Masurat, F. | bioRxiv Science

bioRxiv2020

Antimicrobial peptides signal need for sleep from peripheral wounds to the nervous system

Wounding triggers a protective innate immune response that includes the production of antimicrobial peptides and increased sleep. Little is known, however, about how peripheral wounds signal need for sleep to the nervous system. We found that during C. elegans larval molting, a tolloid/BMP-1-like protein promotes sleep through an epidermal innate immune pathway and the expression of more than a dozen antimicrobial peptide (AMP) genes. In the adult, epidermal injury activates innate immunity and turns up AMP production to trigger sleep. We show for one AMP, NLP-29, that it acts through the neuropeptide receptor NPR-12 in neurons that depolarize the sleep-active RIS neuron to induce sleep. Sleep in turn increases the chance of surviving injury. Thus, we found a novel mechanism by which peripheral wounds signal to the nervous system to increase protective sleep. Such a long-range somnogen signaling function of AMPs might also boost sleep in other animals including humans. Highlights- Gain-of-function mutation in the tolloid/BMP-1-like NAS-38 protein increases sleep - NAS-38 activates innate immunity pathways to ramp up STAT-dependent antimicrobial peptide (AMP) expression - Wounding increases sleep through the innate immune response and AMPs - Antimicrobial peptides are long-range somnogens that act through neuronal neuropeptide receptors to depolarize a sleep-active neuron - Sleep increases the chance to survive injury Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=83 HEIGHT=200 SRC="FIGDIR/small/183806v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@213601org.highwire.dtl.DTLVardef@60955dorg.highwire.dtl.DTLVardef@ee1e4corg.highwire.dtl.DTLVardef@1074a86_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2019

A tripartite flip-flop sleep circuit switches sleep states

Sleep-active neurons depolarize during sleep to suppress wakefulness circuits. Wake-active wake-promoting neurons in turn shut down sleep-active neurons, thus forming a bipartite flip-flop switch. However, how sleep is switched on is unclear because it is not known how wakefulness is translated into sleep-active neuron depolarization when the system is set to sleep. Using optogenetics in C. elegans, we solved the presynaptic circuit for depolarization of the sleep-active RIS neuron during developmentally-regulated sleep, also known as lethargus. Surprisingly, we found that RIS activation requires neurons that have known roles in wakefulness and locomotion behavior. The RIM interneurons, which are active during and can induce reverse locomotion, play a complex role and can act as inhibitors of RIS when they are strongly depolarized and as activators of RIS when they are modestly depolarized. The PVC command interneurons, which are known to promote forward locomotion during wakefulness, act as major activators of RIS. The properties of these locomotion neurons are modulated during lethargus. The RIMs become less excitable. The PVCs become resistant to inhibition and have an increased capacity to activate RIS. Separate activation of neither the PVCs nor the RIMs appears to be sufficient for sleep induction; instead, our data suggests that they act in concert to activate RIS. Forward and reverse circuit activity is normally mutually exclusive. Our data suggest that RIS may be activated at the transition between forward and reverse locomotion states, perhaps when both reverse (including RIM) and forward (PVC) circuit activity overlaps. While RIS is not strongly activated outside of lethargus, altered activity of the locomotion interneurons during lethargus favors strong RIS activation and thus sleep. The control of sleep-active neurons by locomotion circuits suggests that sleep may have evolved from locomotion quiescence. The flip-flop sleep switch in C. elegans thus requires an additional component, wake-active sleep-promoting neurons that translate wakefulness into the depolarization of a sleep-active neuron when the worm is sleepy. Wake-active sleep-promoting circuits may also be required for sleep state switching in other animals including in mammals.

neuroscience↗