NF-κB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages

The epigenome of macrophages can be reprogrammed by extracellular cues, but the extent to which different stimuli achieve this is unclear. Nuclear factor κB (NF-κB) is a transcription factor that is activated by all pathogen-associated stimuli and can reprogram the epigenome by activating latent enhancers. However, we show that NF-κB does so only in response to a subset of stimuli. This stimulus specificity depends on the temporal dynamics of NF-κB activity, in particular whether it is oscillatory or non-oscillatory. Non-oscillatory NF-κB opens chromatin by sustained disruption of nucleosomal histone–DNA interactions, enabling activation of latent enhancers that modulate expression of immune response genes. Thus, temporal dynamics can determine a transcription factor’s capacity to reprogram the epigenome in a stimulus-specific manner.

Larval zebrafish display dynamic learning of aversive stimuli in a constant visual surrounding

Balancing exploration and anti-predation are fundamental to the fitness and survival of all animal species from early life stages. How these basic survival instincts drive learning remains poorly understood. Here, employing a light/dark preference paradigm with well-controlled luminance history and constant visual surrounding in larval zebrafish, we analyzed intra- and inter-trial dynamics for two behavioral components, dark avoidance and center avoidance. We uncover that larval zebrafish display short-term learning of dark avoidance with initial sensitization followed by habituation; they also exhibit long-term learning that is sensitive to trial interval length. We further show that such stereotyped learning patterns is stimulus specific, as they are not observed for center avoidance. Finally, we demonstrate at individual levels that long-term learning is under homeostatic control. Together, our work has established a novel paradigm to understand learning, uncovered sequential sensitization and habituation, and demonstrated stimulus specificity, individuality, as well as dynamicity in learning.

Sleep Induction by Mechanosensory Stimulation in Drosophila

SummaryPeople tend to fall asleep when gently rocked or vibrated. Experimental studies have shown rocking promotes sleep in humans and mice. The prevailing “synchronization” model proposes synchronization of brain activity to mechanosensory stimuli mediates the phenomenon. The alternative “habituation” model proposes habituation, a form of non-associative learning, mediates sleep induction by monotonous stimulation. Here we show that gentle vibration promotes sleep in Drosophila in part through habituation. Vibration-induced sleep (VIS) leads to the accrual of homeostatic sleep credit, is associated with reduced arousability, and can be suppressed by heightened arousal. Sleep induction improves over successive blocks of vibration and exhibits stimulus specificity, supporting the habituation model. Multiple mechanosensory organs mediate VIS, and the magnitude of sleep gain depends on the vibration frequency and genetic background. Our findings suggest habituation is a major contributor to VIS, but synchronization of brain activity may play a role under certain stimulus conditions.

A high dimensional quantification of mouse defensive behaviours reveals enhanced diversity and stimulus specificity

SummaryInstinctive defensive behaviours, consisting of stereotyped sequences of movements and postures, are an essential component of the mouse behavioural repertoire. Since defensive behaviours can be reliably triggered by threatening sensory stimuli, the selection of the most appropriate action depends on the stimulus property. However, since the mouse has a wide repertoire of motor actions, it is not clear which set of movements and postures represent the relevant action. So far this has been empirically identified as a change in locomotion state. However, the extent to which locomotion alone captures the diversity of defensive behaviours and their sensory specificity is unknown.To tackle this problem we developed a method to obtain a faithful 3D reconstruction of the mouse body that enabled to quantify a wide variety of motor actions. This higher dimensional description revealed that defensive behaviours are more stimulus-specific than indicated by locomotion data. Thus, responses to distinct stimuli that were equivalent in terms of locomotion (e.g. freezing induced by looming and sound) could be discriminated along other dimensions. The enhanced stimulus-specificity was explained by a surprising diversity. A clustering analysis revealed that distinct combinations of movements and postures, giving rise to at least 7 different behaviours, were required to account for stimulus-specificity. Moreover, each stimulus evoked more than one behaviour revealing a robust one-to-many mapping between sensations and behaviours that was not apparent from locomotion data. Our results indicate that diversity and sensory specificity of mouse defensive behaviours unfold in a higher dimensional space spanning multiple motor actions.

Heat shock response pathways regulate stimulus-specificity and sensitivity of NF-κB signalling to temperature stress

Ability to adapt to temperature changes trough the Heat Shock Response (HSR) pathways is one of the most fundamental and clinically relevant cellular response systems. Here we report that Heat Shock (HS) induces a temporally-coordinated and stimulus-specific adaptation of the signalling and gene expression responses of the Nuclear Factor κB (NF-κB) transcription factor. We show that exposure of MCF7 breast adenocarcinoma cells to 43°C 1h HS inhibits the immediate signalling response to pro-inflammatory Interleukin 1β (IL1β) and Tumour Necrosis Factor α (TNFα) cytokines. Within 4h after HS treatment IL1β-induced responses return to normal levels, but the recovery of the TNFα-induced responses is delayed. Using siRNA knock-down of Heat Shock Factor 1 and mathematical modelling we show that the stimulus-specificity is conferred via the Inhibitory κB kinase signalosome, with HSR differentially controlling individual cytokine transduction pathways. Finally, using a novel mathematical model we predict and experimentally validate that the HSR cross-talk confers differential cytokine sensitivity of the NF-κB system to a range of physiological and clinically-relevant temperatures. This quantitative understanding of NF-κB and HSR cross-talk mechanisms is fundamentally important for the potential improvement of current hyperthermia protocols.

Habituation underpins preference for mates with novel phenotypes in the guppy

Populations harbour enormous genetic diversity in ecologically important traits. Understanding the processes that maintain this variation is a long-standing challenge in evolutionary biology. Recent evidence indicates that a mating preference for novel sexual signals can be a powerful force maintaining genetic diversity. However, the proximate underpinnings of this preference, and its generality, remain unclear. Here, we test the hypothesis that preference for novel sexual signals is underpinned by habituation, a nearly ubiquitous form of learning whereby individuals become less responsive to repetitive stimuli. We use the Trinidadian guppy ( Poecilia reticulata ), in which male colour patterns are diverse yet heritable. We show that repeated exposure to males with a given colour pattern reduces female interest in males with that pattern, and that interest recovers following brief isolation. These results fulfil two core criteria of habituation: responsiveness decline and spontaneous recovery. To distinguish habituation from sensory adaptation and fatigue, we also demonstrate stimulus specificity and dishabituation. These results provide the first evidence that habituation causes a preference for novel sexual signals, addressing the mechanistic underpinnings of this mating preference. Given the pervasiveness of habituation among taxa and sensory contexts, our findings suggest that preference for novelty may play an underappreciated role in mate choice and the maintenance of genetic variation.