Cortical acetylcholine response to deep brain stimulation of the basal forebrain in mice

Deep brain stimulation (DBS) using electrical stimulation of neuronal tissue in the basal forebrain to enhance release of the neurotransmitter acetylcholine is under consideration to improve executive function in patients with dementia. Although some small studies indicate a positive response in the clinical setting, the relationship between DBS and acetylcholine pharmacokinetics is incompletely understood. We examined the cortical acetylcholine response to different stimulation parameters of the basal forebrain. Two-photon in vivo imaging was combined with deep brain stimulation in C57BL/6J mice. Stimulating electrodes were implanted in the subpallidal basal forebrain, and the ipsilateral somatosensory cortex was imaged. Acetylcholine activity was determined using the GRAB_ACh-3.0 acetylcholine receptor sensor, and blood vessels were visualized with Texas red. Experiments manipulating stimulation frequency demonstrated that integrated acetylcholine-induced fluorescence was insensitive to frequency with the same number of pulses, and that maximum peak levels were achieved with frequencies from 60 to 130 Hz. Altering pulse train length indicated that longer stimulation resulted in higher peaks and more activation with sublinear summation. The acetylcholinesterase inhibitor, donepezil, increased the peak response to 600 pulses of stimulation at 60 Hz, and the integrated response increased by 57% with the 2 mg/kg dose and 126% with the 4 mg/kg dose. Acetylcholine levels returned to baseline with a time constant of 14-18 s. Donepezil increases total acetylcholine receptor activation associated with DBS but does not change temporal kinetics. The long time constants observed in the cerebral cortex add to the evidence supporting volume and synaptic neurotransmission.NEW & NOTEWORTHY Peak acetylcholine responses to deep brain stimulation of the subpallidal basal forebrain increases with increased frequency and number of pulses. Long recovery periods in the 10s of seconds support "volume" versus "phasic" transmission of acetylcholine. Donepezil administration enhances the effect of stimulation on cortical acetylcholine release.