Neuroinflammation, Sleep, and Circadian Rhythms

Abstract

Molecules involved in innate immunity affect sleep and circadian oscillators and vice versa. Sleep-inducing inflammatory molecules are activated by increased waking activity and pathogens. Pathologies that alter inflammatory molecules, such as traumatic brain injury, cancer, cardiovascular disease, and stroke often are associated with disturbed sleep and electroencephalogram power spectra. Moreover, sleep disorders, such as insomnia and sleep disordered breathing, are associated with increased dysregulation of inflammatory processes. Inflammatory molecules in both the central nervous system and periphery can alter sleep. Inflammation can also modulate cerebral vascular hemodynamics which is associated with alterations in electroencephalogram power spectra. However, further research is needed to determine the interactions of sleep regulatory inflammatory molecules and circadian clocks. The purpose of this review is to: 1) describe the role of the inflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha and nucleotide-binding domain and leucine-rich repeat protein-3 inflammasomes in sleep regulation, 2) to discuss the relationship between the vagus nerve in translating inflammatory signals between the periphery and central nervous system to alter sleep, and 3) to present information about the relationship between cerebral vascular hemodynamics and the electroencephalogram during sleep.

Keywords: NLRP3 inflammasome; cytokines; electroencephalogram power; inflammation; neurovascular unit; vagus nerve.

Figure 1

Major inflammasomes, their activators, and mechanisms that lead them to activate the somnogenic cytokines IL-1β and IL-18. NLRP3, RIG-1, AIM2, and NLRP1 are activated to combine with ASC and pro-caspase-1 to activate mature caspase-1, which will cleave the pro-forms of IL-1β and IL-18 into their mature active forms. NLRP3 is activated by multiple mechanisms including by extracellular ATP through the purine type 2 X7 receptor, oxidative stress involving TRX1 and TXNIP, and involves the priming of inflammasomes through NF-κB transcriptional processing of components of the inflammasome. This priming step can be activated by several somnogenic substances including LPS, IL-1β, and TNF-α through the TLR4, IL-1R1, and TNFR1, respectively.

Figure 2

Pro-inflammatory and reductions in inflammatory responses occur in the brain and periphery, respectively, and are controlled by the vagus nerve. The vagal afferents can relay inflammatory stimuli from peripheral viscera to stimulate the NTS of the brain stem. The NTS projects to multiple sleep regulatory brain areas, which can induce pro-inflammatory somnogenic molecules and actions. The vagal efferents have anti-inflammatory actions that, in part, occur from acetylcholine receptor activation in the dorsal motor nucleus (DMN) and nucleus ambiguus (NA) to stimulate the vagal efferents to reduce inflammatory molecules in the periphery. The SCN plays a role in modulating the circadian actions of molecules in the brain and periphery. Additionally, peripheral clocks can affect these peripheral molecules that potentially can affect actions of vagal stimulation. Moreover, circadian clocks can alter glucocorticoids and epinephrine and norepinephrine, which can further modulate inflammatory responses to affect signaling between the periphery and brain.

Figure 3

The neurovascular unit (NVU) tightly and rapidly regulates homeostasis in the brain by controlling the cerebral microvasculature. The neurovascular unit is comprised of endothelial cells, pericytes, astrocytes with end-feet that encompass the vasculature, neurons, interneurons, perivascular macrophages, and surrounding microglia. The NVU regulates blood flow in the brain in order to maintain the need from local use. The NVU also functions to sense local changes in the environment and responds to maintain homeostasis. The NVU acts in immunosurveillance to respond to potential pathogenic challenge or energy demand changes and responds with the release of inflammatory molecules. Sleep regulatory pro-inflammatory molecules can vasodilate to increase cerebral blood flow while other molecules, while many wake promoting molecules produced by neurons and glia have vasoconstrictive functions. Thus, the NVU likely has a major role in modulating cerebral blood flow changes occurring during sleep/wake states.

Figure 4

The Sleep, Slow-Wave, Vasohemodynamic Equipoise Hypothesis of Sleep Regulation. We hypothesize that sleep and SWA are regulated by specific inflammatory pathways and mechanisms that are modulated by or modulate circadian factors to enhance or diminish their effects. These inflammatory sleep regulatory molecules modulate neurotransmitters and physiological functions of the brains vasculature to affect sleep and/or SWA. Consequently, the summation of the effects on neurons and vasohemodynamics ultimately leads to localized changes in brain areas to induce sleep or alter SWA.