Calcium imaging studies showed that calcium activities in dorsal CA1 pyramidal neurons are high during theta states including active exploration and REM sleep, and low during non-theta states including quiet wakefulness and slow wave sleep. Systemic or local hippocampal administrated mAChR antagonist scopolamine significantly reduced calcium activities in pyramidal neurons
[35]. Higher calcium activities associated with theta states may promote synaptic plasticity and memory encoding
[4], or place field stabilization
[36]. Theta oscillations have been proposed as a mechanism for temporal coding due to phase precession and theta sequences of place cell firing
[37,38][37][38]. Phase precession refers to the progressively earlier spiking time of a place cell relative to the theta phase when the animal traverses a place field. Accordingly, there can be several place cells firing sequentially in one theta cycle, representing the temporal order of the place fields the animal travels through. Systemic administration of mAChR antagonist scopolamine significantly impairs place cell phase precession
[39,40][39][40]. Scopolamine significantly reduces the firing frequency of place cells to the same level as local field theta frequency, and thus eliminates the progressive phase precession. As such, the theta phase of individual place cell firing can no longer predict the position the animal travels
[40]. Phase precession also depends on intact medial entorhinal cortical inputs to the hippocampus
[41]. Scopolamine likely reduces phase precession through disrupting the entorhinal hippocampal interaction. However, theta sequences and place cell assemblies remained intact after the disruption of phase precession by scopolamine
[39], suggesting differential mechanisms may underlie phase precession and theta sequence generation. Phase precession also occurred during the first lap on a novel linear track, but theta sequences were absent on the first lap and developed immediately afterwards and were stable once established
[42]. Some studies show that place cell sequences formed in a novel spatial experience significantly correlates with spiking events before the novel experience, suggesting the place cell sequences formed during a novel experience result from the interplay of internal drives that likely arise from past experiences and external drives that come from the current novel experience
[43,44][43][44]. Place cell sequences are more dynamic in the earlier stage and stabilize in the later stage. Taken together, cholinergic transmission may thus promote phase precession and the integration of constantly updated entorhinal cortical inputs during the whole course of an experience, but likely facilitates the formation and stabilization of theta sequences during the early stage of the experience. Once the theta sequences are established, they are no longer sensitive to cholinergic modulation. This is consistent with the general observation that cholinergic transmission is primarily involved in memory encoding but not memory retrieval
[45]. It is also consistent with a brain slice study where cholinergic activation promotes synaptic plasticity and theta induction, but once theta was induced and stabilized it was no longer cholinergic sensitive
[24].