A mechanism for sickness sleep: lessons from invertebrates

Abstract

During health, animal sleep is regulated by an internal clock and by the duration of prior wakefulness. During sickness, sleep is regulated by cytokines released from either peripheral cells or from cells within the nervous system. These cytokines regulate central nervous system neurons to induce sleep. Recent research in the invertebrates Caenorhabditis elegans and Drosophila melanogaster has led to new insights into the mechanism of sleep during sickness. Sickness is triggered by exposure to environments such as infection, heat, or ultraviolet light irradiation, all of which cause cellular stress. Epidermal growth factor is released from stressed cells and signals to activate central neuroendocrine cell(s). These neuron(s) release neuropeptides including those containing an amidated arginine(R)-phenylalanine(F) motif at their C-termini (RFamide peptides). Importantly, mechanisms regulating sickness sleep are partially distinct from those regulating healthy sleep. We will here review key findings that have elucidated the central neuroendocrine mechanism of sleep during sickness. Adaptive mechanisms employed in the control of sickness sleep may play a role in correcting cellular homeostasis after various insults. We speculate that these mechanisms may play a maladaptive role in human pathological conditions such as in the fatigue and anorexia associated with autoimmune diseases, with major depression, and with unexplained chronic fatigue.

Genetic and neuronal regulation of sleep by neuropeptide VF

“…In C. elegans , the neurosecretory ALA neuron produces several sleep-promoting RFamide neuropeptides including FLP-13 ( Nath et al, 2016 ; Nelson et al, 2014 ), and is required for sleep that is induced by cellular stressors, including noxious temperature, hypertonicity and tissue damage ( Hill et al, 2014 ; Nath et al, 2016 ). It remains unclear whether cellular stress induces sleep in vertebrates, but the increased sleep in observed in mammals during illness and following cellular injury might be regulated by mechanisms analogous to those that promote cellular stress-induced sleep in C. elegans ( Davis and Raizen, 2017 ). We speculate that NPVF neurons may have a sensory function to detect physiological changes such as cellular stress, integrate this information, and promote a behavioral state change from wake to sleep.…”

A salt-induced kinase (SIK) is required for the metabolic regulation of sleep

“…C. elegans sleeps during development in a stage known as developmentally-timed sleep (DTS), or lethargus [37, 38]. They also sleep after exposure to environmental conditions that cause cellular stress in a behavior termed stress-induced sleep (SIS) [39, 40]. Additionally, C. elegans sleep when satiated [32, 41] and in the setting of starvation [4, 32].…”

Stress-Induced Sleep After Exposure to Ultraviolet Light Is Promoted by p53 inCaenorhabditis elegans

“…C. elegans SIS fulfills behavioral criteria for sleep in nonmammalian models (Trojanowski and Raizen 2016). The C. elegans model of SIS has similarities to sleep in response to illness in mammals (reviewed in Davis and Raizen 2016). The function of sleep as a restorative state has also been demonstrated in both mammals and nematodes.…”