Cholinergic modulation of the CAN current may adjust neural dynamics for active memory maintenance, spatial navigation and time-compressed replay

Abstract

Suppression of cholinergic receptors and inactivation of the septum impair short-term memory, and disrupt place cell and grid cell activity in the medial temporal lobe (MTL). Location-dependent hippocampal place cell firing during active waking, when the acetylcholine level is high, switches to time-compressed replay activity during quiet waking and slow-wave-sleep (SWS), when the acetylcholine level is low. However, it remains largely unknown how acetylcholine supports short-term memory, spatial navigation, and the functional switch to replay mode in the MTL. In this paper, we focus on the role of the calcium-activated non-specific cationic (CAN) current which is activated by acetylcholine. The CAN current is known to underlie persistent firing, which could serve as a memory trace in many neurons in the MTL. Here, we review the CAN current and discuss possible roles of the CAN current in short-term memory and spatial navigation. We further propose a novel theoretical model where the CAN current switches the hippocampal place cell activity between real-time and time-compressed sequential activity during encoding and consolidation, respectively.

Cholinergic receptor activation supports persistent firing in layer III neurons in the medial entorhinal cortex

“…This could contribute to the impairment of encoding of episodic memories caused by muscarinic cholinergic antagonists such as scopolamine [76;77]. In addition, this cholinergic modulation of the persistent firing property might support switching between encoding and consolidation functions of the MTL [16;63]. …”

“…Active maintenance of memory may help association of temporally separated information which is thought to be necessary for the formation of long-term episodic and sequential memory [11–13]. In vivo recordings in animals [14–16] and fMRI in humans [14;15] have revealed persistent activity during the trace or delay period of memory tasks when information retention is necessary (reviewed in [16]). These indicate that persistent neural firing may support temporal association by providing a means to retain necessary information across the temporal gap.…”

Muscarinic Receptors in Amygdala Control Trace Fear Conditioning

“…Most recently, persistent firing was also detected in the hippocampus (HC) [19], [26], [27], which has long been recognized as important for normal trace conditioning [32], [34], [35]. In support of the persistent-firing hypothesis, trace but not delay, fear conditioning is profoundly impaired by infusions of mAChR antagonists into PR [30], EC [16], and HC [36].…”

Entorhinal–hippocampal neuronal circuits bridge temporally discontiguous events

“…These two protocols, along with additional control conditions (e.g., unpaired pseudo-random CS-US presentations), provide a powerful means to evaluate the contribution of different brain regions to temporal associative learning. For these reasons, in this review we focus discussion primarily on these behavioral paradigms, the functional dissections of the EC-HPC circuits and the physiological mechanisms that subserve temporal aspects of episodic memory, although there are reviews that discuss additional physiological mechanisms of temporal associative learning (Hasselmo and Stern 2006;Yoshida et al 2012;Eichenbaum 2014).…”