The cholinergic forebrain arousal system acts directly on the circadian pacemaker

Abstract

Sleep and wake states are regulated by a variety of mechanisms. One such important system is the circadian clock, which provides temporal structure to sleep and wake. Conversely, changes in behavioral state, such as sleep deprivation (SD) or arousal, can phase shift the circadian clock. Here we demonstrate that the level of wakefulness is critical for this arousal resetting of the circadian clock. Specifically, drowsy animals with significant power in the 7-to 9-Hz band of their EEGs do not exhibit phase shifts in response to a mild SD procedure. We then show that treatments that both produce arousal and reset the phase of circadian clock activate (i.e., induce Fos expression in) the basal forebrain. Many of the activated cells are cholinergic. Using retrograde tract tracing, we demonstrate that cholinergic cells activated by these arousal procedures project to the circadian clock in the suprachiasmatic nuclei (SCN). We then demonstrate that arousal-induced phase shifts are blocked when animals are pretreated with atropine injections to the SCN, demonstrating that cholinergic activity at the SCN is necessary for arousal-induced phase shifting. Finally, we demonstrate that electrical stimulation of the substantia innominata of the basal forebrain phase shifts the circadian clock in a manner similar to that of our arousal procedures and that these shifts are also blocked by infusions of atropine to the SCN. These results establish a functional link between the major forebrain arousal center and the circadian system. arousal | phase shift | nonphotic | sleep/wake | brain stimulation T he states of wake and sleep in mammals are regulated by interactions between brainstem and forebrain regions (1, 2), with some areas actively promoting sleep and others promoting wake. The allied circadian clock located in the suprachiasmatic nuclei (SCN) (3) provides temporal structure to behavior and physiology. The sleep/wake systems and circadian systems interact (4), with the circadian system providing temporal input to the sleep and wake systems, thus promoting both states, and ensuring that these behaviors occur at species-specific times of day (5).The activity of the SCN is endogenously regulated and tightly linked to behavioral state. SCN electrical activity is highest during the day, when nocturnal rodents are asleep, with higher activity during rapid-eye-movement (REM) sleep than during slow wave sleep (6). During the waking phase, SCN activity is suppressed by spontaneous behavior (7). Critically, triggering activity or wakefulness, so-called "nonphotic zeitgebers" (time givers), during the sleep phase can reset the phase of the circadian clock (8, 9). There is an inverse relationship between the size of the phase shift due to sleep deprivation (SD) and the amount of effort required to maintain wakefulness during the procedure (8). Specifically, animals that remain awake and alert on their own exhibit large phase shifts, whereas those that require frequent intervention to maintain wakefulness do not shift. These factors su...

Propofol decreases the excitability of cholinergic neurons in mouse basal forebrain via GABAA receptors

“…The cholinergic neurons are distributed throughout the BF and mainly arise from the SI of the BF [37]. Many ChAT + neurons located in the rostral BF maintain wakefulness, while the other ChAT neurons, located in the caudal region of the BF, innervate the suprachiasmatic nucleus, the circadian pacemaker [38,39]. In our study, the neurons were mainly selected from these two regions.…”

Neuronal oscillations on an ultra‐slow timescale: daily rhythms in electrical activity and gene expression in the mammalian master circadian clockwork

“…Several internal physiological signals emerging from the body's arousal/wakefulness and homeostatic brain circuits feedback to influence circadian timing in the SCN [ (Mrosovsky, 1996;Hut & Van der Zee, 2011;Hughes & Piggins, 2012;Belle, 2015;Meijer & Michel, 2015); see next section below]. These non-photic inputs include neuropeptide Y (NPY) neurons of the thalamic intergeniculate leaflet (IGL) which send axonal projections through the geniculo-hypothalamic tract (GHT), the serotonergic system of the raphe nuclei (Harrington, 1997;Morin, 2013), the basal forebrain cholinergic system (Bina et al, 1993;Yamakawa et al, 2016), as well as the arousal-promoting orexinergic neurons of the lateral hypothalamus (Mieda & Sakurai, 2012) which projects in the vicinity of SCN neurons (Date et al, 1999;Belle et al, 2014). In nocturnal rodents, a dark-pulse during the daytime causes increased locomotor activity together with a reduction of c-fos expression in the SCN (Marston et al, 2008).…”

The genetics of circadian rhythms, sleep and health

“…2 ). Peripheral circadian clocks throughout the body receive inputs from the SCN and numerous additional signals, including feeding ( 13 ); glucocorticoids ( 14 ); temperature ( 15 ); and indicators of physiological condition such as metabolic state ( 16 ) and sleep history ( 17 , 18 ). The mechanisms by which many of these these zeitgebers interact with the molecular clockwork of the peripheral clocks remains unclear.…”