The role of cholinergic signaling in multi-sensory gamma stimulation induced perivascular clearance of amyloid

ABSTRACT Modulatory neurotransmitters exert powerful control over neurons and the brain vasculature. Gamma Entrainment Using Sensory Stimuli (GENUS) promotes amyloid clearance via increased perivascular cerebral spinal fluid (CSF) flux in mouse models of Alzheimer’s Disease. Here we use whole-brain activity mapping to identify the cholinergic basal forebrain as a key region responding to GENUS. In line with this, GENUS promoted cortical acetylcholine release, vascular dilation, vasomotion and perivascular clearance. Inhibiting cholinergic signaling abolished the effects of GENUS, including the promotion of arterial pulsatility, periarterial CSF influx, and the reduction of cortical amyloid levels. Our findings establish cholinergic signaling as an essential component of the brain’s ability to promote perivascular amyloid clearance via non-invasive sensory stimulation.