Cerebral Arterial Pulsation Drives Paravascular CSF–Interstitial Fluid Exchange in the Murine Brain

TLDR

The glymphatic system describes rapid CSF movement along paravascular routes around cerebral arteries to clear interstitial solutes such as amyloid β, and prior work has suggested arterial pulsation may drive this bulk flow, though direct assessment was lacking. Using in vivo two‑photon microscopy, the study visualized pulsatility of penetrating intracortical arteries in mice. Ligation of the internal carotid artery reduced arterial pulsatility by ~50% and slowed CSF–ISF exchange, while dobutamine increased pulsatility by ~60% and accelerated exchange, demonstrating arterial pulsatility as a key driver of paravascular CSF influx and implicating its role in amyloid β accumulation.

Abstract

CSF from the subarachnoid space moves rapidly into the brain along paravascular routes surrounding penetrating cerebral arteries, exchanging with brain interstitial fluid (ISF) and facilitating the clearance of interstitial solutes, such as amyloid β, in a pathway that we have termed the “glymphatic” system. Prior reports have suggested that paravascular bulk flow of CSF or ISF may be driven by arterial pulsation. However, cerebral arterial pulsation could not be directly assessed. In the present study, we use in vivo two-photon microscopy in mice to visualize vascular wall pulsatility in penetrating intracortical arteries. We observed that unilateral ligation of the internal carotid artery significantly reduced arterial pulsatility by ∼50%, while systemic administration of the adrenergic agonist dobutamine increased pulsatility of penetrating arteries by ∼60%. When paravascular CSF–ISF exchange was evaluated in real time using in vivo two-photon and ex vivo fluorescence imaging, we observed that internal carotid artery ligation slowed the rate of paravascular CSF–ISF exchange, while dobutamine increased the rate of paravascular CSF–ISF exchange. These findings demonstrate that cerebral arterial pulsatility is a key driver of paravascular CSF influx into and through the brain parenchyma, and suggest that changes in arterial pulsatility may contribute to accumulation and deposition of toxic solutes, including amyloid β, in the aging brain.