Stargazing in the brain: “Star-like” cells display unique activity patterns
Advances in optical imaging and image analysis have revealed the tantalizing possibility that astrocytes, star-shaped cells in the brain, might play a role in how we process information and store memories.
Researchers have developed a new toolbox, allowing them to image single astrocytes in the brains of awake mice at an unprecedented level of detail
The study shows for the first time ‘in vivo’ that astrocytes generate calcium signals which are as fast as that of neurons, lasting fewer than 300 milliseconds
The scientists also found that astrocytes have hotspots, where the frequency of activity was higher
The hotspot maps were stable over time with unique patterns for specific behaviors
These findings are potential evidence for astrocytes playing a role in processing information and storing memories
The way we experience the world occurs due to complex and intricate interactions between neurons in the brain. Now, a study, published 9th February 2022 in Science Advances, suggests that astrocytes – star-shaped, non-neuronal cells in the brain – might also play an important role in processing information, and perhaps even memory.
Using advanced imaging and analysis techniques, researchers from the Okinawa Institute of Science and Technology Graduate University (OIST) recorded signaling within single astrocytes at a previously unseen level of detail and speed in the brains of awake mice.
Their findings, including ultra-fast signals on par with those seen in neurons and patterns of signaling activity that correspond to different behaviors, suggest that astrocytes may play a crucial role in many functions of our brain, including how we think, move, and learn.
“If these implications are true, it will fundamentally transform how we think about neuroscience, and the way the brain works,” said first author Dr. Leonidas Georgiou, a former PhD student in the Optical Neuroimaging Unit at OIST.
When we picture our brain, we typically imagine a messy tangle of long, wire-like neurons that send electrical signals to each other across different regions of the brain. But neurons only make up half the cells in our brain. Crammed into all the remaining space between the jumble of neurons are many other types of brain cells, including astrocytes.
“Compared to neurons, astrocytes have received very little attention. It was thought that astrocytes are just helper cells, supplying the neurons with nutrients and removing their waste,” said Professor Bernd Kuhn, senior author and head of the Optical Neuroimaging Unit.
Caption: Astrocytes (meaning ‘star-cells’) have a unique morphology. While the internal structure is star-like, tiny protrusions of the cell form a cloud-like region that surround all nearby synapses – the junctions where different neurons meet and communicate. In mice, astrocytes are estimated to be in contact with, and take care of, around 300,000 synapses.
But in recent years, there’s been increasing amounts of evidence that astrocytes can listen to chemical messages sent between neurons at synapses, and can respond with their own signals, providing an extra layer of complexity to how our brain receives and responds to information.
Still, the previously detected signals in astrocytes were about ten times slower than signals seen in neurons, with scientists therefore believing the cells were too slow for information processing.
However, by developing a new toolkit that allows the study of astrocyte activity in awake mice with unprecedented detail, the researchers at OIST showed for the first time that astrocytes generate signals in vivo which are as fast as that of neurons, lasting fewer than 300 milliseconds.
Their toolkit relied on a new discovery: that a virus regularly used for gene therapy could “jump” from neurons to connected astrocytes. The scientists used an adeno-associated virus that contained a gene that makes infected cells fluoresce. The fluorescence increases in intensity in the presence of calcium – an important indicator of signal activity within living cells.
Once labelled, the research team were able to use a powerful, homebuilt microscope to pinpoint and image a single astrocyte, over multiple days for up to an hour at a time, while the mouse was awake and moving.
The scientists then used an advanced computer program to analyze the recorded images, allowing them to detect the never-before-seen ultra-fast flashes of calcium signals, and evaluate signal patterns in an unbiased way.
They found that sensory stimulation, by tickling the whiskers, resulted in very little calcium signaling, while certain behaviors, like running or walking, resulted in high levels of activity.
The scientists also realized that there were certain areas in the astrocyte, or hotspots, where levels of activity were higher.
“These hotspot maps are like fingerprints – for a specific behavior, they are stable over time, remaining the same over a period of days, and unique to each astrocyte,” said Dr. Georgiou.
Even more surprisingly, the team noticed that different behaviors corresponded to unique hotspot patterns.
“So, when the mouse is resting, you see one pattern. And then when the mouse is running, you see a different pattern,” said Prof. Kuhn.
Caption: The scientists found that specific locations within an astrocyte showed higher levels of activity. The hotspot map changed depending on the behavior of the mouse, for example, resting or running, during the recording.
From Georgiou et al., Sci. Adv. 8, eabe5371 (2022). This work is licensed under CC BY (https://creativecommons.org/licenses/by/4.0/).
One hypothesis suggested by Prof. Kuhn is that these hotspot maps could represent memory engrams – a pattern that represents a specific behavior or a memory. Different neuron networks are active during specific behaviors or when learning and recalling information, which could also change the activity of nearby astrocytes. Memory engrams are still theoretical, and highly controversial, he acknowledged.
“We still don’t know how memories are stored in a brain, but it’s incredible to think that it could involve astrocytes,” he said. “It’s likely too good to be true, but it’s an exciting hypothesis to follow up on.”
In the future, the research team plans to study a larger number of astrocytes, to see how drugs, or teaching the mice new behaviors, affects the activity pattern.
Prof. Kuhn concluded: “Somehow, these activity maps of calcium signals represent different behaviors, but we have no idea why or how. It will be very exciting to take this research further.”
Title: Ca+ activity maps of astrocytes tagged by axoastrocytic AAV transfer Journal: Science Advances Authors: Leonidas Georgiou, Anai Echeverría, Achilleas Georgiou, Bernd Kuhn Date: 9th February 2PM ET DOI: 10.1126/sciadv.abe5371