Both hippocampal muscarinic and nicotinic receptors may contribute to theta regulation
[14][15][24][25][26][27][28]. Systemic administration of an α7 nicotinic ACh receptor (nAChR)-selective agonist significantly enhanced brainstem stimulation-induced hippocampal theta power in anaesthetized rats and mice
[25][26]. Local hippocampal infusion of either muscarinic or α7 nAChR antagonists reduced peak theta power in freely moving mice, while ipsilateral entorhinal cortical infusion of a cocktail of cholinergic receptor antagonists had little effect on theta power, suggesting that the hippocampus but not entorhinal cortex was the primary target of cholinergic transmission in regulating theta oscillations
[14][24]. Furthermore, cholinergic receptor subtype knockout studies suggest that mAChRs expressed in glutamatergic neurons (but not interneurons), and α7 nAChRs expressed in interneurons especially oriens lacunosum moleculare (OLM) interneurons (but not glutamatergic neurons), regulated theta oscillations
[14][24]. OLM neurons are a subset of somatostatin-positive interneurons in the CA1 stratum oriens hippocampal layer that primarily target the distal dendrites of pyramidal neurons in stratum lacunosum–moleculare (SLM), overlapping with entorhinal cortical excitatory inputs. OLM neurons may play an important role in theta generation and learning and memory processes
[29][30][31][32]. OLM neurons usually have larger α7 nAChR currents than pyramidal neurons and other hippocampal interneurons
[14]. α7 nAChR activation on OLM interneurons can directly inhibit EC inputs in SLM but can enhance SC inputs through disinhibition
[33]. In addition, α7 nAChR activation on OLM interneurons likely contribute to theta regulation through the disinhibition pathway
[14]. Interestingly, direct optogenetic activation of ventral hippocampal OLM neurons can induce type II theta that can be blocked by systemic administration of atropine
[34], providing a potential role for OLM neurons to coordinate mAChR and nAChR pathways in regulating theta oscillations. In vitro brain slice studies suggest that mAChR activation may primarily contribute to transient increases of theta power while α7 nAChR activation, together with mAChR activation, may promote synaptic plasticity and prime the network for theta generation by similar stimuli in the future
[14]. Therefore, hippocampal cholinergic transmission may recruit different neuronal subpopulations through different receptor subtypes to regulate different aspects of theta oscillations.
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]. 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]. 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]. 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].