AUTHOR=Dobryakova Yulia V. , Bolshakov Alexey P. , Korotkova Tinna , Rozov Andrey V. TITLE=Acetylcholine in the hippocampus: problems and achievements JOURNAL=Frontiers in Neural Circuits VOLUME=Volume 19 - 2025 YEAR=2025 URL=https://www.frontiersin.org/journals/neural-circuits/articles/10.3389/fncir.2025.1491820 DOI=10.3389/fncir.2025.1491820 ISSN=1662-5110 ABSTRACT=Cholinergic septohippocampal projections originating from the medial septal area (MSA) play a critical role in regulating attention, memory formation, stress responses, and synaptic plasticity. Cholinergic axons from the MSA extensively innervate all hippocampal regions, providing a structural basis for the simultaneous release of acetylcholine (ACh) across the entire hippocampus. However, this widespread release appears inconsistent with the specific functional roles that ACh is thought to serve during distinct behaviors. A key unresolved question is how the dynamics of ACh tissue concentrations determine its ability to activate different receptor types and coordinate individual synaptic pathways. Here, we highlight several debated issues, including the potential intrinsic source of ACh within the hippocampus – such as cholinergic interneurons – and the co-release of ACh with GABA. Furthermore, we discuss recent findings on in vivo ACh concentration dynamics, which present a new dilemma for understanding ACh signaling in the hippocampus: the contrast between “global” ACh release, driven by synchronous activation of MSA neurons, and “local” release, which may be influenced by yet unidentified factors.