Geon Memory Retrieval: The Role of Acetylcholine Memory


The mind is restless. Even when you are alone, without any sensory inputs into your brain, the thoughts still cannot stop. Especially if you come back home from a date with a new girlfriend, the memorable memories still linger on. They may keep coming to your mind in the next few days whenever you are awake and quiet. This phenomenon is known as "hippocampal replay", namely, the hippocampus recalls previous memories spontaneously, without any sensory inputs. It is basically a memory retrieving process in the absence of reminding cues. Acetylcholine (ACh) has been demonstrated to play an important role.

Sharp Wave Ripples

During hippocampal replay, the electroencephalography (EEG) exhibits "sharp wave ripples" (SWRs) which are generated by the recurrent network (Figure 22-1) in the CA3 subregion of the hippocampus (Buzsáki, 2015). Since the dentate gyrus (DG) provides major inputs to CA3, they are also influenced by DG. In CA3, pyramidal cells are strongly associated so that a large ensemble can be reactivated when only a small subset has been activated by external sources, such as the stimulation of ACh.


Figure 22-1. The DG-CA3 microcircuit. EC2: entorhinal cortex layer II. [Source: Prince et al., 2016]

SWRs oscillate in the frequency range, 110–200 Hz, which can be induced by low ACh level. As mentioned above, they are related to memory retrieval. The high ACh level, through complex interactions (Dannenberg et al., 2017), causes the recurrent network to oscillate at the theta band (4 - 7 Hz), which is known to engage in memory encoding.


Figure 22-2. The effects of ACh on the CA3 network. Low ACh induces SWRs for memory retrieval whereas high ACh leads to theta rhythm for memory encoding. [Adapted from: Dannenberg et al., 2017]

Memory Retrieval by ACh

In the hippocampus, ACh is released primarily from the cholinergic fibers that originate in the medial septum/diagonal band of Broca (MSDB). ACh has four muscarinic receptors, M1 - M4, which belong to G protein-coupled receptors. Blockade of M1 has been shown to impair the retrieval of well-trained memory (Soma et al., 2014).


Figure 22-3. ACh-induced signaling. Binding to M1 causes dissociation of Gαq from Gβγ. Gαq may stimulate the activity of phospholipase C (PLC), resulting in release of Ca2+ from the internal store. The elevated Ca2+ level further activates adenylyl cyclase type 1 (AC1) to convert ATP into cAMP which enhances PKA activity. [Adapted from: Wikipedia]

M1 receptors are highly expressed in DG granule cells and the pyramidal cells of CA3 and CA1. Importantly, they preferentially distribute on the extrasynaptic membrane of pyramidal cell dendrites and spines (Yamasaki et al., 2010), suggesting that their major targets are not located at synapses. Rather, ACh could regulate NMDA plateau. By acting on the M1 receptor, ACh may increase Ca2+ level, which in turn enhances PKA activity via AC1 (Figure 22-3). The enhanced PKA activity then phosphorylates S1166 of GluN2B, relieve tubulin inhibition, and consequently facilitating memory retrieval (Chapter 17).


Author: Frank Lee
First published: January, 2018