Cholinergic control of visual categorization in macaques

Abstract

Acetylcholine (ACh) is a neurotransmitter acting via muscarinic and nicotinic receptors that is implicated in several cognitive functions and impairments, such as Alzheimer's disease. It is believed to especially affect the acquisition of new information, which is particularly important when behavior needs to be adapted to new situations and to novel sensory events. Categorization, the process of assigning stimuli to a category, is a cognitive function that also involves information acquisition. The role of ACh on categorization has not been previously studied. We have examined the effects of scopolamine, an antagonist of muscarinic ACh receptors, on visual categorization in macaque monkeys using familiar and novel stimuli. When the peripheral effects of scopolamine on the parasympathetic nervous system were controlled for, categorization performance was disrupted following systemic injections of scopolamine. This impairment was observed only when the stimuli that needed to be categorized had not been seen before. In other words, the monkeys were not impaired by the central action of scopolamine in categorizing a set of familiar stimuli (stimuli which they had categorized successfully in previous sessions). Categorization performance also deteriorated as the stimulus became less salient by an increase in the level of visual noise. However, scopolamine did not cause additional performance disruptions for difficult categorization judgments at lower coherence levels. Scopolamine, therefore, specifically affects the assignment of new exemplars to established cognitive categories, presumably by impairing the processing of novel information. Since we did not find an effect of scopolamine in the categorization of familiar stimuli, scopolamine had no significant central action on other cognitive functions such as perception, attention, memory, or executive control within the context of our categorization task.

Keywords: acetylcholine; categorization; cognition; cognitive; learning; macaque; muscarinic; scopolamine.

Figure 1

Categorization task. After successfully fixating on a central fixation spot and concurrently pressing two levers for 500 ms, a stimulus was presented for 200 ms. Immediately afterward, a light gray response cue was presented for 1200 ms during which the macaque had the opportunity to categorize the previously seen image as a “flower” or a “monkey” by releasing the appropriate lever.

Figure 2

Parametric interpolation with random phases of one monkey and one flower exemplar. Numbers on top of each image refer to % coherence. At 0 level, the image therefore contains only noise.

Figure 3

Set of 12 familiar stimuli (100% coherence).

Figure 4

Average psychometric functions of the behavioral performance for the two monkeys, (A) Effect of scopolamine on the performance of the categorization task for monkey. D07 (seven scopolamine experiments, 7.5–10 μg/kg dose) and monkey K03 (four scopolamine experiments, 7.5 μg/kg dose). On the Y axis is plotted the proportion of correct responses (probability of a correct response, mean ± 1SE). The color coding scheme is indicated in the lower right. Both animals showed worst performance when categorizing novel images under scopolamine. (B) Butyl-scopolamine experiments: performance under butyl-scopolamine (2–4 mg/kg), a scopolamine analog that cannot cross the blood brain barrier (three and six experiments, respectively). Experiments within a panel consist of scopolamine and control experiments on successive days whereas comparisons between panels involve experiments spaced potentially weeks or months apart.

Figure 5

Mean percent impairment of performance for each monkey for the categorization of familiar or novel stimuli compared to control. The means of the three highest coherence levels have been used in making these comparisons. The colors of the bars match the colors of the curves in Figure 4, other than that the control in this case is not saline but butyl-scopolamine. (A) Mean percent performance change (Mean ± SE) of drug treatment relative to saline. Positive values are for impairment, negative values for improvement. The categorization of novel stimuli was significantly impaired by scopolamine compared to the other treatments which were not significantly different from each other in either monkey. (B) Effect on performance due to the central action of scopolamine: mean percent impairment due to scopolamine after subtracting the mean impairment due to butyl-scopolamine, the peripherally acting analog. On the basis of the result shown in (A), the impairment in the categorization of the familiar stimuli is not significant in either monkey. The categorization of novel stimuli but not of familiar stimuli was significantly impaired by the central actions of scopolamine, based on the butyl-scopolamine control. Statistics in the text.

Figure 6

Response latencies under the four different conditions at the seven different coherence levels. Response is measured from the time the stimulus is presented to the time the appropriate lever is released and is shown here for the correct responses only. In monkey D07 (scopolamine drug injections 7.5 and 10 μg/kg combined), response latencies were shorter for the more coherent stimulus levels (ANOVA, p < 1.96e⁻¹⁴). Scopolamine significantly slowed categorization responses for novel stimuli at the more coherent levels (55–100) as compared to categorizing the novel stimuli after injection of saline, while the categorization of familiar stimuli under saline was generally the fastest. In monkey K03 response latencies were also shorter for the more coherent stimulus levels (ANOVA, p <  6.81e⁻¹⁵) at the 7.5 μg/kg dose level.