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▶ 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.
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.