The role of acetylcholine in learning and memory - PubMed (original) (raw)

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The role of acetylcholine in learning and memory

Michael E Hasselmo. Curr Opin Neurobiol. 2006 Dec.

Abstract

Pharmacological data clearly indicate that both muscarinic and nicotinic acetylcholine receptors have a role in the encoding of new memories. Localized lesions and antagonist infusions demonstrate the anatomical locus of these cholinergic effects, and computational modeling links the function of cholinergic modulation to specific cellular effects within these regions. Acetylcholine has been shown to increase the strength of afferent input relative to feedback, to contribute to theta rhythm oscillations, activate intrinsic mechanisms for persistent spiking, and increase the modification of synapses. These effects might enhance different types of encoding in different cortical structures. In particular, the effects in entorhinal and perirhinal cortex and hippocampus might be important for encoding new episodic memories.

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Figures

Figure 1

Figure 1

Effect of acetylcholine on cortical dynamics. Left: High acetylcholine (ACh) levels enhance the magnitude of afferent input to cortex through action at nicotinic receptors. High ACh also suppresses the magnitude of feedback excitation in cortex via presynaptic inhibition of glutamate release. Right: Low acetylcholine levels result in a weaker influence of afferent input relative to the strength of excitatory feedback.

Figure 2

Figure 2

Schematic of functional dynamics during theta rhythm. Modeling [39] suggests that encoding occurs at the trough and rising slope of theta, when current sinks are strong in stratum lacunosum-moleculare (SLM), where entorhinal input terminates, and currents in layers receiving CA3 input are weak. Retrieval would occur near the peak and falling slope of theta, when current sinks in SLM are weak and sinks in layers receiving CA3 input are strong. Selective cholinergic modulation of SLM interneurons [43] and oriens-lacunosum-moleculare (OLM) cells [47] could selectively regulate inhibition of entorhinal input from weak to strong during different phases of theta.

Figure 3

Figure 3

Model of how acetylcholine induces persistent activity during the delay period of a delayed match to sample task. Top: In control conditions, a neuron responds to depolarizing input representing sample and test by spiking only during the depolarization. Bottom: Muscarinic cholinergic activation (High ACh) of intrinsic mechanisms allows persistent spiking to continue after the sample stimulus, resulting in spiking during the delay period for active maintenance of the stimulus, and causing greater spiking response during the matching test stimulus. Green - **Study showing that systemic administration of scopolamine causes an impairment in working memory during a delayed matching task. Winters - *Local infusion of scopolamine impairs spontaneous recognition of novel objects in rats. Bunce - **Septal infusion of carbachol after initial trials causes impairments of memory for visited arms after a delay. This could be due to acetylcholine interfering with consolidation. McGaughy - **Selective lesions of the cholinergic innervation of entorhinal cortex selectively interferes with maintenance and encoding of novel odors for delayed matching, suggesting the loss of intrinsic mechanisms of persistent spiking, while not impairing delayed matching for familiar odors, suggesting that synaptic mechanisms can take over for inducing persistent spiking. Turchi - **Selective lesions of cholinergic innervation of perirhinal cortex interfere with encoding of novel visual stimuli for subsequent recognition after a delay. Giocomo - *Nicotinic modulation enhances excitatory transmission at entorhinal input to region CA3 of the hippocampus in stratum lacunosum-moleculare, but does not enhance recurrent excitatory transmission in stratum radiatum. De Sevilla - *Cholinergic presynaptic inhibition of synaptic transmission affects functional AMPA synapses, but does not affect NMDA currents at “silent synapses.” Gais - **The theory that low levels of acetylcholine are necessary for consolidation is supported by data showing that administration of the acetylcholinesterase blocker physostigmine after training (but before sleep) causes an impairment in memory function after sleep, possibly due to reduction of consolidation. Griffin - *Demonstration that learning is enhanced when stimuli for conditioning are presented during periods of time in which theta rhythm has been detected, compared to slower learning during periods without theta rhythm. Fransen - *Detailed computational modeling demonstrating a potential mechanism for graded persistent spiking activity, in which stability is obtained with a neutral zone in which cation currents do not change, between a high and a low threshold which induces changes in cation current. Olson - *Demonstration that medial temporal lobe structures may be involved in working memory for complex novel stimuli, in addition to encoding into long-term memory. This working memory may depend on persistent spiking. Ovsepian - *Demonstration that activation of cholinergic receptors in vivo enhances the induction of long-term potentiation.

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