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Choline: An Integral Circadian System (4)

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To read the previous article in this series, click here.

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As with much else in the body, the cholinergic system is circadian[1], meaning that it functions circa diem (or about the day, in Latin). Cholinergic neurons exist in the master regulator of our body’s clocks, the suprachiasmatic nucleus, where they enable us to ‘time stamp’ our memories[2]. Acetylcholine levels, or cholinergic tone, are higher when our brains are more active than when they are not. They are high during active wakefulness, lower during quiet wakefulness, the lowest during non-REM or slow wave sleep (SWS), and high again during the REM sleep (dream sleep) portions of our sleep cycles.

Cholinergic tone plays a key role in regulating our sleep. Low cholinergic tone is necessary for the consolidation of memory during non-REM/SWS sleep[3][4]. A higher cholinergic tone is apparently necessary to induce dreaming during REM sleep[5]. Moreover, it has been shown that without cholinergic neurons, REM sleep is diminished to almost undetectable levels[6].


Acetylcholine is the neurotransmitter of cholinergic neurons, which are distributed throughout the brain[7] and critical to all aspects of our cognition. Cholinergic neurons have two broad categories of receptors, distinguished by the compounds (other than acetylcholine) that activate them. Nicotinic acetylcholine receptors (nAChR) are ionotropic and all respond to nicotine, in addition to acetylcholine. Muscarinic acetylcholine receptors (mAChR) are metabotropic and all respond to the mushroom toxin muscarine, in addition to acetylcholine.


The cholinergic system was first understood to affect cognition from clinical observations in the 1950’s that anticholinergic drugs, then used to sedate birthing women, led to memory loss and the exhibition of symptoms that characterize dementia[8]. In the 1970’s, it was shown that memory deficits caused by the muscarinic cholinergic receptor (mAChR) antagonist scopolamine were not reversible with amphetamines but were reversible with the acetylcholinesterase inhibitor physostigmine[9]. The nicotinic system was introduced into the study of cognition when it was discovered that smokers who quit their habit experienced declining cognitive performance, which improved with the re-administration of nicotine[10][11].


It was later discovered that the nicotinic and muscarinic cholinergic systems of the brain have activity on other neurotransmitters, including the monoamines. Cholinergic neurons can trigger or suppress the release of dopamine, depending on the cognitive environment[12]. There is crosstalk between cholinergic receptors and dopamine receptors, such as dopamine receptor D3[13]. Agonists of cholinergic receptors, such as nicotine, can also evoke serotonin release[14], alter serotonin receptor function[15], and increase the firing frequency of serotonergic neurons[16]. Broadly, acetylcholine can be characterized as modulating the neurotransmitters dopamine, norepinephrine, serotonin, glutamate, and GABA[17].

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To return to an overview of the blog series on the cholinergic system, click here.

[1] Kametani, H., & Kawamura, H. (1991). Circadian rhythm of cortical acetylcholine release as measured by in vivo microdialysis in freely moving rats. Neuroscience letters, 132(2), 263-266. [2] Hut, R. A., & Van der Zee, E. A. (2011). The cholinergic system, circadian rhythmicity, and time memory. Behavioural brain research, 221(2), 466-480. [3] Gais, S., & Born, J. (2004). Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation. Proceedings of the National Academy of Sciences, 101(7), 2140-2144. [4] Inayat, S., Nazariahangarkolaee, M., Singh, S., McNaughton, B. L., Whishaw, I. Q., & Mohajerani, M. H. (2019). Low acetylcholine during early sleep is important for motor memory consolidation. bioRxiv, 494351. [5] Singh, A., & Gupta, D. (2019). Can Acetylcholine make you dream?. Sleep Science, 12(3), 240. [6] Niwa, Y., Kanda, G. N., Yamada, R. G., Shi, S., Sunagawa, G. A., Ukai-Tadenuma, M., ... & Kasukawa, T. (2018). Muscarinic acetylcholine receptors Chrm1 and Chrm3 are essential for REM Sleep. Cell reports, 24(9), 2231-2247. [7] Li, X., Yu, B., Sun, Q., Zhang, Y., Ren, M., Zhang, X., ... & Zeng, H. (2018). Generation of a whole-brain atlas for the cholinergic system and mesoscopic projectome analysis of basal forebrain cholinergic neurons. Proceedings of the National Academy of Sciences, 115(2), 415-420. [8] Bartus, R. T., Dean, R. L., Pontecorvo, M. J., & Flicker, C. (1985). The cholinergic hypothesis: a historical overview, current perspective, and future directions. Annals of the New York Academy of Sciences, 444(1), 332-358. [9] Drachman, D. A., & Leavitt, J. (1974). Human memory and the cholinergic system: a relationship to aging?. Archives of neurology, 30(2), 113-121. [10] Frankenhaeuser, M., Myrsten, A. L., Post, B., & Johansson, G. (1971). Behavioural and physiological effects of cigarette smoking in a monotonous situation. Psychopharmacologia, 22(1), 1-7. [11] Heimstra, N. W., Bancroft, N. R., & DeKock, A. R. (1967). Effects of smoking upon sustained performance in a simulated driving task. [12] Collins, A. L., Aitken, T. J., Greenfield, V. Y., Ostlund, S. B., & Wassum, K. M. (2016). Nucleus accumbens acetylcholine receptors modulate dopamine and motivation. Neuropsychopharmacology, 41(12), 2830-2838. [13] Bontempi, L., Savoia, P., Bono, F., Fiorentini, C., & Missale, C. (2017). Dopamine D3 and acetylcholine nicotinic receptor heteromerization in midbrain dopamine neurons: relevance for neuroplasticity. European Neuropsychopharmacology, 27(4), 313-324. [14] Filip, M., Smaga, I., & Przegaliński, E. (2020). The role of serotonin in nicotine abuse and addiction. In Handbook of Behavioral Neuroscience (Vol. 31, pp. 829-841). Elsevier. [15] Bombardi, C., Delicata, F., Tagliavia, C., Pierucci, M., Deidda, G., Casarrubea, M., ... & Di Giovanni, G. (2020). Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula. International Journal of Molecular Sciences, 21(5), 1873. [16] Hernández-López, S., Colín, R. D., & Mihailescu, S. (2016). Nicotine and Stimulatory Effects on 5-HT DRN Neurons. In Neuropathology of Drug Addictions and Substance Misuse (pp. 146-157). Academic Press. [17] Jensen, A. A., Frølund, B., Liljefors, T., & Krogsgaard-Larsen, P. (2005). Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations. Journal of medicinal chemistry, 48(15), 4705-4745.

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