Cholinergic-sensitive theta oscillations in memory encoding in mice

Abstract

Cholinergic regulation of hippocampal theta oscillations has long been proposed to be a potential mechanism underlying hippocampus-dependent memory encoding processes. However, cholinergic transmission has been traditionally associated with type II theta under urethane anesthesia. The mechanisms and behavioral significance of cholinergic regulation of type I theta in freely exploring animals is much less clear. In this study, we examined the potential behavioral significance of cholinergic regulation of theta oscillations in the object location task in male mice that involves training and testing trials and provides an ideal behavioral task to study the underlying memory encoding and retrieval processes, respectively. Cholinergic regulation of hippocampal theta oscillations and the behavioral outcomes was examined by either intrahippocampal infusion of cholinergic receptor antagonists or knocking out cholinergic receptors in excitatory neurons or interneurons. We found that both muscarinic acetylcholine receptors (mAChRs) and α7 nicotinic AChRs (α7 nAChRs) regulated memory encoding by engaging excitatory neurons and interneurons, respectively. There is a transient upregulated theta oscillation at the beginning of individual object exploration events that only occurred in the training trials, but not in the testing trials. This transient upregulated theta is also the only theta component that significantly differed between training and testing trials and was sensitive to mAChR and α7 nAChR antagonists. Thus, our study has revealed a transient cholinergic-sensitive theta component that is specifically associated with memory encoding, but not memory retrieval, in the object location task, providing direct experimental evidence supporting a role for cholinergic-regulated theta oscillations in hippocampus-dependent memory encoding processes.Significance statementIn this study, we made several important findings regarding cholinergic mechanisms regulating hippocampal memory formation in the object location task. Firstly, both hippocampal mAChRs and the α7 nAChRs regulated the memory encoding process in the object location task by engaging glutamatergic neurons and interneurons, respectively. Secondly, upregulated theta oscillations were observed in the pre-exploration period in training trials, but not in the testing trials, suggesting a role in novelty encoding/learning. Thirdly, the upregulated theta was sensitive to mAChR and α7 nAChR antagonists and receptor knockouts in neuronal subpopulations. Taken together, these observations provide direct experimental evidence supporting a role for cholinergic-regulated theta oscillations in hippocampal memory encoding process.