State-Dependent Modulation of Visual Evoked Potentials in a Rodent Genetic Model of Electroencephalographic Instability

Despite normal sleep timing and duration, Egr3-deficient (Egr3−/−) mice exhibit electroencephalographic (EEG) characteristics of reduced arousal, including elevated slow wave (1–4 Hz) activity during wakefulness. Here we show that these mice exhibit state-dependent instability in the EEG. Intermittent surges in EEG power were found in Egr3−/− mice during wakefulness and rapid eye movement sleep, most prominently in the beta (15–35 Hz) range compared to wild type (Egr3+/+) mice. Such surges did not coincide with sleep onset, as the surges were not associated with cessation of electromyographic tone. Cortical processing of sensory information by visual evoked responses (VEP) were found to vary as a function of vigilance state, being of higher magnitude during slow wave sleep (SWS) than wakefulness and rapid eye movement sleep. VEP responses were significantly larger during quiet wakefulness than active wakefulness, in both Egr3−/− mice and Egr3+/+ mice. EEG synchronization in the beta range, previously linked to the accumulation of sleep need over time, predicted VEP magnitude. Egr3−/− mice not only displayed elevated beta activity, but in quiet wake, this elevated beta activity coincides with an elevated evoked response similar to that of animals in SWS. These data confirm that (a) VEPs vary as a function of vigilance state, and (b) beta activity in the EEG is a predictor of state-dependent modulation of visual information processing. The phenotype of Egr3−/− mice indicates that Egr3 is a genetic regulator of these phenomena

Mathematical modeling of sleep state dynamics in a rodent model of shift work

Millions of people worldwide are required to work when their physiology is tuned for sleep. By forcing wakefulness out of the body’s normal schedule, shift workers face numerous adverse health consequences, including gastrointestinal problems, sleep problems, and higher rates of some diseases, including cancers. Recent studies have developed protocols to simulate shift work in rodents with the intention of assessing the effects of night-shift work on subsequent sleep (Grønli et al., 2017). These studies have already provided important contributions to the understanding of the metabolic consequences of shift work (Arble et al., 2015; Marti et al., 2016; Opperhuizen et al., 2015) and sleep-wake-specific impacts of night-shift work (Grønli et al., 2017). However, our understanding of the causal mechanisms underlying night-shift-related sleep disturbances is limited. In order to advance toward a mechanistic understanding of sleep disruption in shift work, we model these data with two different approaches. First we apply a simple homeostatic model to quantify differences in the rates at which sleep need, as measured by slow wave activity during slow wave sleep (SWS) rises and falls. Second, we develop a simple and novel mathematical model of rodent sleep and use it to investigate the timing of sleep in a simulated shift work protocol (Grønli et al., 2017). This mathematical framework includes the circadian and homeostatic processes of the two-process model, but additionally incorporates a stochastic process to model the polyphasic nature of rodent sleep. By changing only the time at which the rodents are forced to be awake, the model reproduces some key experimental results from the previous study, including correct proportions of time spent in each stage of sleep as a function of circadian time and the differences in total wake time and SWS bout durations in the rodents representing night-shift workers and those representing day-shift workers. Importantly, the model allows for deeper insight into circadian and homeostatic influences on sleep timing, as it demonstrates that the differences in SWS bout duration between rodents in the two shifts is largely a circadian effect. Our study shows the importance of mathematical modeling in uncovering mechanisms behind shift work sleep disturbances and it begins to lay a foundation for future mathematical modeling of sleep in rodents

Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia

金沢大学医薬保健研究域医学系Stress-induced analgesia (SIA) is a key component of the defensive behavioral "fight-or-flight" response. Although the neural substrates of SIA are incompletely understood, previous studies have implicated the hypocretin/orexin (Hcrt) and nociceptin/orphanin FQ (N/OFQ) peptidergic systems in the regulation of SIA. Using immunohistochemistry in brain tissue from wild-type mice, we identified N/OFQ-containing fibers forming synaptic contacts with Hcrt neurons at both the light and electron microscopic levels. Patch clamp recordings in GFP-tagged mouse Hcrt neurons revealed that N/OFQ hyperpolarized, decreased input resistance, and blocked the firing of action potentials in Hcrt neurons. N/OFQ postsynaptic effects were consistent with opening of a G protein-regulated inwardly rectifying K+ (GIRK) channel. N/OFQ also modulated presynaptic release of GABA and glutamate onto Hcrt neurons in mouse hypothalamic slices. Orexin/ataxin-3 mice, in which the Hcrt neurons degenerate, did not exhibit SIA, although analgesia was induced by i.c.v. administration of Hcrt-1. N/OFQ blocked SIA in wild-type mice, while coadministration of Hcrt-1 overcame N/OFQ inhibition of SIA. These results establish what is, to our knowledge, a novel interaction between the N/OFQ and Hcrt systems in which the corticotropin-releasing factor and N/OFQ systems coordinately modulate the Hcrt neurons to regulate SIA

Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions

Modafinil, in its two clinical formulations (Provigil® and Nuvigil®), is a widely prescribed wake-promoting therapeutic agent. It binds competitively to the cell membrane dopamine transporter and is dependent on catecholaminergic (dopaminergic and adrenergic) signaling for its wake-promoting effects. The clinical spectrum of effects for modafinil is distinct from the effects seen with other catecholaminergic agents. Relative to other commonly used agents that act through catecholaminergic mechanisms, modafinil has a relatively low abuse potential, produces wakefulness with an attenuated compensatory sleep recovery thereafter, and does not ameliorate cataplexy in narcolepsy. These clinically relevant phenomenological differences between modafinil and agents such as amphetamines and cocaine do not eliminate catecholaminergic effects as a possible mediator of its wake-promoting action; they merely reflect its unique pharmacological profile. Modafinil is an exceptionally weak, but apparently very selective, dopamine transporter inhibitor. The pharmacodynamic response to modafinil, as measured by dopamine levels in brain microdialysate, is protracted relative to other agents that act via catecholaminergic mechanisms. The conformational constraints on the interaction of modafinil with the dopamine transporter—and probably, as a consequence, its effects on trace amine receptor signaling in the catecholaminergic cell—are unique among catecholaminergic agents. These unique pharmacological properties of modafinil should be considered both in seeking to thoroughly understand its putatively elusive mechanism of action and in the design of novel therapeutic agents

A metabolic-transcriptional network links sleep and cellular energetics in the brain

This review proposes a mechanistic link between cellular metabolic status, transcriptional regulatory changes and sleep. Sleep loss is associated with changes in cellular metabolic status in the brain. Metabolic sensors responsive to cellular metabolic status regulate the circadian clock transcriptional network. Modifications of the transcriptional activity of circadian clock genes affect sleep/wake state changes. Changes in sleep state reverse sleep loss-induced changes in cellular metabolic status. It is thus proposed that the regulation of circadian clock genes by cellular metabolic sensors is a critical intermediate step in the link between cellular metabolic status and sleep. Studies of this regulatory relationship may offer insights into the function of sleep at the cellular level

Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks

The circadian clock is a fundamental biological timing mechanism that generates nearly 24 h rhythms of physiology and behaviors, including sleep/wake cycles, hormone secretion, and metabolism. Evolutionarily, the endogenous clock is thought to confer living organisms, including humans, with survival benefits by adapting internal rhythms to the day and night cycles of the local environment. Mirroring the evolutionary fitness bestowed by the circadian clock, daily mismatches between the internal body clock and environmental cycles, such as irregular work (e.g., night shift work) and life schedules (e.g., jet lag, mistimed eating), have been recognized to increase the risk of cardiac, metabolic, and neurological diseases. Moreover, increasing numbers of studies with cellular and animal models have detected the presence of functional circadian oscillators at multiple levels, ranging from individual neurons and fibroblasts to brain and peripheral organs. These oscillators are tightly coupled to timely modulate cellular and bodily responses to physiological and metabolic cues. In this review, we will discuss the roles of central and peripheral clocks in physiology and diseases, highlighting the dynamic regulatory interactions between circadian timing systems and multiple metabolic factors

Sleep-active cells in the cerebral cortex and their role in slow-wave activity

We recently identified neurons in the cerebral cortex that become activated during sleep episodes with high slow-wave activity (SWA). The distinctive properties of these neurons are the ability to produce nitric oxide and their long-range projections within the cortex. In this review, we discuss how these characteristics of sleep-active cells could be relevant to SWA production in the cortex. We also discuss possible models of the role of nNOS cells in SWA production