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J Neurosci. 2015 Jun 3;35(22):8394-410. doi: 10.1523/JNEUROSCI.4460-14.2015.

Synergy of direct and indirect cholinergic septo-hippocampal pathways coordinates firing in hippocampal networks.

Author information

  • 1Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology.
  • 2Section of Translational Epileptology, Institute for Neuropathology, and.
  • 3Cognitive and Clinical Electrophysiology, Department of Epileptology, University of Bonn Medical Center, 53105 Bonn, Germany, and.
  • 4Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, Deutsches Zentrum für Neurodegenerative Erkrankungen, 53105 Bonn, Germany


The medial septum/diagonal band of Broca complex (MSDB) is a key structure that modulates hippocampal rhythmogenesis. Cholinergic neurons of the MSDB play a central role in generating and pacing theta-band oscillations in the hippocampal formation during exploration, novelty detection, and memory encoding. How precisely cholinergic neurons affect hippocampal network dynamics in vivo, however, has remained elusive. In this study, we show that stimulation of cholinergic MSDB neurons in urethane-anesthetized mice acts on hippocampal networks via two distinct pathways. A direct septo-hippocampal cholinergic projection causes increased firing of hippocampal inhibitory interneurons with concomitantly decreased firing of principal cells. In addition, cholinergic neurons recruit noncholinergic neurons within the MSDB. This indirect pathway is required for hippocampal theta synchronization. Activation of both pathways causes a reduction in pyramidal neuron firing and a more precise coupling to the theta oscillatory phase. These two anatomically and functionally distinct pathways are likely relevant for cholinergic control of encoding versus retrieval modes in the hippocampus.


acetylcholine; encoding; hippocampus; in vivo electrophysiology; medial septum; theta oscillation

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