In some studies, we use the cholinesterase inhibitor and Alzheimer’s medication donepezil (trade name Aricept) to enhance the actions of the naturally-occurring neurotransmitter acetylcholine. Blocking cholinesterase activity results in a prolonged lifetime and effectiveness of acetylcholine after it is released by presynaptic terminals and is therefore a useful method for studying the role of this neurotransmitter in cognitive and perceptual processes. In other studies, we administer nicotine to directly activate the nicotinic subclass of acetylcholine receptors.
Effects of acetylcholine on perceptual measures of spatial integration
We previously found that donepezil reduces the spatial spread of fMRI responses to visual stimulation in early visual cortex (Silver et al. 2008). This is consistent with research from non-human animal models showing that acetylcholine reduces receptive field size in these cortical areas. Although these data suggest that acetylcholine improves the spatial resolution of stimulus representations in visual cortex, the perceptual consequences of this were not known. We tested the effects of donepezil on surround suppression and crowding, two phenomena that involve spatial interactions between visual field locations. We found that cholinergic enhancement reduces orientation-specific surround suppression of gratings but had no effect on visual crowding of letters (Kosovicheva et al., 2012).
We have also examined the effects of donepezil on a measure of spatial tuning of visual perception. We found that cholinergic enhancement with donepezil improved target detection performance on this task, and computational modeling suggested that this improvement was mainly due to a narrowing of the extent of facilitatory perceptual spatial interactions (Gratton et al., 2017). In another study, we found no detectable effect of donepezil on the spatial precision of visual working memory, indicating fundamental differences in the neural substrates underlying spatial precision of perception versus working memory (Harewood Smith et al., 2017).
Investigating the potential of nicotine to treat age-related hearing loss
Age-related decline in central auditory function significantly affects quality of life in the elderly, with impaired speech perception leading to increased risk for depression, social isolation and cognitive decline. There is currently no medication-based treatment of age-related central auditory decline. Activation of acetylcholine receptors with nicotine provides a potential means of reducing and/or reversing age-related auditory decline. We are measuring auditory tuning curves in individual voxels in auditory cortex with fMRI in both younger and older adults and assessing the acute effects of nicotine gum (which is non-addictive when administered in this form) on excitatory and inhibitory components of these tuning curves. This work is supported by the National Institute on Aging and is being done in collaboration with three other laboratories that are studying effects of nicotine on auditory perception and electroencephalographic (EEG) measurements in humans (Fan-Gang Zeng) and associated cellular and molecular mechanisms in mouse models (Raju Metherate and Khaleel Razak).