ReviewAcetylcholine and memory: A long, complex and chaotic but still living relationship
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”.
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2022, Behavioural Brain ResearchCitation 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.