Cholinergic enhancement augments magnitude and specificity of visual perceptual learning in healthy humans

Abstract

Learning through experience underlies the ability to adapt to novel tasks and unfamiliar environments. However, learning must be regulated so that relevant aspects of the environment are selectively encoded. Acetylcholine (ACh) has been suggested to regulate learning by enhancing the responses of sensory cortical neurons to behaviorally relevant stimuli. In this study, we increased synaptic levels of ACh in the brains of healthy human subjects with the cholinesterase inhibitor donepezil (trade name: Aricept) and measured the effects of this cholinergic enhancement on visual perceptual learning. Each subject completed two 5 day courses of training on a motion direction discrimination task, once while ingesting 5 mg of donepezil before every training session and once while placebo was administered. We found that cholinergic enhancement augmented perceptual learning for stimuli having the same direction of motion and visual field location used during training. In addition, perceptual learning with donepezil was more selective to the trained direction of motion and visual field location. These results, combined with previous studies demonstrating an increase in neuronal selectivity following cholinergic enhancement, suggest a possible mechanism by which ACh augments neural plasticity by directing activity to populations of neurons that encode behaviorally relevant stimulus features.

Figure 1. Experimental procedure

a, Task description. In each trial, two fields of dots with 100% coherent motion were sequentially presented. The two fields contained either the same or slightly different directions of motion. b, Stimulus configuration. Coherent motion was presented in one of two pairs of spatial locations (1 or 2) and in the same direction of motion throughout the course of training. c, Training procedure. Subjects participated in two courses of training. Donepezil or placebo was administered beginning three days before the pre-training measurement and daily throughout training and the post-training measurement.

Figure 2. Effects of training and cholinergic enhancement with donepezil on motion direction discrimination thresholds

Each plot displays angular difference thresholds in degrees (Figure 1A) for different directions of motion, where zero degrees corresponds to the direction used for training. There was a significant improvement in performance for the trained condition (trained direction and visual field location), and this improvement was substantially larger under donepezil than under placebo. Error bars denote SEM. Single-subject data are presented in Supplemental Figure 1.

Figure 3. Donepezil increases magnitude and specificity of perceptual learning

Percent reduction in threshold following training was significantly larger under donepezil in the trained condition, and learning under donepezil was more specific to the direction of motion and visual field location used for training. Error bars denote SEM. These data are presented without normalization (i.e., raw threshold values) in Supplemental Figure 2.

Figure 4. Donepezil increases rate of perceptual learning

Percent learning in the trained condition is presented as a function of training session. Training under donepezil (filled circles) proceeded at a more rapid rate than training under placebo (empty circles). Learning rates were computed by fitting a single-parameter model of learning to the data (gray continuous lines, where the shaded area is the standard deviation derived from a jackknife estimate; see Supplemental Experimental Procedures). Error bars denote SEM.