Sage said. “Maybe that’s why these cancer cells with some neuronal traits are happy in the brain and are accepted into that environment.”

Qu and Sage developed a way to inject mouse small cell lung cancer cells grown in the laboratory into the brains of mice to spark the development of brain tumours. They saw that astrocytes, a subtype of glial cell, flocked to the infant tumours and began to churn out proteins critical during brain development, including factors that stimulate nerve growth.

A plethora of astrocytes

A similar call happens in human brains, they noted: Brain tissue samples from people who had died of metastatic small cell lung cancer, shared by professor of pathology and paper co-author Christina Kong, MD, had many more protective astrocytes in the interior of the tumours than did metastases of melanoma, breast cancer and another type of lung cancer called adenocarcinoma.

Qu worked with assistant professor of paediatrics and co-author Anca Pasca, MD, to fuse aggregates of small cell lung cancer, lung adenocarcinoma or breast cancer cells with what are called cortical organoids – in vitro-grown clumps of brain cells including neurons and astrocytes that begin to mimic the organisation and connectivity of a human cortex. Within 10 days, many more protective astrocytes had infiltrated the small cell lung cancer pseudo-tumours than the adenocarcinoma or breast cancer.

“This showed us that the astrocytes actively move toward the small cell lung cancer cells, rather than simply being engulfed by the growing tumour,” Sage said. “What’s more exciting, though, is that these organoids, or mini-brains, realistically model the developing human brain. So, we’re no longer relying on a mouse model. It’s a perfect system to study brain metastases.”

Further research showed that the small cell lung cancer cells summon protective astrocytes by secreting a protein called Reelin that mediates the migration of neuronal and glial cells during brain development. Triggering Reelin expression in mouse breast cancer cells injected into the brain significantly increased the number of astrocytes in the resulting tumours in the mice, and the tumours were larger than in control animals injected with cells with low Reelin expression.

The apparent reliance of the cancer cells on chemical signals and responses specific to the developing brain may give clues for the development of future therapies, Sage believes.

“Some of these signals may not be as relevant or as highly expressed in the adult brain,” Sage said. “As a result, perhaps they could still be targeted to slow or prevent brain metastases without harming a normal brain. This might be an important window of opportunity for therapy.”

Source: Stanford Medicine