Astrocytes Detect Changes in Intracranial Pressure and Maintain the Homeostatic Control of Brain Blood Flow

Post by Amanda McFarlan 

What's the science?

Cerebral perfusion pressure, determined by the difference between mean arterial blood pressure and intracranial pressure (pressure inside the skull), is responsible for driving blood flow and delivering oxygen to brain tissue. Cerebral blood vessels within the brain are wrapped with the endfeet of astrocytes, a type of glial cell important for the metabolic and structural support of neurons. Blood vessels respond to changes in intracranial pressure by dilating or constricting, which likely causes structural changes to the astrocyte endfeet, and thus makes astrocytes ideally located to act as pressure sensors in the brain. This week in Nature Communications, Marina and colleagues tested the hypothesis that astrocytes in the brain act as physiological sensors that detect changes in blood flow. 

How did they do it?

The authors investigated how decreasing cerebral perfusion pressure affects cerebral blood flow. To induce acute decreases in cerebral perfusion pressure, the authors increased intracranial pressure in adult rats by infusing saline into the lateral cerebral ventricle. Then, they recorded changes in calcium levels from cortical astrocytes in response to increased intracranial pressure using in vivo 2-photon imaging. Next, the authors studied how astrocytes in the brainstem (close to the sympathetic nervous system control circuits) respond to changes in cerebral perfusion pressure. To do this, they used confocal microprobe imaging to record the frequency and duration of calcium signals from astrocytes of the ventrolateral medulla oblongata (part of the brainstem) in response to changes in cerebral perfusion pressure. Finally, the authors investigated the role of brainstem astrocytes in mediating homeostatic mechanisms that are initiated with increased intracranial pressure. To accomplish this, they interrupted the signalling between astrocytes and sympathetic nervous system neurons by virally expressing either the light chain of tetanus toxin (TeLC), the dominant negative SNARE (dnSNARE), or an ATP-degrading enzyme transmembrane prostatic acid phosphatase (TMPAP) in astrocytes of the ventrolateral medulla oblongata. They then measured arterial blood pressure, heart rate and sympathetic nerve activity in response to increased intracranial pressure.

What did they find?

The authors found that increasing the intracranial pressure by 10-15 mmHg (i.e. what would be expected to occur in response to an acute change in posture) caused a reduction in cerebral blood flow in the brain by 40% as well as increased systemic arterial blood pressure and heart rate, which facilitated oxygen delivery to the brain. Then, using 2-photon imaging, they revealed that cortical astrocytes had robust calcium signals in response to increased intracranial pressure, suggesting that the astrocyte activity was elevated. They also showed that the dilation of cortical blood vessels (that are wrapped by astrocyte endfeet) in response to increased intracranial pressure preceded the increased calcium signals in astrocytes. This suggests that astrocytes may play a role in mediating blood vessel dilation. Next, the authors found that, similar to astrocytes in the cortex, the frequency and duration of astrocyte calcium signals in the ventrolateral medulla oblongata (a region of the brainstem) was increased. Finally, they determined that control rats with intact astrocyte signalling showed increased levels of arterial blood pressure, heart rate and sympathetic nerve activity in response to increased intracranial pressure, while rats expressing either TeLC, dnSNARE or TMPAP in brainstem astrocytes did not show any change. Together, these findings suggest that brainstem astrocytes may use calcium-dependent signalling to activate sympathetic control circuits in response to changes in intracranial pressure.

What’s the impact?

This is the first study to show that both cortical and brainstem astrocytes sense changes in cerebral perfusion pressure in the brain. Moreover, brainstem astrocytes use calcium-dependent signalling to activate compensatory mechanisms that maintain blood flow and oxygen delivery to the brain. Together, these findings suggest that astrocytes may be important physiological sensors in the brain, responding to changes in pressure and activating sympathetic control circuits that help to maintain homeostatic control of cerebral blood flow. 

Marina et al. Astrocytes monitor cerebral perfusion and control systemic circulation to maintain brain blood flow. Nature Communications (2020). Access the original scientific publication here.