Cholinergic modulation of cognitive processing: insights drawn from computational models

Abstract

Acetylcholine plays an important role in cognitive function, as shown by pharmacological manipulations that impact working memory, attention, episodic memory, and spatial memory function. Acetylcholine also shows striking modulatory influences on the cellular physiology of hippocampal and cortical neurons. Modeling of neural circuits provides a framework for understanding how the cognitive functions may arise from the influence of acetylcholine on neural and network dynamics. We review the influences of cholinergic manipulations on behavioral performance in working memory, attention, episodic memory, and spatial memory tasks, the physiological effects of acetylcholine on neural and circuit dynamics, and the computational models that provide insight into the functional relationships between the physiology and behavior. Specifically, we discuss the important role of acetylcholine in governing mechanisms of active maintenance in working memory tasks and in regulating network dynamics important for effective processing of stimuli in attention and episodic memory tasks. We also propose that theta rhythm plays a crucial role as an intermediary between the physiological influences of acetylcholine and behavior in episodic and spatial memory tasks. We conclude with a synthesis of the existing modeling work and highlight future directions that are likely to be rewarding given the existing state of the literature for both empiricists and modelers.

Keywords: acetylcholine; attention; computational model; entorhinal cortex; memory; oscillatory interference; spatial navigation; theta.

Figure 1

Major cholinergic projections of the central nervous system. Two groups of projections exist: the magnocellular basal forebrain cholinergic system and the brainstem cholinergic system. The magnocellular basal forebrain cholinergic system includes the medial septal nucleus (MS), the vertical and horizontal limbs of the diagonal band of Broca (DB), and the nucleus basalis magnocellularis (nBM). The horizontal limb of the DB and nBM has extensive diffuse projections to neocortex as well as projections to basolateral amygdala and olfactory bulb (these latter two are not shown here). The MS and vertical limb of the DB project to hippocampus and entorhinal cortices. The brainstem cholinergic system includes the pedunculopontine tegmental nucleus (PPT) and laterodorsal pontine tegmentum (LDT) and projects predominantly to the thalamus but also to the basal forebrain region.

Figure 2

Summary of modulatory effects of acetylcholine (ACh) on cortical circuit dynamics. Increased ACh (left) boosts the processing of extrinsic afferent projections, suppresses intrinsic projections, and lowers the threshold for the induction of long-term potentiation (LTP). Reduced ACh boosts processing of intrinsic projections, raises the threshold for the induction of LTP and increases the likelihood that LTD is induced.

Figure 3

Activation dynamics and plasticity in Norman et al. (2006) model of theta function. Inhibitory oscillations convert differences in the amount of excitation received by cells within a network into a time (phase) code. Three example cells are shown, each receiving a different amount of excitatory input: 0.0—this cell receives no input and never activates, it incurs no LTP or LTD; 0.3—this cell receives moderate input and activates only during the trough of the oscillations, it incurs LTD as a result; and 0.6—this cell receives strong input and activates during more than half of the oscillation, it incurs LTP as a result. See text for additional details.

Figure 4

Suggested role for acetylcholine in driving the tuning of grid cells. (A) Three example movements are shown by the white arrow in a circular arena. The cardinal direction of each of these movements is projected onto a set of cells cosine tuned to fire in a specific direction. (B) The movement direction for the examples shown in (A) are shown projected onto an example directionally tuned cell that prefers head directions pointing east. (C) Differences in the strength of the projection onto the head direction cell changes the rate at which two oscillators phase shift inducing an oscillatory interference pattern. Movement is depicted as a step function (top line). The movement causes one of two oscillators (the second line) to shift frequency changing its phase alignment to a baseline oscillator (the third line) so that summation of the oscillators shifts from constructive interference to destructive interference and back again (the fourth line). Windows of constructive interference induce activity in a cell in which these oscillations are summed (hash marks shown at the bottom). (D–F) Patterns of constructive and destructive interference shown for cells with three different preferred headings. (G) The pattern of constructive interference resembling the firing pattern of an entorhinal grid cell that results from the summation of three oscillators that reflect movement in three headings spaced by 120°.