BackgroundThe mammalian brain expresses a wide range of state-dependent network oscillations which vary in frequency and spatial extension. Such rhythms can entrain multiple neurons into coherent patterns of activity, consistent with a role in behaviour, cognition and memory formation. Recent evidence suggests that locally generated fast network oscillations can be systematically aligned to long-range slow oscillations. It is likely that such cross-frequency coupling supports specific tasks including behavioural choice and working memory.Principal FindingsWe analyzed temporal coupling between high-frequency oscillations and EEG theta activity (4–12 Hz) in recordings from mouse parietal neocortex. Theta was exclusively present during active wakefulness and REM-sleep. Fast oscillations occurred in two separate frequency bands: gamma (40–100 Hz) and fast gamma (120–160 Hz). Theta, gamma and fast gamma were more prominent during active wakefulness as compared to REM-sleep. Coupling between theta and the two types of fast oscillations, however, was more pronounced during REM-sleep. This state-dependent cross-frequency coupling was particularly strong for theta-fast gamma interaction which increased 9-fold during REM as compared to active wakefulness. Theta-gamma coupling increased only by 1.5-fold.SignificanceState-dependent cross-frequency-coupling provides a new functional characteristic of REM-sleep and establishes a unique property of neocortical fast gamma oscillations. Interactions between defined patterns of slow and fast network oscillations may serve selective functions in sleep-dependent information processing.

SUMMARYSpatiotemporal activity patterns of neurones are organized by different types of coherent network oscillations. Frequency content and crossfrequency coupling of cortical oscillations are strongly state-dependent, indicating that different patterns of wakefulness or sleep, respectively, support different cognitive or mnestic processes. It is therefore crucial to analyse specific sleep patterns with respect to their oscillations, including interaction between fast and slow rhythms. Here we report the oscillation profile of phasic rapid eye movement (REM), a form of REM sleep which has been implicated in hippocampus-dependent memory processing. In all analysed frequency bands (theta, gamma and fast gamma, respectively) we find higher frequencies and higher power in phasic REM compared to tonic REM or wakefulness. Theta-phase coupling of fast oscillations, however, was highest in tonic REM, followed by phasic REM and wakefulness. Our data suggest different roles of phasic and tonic REM for information processing or memory formation during sleep.

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Respiratory infections by Gram-negative bacteria are a major cause of global morbidity and mortality. Alveolar macrophages (AMs) play a central role in maintaining lung immune homeostasis and host defense by sensing pathogens via pattern recognition receptors (PRR). The PRR Toll-like receptor (TLR) 4 is a key sensor of lipopolysaccharide (LPS) from Gram-negative bacteria. Pulmonary surfactant is the natural microenvironment of AMs. Surfactant protein A (SP-A), a multifunctional host defense collectin, controls LPS-induced pro-inflammatory immune responses at the organismal and cellular level via distinct mechanisms. We found that SP-A post-transcriptionally restricts LPS-induced TLR4 protein expression in primary AMs from healthy humans, rats, wild-type and SP-A -/- mice by further decreasing cycloheximide-reduced TLR4 protein translation and enhances the co-localization of TLR4 with the late endosome/lysosome. Both effects as well as the SP-A-mediated inhibition of LPS-induced TNFα release are counteracted by pharmacological inhibition of the small GTPase Rab7. SP-A-enhanced Rab7 expression requires β-arrestin2 and, in β-arrestin2 -/- AMs and after intratracheal LPS challenge of β-arrestin2 -/- mice, SP-A fails to enhance TLR4/lysosome co-localization and degradation of LPS-induced TLR4. In SP-A -/- mice, TLR4 levels are increased after pulmonary LPS challenge. SP-A-induced activation of mechanistic target of rapamycin complex 1 (mTORC1) kinase requires β-arrestin2 and is critically involved in degradation of LPS-induced TLR4. The data suggest that SP-A post-translationally limits LPS-induced TLR4 expression in primary AMs by lysosomal degradation comprising Rab7, β-arrestin2, and mTORC1. This study may indicate a potential role of SP-A-based therapeutic interventions in unrestricted TLR4-driven immune responses to lower respiratory tract infections caused by Gram-negative bacteria.