Deconstructing Neuronal and Astroglial Contributions to Sleep and Inflammatory Immune Responses.

Abstract

Interactions between sleep and immune function are bidirectional. Although the mechanisms that govern these interactions are not fully elucidated, the pro-inflammatory cytokine, interleukin-1beta (IL-1), is a known mediator of sleep and immune responses. To further clarify the underlying substrates of sleep and immune interactions, we engineered two transgenic mouse lines that express interleukin-1 receptor 1 (IL1R1) only in the central nervous system (CNS) and selectively on neurons (NSE-IL1R1) or astrocytes (GFAP-IL1R1). During spontaneous sleep, NSE-IL1R1 and GFAP-IL1R1 mice have more rapid eye movement sleep (REMS) that is characterized by reduced theta power in the electroencephalographic (EEG) spectra compared to wild type (WT) animals. In response to 6 h of sleep deprivation, sleep of transgenic mice is more consolidated than that of WT animals. Additionally, non-REM (NREM) EEG of NSE-IL1R1 mice contains less delta power, suggesting astroglial IL1R1 activity may modulate sleep homeostasis. Upon investigation of responses to central immune challenge, it was determined that intracerebroventricular injection of IL-1 fails to alter sleep or temperature of NSE-IL1R1 and GFAP-IL1R1 mice. These data indicate that IL1R1 expression on neurons or astrocytes alone is not sufficient to manifest responses to central challenge with IL-1. This effect may be mediated, in part, by the inability of transgenic mice to produce IL-6 in brain subsequent to IL-1 administration. Systemic challenge via intraperitoneal injection of lipopolysaccharide (LPS) revealed sleep responses are largely preserved in transgenic mice. However, GFAP-IL1R1 mice exhibit greater REMS suppression compared to NSE-IL1R1 animals and have more NREM delta power than WT and NSE-IL1R1 mice. LPS also induces IL-1 and IL-6 production in NSE-IL1R1 and GFAP-IL1R1 brain tissue but at concentrations generally less than that of WT mice. This effect is more evident in GFAP-IL1R1 brain samples. These data suggest neuronal IL1R1 activity may modulate central elements of pathological sleep and immunomodulatory responses to systemic challenge with LPS. Overall, these studies demonstrate, through the use of novel transgenic mice, that neurons and astrocytes differentially modulate aspects of sleep and immunomodulation under physiological and pathological conditions. Continued study of non-neuronal cells will be crucial to better understanding a variety of CNS-mediated processes and behaviors.