Neurons and Astrocytes Interact to Create Day-Night Cycles
Post by Anastasia Sares
The takeaway
Recent work shows how a partnership between neurons and surrounding cells called astrocytes helps to regulate our body’s central clock. This highlights the importance of non-neuronal cells in brain function, and adds a piece to the puzzle of how the brain manages day/night cycles.
What's the science?
The body’s circadian rhythm includes cycles of wake and sleep, hunger and digestion, blood pressure, hormones, and many other daily patterns. The brain region responsible for this is the suprachiasmatic nucleus, which maintains a circadian rhythm even in the absence of any light. But how do all the cells in this nucleus stay synchronized with each other and avoid sending out contradictory signals? This mystery becomes even more puzzling given that the main neurotransmitter in this region, GABA, is inhibitory, which should inhibit activity across the whole network instead of creating the cycling behavior we actually see.
This week in PNAS, Patton and colleagues demonstrated that support cells called astrocytes help to regulate the activity of neurons in this area by “vacuuming up” the GABA floating around outside of cells during the day and letting it accumulate at night.
How did they do it?
The authors obtained the brains of mice and extracted the suprachiasmatic nucleus, slicing it so it was only micrometers thick and mounting these slices on membranes. The slices were kept in a solution that would allow the cells to live and the neurons to keep firing. Each of these slices was then infected with adeno-associated viral vectors (AAV), which introduce genetic material so that the cell itself produces a custom molecule. In this case, the inserted gene encoded for a fluorescent protein that would latch on to GABA molecules. With the fluorescent molecules active, the brain slices would glow when there was GABA present, and go dark when the GABA disappeared. The authors observed that GABA concentrations were low during the day and peaked at night, even though the neurons that should release the GABA were firing more during the day.
The authors then re-analyzed their previously published single-cell RNA-sequencing studies of suprachiasmatic nucleus slices harvested in daytime vs nighttime. Some of the genes being transcribed differently in day and night were involved in GABA transport by astrocytes, which are support cells present in brain tissue. Using the same fluorescent tagging method, they investigated the activity of these GABA transporters, and what happens when they are chemically blocked.
What did they find?
GABA transport proteins in astrocytes were up-regulated during the day, meaning that the astrocytes are likely “installing” them in their membranes and using them to move GABA out of the intercellular space. At night, the opposite is true: there are fewer GABA transport proteins, and thus GABA builds up in the intercellular space. This cycle, in turn, influences how often neurons in the suprachiasmatic nucleus fire, and how often secondary transmitter molecules called neuropeptides are released—these neuropeptides go on to influence circadian behavior.
Inhibiting the activity of GABA transport proteins disrupted the circadian rhythm in the brain slices, and initiating the clock of the astrocytes was able to restore circadian rhythm to “clock-less” neurons in slices genetically engineered to lack certain proteins that would help the circadian clock function. So, although it was previously thought that GABA control of neuronal activity was not important, it is now thought that astrocytes actively remove it during the day instead, and allow it to accumulate at night supporting daily cycles of neuronal activity.
What's the impact?
These findings call attention to the often-forgotten “support” cells that can be found throughout neural tissue, showing that they may in fact be orchestrating important brain functions. It also brings us closer to understanding how our day/night cycles work, how they might be disrupted, and what might be the consequences of that disruption.
