Elsevier

Behavioural Brain Research

Volume 221, Issue 2, 10 August 2011, Pages 466-480
Behavioural Brain Research

Review
The cholinergic system, circadian rhythmicity, and time memory

https://doi.org/10.1016/j.bbr.2010.11.039Get rights and content

Abstract

This review provides an overview of the interaction between the mammalian cholinergic system and circadian system, and its possible role in time memory. Several studies made clear that circadian (daily) fluctuations in acetylcholine (ACh) release, cholinergic enzyme activity and cholinergic receptor expression varies remarkably between species and even strains. Apparently, cholinergic features can be flexibly adjusted to the needs of a species or strain. Nevertheless, it can be generalized that circadian rhythmicity in the cholinergic system is characterized by high ACh release during the active phase of an individual. During the active phase, the activity of the ACh synthesizing enzyme Choline Acetyltransferase (ChAT) is enhanced, and the activity of the ACh degrading enzyme Acetylcholinesterase (AChE) is reduced. The number of free, unbound and thus available muscarinic acetylcholine receptors (mAChRs) is highest when ACh release is lowest. The cholinergic innervation of the suprachiasmatic nucleus (SCN), the hypothalamic circadian master clock, arises from the cholinergic forebrain and brain stem nuclei. The density of cholinergic fibers and terminals is modest as compared to other hypothalamic nuclei. This is the case for rat, hamster and mouse, three chronobiological model rodent species studied by us. A new finding is that the rat SCN contains some local cholinergic neurons. Hamster SCN contains less cholinergic neurons, whereas the mouse SCN is devoid of such cells. ACh has an excitatory effect on SCN cells (at least in vivo), and functions in close interaction with other neurotransmitters. Originally it was thought that ACh transferred retinal light information to the SCN. This turned out to be wrong. Thereafter, the phase shifting effects of ACh prompted researches to view ACh as an agent for nocturnal clock resetting. It is still not clear, however, what the function consequence is of SCN cholinergic neurotransmission. Here, we postulate the hypothesis that cholinergic neurotransmission in the SCN provides the brain with a mechanism to support the formation of time memory via ‘time stamping’. We define time memory as the memory of a specific time of the day, for which an animal made an association with a certain event and/or location (for example in case of time-place association). We use the term ‘time stamping’ to refer to the process underlying the encoding of a specific time of day (the time stamp). Only relatively brief but arousing events seem to be time stamped at SCN level. This time stamping requires the engagement of mAChRs. New data suggests that the SCN uses the neuropeptide vasopressin (AVP) as an output system to transfer the specific time of day information to other brain regions such as hippocampus and neocortex where time memory is supposed to be acquired, consolidated and stored. Since time stamping is a cholinergically mediated function of the circadian system, the early disruption of the cholinergic and circadian systems as seen in Alzheimer's disease (AD) may contribute to the cognitive disruption of temporal organization of memory and behavior in these patients.

Research highlights

► Rat but not mouse SCN contains cholinergic neurons. ► SCN cholinergic neurotransmission supports time memory formation via time stamping. ► The neurppeptide AVP acts as an SCN output for time stamping.

Introduction

Circadian rhythms are synchronized to the environmental day by external cues, with the light/dark (L/D) cycle as the predominant one. The hypothalamic SCN is considered to be the main circadian pacemaker of the circadian system in mammals. The SCN is critical in synchronizing circadian rhythms in various peripheral tissues and organs [64], [90], [107], [117], [154], [165]. Various brain systems, of which the cholinergic system is one, are hypothesized to influence the SCN in its time-of-day communication to the rest of the brain.

The interaction between the cholinergic system and the circadian system has been studied for long. ACh is one of the first suggested transmitters to play a key role in circadian rhythmicity, nevertheless the available data is not very extensive [41], [116], [144], [191], [192]. There is a pronounced circadian (daily) rhythm in the activity of the cholinergic system in mammals (including men) housed under L/D conditions (Fig. 1). ACh is considered to be a “transmitter of wakefulness”. It is released during wakefulness and motor activity. Its release is decreased during sleep other than Rapid Eye Movement sleep (for review see [34], and references therein). It was therefore supposed that behavioral activity patterns, circadian rhythms, and cholinergic neurotransmission were tightly coupled.

Several studies have indeed provided evidence for a role of cholinergic signaling in the regulation and maintenance of circadian rhythms via nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs, respectively). Around 1980, ACh was thought to mediate the effects of light via nAChRs. SCN neurons responded similarly to cholinergic drugs as to light. A cholinergic agonist (carbachol, a nonselective cholinergic agonist with higher affinity for mAChRs than nAChRs) seemed to mimick the effects of light in the circadian system, whereas a cholinergic antagonist blocked circadian light effects [38], [86], [112], [122], [126], [183], [191], [192], [193], [194]. In addition, ACh content within the SCN increased upon a light pulse, but not in most other brain regions [123]. Thereafter, SCN cholinergic binding sites were studied, first with the nicotinic antagonist α-bungarotoxin (α-Btx), and later with other nicotinic and muscarinic agents (further discussed below). Gradually, doubts about the functional role of ACh in mediating light effects in the SCN arose. Depletion of presynaptic cholinergic stores by hemicholinium did not affect the behavioral effects of light pulses [133], and no support was found for a role of ACh in mediating the effect of light in the SCN upon stimulation of the optic nerve in a slice preparation [22]. Additionally, carbachol injections into the third or lateral ventricle did only partly resemble, or did not at all resemble light-pulse induced phase shifts [40], [41], [106]. These conflicting carbachol findings were referred to as “the carbachol paradox” [31]. It became clear that it was unlikely that ACh is the primary mediator of the effects of light on the SCN (which turned out to be glutamate and PACAP (Pituitary adenylate cyclase activating polypeptide) [35], [42], [57], [96], [105]. Lately, Buchanan and Gillette [19] suggested that the light-like effects of carbachol were caused by stimulation of extra-SCN cholinoceptive areas, whereas direct cholinergic stimulation of the SCN results in responses different from light.

In this review, we will discuss functional roles of cholinergic neurotransmission in circadian rhythmicity and specifically the SCN. We will present a hypothetical scenario, corroborated with new data, in which mAChRs play a key role in time stamping and the formation of time memory.

Section snippets

Circadian rhythmicity in cholinergic markers

If the cholinergic system is functionally linked to the circadian system, one may expect to see clear circadian rhythmicity in ACh itself or cholinergic markers such as the ACh synthesizing enzyme ChAT, the ACh degrading enzyme AChE, the vesicular acetylcholine transporter (VAChT), or the two major types of receptors (nAChRs and mAChRs), either in the SCN or within circadian system related brain areas. Studies on circadian fluctuations in these cholinergic markers have been performed

Cholinergic input to the SCN

The neuroanatomical characteristic of cholinergic innervation patterns of the SCN can implicate and contribute to our understanding of its functional consequence. Here, we summarize these characteristics as published in the literature and our own data.

Cholinergic neurotransmission in the SCN

Ultimately, the impact of ACh release in the SCN depends on the density and anatomical (subcellular) localization of cholinergic receptors in SCN neurons. In this section we will therefore first briefly describe the distribution studies of mAChRs and nAChRs, and then review reported cholinergic regulation of SCN signal transduction.

Phase shifts and sleep

Phase shifts in behavioral activity or firing frequency of SCN neurons have been studied for cholinergic agents. Earlier studies used intraventricular injections of carbachol or mecamylamine, a nAChR antagonist, and reported conflicting results (as mentioned above; see introduction and references there). Direct application of nicotine to SCN slices resulted in modest phase advances across the circadian cycle [161]. It can be summarized that carbachol applied directly to the SCN during the

New functional aspects of cholinergic neurotransmission in the SCN

Although the cholinergic input to the SCN is rather limited (as compared to most other cholinoceptive regions) and only a minority of cholinergic forebrain and brainstem cells project to this area, several putative functional aspects (besides ACh as an agent for nocturnal clock resetting via mAChRs) have been described for cholinergic receptors in the SCN.

Critical components of circadian pacemaker function of the SCN are its output mechanisms and pathways: to what brain regions does it project

Conclusions and future directions

This review shows that the cholinergic system and the circadian system, after many initial studies in the 1970s and 1980s, deserves revival. The presence of ChAT-positive SCN neurons in rat and hamster opens new avenues in our thinking of the functional interaction between the two systems, but also requires further investigation with VAChT to determine the true cholinergic nature of these cells [9]. In addition, it should be determined if local cholinergic exist in human SCN and if they are

Acknowledgements

This work was partly supported by the EU FP6 Integrated Project EUCLOCK (RAH).

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