astrocytes

Social Isolation Triggers Astrocyte-Mediated Deficits in Learning and Memory

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Summary: During periods of social isolation, astrocytes in the brain become hyperactive. This suppresses circuit formation and memory formation. Reversing astrocyte hyperactivity can help mitigate memory deficits associated with social isolation.

Source: Baylor College of Medicine

Here is an important reason to stay in touch with friends and family: social isolation causes memory and learning deficits and other behavioral changes. Many brain studies have focused on the effects social deprivation has on neurons, but little is known about the consequences for the most abundant brain cell, the astrocyte.

Researchers at Baylor College of Medicine working with animal models report in the journal Neuron that during social isolation, astrocytes become hyperactive, which in turn suppresses brain circuit function and memory formation. Importantly, inhibiting astrocyte hyperactivity reversed the cognitive deficits associated with social deprivation.

“One thing we have learned during the COVID pandemic is that social isolation can influence cognitive functions, as previous studies suggested,” said co-first author, Yi-Ting Cheng, graduate student in Dr. Benjamin Deneen’s lab at Baylor. “This motivated co-first author Dr. Junsung Woo and me to further investigate the effects of social isolation in the brain, specifically in astrocytes.”

Astrocytes play diverse roles in the brain such as supporting the functions of neurons, participating in synapse formation and function, releasing neurotransmitters and making the blood-brain barrier.

“Under normal group housing conditions, astrocytes facilitate and promote circuit function and memory,” said Deneen, professor and Dr. Russell J. and Marian K. Blattner Chair of neurosurgery and director of the Center for Cancer Neuroscience at Baylor. He also is the corresponding author of the work.

“However, we found that during social deprivation, astrocytes in the brain region known as the hippocampus actually suppress circuit function and memory formation. The broad conclusion is that astrocyte function is tuned to social experiences.”

This shows a woman sitting alone
Astrocytes play diverse roles in the brain such as supporting the functions of neurons, participating in synapse formation and function, releasing neurotransmitters and making the blood-brain barrier.

Looking for a deeper understanding of the mechanism by which astrocytes of socially-isolated mice cause learning and memory deficits, the researchers studied calcium ions (Ca2+), which previous studies had shown play a central role in astrocyte-mediated learning and memory behaviors.

“We evaluated the effect of social deprivation on astrocyte Ca2+ activity and discovered that social isolation greatly increased it, specifically the activity involving Ca2+ channel TRPA1. This in turn was followed by the release of the inhibitory neurotransmitter GABA that put a break on neural circuits involved in memory and learning,” Cheng said.

“Importantly, both pharmacological and genetic inhibition of TRPA1 reversed the physiological and cognitive deficits associated with social deprivation.”

“Although social isolation also affects other brain cells, we are very excited about the discovery that specifically manipulating astrocytes is enough to restore learning and memory deficits triggered by social isolation in animal models,” Deneen said.

“Our findings show a new role for astrocytes in brain physiology,” Cheng said. “What astrocytes do is affected by changes in the environment and will reflect in the animal’s behavior. In this case, we learned that social interaction is good for astrocytes and therefore, for the brain.”

Beyond Neurons: How Astrocytes Contribute to Brain Disorders

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Summary: Study reveals how a molecule produced by astrocytes interferes with normal neuron development in a range of neurodevelopmental disorders.

Source: Salk Institute

Neurons often get most of the credit for keeping our brains sharp and functioning—as well as most of the blame when it comes to brain diseases. But star-shaped cells called astrocytes, another abundant cell in the human brain, may bear the brunt of the responsibility for exacerbating the symptoms of some neurodevelopmental disorders.

Salk Institute scientists have now identified a molecule produced by astrocytes that interferes with normal neuron development in Rett, fragile X and Down syndromes.

As the team reports in Nature Neuroscience on August 30, 2022, blocking the molecule reduces the signs of disease in mice brains.  

“These findings are part of a new push to look at how all the cells in the brain, not just neurons, interact in neurodevelopmental disorders,” says Associate Professor Nicola Allen, who led the new study. “This opens the door to potential therapeutics to treat these disorders by targeting astrocytes.”

In recent years, scientists have discovered that astrocytes play key roles in brain development and disease. Isolated neurons, for instance, don’t form connections and communicate unless astrocytes are present. If astrocytes affected by disease are mixed with healthy neurons, the neurons begin showing signs of disease. Similarly, if neurons affected by neurodevelopmental disorders are exposed to healthy astrocytes, their function improves.

However, researchers haven’t been able to pin down what molecules from astrocytes are responsible.

In the new study, Allen and colleagues isolated astrocytes and neurons from the developing brains of mice with genetic mutations causing Rett, fragile X or Down syndrome or from healthy animals. Then they determined the levels of 1,235 different proteins produced by each set of astrocytes. They found hundreds of proteins present at higher or lower levels in each disease, with 120 proteins in common between all three diseases—88 at higher-than-usual levels, and 32 at lower-than-usual levels.

“From a basic science perspective, it’s fascinating that there are so many changes seen in astrocyte protein secretion in these genetic disorders—and more importantly, that so many of those changes overlap between the disorders,” says Alison Caldwell, first author of the paper and a former graduate student in Allen’s lab. “To me, this highlights how important astrocytes are for normal neuronal development.”

One molecule stood out to the scientists. They knew that insulin-like growth factor (IGF) could sometimes reduce symptoms of disease in mice with neurodevelopmental disorders. Researchers had long assumed the treatment worked because diseased neurons weren’t producing enough IGF. But they found a different explanation—astrocytes impacted by Rett, fragile X or Down syndrome make high levels of Igfbp2, a protein that blocks IGF.

This shows astrocytes
Salk researchers studied the molecules produced by astrocytes, like those pictured, to understand how the cells play a role in neurodevelopmental disorders.

“It turns out that neurons are making plenty of IGF, but it can’t get where it needs to be because these molecules made by astrocytes are interfering with it,” says Allen.

The group went on to show that excess Igfbp2 produced by astrocytes is responsible for slowing the growth of neurons and that blocking Igfbp2 made by Rett syndrome astrocytes enhanced neuron growth. Moreover, when mice with Rett syndrome were treated with antibodies blocking Igfbp2, signs of disease in the brain were lessened.

“We still have a long way to go to get a therapy based on this to humans, but we think it has promise,” says Allen. “Rather than giving an IGF treatment that has actions throughout the whole body, it makes sense to target Igfbp2 in the brain, where we want IGF to act.”

Allen’s lab group is planning follow-up studies on other proteins they identified in diseased astrocytes, as well as future experiments to better understand Igfbp2.

Other authors included Laura Sancho, James Deng, Alexandra Bosworth, Audrey Miglietta, Jolene Diedrich and Maxim Shokhirev of Salk.

Funding: The work was supported in part by Autism Speaks (Dennis Weatherstone Predoctoral Fellowship), the Chapman Foundation, the National Institute of Child Health and Human Development (F30HD106699), the Chan Zuckerberg Initiative, the Hearst Foundation and the Pew Foundation.

Aberrant astrocyte protein secretion contributes to altered neuronal development in multiple models of neurodevelopmental disorders

Astrocytes negatively impact neuronal development in many models of neurodevelopmental disorders (NDs); however, how they do this, and if mechanisms are shared across disorders, is not known.

In this study, we developed a cell culture system to ask how astrocyte protein secretion and gene expression change in three mouse models of genetic NDs (Rett, Fragile X and Down syndromes).

ND astrocytes increase release of Igfbp2, a secreted inhibitor of insulin-like growth factor (IGF). IGF rescues neuronal deficits in many NDs, and we found that blocking Igfbp2 partially rescues inhibitory effects of Rett syndrome astrocytes, suggesting that increased astrocyte Igfbp2 contributes to decreased IGF signaling in NDs.

We identified that increased BMP signaling is upstream of protein secretion changes, including Igfbp2, and blocking BMP signaling in Fragile X and Rett syndrome astrocytes reverses inhibitory effects on neurite outgrowth.

This work provides a resource of astrocyte-secreted proteins in health and ND models and identifies novel targets for intervention in diverse NDs.

How Brain Tissue Recovers Following an Injury

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Summary: Findings could lead to new treatments to help regeneration following trauma.

Source: Kobe University.

A research team led by Associate Professor Mitsuharu Endo and Professor Yasuhiro Minami has pinpointed the mechanism underlying astrocyte-mediated restoration of brain tissue after an injury. This could lead to new treatments that encourage regeneration by limiting damage to neurons incurred by reduced blood supply or trauma. The findings were published on October 11 in the online version of GLIA ahead of print release in January 2017.

When the brain is damaged by trauma or ischemia (restriction in blood supply), immune cells such as macrophages and lymphocytes dispose of the damaged neurons with an inflammatory response. However, an excessive inflammatory response can also harm healthy neurons.

Astrocytes are a type of glial cell, and the most numerous cell within the human cerebral cortex. In addition to their supportive role in providing nutrients to neurons, studies have shown that they have various other functions, including the direct or active regulation of neuronal activities.

It has recently become clear that astrocytes also have an important function in the restoration of injured brain tissue. While astrocytes do not normally proliferate in healthy brains, they start to proliferate and increase their numbers around injured areas and minimize inflammation by surrounding the damaged neurons, other astrocytes, and inflammatory cells that have entered the damaged zone. Until now the mechanism that prompts astrocytes to proliferate in response to injury was unclear.

The research team focused on the fact that the astrocytes which proliferate around injured areas acquire characteristics similar to neural stem cells. The receptor tyrosine kinase Ror2, a cell surface protein, is highly expressed in neural stem cells in the developing brain. Normally the Ror2 gene is “switched off” within adult brains, but these findings showed that when the brain was injured, Ror2 was expressed in a certain population of the astrocytes around the injured area.

Ror2 is an important cell-surface protein that regulates the proliferation of neural stem cells, so the researchers proposed that Ror2 was regulating the proliferation of astrocytes around the injured areas. They tested this using model mice for which the Ror2 gene did not express in astrocytes. In these mice, the number of proliferating astrocytes after injury showed a remarkable decrease, and the density of astrocytes around the injury site was reduced. Using cultured astrocytes, the team analyzed the mechanism for activating the Ror2 gene, and ascertained that basic fibroblast growth factor (bFGF) can “switch on” Ror2 in some astrocytes.

Image shows a diagram of the findings.

bFGF is produced in the injured zone of the cerebral cortex. Ror2 expression is induced in some population of the astrocytes that receive the bFGF signal, restarting their proliferation by accelerating the progression of their cell cycle. NeuroscienceNews.com image is credited to Kobe University.

This research showed that in injured brains, the astrocytes that show (high) expression of Ror2 induced by bFGF signal are primarily responsible for starting proliferation. bFGF is produced by different cell types, including neurons and astrocytes in the injury zone that have escaped damage. Among the astrocytes that received these bFGF signals around the injury zone, some express Ror2 and some do not. The fact that proliferating astrocytes after brain injury are reduced during aging raises the possibility that the population of astrocytes that can express Ror2 might decrease during aging, which could cause an increase in senile dementia. Researchers are aiming to clarify the mechanism that creates these different cell populations of astrocytes.

By artificially controlling the proliferation of astrocytes, in the future we can potentially minimize damage caused to neurons by brain injuries and establish a new treatment that encourages regeneration of damaged brain areas.

ABOUT THIS NEUROSCIENCE DISEASE RESEARCH ARTICLE

Funding: Funding provided by Japan Society for the Promotion of Science, Ministry of Education, Culture, Sports, Science and Technology Japan, Takeda Science Foundation.

Source: Eleanor Wyllie – Kobe University
Image Source: NeuroscienceNews.com image is credited to Kobe University.
Original Research: Abstract for “Critical role of Ror2 receptor tyrosine kinase in regulating cell cycle progression of reactive astrocytes following brain injury” by Mitsuharu Endo, Guljahan Ubulkasim, Chiho Kobayashi, Reiko Onishi, Atsu Aiba, and Yasuhiro Minami in Glia. Published online October 11 2016 doi:10.1002/glia.23086

Abstract

Critical role of Ror2 receptor tyrosine kinase in regulating cell cycle progression of reactive astrocytes following brain injury

Ror2 receptor tyrosine kinase plays crucial roles in developmental morphogenesis and tissue-/organo-genesis. In the developing brain, Ror2 is expressed in neural stem/progenitor cells (NPCs) and involved in the regulation of their stemness. However, it remains largely unknown about its role in the adult brain. In this study, we show that Ror2 is up-regulated in reactive astrocytes in the neocortices within 3 days following stab-wound injury. Intriguingly, Ror2-expressing astrocytes were detected primarily at the area surrounding the injury site, where astrocytes express Nestin, a marker of NPCs, and proliferate in response to injury. Furthermore, we show by using astrocyte-specific Ror2 knockout (KO) mice that a loss of Ror2 in astrocytes attenuates injury-induced proliferation of reactive astrocytes. It was also found that basic fibroblast growth factor (bFGF) is strongly up-regulated at 1 day post injury in the neocortices, and that stimulation of cultured quiescent astrocytes with bFGF restarts their cell cycle and induces expression of Ror2 during the G1 phase predominantly in proliferating cells. By using this culture method, we further show that the proportions of Ror2-expressing astrocytes increase following treatment with the histone deacetylases inhibitors including valproic acid, and that bFGF stimulation increases the levels of Ror2 expression within the respective cells. Moreover, we show that bFGF-induced cell cycle progression into S phase is inhibited or promoted in astrocytes from Ror2 KO mice or NPCs stably expressing Ror2-GFP, respectively. Collectively, these findings indicate that Ror2 plays a critical role in regulating the cell cycle progression of reactive astrocytes following brain injury.

ALS: Renewing brain’s aging support cells may help neurons survive

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Thick section of mammalian brain, gold stained for astrocytes.

ALS research shows that aging astrocytes lose the ability to protect motor neurons, but replacing old cells with younger ones engineered to restore an important protein may improve neuron survival

Amyotrophic lateral sclerosis (ALS), attacks motor neurons in the brain, brainstem and spinal cord, leading to progressive weakness and eventual paralysis of muscles throughout the body. Patients typically survive only three to five years after diagnosis.

Now, with publication of a study by investigators at the Cedars-Sinai Board of Governors Regenerative Medicine Institute, ALS researchers know the effects of the attack are worsened, at least in part, by the aging and failure of support cells called astrocytes, which normally provide nutrients, housekeeping, structure and other forms of assistance for neurons.

Earlier studies suggested the possible involvement of these support cells in ALS development and progression, but the new research is believed to be the first to directly measure the effects of aging on the ability of astrocytes to sustain motor neurons. Results are published online inNeurobiology of Aging.

The Cedars-Sinai researchers first tried to repeat previous studies showing that astrocytes from laboratory animals with an ALS mutation failed to support normal motor neurons. They were surprised to find that very young ALS astrocytes were supportive, but ALS astrocytes from older animals were not. More surprisingly, it wasn’t just diseased astrocytes that were affected by age. The scientists discovered — and reported for the first time — that even normal aging of astrocytes reduces their ability to support motor neurons.

“Aging astrocytes lose their ability to support motor neurons in general, and they clearly fail to help those attacked by ALS,” said Clive Svendsen, PhD, professor and director of the Board of Governors Regenerative Medicine Institute, the article’s senior author.

He said old astrocytes and ALS-affected astrocytes have lower death rates in the petri dish than younger ones — they seem to hang around longer and accumulate. But while older astrocytes and those with the ALS mutation live longer, they appear to have significant damage to their DNA. Instead of being cleared away for replacement by new, healthy cells, the old, defective cells become useless clutter, producing chemicals that cause harmful inflammation. The process is accelerated in ALS astrocytes.

“Our findings have implications for scientists studying neurodegenerative diseases like ALS and Alzheimer’s and the aging process in general. In younger animals modeling ALS and in older ‘normal’ animals, the accumulations of defective astrocytes in the nervous system look similar,” said Melanie Das, PhD, a student in the Cedars-Sinai Graduate Program in Biomedical Science and Translational Medicine, the article’s first author.

After establishing the effects of aging on astrocytes, the researchers took another step — evaluating the potential therapeutic effects of a specially engineered protein.

“We found that by culturing aging astrocytes and those harboring the ALS mutation with a neuron-protective protein called GDNF, we could increase motor neuron survival. We already knew that GDNF was protective directly on motor neurons, but we believe this is the first time that the delivery of GDNF has been shown to have a direct beneficial effect on astrocytes, perhaps resetting their aging clock, which ultimately benefits neurons,” Svendsen said.

Svendsen and scientists in his laboratory have studied GDNF extensively, devising experimental methods to restore beneficial levels in the brain and spinal cord — where the disease originates — and in muscles, at the point where nerve fibers connect with muscle fibers to stimulate muscle action. Several large GDNF-related research projects taking shape at Cedars-Sinai are funded by the California Institute for Regenerative Medicine.

“Our major CIRM-funded programs, aimed at engineering young stem cell-derived astrocytes to secrete GDNF, then transplanting those cells back into patients, take on even greater importance, given this aging phenomenon,” said Svendsen, the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine.