What happens in the brain when sensory stimulation continues over time—for example, while jogging, reading, or listening to music? Sensory input activates specific groups of neurons, increasing their demand for oxygen and nutrients. In response, nearby blood vessels dilate and increase blood flow, a process known as neurovascular coupling. Although astrocytes—star-shaped non-neuronal cells in the brain—have long been thought to participate in this process, exactly how they contribute has remained unclear.
A research team led by Director C. Justin LEE of the Institute for Basic Science (IBS) Center for Memory and Glioscience and Professor SUH Minah of Sungkyunkwan University has now shown that astrocytes play a key role in coordinating both neuronal activity and blood-flow responses during prolonged sensory stimulation. The researchers identified a signaling pathway involving AQP4, TRPA1, BEST1, and D-serine, and proposed a new model in which neurons, astrocytes, and blood vessels work together to sustain brain activity when sensory demand continues over time.
Astrocytes are widely distributed throughout the brain and were once viewed mainly as support cells that provide structural and metabolic assistance to neurons. More recent studies, however, have shown that they actively communicate with both neurons and blood vessels and can influence brain function.
To determine whether their contribution depends on how long sensory stimulation lasts, the researchers compared brain responses to brief, 5-second stimulation and prolonged, 20-second stimulation in mice. During brief stimulation, neuronal activity and vascular responses increased transiently. When the stimulation continued for 20 seconds, however, astrocytes became much more strongly engaged and helped sustain both neuronal activity and cerebral blood-volume responses.
The team then identified a four-step signaling pathway underlying this effect. First, sustained neuronal activity promotes water movement into astrocytes through AQP4, a water-channel protein, causing the cells to increase in volume. This volume change is associated with activation of TRPA1, a mechanosensitive channel that allows calcium to enter astrocytes. The resulting rise in intracellular calcium opens BEST1, a calcium-activated channel. Through BEST1, astrocytes release D-serine, an amino acid that helps regulate neuronal signaling.
The released D-serine supports neuronal activity and contributes to dilation of brain blood vessels, helping maintain blood flow during prolonged sensory stimulation.
To test the importance of this pathway, the researchers selectively suppressed AQP4 or TRPA1 in astrocytes. In both cases, neuronal activity and vascular responses during prolonged stimulation were reduced. By contrast, brief sensory responses were much less affected.
The role of D-serine became particularly clear when the researchers supplied D-serine to mice in which astrocytic TRPA1 had been suppressed. The treatment restored the reduced cerebral blood-volume response, neuronal activity, and sensory responsiveness observed during prolonged stimulation. The team also confirmed that D-serine is released through BEST1.
Together, these findings show that the AQP4–TRPA1–BEST1–D-serine pathway acts as a mechanism that helps prevent neuronal and vascular responses from fading during sustained sensory activity.
Professor SUH Minah, co-corresponding author of the study, said, “This study provides a clear model for how astrocytes communicate with neurons and regulate brain function during sustained sensory stimulation. The mechanism identified here may provide an important basis for future studies of neurological disorders involving impaired sensory processing or cognitive function.”
The researchers also uncovered a second role for astrocytic D-serine. Even in the absence of sensory stimulation, astrocytes continuously release D-serine, helping regulate the resting diameter, or basal vascular tone, of penetrating arterioles in the brain.
In brain-slice experiments, supplying D-serine directly through astrocytes caused penetrating arterioles to dilate. This effect required BEST1 and persisted even when neuronal electrical activity was blocked, indicating that astrocyte-derived D-serine can directly contribute to vascular regulation independently of ongoing neuronal firing. Additional in vivo experiments showed that D-serine administration also increased the diameter of penetrating arterioles in living animals.
These results suggest that astrocytes perform two related but distinct functions. During prolonged sensory stimulation, D-serine helps sustain neuronal activity and the accompanying increase in blood flow. Under resting conditions, continuous D-serine release contributes to maintaining baseline vascular tone.
Director C. Justin LEE, corresponding author of the study, said, “We identified an integrated molecular signaling pathway that helps regulate both sustained brain activity and vascular stability, while also revealing a new role for astrocytes in controlling blood vessels. We hope these findings will provide new clues for understanding neurovascular dysfunction in difficult-to-treat neurological disorders such as Alzheimer’s disease and stroke.”
The study also helps explain why previous research has produced differing conclusions about the role of astrocytes in neurovascular coupling. Rather than acting as the primary trigger for every vascular response, astrocytes appear to become particularly important when neuronal activity must be maintained over longer periods.
The findings therefore place astrocytes in a broader role than simply supporting neurons. By sensing sustained neural activity and coordinating both neuronal signaling and vascular responses, astrocytes act as key integrators that help the brain maintain stable function during prolonged sensory demand.
The research was published online on September 29 in Advanced Science.