Carbon Monoxide and Nitric Oxide: Interacting Messengers in Muscarinic Signaling to the Brain's Circadian Clock

doi:10.1006/exnr.2001.7781

Experimental Neurology

Volume 171, Issue 2, October 2001, Pages 293-300

https://doi.org/10.1006/exnr.2001.7781 Get rights and content

Abstract

Within the central nervous system, acetylcholine (ACh) functions as a state-dependent modulator at a range of sites, but its signaling mechanisms are yet unclear. Cholinergic projections from the brain stem and basal forebrain innervate the suprachiasmatic nucleus (SCN), the master circadian clock in mammals, and cholinergic stimuli adjust clock timing. Cholinergic effects on clock state require muscarinic receptor-mediated activation of guanylyl cyclase and cGMP synthesis, although the effect is indirect. Here we evaluate the roles of carbon monoxide (CO) and nitric oxide (NO), major activators of cGMP synthesis. Both heme oxygenase 2 (HO-2) and neuronal nitric oxide synthase (nNOS), enzymes that synthesize CO and NO, respectively, are expressed in rat SCN, with HO-2 localized to the central core of the SCN, whereas nNOS is a punctate plexus. Hemin, an activator of HO-2, but not the NO donor, SNAP, mimicked cholinergic effects on circadian timing. Selective inhibitors of HO fully blocked cholinergic clock resetting, whereas NOS inhibition partially attenuated this effect. Hemoglobin, an extracellular scavenger of both NO and CO, blocked cholinergic stimulation of cGMP synthesis, whereas $l$ -NAME, a specific inhibitor of NOS, had no effect on cholinergic stimulation of cGMP, but decreased the cGMP basal level. We conclude that basal NO production generates cGMP tone that primes the clock for cholinergic signaling, whereas HO/CO transmit muscarinic receptor activation to the cGMP-signaling pathway that modulates clock state. In light of the recently reported inhibitory interaction between HO-2/CO and amyloid-β, a marker of Alzheimer's disease (AD), we speculate that HO-2/CO signaling may be a defective component of cholinergic neurotransmission in the pathophysiology of AD, whose manifestations include disintegration of circadian timing.

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Carbon monoxide (CO) is typically perceived as a toxic gas; however, the identification of its endogenous production in numerous species (Sjostrand, 1949; Maines, 1997; Wu and Wang, 2005) has led to its description as an important physiological signaling molecule. Within the nervous system, CO affects mammalian circadian rhythms (Artinian et al., 2001), learning and memory (Cutajar and Edwards, 2007), nociception (Steiner et al., 2001; Carvalho et al., 2011), and olfaction (Ingi and Ronnett, 1995). In non-mammalian models, CO affects the sensitivity of olfactory receptor neurons of the salamander, Ambystoma tigrinum, (Zufall and Leinders-Zufall, 1997) and neuronal migration of enteric neurons of the locust, Locusta migratoria (Knipp and Bicker, 2009), indicating that CO serves as a neuronal signal across a range of species affecting numerous aspects of the nervous system.
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We have documented that the locus coeruleus (LC), the main noradrenergic nucleus in the brain, is part of a thermoeffector neuronal pathway in fever induced by lipopolysaccharide (LPS). Following this pioneering study, we have investigated the role of the LC carbon monoxide (CO) and nitric oxide (NO) pathways in fever. Interestingly, despite both CO and NO are capable of activating the same intracellular target, soluble guanylate cyclase (sGC), our data have shown that LC CO is an antipyretic molecule, whereas LC NO is propyretic. Thus, aiming at further exploring the mechanisms underlying their anti- and propyretic properties, we investigated the putative interplay between the LC CO and NO pathways. Male Wistar rats were implanted with a guide cannula in the fourth ventricle (4V) and a temperature datalogger capsule in the peritoneal cavity. The animals were microinjected into the 4V with an inhibitor of heme oxygenase (HO) (ZnDPBG [zinc(II)deuteroporphyrin IX 2,4 bis ethylene glycol]), or a CO donor (CORM-2 [tricarbonyldichlororuthenium-(II)-dimer]), or an inhibitor of nitric oxide synthase (NOS) (l-NMMA [N^G-monomethyl-l-arginine acetate]), or an NO donor (NOC12 [3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene]), and injected with LPS (100 μg/kg i.p.). Two hours later, the rats were decapitated, and the brains were frozen and cut in a cryostat. LC punches were processed to assess LC bilirubin and nitrite/nitrate (NOx) levels. Microinjection of ZnDPBG reduced LC bilirubin and increased LC NOx, whereas l-NMMA diminished LC NOx and reduced LC bilirubin. Furthermore, NOC12 caused an increase in LC bilirubin, whereas CORM-2 caused a reduction in LC NOx. These findings are consistent with the notion that in the LC during LPS fever the CO pathway downmodulates NOS activity and the NO pathway upmodulates HO activity, and, together with previous data, allow us to conjecture that LC CO blunts fever by downmodulating NOS (antipyretic property), LC NO upmodulates HO and sGC activities favoring the development of LPS fever (propyretic effect).
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For example, nicotine induced c-fos expression in the prenatal rat SCN, but not so in the adult rat SCN (in contrast to many brain regions that do not show this developmental change, [130]). Nicotine application to the rat SCN resulted in minor responses only at relative high concentrations [4,97]. Many different nAChR subunits have now been characterized in the SCN of mouse and rat, including their characteristic developmental patterns in intensity [130].
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.
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Although the physiological relevance of Fe2+-heme binding is not very well established (73), it is clear that replacement of a strong ligand (like thiolate) by a weak ligand facilitates reduction of the iron and promotes binding of extrinsic axial ligands, like CO or NO (Fig. 7). We propose that CO and/or NO binding to Rev-erb may help explain the signaling role of CO in the circadian clock (74). Although previous studies have shown that CO can interact with Rev-erbβ (11, 22), the high affinity (60 nm) for CO demonstrated here emphasizes the potential role for CO in regulating the properties of Rev-erbβ.
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¹: Present address: Department of Cell Biology, School of Medicine, Emory University, 1648 Pierce Drive, Atlanta, GA, 30322.

²: Present address: Department of Medicine, Hennepin County Medical Center, and the Neuroscience Program, University of Minnesota, 914 South 8th Street, D-3, Minneapolis, MN 55404.

³: To whom correspondence and reprint requests should be addressed at Department of Cell and Structural Biology, University of Illinois at Urbana–Champaign, B107 CLSL, 601 South Goodwin Avenue, Urbana, IL 61801. Fax: (217) 333-4561. E-mail: [email protected].

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Regular ArticleCarbon Monoxide and Nitric Oxide: Interacting Messengers in Muscarinic Signaling to the Brain's Circadian Clock

Abstract

Brain Res.

Brain Res. Bull.

Trends Pharmacol. Sci.