Ingredients in SleepScape
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Choline in Brain Function
and Sleep

Acetylcholine (made from choline) is an important part of
regulatory pathways in sleep and many cognitive functions.

By Durk Pearson & Sandy Shaw

A

review in Neuron1 described the function of acetylcholine (a ubiquitous neurotransmitter) in the brain as follows: “Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons.” Its many effects make acetylcholine “an essential mechanism underlying complex behaviors.”1 Further, they propose a common theme for the activities of acetylcholine: “that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action.”

The complex interaction between the cholinergic nervous system and the dopaminergic system includes regulation by cholinergic interneurons through muscarinic cholinergic receptor signaling as critical components in striatum-dependent decision making, which also involves dopaminergic signaling for the detection of rewarding stimuli.2 Cholinergic interneurons “can regulate the duration, magnitude, and spatial pattern of activity of striatal neurons, potentially creating an attentional gate that facilitates movement toward salient stimuli.”1 Moreover, as noted in the review,1 “the function of striatal cholinergic interneurons is also impaired in patients with movement disorders involv[ing] the dopaminergic system, such as Parkinson’s and Huntington’s disease …”


References

1. Picciotto et al. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 76:116-28 (2012).
2. Mark et al. Cholinergic modulation of mesolimbic dopamine function and reward. Physiol Behav. 104:76-81 (2011).


Circadian Rhythm of the Cholinergic Nervous System

As described in another paper,7 “[t]here is [] a pronounced circadian rhythm in the activity of the cholinergic system, upon which sleep, waking, and fundamental aspects of learning depend. These rhythms may deteriorate with aging, and sleep disturbance is a particular problem in AD [Alzheimer’s disease].” The authors focused upon the differences between the effects of administering cholinergic agonists during specific times of day. As they explain, “[t]he cholinergic system is regulated for increased transmission during waking and motor activity and decreased transmission (in general, during sleep, with brief, localized increases during rapid eye movement (REM) sleep. The elements of the cholinergic system—synaptic acetylcholine (ACh), stored ACh, acetylcholinesterase (AChE) activity and cholinergic receptors—are coordinated to achieve this end.” The experiments were done using cats.

In the cortex of the cats, ACh was reported to be doubled during quiet waking and nearly tripled when cats were activated by listening to tapes of singing birds. By contrast, during REM sleep, ACh was doubled in the cortex and tripled in the hippocampus. Thus, as has been reported elsewhere, ACh release is increased during waking, motor activity, and REM sleep.

As also reported in paper #7, cholinergic stimulation during the night in humans has effects similar to that seen in the animal studies. Cholinergic stimulation during NREM (non-REM) sleep induces awakenings and decreases in sleep time and efficiency, while cholinergic activity can enhance REM sleep. The authors describe studies that suggest that cholinergic inactivity during non-REM sleep may be a critical link in the consolidation of declarative memory (that includes word lists and places). Specific studies on galantamine (described in detail) did not find significant changes in the Pittsburgh Sleep Quality Index, did not find increased insomnia/sleep problems as compared to patients on placebo, but there was a suggestion of increased REM sleep activity (nightmares) at 24 mg/day. The authors7 note that the key to avoid unwanted cholinergic effects on sleep with cholinesterase inhibitors is to note their half-life (about 7 hours with galantamine)—indicating the period of increase and decrease of cholinergic activity—so as not to be increasing cholinergic activity excessively during sleep. With a 7 hour half-life, twice daily administration of immediate-release galantamine with meals, thus covers the normal waking day (data on file, Janssen Pharmaceutica Products LP, 2004) Low-dose choline taken by late afternoon should not have these effects.


7. Davis and Sadik. Circadian cholinergic rhythms: implications for cholinesterase inhibitor therapy. Dement Geriatr Cogn Disord. 21:120-9 (2006).


Cholinergic Mechanisms for REM Sleep Control

“Rapid eye movement (REM) sleep is a distinct high frequency oscillation arousal state that has been linked to several aspects of brain function including developmental maturation of the brain, modification of synaptic plasticity and memory formation, as well as regulation of metabolic functions.”6 “Of particular importance are clusters of putative cholinergic neurons within the pedunculopontine (PPN) and laterodorsal tegmental (LDT) nuclei that have been characterized as ‘REM-on’ neurons because of increased firing during REM sleep. The combined data obtained from in vivo, lesion, transection, and pharmacological studies have suggested that these putative cholinergic ‘REM-on’ neurons in the brainstem are critically important for the generation and maintenance of the REM sleep state via widespread projections to the thalamus, brainstem, and specifically to the anterior pons.”6

The authors of paper #6 explain that various lesion and anatomical studies have suggested that the dorsal subcoeruleus (SubCD) area of the brain plays a major role in the production of REM sleep atonia (muscle paralysis) via descending projections to the medulla and spinal cord. The researchers performed experiments on SubCD brain slices to study the effects of the cholinergic agonist carbachol on SubCD brain activity, finding that carbachol “exerts a predominantly inhibitory role on fast synaptic glutamatergic activity and a predominantly excitatory role on fast synaptic GABAergic/glycinergic activity in the SubCD.” They conclude by hypothesizing that during REM sleep, cholinergic “REM-on” neurons that project to the SubCD induce an “excitation of inhibitory interneurons and inhibition of excitatory events leading to the production of coordinated activity in the SubCD projection neurons,” in which this coordination may be essential for the production of REM sleep.

This provides a sample of the complexity of sleep research at the molecular level and the contribution of the cholinergic nervous system to REM sleep. The authors remind readers that brain slices do not have sleep-wake cycles and, therefore, this is a limitation of the study. The work thus reveals the details of biochemical interactions in the SubCD at the molecular level but these do not provide the wider picture available with the addition of sleep-wake cycles that also involve other areas of the brain.


6. Heister et al. Cholinergic modulation of GABAergic and glutamatergic transmission in the dorsal subcoeruleus: mechanisms for REM sleep control. Sleep. 32(9):1135-47 (2009).


The Cholinergic Nervous System as a Major Regulator of Inflammation

The parasympathetic nervous system is regulated by acetylcholine and plays a major role in modulating inflammation induced by the immune system in response to pathogens and inflammatory cytokines released in the process of tissue repair. In a severe form of runaway inflammation, sepsis resulting from infection has a high mortality rate. The vagus nerve, carrying cholinergic signals, is an important part of the parasympathetic nervous system anti-inflammatory activity via the conveyance of information to and from the brain. For example, in a model of endotoxemia (bacterial infection releasing endotoxins that stimulate release of inflammatory cytokines), “electrical stimulation of the vagus nerve significantly reduced serum and liver TNF [tumor necrosis factor, a major inflammatory cytokine] levels, prevented development of haemodynamic shock and improved survival without significantly altering IL-10 [an antiinflammatory cytokine] or corticosterone serum levels.”3

As reported in paper #3, “[s]uppression of inflammation in the brain and in the periphery can be achieved by enhancing cholinergic signaling by administration of acetylcholinesterase inhibitors. The acetylcholinesterase inhibitor galantamine, acting through a central mechanism, has been shown to attenuate serum TNF and IL-6 and improve survival in a murine [mouse] model of endotoxaemia.” Choline, as the precursor to the production in the body and brain of acetylcholine, is also able to enhance cholinergic signaling. “This mechanism could explain the association between high choline dietary intake with reduced pro-inflammatory markers in serum.”3

In fact, an editorial in a 2008 issue of the American Journal Of Clinical Nutrition4 commented on the finding of a paper in that issue that higher dietary intakes of choline and betaine decreased biomarkers of inflammation and was of the same magnitude as those reported for the Mediterranean Diet as a whole. (This was an epidemiological study; thus, this was an association that didn’t by itself prove causality.) Still, the author titled his editorial, “Is there a new component of the Mediterranean diet that reduces inflammation?”


3. Rosas-Balina and Tracey. Cholinergic control of inflammation. J Intern Med. 265:663-79 (2009).
4. Zeisel. Is there a new component of the Mediterranean diet that reduces inflammation? Am J Clin Nutr. 87:277-8 (2008).


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