Elsevier

Behavioural Brain Research

Volume 221, Issue 2, 10 August 2011, Pages 424-429
Behavioural Brain Research

Review
Acetylcholine and memory: A long, complex and chaotic but still living relationship

https://doi.org/10.1016/j.bbr.2010.11.052Get rights and content

Abstract

Even though “procholinergic” drugs are almost the sole kind of treatments currently used as cognitive enhancers in patients with Alzheimer's disease, the role of acetylcholine (ACh) in learning and memory is still poorly understood. In this short review, we focus on the septo-hippocampal cholinergic system and try to demonstrate that understanding ACh-memory relationships requires taking into account two characteristics of memory function. First, this function is polymorphic and relies on multiple neural systems. It appears that hippocampal ACh may not only modulate specific computational function of the hippocampus but also contributes to the functional coordination of multiple memory systems in a task-dependent manner. Second, memorization implies different phases which are differentially regulated by ACh. Namely, several lines of evidence suggest a “biphasic” involvement with hippocampal ACh facilitating memory encoding but hampering memory consolidation and retrieval, and low hippocampal ACh promoting consolidation of declarative memory. By spotting major determinants of memory modulation by hippocampal ACh, we hope that the present non exhaustive review will help to improve our understanding of the complexity of ACh-memory relationships.

Research highlights

Acetylcholine and memory had a long common story until the discovery of a more specific neurotoxin. ▶ The current review proposes to revisit the cholinergic hypothesis by spotting the dynamics of its modulating influence. ▶ We suggest that the septo-hippocampal ACh system contributes to memory systems selection and coordination. ▶ Computational models of hippocampal function and experimental findings are converging to relate ACh level to the phase of memory formation. ▶ This “biphasic” hypothesis of cholinergic modulation finds validation in both animals and humans.

Introduction

As pointed out by Davies [1], “if there is a key transmitter for memory and perhaps, for other aspects of cognition, the best bet for that transmitter would be acetylcholine”. Indeed, at that time several lines of evidence were converging to promote the importance of the role of acetylcholine (ACh) in learning and memory processes. Since the seventies, pharmacological experiments conducted in both animals [2] and humans [3] have shown learning and memory deficits after anticholinergic treatments. In addition, impaired function of cholinergic neurons in the basal forebrain has been associated with memory alteration in aged subjects [4], [5], [6]. Basal forebrain cholinergic cell loss is also a consistent feature of Alzheimer's disease (AD), which has been related to cognitive deficits (see review in [6]). These observations have naturally led to the formulation of the cholinergic hypothesis of geriatric memory dysfunction by Bartus et al. [4]. Therefore, a potential treatment strategy was aimed at enhancing cholinergic function by using cholinesterase inhibitors. These compounds have demonstrated some beneficial effects and with the exception of memantine they are to date, the only compounds that have received Food and Drug Administration approval for AD treatment. Altogether, these considerations are consistent with the hypothesis linking cholinergic involvement in memory processes.

However, the link between ACh and memory has somehow lost its conclusiveness within these last 15 years, mainly because selective cholinergic lesions were found to have little or no effect on memory.

In this short paper we will focus on the septo-hippocampal cholinergic system as a more comprehensive review on ACh and learning and memory is presented in several contributions of this special issue, and we will review evidences supporting the view that understanding ACh-memory relationships requires to take into account two principal characteristics of memory that make the story complex: (1) first, memory is not a unitary function; it relies on multiple cognitive processes sustained by multiple brain systems. It appears that ACh implication depends on the memory demand, and it has been suggested that ACh would contribute to the coordination of memory systems. (2) Second, memory is a dynamic process implying different phases. It appears that ACh function depends on the memory phase considered and a “biphasic” involvement has been demonstrated: ACh facilitates memory encoding but hampers memory consolidation and retrieval.

In this review, our aim is to highlight the importance and complexity of ACh-Memory relationships. First we will make a brief report on the reasons why the classical cholinergic hypothesis is being questioned. Then we will develop the principal points of this review: (1) Hippocampal ACh: from memory demand to system selection; (2) Biphasic cholinergic modulation of memory.

Section snippets

Why is the classical cholinergic hypothesis being questioned?

If pharmacological data and clinical observations are converging to support the necessary implication of the cholinergic septo-hippocampal system in learning and memory, data from lesion studies call into question the essential role of this system (see [7]). Until the mid nineties no neurotoxins were available to selectively target cholinergic neurons. Therefore, non-selective neurotoxin lesions of the basal forebrain cholinergic systems were shown to produce profound deficits in learning and

Conclusion

We hope that our attempt to spot the major determinants of memory modulation by hippocampal ACh through the present selective review of existing literature on ACh and memory will help to improve our understanding of this complex relationship which, at the moment may appear essentially as “chaotic”.

References (72)

  • H. Eichenbaum

    Hippocampus: cognitive processes and neural representations that underlie declarative memory

    Neuron

    (2004)
  • G. Wenk et al.

    Behaviour alters the uptake of [H3]choline into acetylcholinergic neurons of the nucleus basalis magnocellularis and medial septal area

    Behav Brain Res

    (1984)
  • A. Marighetto et al.

    Effects of intraseptally injected noradrenergic drugs on hippocampal sodium-dependent high-affinity choline uptake in resting and trained mice

    Brain Res

    (1994)
  • A. Marighetto et al.

    Effects of intraseptally injected glutamatergic drugs on hippocampal sodium-dependent high-affinity choline uptake in naive and trained mice

    Pharmacol Biochem Behav

    (1994)
  • K. Nail-Boucherie et al.

    Contextual fear conditioning is associated with an increase of acetylcholine release in the hippocampus of rat

    Brain Res Cogn Brain Res

    (2000)
  • C.K. McIntyre et al.

    Patterns of brain acetylcholine release predict individual differences in preferred learning strategies in rats

    Neurobiol Learn Mem

    (2003)
  • P.E. Gold

    Acetylcholine modulation of neural systems involved in learning and memory

    Neurobiol Learn Mem

    (2003)
  • P.E. Gold

    Coordination of multiple memory systems

    Neurobiol Learn Mem

    (2004)
  • J.L. McGaugh

    Memory consolidation and the amygdala: a systems perspective

    Trends Neurosci

    (2002)
  • R.P. Vetreno et al.

    Impaired, spared, and enhanced ACh efflux across the hippocampus and striatum in diencephalic amnesia is dependent on task demands

    Neurobiol Learn Mem

    (2008)
  • G. Buzsaki

    Two-stage model of memory trace formation: a role for noisy brain states

    Neuroscience

    (1989)
  • M.E. Hasselmo et al.

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

    Prog Brain Res

    (2004)
  • M.E. Hasselmo et al.

    Mechanisms underlying working memory for novel information

    Trends Cogn Sci

    (2006)
  • J.L. Rogers et al.

    Cholinergic modulation of the hippocampus during encoding and retrieval

    Neurobiol Learn Mem

    (2003)
  • S.L. Young et al.

    Scopolamine impairs acquisition and facilitates consolidation of fear conditioning: differential effects for tone versus context conditioning

    Neurobiol Learn Mem

    (1995)
  • L. Marshall et al.

    The contribution of sleep to hippocampus-dependent memory consolidation

    Trends Cogn Sci

    (2007)
  • M.E. Hasselmo

    Neuromodulation: acetylcholine and memory consolidation

    Trends Cogn Sci

    (1999)
  • Davies P. A critical review of the role of the cholinergic system in human memory. In: Olton DS, Gamzu E, Corkin S,...
  • J.A. Deutsch

    The cholinergic synapse and the site of memory

    Science

    (1971)
  • D.A. Drachman et al.

    Human memory and the central cholinergic system: a relationship to aging?

    Arch Neurol

    (1974)
  • R.T. Bartus et al.

    The cholinergic hypothesis of geriatric memory dysfunction

    Science

    (1982)
  • P.J. Whitehouse et al.

    Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain

    Science

    (1982)
  • R. Schliebs et al.

    The significance of the cholinergic system in the brain during aging and in Alzheimer's disease

    J Neural Transm

    (2006)
  • M.B. Parent et al.

    Septo-hippocampal acetylcholine: involved in but not necessary for learning and memory?

    Learn Mem

    (2004)
  • I.Q. Whishaw

    Cholinergic receptor blockade in the rat impairs locale but not taxon strategies for place navigation in a swimming pool

    Behav Neurosci

    (1985)
  • J.L. Muir et al.

    AMPA-induced excitotoxic lesions of the basal forebrain: a significant role of the cortical cholinergic system in attentional function

    J Neurosci

    (1994)
  • Cited by (130)

    • Memory impairments in rodent depression models: A link with depression theories

      2023, Progress in Neuro-Psychopharmacology and Biological Psychiatry
    • Inactivation of the cholinergic M<inf>4</inf> receptor results in a disinhibited endophenotype predicting alcohol use

      2022, Behavioural Brain Research
      Citation Excerpt :

      The role of anxiety in the development of these disorders is less clear; however, anxiety-like behaviours have been linked to both changes in dopamine function and drug self-administration behaviours [28,29] and M4−/−mice were previously found to exhibit decreased burying behaviour in the shock-probe burying model of anxiety-like behaviour, while they did not differ from wild type mice in the light-dark transition test [30,31]. Addiction may also be viewed as a disorder of learning and memory, as converging evidence points to addiction representing a pathological usurpation of normal mechanisms of learning and memory [32] and the cholinergic system is clearly implicated in these functions [33]. Consequently, it is plausible that the M4 receptor influences drug taking behaviour via this avenue.

    View all citing articles on Scopus
    View full text