High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation

doi:10.1016/S0079-6123(03)45015-2

Progress in Brain Research

Volume 145, 2004, Pages 207-231

https://doi.org/10.1016/S0079-6123(03)45015-2 Get rights and content

Publisher Summary

This chapter focuses on how the different physiological effects of acetylcholine could interact to alter specific functional properties of the cortex. Computational modeling demonstrates that the combined physiological effects of acetylcholine serve to enhance the influence of afferent input on neuronal spiking activity, while reducing the influence of internal and feedback processing. Computational models also demonstrate how these network properties can be interpreted functionally as both enhancing attention to sensory stimuli and enhancing the encoding of new memories. The levels of acetylcholine in the hippocampus and neocortex change dramatically during different stages of waking and sleep. High levels of acetylcholine during active waking may set appropriate dynamics for attention to sensory input or encoding of new information. At the same time, the cholinergic suppression of excitatory feedback connections prevents interference from internal processing of previously stored information. Lower levels of acetylcholine during quiet waking and slow wave sleep may provide a release from this suppression of excitatory feedback, allowing stronger spread of activity within the hippocampus and from hippocampus to entorhinal cortex, thereby facilitating the process of consolidation of separate memory traces.

Introduction

Extensive physiological research has demonstrated a number of effects of acetylcholine within the hippocampus, piriform cortex, neocortex, and thalamus (Krnjević and Phillis, 1963, Krnjević et al., 1971; see review in Hasselmo, 1995). Here the review will focus on data regarding cholinergic modulation in the hippocampus and piriform cortex, but data from the neocortex suggests similar principles apply in other cortical structures.

At times the effects of acetylcholine on specific neuron types and synaptic pathways in cortical structures appear paradoxical and inconsistent. For example, why should acetylcholine simultaneously enhance pyramidal cell spiking through depolarization (Krnjević et al., 1971, Cole and Nicoll, 1984), while suppressing excitatory glutamatergic synaptic transmission at intrinsic synapses in the hippocampus (Hounsgaard, 1978, Valentino and Dingledine, 1981, Dutar and Nicoll, 1988, Hasselmo and Bower, 1992, Hasselmo and Schnell, 1994) and neocortex (Brocher et al., 1992, Gil et al., 1997, Hsieh et al., 2000)? Similarly, why should acetylcholine in the hippocampus simultaneously depolarize interneurons (Frazier et al., 1998, McQuiston and Madison, 1999a, McQuiston and Madison, 1999b, Alkondon and Albuquerque, 2001) while suppressing hippocampal inhibitory synaptic transmission (Pitler and Alger, 1992, Patil and Hasselmo, 1999)? A unifying theoretical framework is required for understanding these disparate physiological effects.

Computational modeling offers a unifying theoretical framework for understanding the functional properties of acetylcholine within cortical structures (Hasselmo, 1995, Hasselmo, 1999). This chapter will provide a description of how the different physiological effects of acetylcholine could interact to alter specific functional properties of the cortex. In particular, acetylcholine enhances the response to afferent sensory input while decreasing the internal processing based on previously formed cortical representations. These same circuit level effects can be categorized with different colloquial terms at a behavioral level, sometimes being interpreted as an enhancement of attention, sometimes as an enhancement of memory encoding. But the same change in circuit level dynamics could underlie all these behavioral effects. In this chapter, we will present the basic theoretical framework of enhanced response to input, with reduced feedback processing. We will then discuss individual physiological effects of acetylcholine in the context of this framework. Finally, we will discuss how the loss of cholinergic modulation will shift network dynamics toward those appropriate for the consolidation of previously encoded information.

Section snippets

Evidence for diffuse modulatory state changes caused by acetylcholine

The computational models described here assume that acetylcholine causes diffuse modulatory state changes within cortical structures. This assumption is based on the following evidence: (1) microdialysis studies show dramatic changes in acetylcholine level in cortex during different stages of waking and sleep; (2) anatomical studies of cholinergic fibers suggest diffuse modulatory influences on cortical function; and (3) the slow transition between different states is supported by data showing

Acetylcholine enhances input relative to feedback

This chapter focuses on a single general framework for interpreting effects of acetylcholine within cortical structures. As summarized in Fig. 2, acetylcholine appears to enhance the strength of input relative to feedback in the cortex. The physiological effects of acetylcholine serve to enhance the influence of feedforward afferent input to the cortex, while decreasing background activity due to spontaneous spiking and the spread of activity via excitatory feedback connections within cortical

Acetylcholine enhances spiking response to afferent input

The physiological effects of acetylcholine on cortical pyramidal cells act to enhance the spiking response to excitatory afferent input, consistent with the enhanced response to input summarized in Fig. 2. Early studies using single unit recordings from the neocortex showed that application of cholinergic agonists to the cortex would cause a strong increase in firing rate of neurons (Krnjević and Phillis, 1963, Krnjević et al., 1971, Krnjević,1984). This increase in firing rate was demonstrated

Cholinergic modulation of inhibitory interneurons suppresses background activity while enhancing response to input

Acetylcholine also regulates the functional properties of cortical circuits through modulation of inhibitory interneurons. On first inspection, some of the data on these modulatory effects of acetylcholine appear contradictory and paradoxical, but they make sense when analyzed computationally, as shown in Fig. 4. Experimental data in the hippocampus demonstrates that acetylcholine simultaneously depolarizes inhibitory interneurons, while suppressing the evoked release of GABA at inhibitory

Acetylcholine selectively suppresses excitatory feedback but does not suppress afferent input

Acetylcholine appears to reduce the internal processing of information by cortical structures, due to suppression of excitatory synaptic transmission at excitatory feedback connections within cortical circuits. This suppression of excitatory glutamatergic transmission contrasts with the depolarization of excitatory pyramidal cells in the same manner that the suppression of inhibitory GABAergic transmission contrasts with the depolarization of inhibitory interneurons. In the framework of

Functional data

The theoretical framework presented in Fig. 2 raises the question: What is the functional purpose of the alteration in circuit dynamics induced by cholinergic modulation? Why would it be necessary to selectively enhance the afferent input relative to feedback excitation? This section will review behavioral evidence demonstrating the potential role of this change in circuit dynamics, showing how acetylcholine effects may enhance attention to external stimuli, and may enhance encoding of new

Acetylcholine and the enhancement of attention

Behavioral data supports the functional framework presented here for the role of acetylcholine within cortical structures. In particular, the enhancement of afferent input relative to internal processing could enhance performance in attention tasks. The performance in attention tasks often depends on the sensitivity to specific weak stimuli over an extended period of time. Performance in these tasks will be enhanced if the neuronal response to the stimulus is strong (allowing rapid and accurate

Acetylcholine and the enhancement of encoding

As noted earlier, the enhanced response to afferent input with the reduction of feedback can play a role in enhancing performance in attention tasks. But this same change in dynamics could also be important for the encoding of new information in memory. Traditionally, researchers have attempted to distinguish and differentiate the role of acetylcholine in attention from the role in encoding. However, in this section we will review how these may not be separable functions. The same enhancement

Cholinergic suppression of feedback may prevent interference

The cholinergic suppression of excitatory transmission might appear somewhat paradoxical when considering encoding. Why would a substance that is important for learning cause suppression of excitatory transmission? As noted earlier, it is important to emphasize the selectivity of this suppression for intrinsic but not afferent fibers. The importance of this selective suppression of transmission has been analyzed in computational models of associative memory function (Hasselmo et al., 1992,

Acetylcholine enhances long-term potentiation

Activation of acetylcholine receptors also enhances synaptic modification in long-term potentiation experiments. This enhancement would naturally be important for the encoding of new information. Physiological experiments in brain slice preparations have demonstrated enhancement of LTP by cholinergic agonists at a number of different synaptic pathways, including the perforant path input to the dentate gyrus (Burgard and Sarvey, 1990), the Schaffer collateral input to region CA1 (Blitzer et al.,

Acetylcholine enhances sustained spiking activity

Acetylcholine also appears to influence the firing activity of cortical circuits by enhancing intrinsic mechanisms for sustained spiking activity in individual neurons. Data from slice preparations of entorhinal cortex demonstrate this cellular mechanism for sustained spiking activity. In physiological recordings from non-stellate cells in slice preparations (Klink and Alonso, 1997a, Klink and Alonso, 1997b), application of the cholinergic agonist carbachol causes long-term depolarizations,

Low levels of acetylcholine set appropriate dynamics for consolidation

If acetylcholine plays such an important role in attention and encoding, then why is it not present at high concentrations at all times? Or why could the modulatory effects of acetylcholine not be maintained as the baseline parameters for cortical circuits? The ability of acetylcholine to selectively regulate these parameters suggests that the low acetylcholine state has functional importance. In this section, we review the hypothesis that low levels of acetylcholine are important for the

Concluding remarks

Acetylcholine has a number of different physiological effects on cortical circuits which often appear inconsistent. Computational modeling provides a unifying theoretical framework for understanding these different physiological effects, as summarized in this paper. Modeling demonstrates that the combined physiological effects of acetylcholine serve to enhance the influence of afferent input on neuronal spiking activity, while reducing the influence of internal and feedback processing.

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High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation

Publisher Summary

Introduction

Section snippets

Evidence for diffuse modulatory state changes caused by acetylcholine

Acetylcholine enhances input relative to feedback

Acetylcholine enhances spiking response to afferent input

Cholinergic modulation of inhibitory interneurons suppresses background activity while enhancing response to input

Acetylcholine selectively suppresses excitatory feedback but does not suppress afferent input

Functional data

Acetylcholine and the enhancement of attention

Acetylcholine and the enhancement of encoding

Cholinergic suppression of feedback may prevent interference

Acetylcholine enhances long-term potentiation

Acetylcholine enhances sustained spiking activity

Low levels of acetylcholine set appropriate dynamics for consolidation

Concluding remarks

Behav. Neurosci.

Behav. Neural Biol.

Behav. Brain Res.

Neurobiol Learn Mem.

Neuropsychopharmacology

Neurosci.

Behav. Neural Biol.

Brain Res.

Neurobiol. Learn Mem.

Prog. Neurobiol.

Neurosci. Lett.

Physiol. Behav.

Brain Res.

Neuropsychologia

Neurosci. Lett.

Brain Res.

Neuroscience

Physiol Behav.

Neurosci. Lett.

Prog. Neurobiol.

Trends Neurosci.

Neuron

Neuroscience

Behav. Brain Res.

Trends Cognitive Sciences

Trends Neurosci.

Behav. Brain Res.

Behav. Brain Res.

Brain Res.

Brain Res.

Cognitive Brain Res.

Cognitive Brain Research

Cognitive Brain Res.

Exp. Neurol.

Brain Res.

Brain Res.

Life Sci.

Neurosci Res.

Exp. Neurol.

Neurosci Lett.

Nicotinic acetylcholine receptor alpha7 and alpha4beta2 subtypes differentially control GABAergic input to CA1 neurons in rat hippocampus

J. Neurophysiol.

A non-alpha7 nicotinic acetylcholine receptor modulates excitatory input to hippocampal CA1 interneurons

J. Neurophysiol.

Ibotenic acid lesions of the medial septum retard delay eyeblink conditioning in rabbits (Oryctolagus cuniculus)

Behav. Neurosci.

Modulation of the input/output function of rat piriform cortex pyramidal cells

J. Neurophysiol.

Short term memory in the rhesus monkey: disruption from the anticholinergic scopolamine

Pharmacol. Biochem. Behav.

Disruption of decrements in conditioned stimulus processing by selective removal of hippocampal cholinergic input

J. Neurosci.

Cholinergic modulation of synaptic inhibition in the guinea pig hippocampus in vitro: excitation of GABAergic interneurons and inhibition of GABA release

J. Neurophysiol.

Medial septal lesions retard classical conditioning of the nicitating membrane response in rabbits

Science

192 IgG-saporin: I. specific lethality for cholinergic neurons in the basal forebrain of the rat

J. Neuropathol. Exp. Neurol.