Our paper demonstrates that neuronal activity-dependent calcium elevations in glial cell astrocytes propagate to perivascular astrocyte endfeet and trigger there the release of arachidonic acid metabolites which dilate cerebral blood vessels. Our paper thus reveals a new function of astrocytes as central mediators of activity-dependent cerebral blood flow regulation, commonly referred to as functional hyperemia. As such, our paper represents a step towards a full understanding of the cellular and molecular mechanism of a phenomenon which is fundamental to brain function.

“An implication of our findings is that a defect in astrocyte function may lead to a defect in the regulation of cerebral blood flow.”

Our paper reveals a novel and, to some extent, surprising, function of astrocytes in the brain. As a result of our finding, new work has been done, including a series of in vivo experiments, which confirms the key role of neuronal activity-dependent calcium elevations in astrocytes in the regulation of cerebral blood flow. In addition, a number of laboratories intensified their ongoing efforts or initiated new studies for fully elucidating the function of astrocytes in both the normal and diseased brain.

Neurons from a specific brain region are activated by distinct stimuli. For example, neurons in the auditory cortex are highly active while listening to a concert. To satisfy the increased demand for energetic metabolites and oxygen, the blood flow in that active region must increase in a temporally and spatially coordinated manner. This phenomenon is fundamental to brain function.

Although it was first described by the Italian physiologist Angelo Mosso (1846–1910) and later by the British physiologist Charles Scott Sherrington (1857-1952) more than a century ago, its mechanism remained elusive for a long time. Our study reveals that a non-neuronal cell, such as the glial cell astrocyte—once thought to have only neuron-supportive functions—plays a crucial role in this phenomenon.

Retrospectively, astrocytes are obviously suited to play such a role since their processes are in close contact with neuronal synapses on the one side, and with cerebral vessels on the other. Thus, highly active neurons can tell nearby astrocytic processes that they need more energy. This request, in the form of intracellular calcium oscillations, diffuses to astrocytic processes in contact with a blood vessel and, through the release of vasoactive agents, results in its dilation. The net result is a local increase in blood flow. Briefly then, our paper provides a plausible cellular and molecular mechanism for neuronal activity-dependent cerebral blood flow regulation.

An implication of our findings is that a defect in astrocyte function may lead to a defect in the regulation of cerebral blood flow. This represents a clue for understanding the mechanism at the basis of brain disorders that have an important vascular component such as stroke, migraine, and Alzheimer’s disease. Finally, our work could help the interpretation of data from modern brain imaging studies, such as functional magnetic resonance imaging (fMRI), which rely on local changes in cerebral blood flow to monitor the parallel changes in brain activity.

I was always interested in studying the rules governing neuronal plasticity. Roughly 10 years ago, my work focused on the possible role of neurotrophins as modulators of glutamate-mediated calcium elevations in neurons. I was attracted by the behavior of the astrocytes that were present in the culture dish. In response to glutamate application, these cells displayed long-lasting calcium oscillations, by far a more fascinating response than the steady-state calcium increase displayed by neurons. Since that time, I have been studying neuronal plasticity, taking into account the possibility that astrocytes strictly cooperate with neurons to make the brain function properly.

Comprehensibly, the emerging novel view of astrocytes was initially not accepted. However, as new, convincing experimental studies appeared in the literature, the scientific community was less and less reluctant in assigning to these glial cells functions once thought to be a business exclusive of neuronal cells.

The emerging view attributes to astrocytes distinct roles in important functional processes in the brain. We need now to proceed rigorously in testing the intriguing possibility that a defect in the multiple actions of astrocytes contributes to the genesis and/or development of brain disorders such as epilepsy, stroke, migraine, and Alzheimer’s disease. Results from the new studies will clarify whether or not these cells could be potential targets for the development of novel, more efficacious, therapeutic approaches for these diseases.