Cholinergic Blockade Reduces Theta-Gamma Phase Amplitude Coupling and Speed Modulation of Theta Frequency Consistent with Behavioral Effects on Encoding

Abstract

Large-scale neural activation dynamics in the hippocampal-entorhinal circuit local field potential, observable as theta and gamma rhythms and coupling between these rhythms, is predictive of encoding success. Behavioral studies show that systemic administration of muscarinic acetylcholine receptor antagonists selectively impairs encoding, suggesting that they may also disrupt the coupling between the theta and gamma bands. Here, we tested the hypothesis that muscarinic antagonists selectively disrupt coupling between theta and gamma. Specifically, we characterized the effects of systemically administered scopolamine on movement-induced theta and gamma rhythms recorded in the superficial layers of the medial entorhinal cortex (MEC) of freely moving rats. We report the novel result that gamma power at the peak of theta was most reduced following muscarinic blockade, significantly shifting the phase of maximal gamma power to occur at later phases of theta. We also characterize the existence of multiple distinct gamma bands in the superficial layers of the MEC. Further, we observed that theta frequency was significantly less modulated by movement speed following muscarinic blockade. Finally, the slope relating speed to theta frequency, a correlate of familiarity with a testing enclosure, increased significantly less between the preinjection and recovery trials when scopolamine was administered during the intervening injection session than when saline was administered, suggesting that scopolamine reduced encoding of the testing enclosure. These data are consistent with computational models suggesting that encoding and retrieval occur during the peak and trough of theta, respectively, and support the theory that acetylcholine regulates the balance between encoding versus retrieval.

Grid cell firing patterns may arise from feedback interaction between intrinsic rebound spiking and transverse traveling waves with multiple heading angles

“…A change in acetylcholine levels could cause a shift in overall speed modulation (Newman et al, 2013, 2014), or could be directly involved in modulating intrinsic resonance frequency relative to running speed. Acetylcholine levels have been shown to change in running vs. stationary rats (Mizuno et al, 1991; Marrosu et al, 1995) and have been shown to change the resonance frequency of medial entorhinal neurons (Heys et al, 2010; Heys and Hasselmo, 2012).…”

Pharmaco-EEG Studies in Animals: An Overview of Contemporary Translational Applications

“…When combined with scopolamine, the cognition enhancers attenuated the leftward shift in coherent slow delta activity combined with altered slow theta and gamma oscillations (see fig. 1 for a case study with rivastigmine), which were induced by scopolamine [7], and reduced the theta-gamma phase amplitude coupling and speed modulation of theta frequency by scopolamine [55]. Oral administration of AC-3933, a benzodiazepine receptor partial inverse agonist indicated for symptomatic treatment of AD, resulted in the amelioration of scopolamine-induced amnesia in rats, as well as in a shift in EEG relative power (i.e.…”

Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus

“…Indeed, the lowfrequency theta present under urethane anesthesia can be fully abolished by antimuscarinic drugs (31). In contrast, atropine or scopolamine fail to abolish theta oscillations during waking exploration (31,32), although they affect the theta waveform and its amplitude-phase depth profile in the hippocampus (33). Although these previous works are compatible with the hypothesis that the role of septal cholinergic projections is mainly permissive and affects theta power without modulating its frequency (20,26,28), direct evidence is missing.…”