Cholinergic basal forebrain neurons regulate vascular dynamics and cerebrospinal fluid flux

• Published in: Nature communications Vol. 16; no. 1; pp. 5343 - 15
• Main Authors: Chuang, Kai-Hsiang, Zhou, Xiaoqing Alice, Xia, Ying, Li, Zengmin, Qian, Lei, Eeles, Eamonn, Ngiam, Grace, Fripp, Jurgen, Coulson, Elizabeth J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.06.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 14; 14/34; 59; 59/36; 59/57; 631/378/2607; 631/378/3920; 692/308/575; Acetylcholinesterase; Aged; Aging; Alzheimer's disease; Animals; Basal forebrain; Basal Forebrain - blood supply; Basal Forebrain - cytology; Basal Forebrain - metabolism; Basal Forebrain - physiology; Blood levels; Brain; Cerebrospinal fluid; Cerebrospinal Fluid - metabolism; Cholinergic Neurons - drug effects; Cholinergic Neurons - metabolism; Cholinergic Neurons - physiology; Cholinergics; Cholinesterase inhibitors; Cholinesterase Inhibitors - pharmacology; Cognitive ability; Coupling; Disease; Efflux; Female; Forebrain; Functional magnetic resonance imaging; Glymphatic System - diagnostic imaging; Glymphatic System - drug effects; Glymphatic System - metabolism; Glymphatic System - physiology; Human subjects; Humanities and Social Sciences; Humans; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Middle Aged; multidisciplinary; Neurons; Oxygen - blood; Oxygenation; Pathogenesis; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-60812-3

Brain waste is cleared via a cerebrospinal fluid (CSF) pathway, the glymphatic system, whose dysfunction may underlie many brain conditions. Previous studies show coherent vascular oscillation, measured by blood oxygenation level-dependent (BOLD) fMRI, couples with CSF inflow to drive fluid flux. Yet, how this coupling is regulated, whether it mediates waste clearance, and why it is impaired remain unclear. Here we demonstrate that cholinergic neurons modulate BOLD-CSF coupling and glymphatic function. We find BOLD-CSF coupling correlates cortical cholinergic activity in aged humans. Lesioning basal forebrain cholinergic neurons in female mice impairs glymphatic efflux and associated changes in BOLD-CSF coupling, arterial pulsation and glymphatic influx. An acetylcholinesterase inhibitor alters these dynamics, primarily through peripheral mechanisms. Our results suggest cholinergic loss impairs glymphatic function by a neurovascular mechanism, potentially contributing to pathological waste accumulation. This may provide a basis for developing diagnostics and treatments for glymphatic dysfunction. The authors find cholinergic neurons regulate glymphatic waste clearance via neurovascular mechanisms, with their loss impairing this process. This finding suggests targets for diagnostics and treatment.