Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain.
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.
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642, Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, Portland, Oregon 97239, and Department of Neurology, Tongii Hospital, Tongii Medical College, Huazhong University of Science and Technology, Wuhan, China 430030.
Jeffrey J
JJ
Iliff
Minghuan
M
Wang
Douglas M
DM
Zeppenfeld
Arun
A
Venkataraman
Benjamin A
BA
Plog
Yonghong
Y
Liao
Rashid
R
Deane
Maiken
M
Nedergaard
D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology*; D001921:Brain / Q000098:blood supply* / Q000502:physiology*; D001923:Brain Chemistry / Q000502:physiology; D002536:Cerebral Arteries / Q000737:chemistry / Q000502:physiology*; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000502:physiology*; D045604:Extracellular Fluid / Q000737:chemistry / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D036641:Microscopy, Fluorescence, Multiphoton / Q000379:methods